WHO MDR-TB Guidelines. Update 2008

8/2/2019 WHO MDR-TB Guidelines. Update 2008

http://slidepdf.com/reader/full/who-mdr-tb-guidelines-update-2008 1/270



i

Guidelies or te

rogrammatic maagemeto drug-resistat

tuberculosis



WHO Library Cataloguing-in-Publication Data

Guidelines or the programmatic management o drug-resistant tuberculosis.« WHO/HTM/TB/2008.402 ».

1.Tuberculosis, Multidrug-resistant – drug therapy. 2.Tuberculosis, Multidrug-resistant – prevention and control. 3.Antitubercular agents – administration anddosage. 4.HIV inections – drug therapy. 5.Antiretroviral therapy, Highly active.6.Guidelines. I.World Health Organization.

ISBN 978 92 4 154758 1 (NLM classication: WF 310)

The 2006 edition was unded by the Bill & Melinda Gates Foundation and the Unit-ed States Agency or International Development to the Green Light Committee sub-

group o the Stop TB Partnership Working Group on MDR-TB.The 2008 emergency update was unded by the UK Department or International

Development and the United States Agency or International Development. Theirnancial contribution was essential or WHO and partners to produce and analysemost o the evidence supporting these guidelines.

Emergency update, 2008

Expiry date: 2010

© World Health Organization 2008

All rights reserved. Publications o the World Health Organization can be obtained rom WHO

Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791

3264; ax: +41 22 791 4857; e-mail: [email protected]). Requests or permission to reproduce or

translate WHO publications – whether or sale or or noncommercial distribution – should be ad-

dressed to WHO Press, at the above address (ax: +41 22 791 4806; e-mail: [email protected]).

The designations employed and the presentation o the material in this publication do not imply theexpression o any opinion whatsoever on the part o the World Health Organization concerning the

legal status o any country, territory, city or area or o its authorities, or concerning the delimitation

o its rontiers or boundaries. Dotted lines on maps represent approximate border lines or which

there may not yet be ull agreement.

The mention o specic companies or o certain manuacturers’ products does not imply that they

are endorsed or recommended by the World Health Organization in preerence to others o a similar

nature that are not mentioned. Errors and omissions excepted, the names o proprietary products are

distinguished by initial capital letters.

All reasonable precautions have been taken by the World Health Organization to veriy the inor-

mation contained in this publication. However, the published material is being distributed without warranty o any kind, either expressed or implied. The responsibility or the interpretation and use

o the material lies with the reader. In no event shall the World Health Organization be liable or

damages arising rom its use.

Designed by minimum graphics

Printed in Switzerland



iii

Cotets

Acknowledgements

Abbreviations

Executive summary xi

Foreword to the 2008 emergency updated edition xvii

Chapter 1 Background inormation on DR-TB 1

Chapter 2 Framework or eective control o DR-TB 8

Chapter 3 Political commitment and coordination 14

Chapter 4 Denitions: case registration, bacteriology and

treatment outcomes 19

Chapter 5 Case-nding strategies 26

Chapter 6 Laboratory aspects 36

Chapter 7 Treatment strategies or MDR-TB and XDR-TB 50

Chapter 8 Mono-resistant and poly-resistant strains (DR-TB other

than MDR-TB) 75

Chapter 9 Treatment o DR-TB in special conditions and situations 79

Chapter 10 HIV inection and MDR-TB 89

Chapter 11 Initial evaluation, monitoring o treatment andmanagement o adverse eects 107

Chapter 12 Treatment delivery and community-based DR-TB support 120

Chapter 13 Management o patients ater MDR-TB treatment ailure 130

Chapter 14 Management o contacts o MDR-TB patients 135

Chapter 15 Drug resistance and inection control 140

Chapter 16 Human resources: training and stang 145

Chapter 17 Management o second-line antituberculosis drugs 150

Chapter 18 Category IV recording and reporting system 154

Chapter 19 Managing DR-TB through patient-centred care 165



iv

GUIDELINES FOR THE PROGRAMMATIC MANAGEMENT OF DRUG-RESISTANT TUBERCULOSIS

Aees

Annex 1 Drug inormation sheets 173

Annex 2 Weight-based dosing o drugs or adults 193

Annex 3 Suggestions or urther reading 195

Annex 4 Legislation, human rights and patients’ rights in

tuberculosis prevention and control 198

Annex 5 Use o experimental drugs outside o clinical trials

(“compassionate use”) 208

Annex 6 Methodology 213

Forms 217



v

Ackoledgemets

WHO grateully acknowledges the contributions o the ollowing individuals

to the 2006 edition and the 2008 emergency edition.

2006 editio

Writing Committee

Jaime Bayona

Karin Bergström

Kai Blöndal

José Caminero

Peter Cegielski

Manred Danilovits

Jennier Furin

Victoria Gammino

Malgorzata Grzemska

Einar Heldal

Myriam Henkens

Vahur Hollo

Ernesto Jaramillo

Fabienne Jouberton

Boris Kazenniy

Michael Kimerling

Hans Kluge

Kitty Lambregts

Kayla Laserson

Vaira Leimane

Andrey Mariandyshev

Fuad Mirzayev

Carole Mitnick

Joia Mukherjee

Edward Nardell

Eva Nathanson

Lisa Nelson

Paul Nunn

Michael Rich

Kwonjune Seung

Alexander Sloutsky

Tamara Tonkel

Arnaud Trébucq

Thelma Tupasi

Francis Varaine

Irina Vasilieva

Fraser Wares

Karin Weyer

Abigail Wright

Matteo Zignol

Expert Reiew Committee

Marcos Espinal

Paul Farmer

Mario Raviglione

Wang Xie Xiu

2008 emergec udate

Steering Group

Ernesto JaramilloSalmaan Kevshavjee

Kitty Lambregts

Michael Rich

Karen Weyer (Chair)



vi


Guidelines Reerence Group

Jaime Bayona, Socios En Salud, Sucursal Peru, Lima, Peru

Jose Caminero, International Union Against Tuberculosis and Lung Disease,

Paris, FranceRichard Coker, London School o Hygiene and Tropical Medicine, London,

UK

Charles Daley, National Jewish Medical and Research Center, Denver, CO,

USA

Hamish Fraser, Partners In Health, USA

Jennier Furin, Partners In Health, Boston, MA, USA

Giuliano Gargioni, WHO Stop TB Department, Geneva, Switzerland

Haileyesus Getahun, WHO Stop TB Department, Geneva, Switzerland

Charles Gilks, WHO HIV Department, Geneva, Switzerland

Case Gordon, World Care Council, Geneva, Switzerland

Reuben Granich, WHO HIV Department, Geneva, Switzerland

Diane Havlir, University o Caliornia, San Francisco, CA, USA

Einar Heldal, Independent consultant

Tim Holtz, United States Centers or Disease Control and Prevention, At-

lanta, GA, USA

Phil Hopewell, University o Caliornia, San Francisco, CA, USA

Ernesto Jaramillo, WHO Stop TB Department, Geneva, SwitzerlandSalmaan Kevshavjee, Partners In Health, Harvard Medical School, Boston,

MA, USA

Catharina (Kitty) Lambregts van Weezenbeek, KNCV Tuberculosis Founda-

tion, Netherlands

Vaira Leimane, State Agency o Tuberculosis and Lung Diseases, Latvia

Reloe Matji, University Research Corporation, South Arica

Fuad Mirzayev, WHO Stop TB Department, Geneva, Switzerland

Carole Mitnick, Harvard Medical School, Boston, MA, USA

Christo van Niekerk, Global Alliance or TB Drug DevelopmentDomingo Palmero, Hospital Muniz, Buenos Aires, Argentina

Geneviève Pinet, WHO Legal Department, Geneva, Switzerland

Mamel Quelapio, Tropical Disease Foundation, Philippines

Michael Rich, Partners In Health/Division o Social Medicine and Health

Inequalities, Brigham and Womens Hospital, Boston, MA, USA

Vija Riekstina, State Agency o Tuberculosis and Lung Diseases, Latvia

Irina Sahakyan, WHO Stop TB Department, Geneva, Switzerland

Fabio Scano, WHO Stop TB Department, Geneva, Switzerland

Adrienne Socci, Partners In Health, Boston, MA, USA Kathrin Thomas, WHO Stop TB Department, Geneva, Switzerland

Arnaud Trébucq, International Union Against Tuberculosis and Lung Dis-

ease, Paris, France



vii

Francis Varaine, Médecins Sans Frontières, France

Marco Vitoria, WHO HIV Department, Geneva, Switzerland

Fraser Wares, WHO Regional Oce or South-East Asia, New Delhi

Karin Weyer, WHO Stop TB Department, Geneva, Switzerland Abigail Wright, WHO Stop TB Department, Geneva, Switzerland

Matteo Zignol, WHO Stop TB Department, Geneva, Switzerland

Declaratio o iterests

All o the above contributors completed a WHO Declaration o Interest orm.

The ollowing interests were declared:

Case Gordon declared that he is an unpaid advocate or patients with anti-

TB drug resistance and or improved access to high-quality care. Hedeclared that he has himsel survived XDR-TB.

Tim Holtz declared that he is an unpaid technical adviser and member o

the Scientic Advisory Board o a manuacturer o anti-TB products, to

advise on the development o a new anti-TB compound that will be tested

in clinical trials o MDR-TB regimens.

Salmaan Keshavjee declared that his employer received unding rom a oun-

dation associated with a manuacturer o anti-TB products to support the

research and training unit that he is heading.

Carole Mitnick declared that she is serving as a paid member o theScientic Advisory Board o a manuacturer o anti-TB products, to ad-

vise on the development o a new anti-TB compound that will be tested in

clinical trials o MDR-TB regimens.

Michael Rich declared that his employer received unding rom a manuac-

turer o anti-TB products, in support o his salary.

ACkNOWLEDGEMENTS



viii

Abbreiatios

ACSM advocacy, communication and social mobilization

AFB acid-ast bacilli

AIDS acquired immunodeciency syndrome ART antiretroviral therapy

CDC United States Centers or Disease Control and Prevention

CHW community health worker

CMV cytomegalovirus

CPT co-trimoxazole preventive therapy

CXR chest X-ray

DOT directly observed therapy

DOTS The internationally recommended strategy or TB control

until 2005, and the oundation o the new Stop TB Strategy

introduced in 2006

DRS drug resistance surveillance

DR-TB drug-resistant tuberculosis

DST drug susceptibility testing

FDC xed-dose combination

FIND Foundation or Innovative New Diagnostics

GLC Green Light Committee

Global Fund Global Fund to Fight AIDS, Tuberculosis and MalariaHAART highly active antiretroviral therapy

HIV human immunodeciency virus

HPF high-power eld

HRD human resource development

IHR International Health Regulations

IRIS immune reconstitution infammatory syndrome

LFT liver unction test

MDR-TB multidrug-resistant tuberculosis

MIC minimum inhibitory concentrationNNRTI non-nucleoside reverse transcriptase inhibitor

NRTI nucleoside reverse transcriptase inhibitor

NTM non-tuberculous mycobacteria

NTP national TB control programme



ix

PI protease inhibitor

PIH Partners In Health

PPD puried protein derivative

PPM public–private mixR&R recording and reporting

SCC short-course chemotherapy

SMX sulamethoxazole

SRL supranational reerence laboratories

STB WHO Stop TB Department

TB tuberculosis

TB/HIV HIV-related TB

TMP trimethroprim

TSH thyroid-stimulating hormone

UNAIDS Joint United Nations Programme on HIV/AIDS

Union International Union Against Tuberculosis and Lung Disease

UVGI ultraviolet germicidal irradiation

WHO World Health Organization

XDR-TB extensively drug-resistant tuberculosis

Antituberculosis drug abbreiations

Group Description DruG AbbreviAtion

1 First-line oral isoniazid H

antituberculosis drugs riampicin R

ethambutol E

prazinamide Z

riabutin Rb

2 Injectable antituberculosis anamcin km

drugs amiacin Am

capreomcin Cm

streptomcin S

3 Fluoroquinolones leooxacin Lx

moxioxacin Mx

ooxacin Ox

4 Oral bacteriostatic second-line ethionamide Eto

antituberculosis drugs protionamide Pto

ccloserine Cs

terizidone Trd

p-aminosaliclic acid PAS

5 Antituberculosis drugs with cloazimine Cz

unclear efcac or unclear role linezolid Lzd

in MDR-TB treatment (not amoxicillin/claulanate Amx/Cl

recommended b WHO or thioacetazone Thz

routine use in MDR-TB patients) clarithromcin Clr

imipenem Ipm

ABBREvIATION



x


Antiretroiral drug abbreiations

DruG clAss nAme AbbreviAtion

Non-nucleoside reerse transcriptase inhibitors eairenz EFvneirapine NvP

Nucleoside reerse transcriptase inhibitors zidoudine AZT

lamiudine 3TC

staudine D4T

didanosine ddI

zalcitabine ddC

abacair ABC

tenooir TDF a

Protease inhibitors indinair IDv

ritonair RTv

saquinair SQv

nelfnair NFv

lopinair/ritonair LPv/RTv

a TDF is a nucleotide reerse transcriptase inhibitor but is tpicall grouped with this class o

drugs.



xi

Eecutie summar

Multidrug-resistant tuberculosis (MDR-TB), dened as TB caused by

organisms that are resistant to isoniazid and riampicin, two rst-line anti-

TB drugs, continues to threaten the progress made in controlling the dis-ease. The emergence o extensively drug-resistant TB (XDR-TB), dened

as MDR-TB that is resistant as well to any one o the fuoroquinolones and

to at least one o three injectable second-line drugs (amikacin, capreomycin

or kanamycin), has heightened this threat. XDR-TB has been identied in

all regions o the world since 2006. Treatment outcomes are signicantly

worse in XDR-TB patients than in MDR-TB patients. Outbreaks o XDR-

TB in populations with high prevalence o HIV have caused alarmingly high

mortality rates. The emergence o XDR-TB as a new threat to global public

health demands that health ocials and health-care providers respond with

a coordinated strategy drawing on the Stop TB Strategy.1

Guidelines or the programmatic management o drug-resistant tuberculosis:emergency update 2008 provides updated guidelines and recommendations

on how to manage drug-resistant TB (DR-TB) based on a rapid assessment o

the best available evidence by a group o experts. A ully revised second edi-

tion will be published in 2010, ollowing WHO guidance on retrieval, syn-

thesis and grading o evidence. Until that time, the emergency update serves

as interim guidance or TB control programmes and medical practitionerson all aspects o the management o DR-TB, including XDR-TB. It contains

19 chapters based on the original 18 chapters rom the rst edition published

by the World Health Organization in 20062 plus an additional chapter on

patient-centered care.

1 The Stop TB Strategy launched by the World Health Organization in 2006 describes the recom-mended interventions that should be implemented to achieve the targets or global TB controlthat have been established within the context o the Millennium Development Goals. See Rav-iglione MC, Uplekar MW. WHO’s new Stop TB Strategy. Lancet , 2006, 367:952–955.

2 Guidelines or the programmatic management o drug-resistant tuberculosis . Geneva, World HealthOrganization, 2006 (WHO/HTM/TB/2006.361).









xv

chApter Key recommenDAtions Key chAnGes(* da dad da)

Cater 11 • Standard monitoring should be • New recommendations or

Initial ealuation, implemented or all patients on monitoring the response tomonitoring o MDR-TB treatment. treatment are described.

treatment and • Results both o sputum smear • Laborator monitoring or

management o and culture should be monitored patients receiing both ART

aderse eects monthl to ealuate treatment and MDR-TB therap is added

response.* to Table 11.1.

• Increased monitoring is

required in HIv cases and or

patients on ART.*

• Health-care worers in MDR-TB

control programmes should be

amiliar with the managemento common aderse eects o

MDR-TB therap.

• Ancillar drugs or the manage-

ment o aderse eects should

be aailable to the patient.

Cater 12 • Use disease education, DOT, • A section on communit-

Treatment socioeconomic support, based care and support is

delier and emotional support, manage- added to this chapter. NTPs

adherence ment o aderse eects and are encouraged to add

monitoring sstems to improe communit-based care and

adherence to treatment. support into their national • National TB control programmes strategies and plans.

(NTPs) are encouraged to

incorporate communit-based

care and support into their

national plans.*

Cater 14 • MDR-TB contact inestigation • NTPs should consider

Management o should be gien high priorit, contact inestigation o

contacts o and NTPs should consider XDR-TB as an emergenc

MDR-TB patients contact inestigation o XDR-TB situation.

as an emergenc situation.*

Cater 15 • Inection control, including • Inection control measures

Drug resistance administratie and engineering are proposed, with special

and inection controls as well as personal attention to XDR-TB and the

control protection, should be made a high mortalit o patients

high priorit in all MDR-TB coinected with HIv and

control programmes. DR-TB.

• XDR-TB patients should be • XDR-TB patients should be

placed isolated ollowing a placed in ward isolation until

patient-centred approach and no longer inectious.

WHO ethical and legal guidance • MDR-TB patients should

until no longer inectious.* receie routine care outside

o normal HIv care settings.

EXECUTIvE SUMMARy



xvi


chApter Key recommenDAtions Key chAnGes(* da dad da)

Cater 18 • A standardized method o • Chapter 18 has been

Categor Iv recording and reporting should rewritten to be simpler andrecording and be implemented in DR-TB more consistent with the

reporting sstem control programmes. DOTS recording and

• DR-TB treatment cards should reporting sstem.

hae an expanded section or • The treatment card described

inormation on patients with in Chapter 18 has an

HIv.* expanded section or

• The International Health inormation on patients with

Regulations (IHR2005) should HIv.

be ollowed.* • Box 18.1 proides additional

recording and reporting

components, which areoptional or programmes.

• The International Health

Regulations 2005 should be

ollowed.

Cater 19 Not applicable • Chapter 19 is the onl

Managing DR-TB completel new chapter in

through patient- this reision.

centered care

An patient in whom MDR-TB or

XDR-TB is suspected or

diagnosed should be proidedwith high-qualit patient-

centered care, as outlined in

both the International

Standards or Tuberculosis

Care, the Patients’ Charter or

Tuberculosis Care and in the

WHO Good Practice in

Legislation and Regulations or

TB Control.



xvii

Foreord to te 2008emergec udated editio

The emergence o resistance to antituberculosis drugs, and particularly o multi-

drug-resistant TB (MDR-TB),1 has become a major public health problem in a

number o countries and an obstacle to eective global TB control. Nearly hal a million cases o MDR-TB emerge every year as a result o under-investment

in basic activities to control TB, poor management o the supply and quality o

antituberculosis drugs, improper treatment o TB patients and transmission o

the disease in congregate settings. However, in many areas such as Arica, the

extent o drug resistance is unknown and in most resource-constrained coun-

tries the treatment o patients with MDR-TB is absent or inadequate.

As with other inectious diseases, rom staphylococcal inections to ma-

laria, pathogens have almost invariably developed resistance to the drugs used

to treat them. Tuberculosis is no exception: strains resistant to streptomycin

were identied within months o the start o use, in the mid 1940s, o this

rst antituberculosis drug. Indeed, the emergence o drug resistance was the

primary reason that therapy or TB evolved to include treatment with more

than one drug or up to 18 to 24 months – the standard o care or over two

decades. The advent o riampicin in the early 1970s permitted a drastic reduc-

tion in the duration o therapy to six months while the ecacy o treatment

improved. But those amiliar with drug resistance in general would have pre-

dicted the emergence o resistance to what are now termed these “rst-line”drugs, and by the mid-1990s, most countries participating in a global survey

o anti-TB drug resistance registered cases o MDR-TB. The worse was yet to

come: in 2006, extensively drug-resistant TB (XDR-TB) emerged. This is de-

ned as resistance to rst- and second-line drugs2 and was rapidly announced

by the World Health Organization (WHO) as a serious emerging threat to

global public health, especially in countries with a high prevalence o human

immunodeciency virus (HIV). In act, reports have identied XDR-TB in

all regions o the world and, to date, treatment outcomes have been shown to

1 MDR-TB is dened as TB caused by Mycobacterium tuberculosis resistant in vitro to the eects o isoniazid and riampicin, with or without resistance to any other drugs. Resistance is dened by specic laboratory criteria (see Chapter 6).

2 XDR-TB is dened as TB resistant to multiple rst-line drugs as well as to any one o the fuo-roquinolones and to at least one o three injectable second-line drugs (amikacin, capreomycin orkanamycin).



xviii


be extremely poor (1–4 ). In one cohort rom KwaZulu-Natal, South Arica,

98% o XDR-TB patients coinected with HIV died, with a median time o

death o only 16 days rom the time o specimen collection.

This rapidly changing terrain requires health ocials and providers torespond with novel and eective responses. These guidelines oer updated

recommendations or TB control programmes and medical workers in mid-

dle- and low-income countries aced with MDR-TB and other drug-resistant

orms o TB. They replace previous publications by WHO on drug-resistant

TB (DR-TB) and are a direct update to the 2006 rst edition o Guidelines or the programmatic management o drug-resistant tuberculosis (5 ). Taking ac-

count o important developments and recent evidence, the new guidelines aim

to disseminate consistent, up-to-date recommendations or the diagnosis and

management o MDR-TB in a variety o geographical, political, economic

and social settings. The guidelines are designed to be o use to both TB con-

trol programmes and medical practitioners. The updated guidelines take into

particular account a number o considerations and developments. First, access

to culture and drug susceptibility testing should be available to all patients in

whom DR-TB is considered likely. Secondly, there is a larger experience in

treating DR-TB, and this experience can guide ormal therapeutic recommen-

dations. Thirdly, the 2006 edition insuciently addressed DR-TB and HIV,

and new knowledge can now guide revised policies. Finally, there now existnovel strategies to prevent and treat XDR-TB.

These updated guidelines expand upon the most recent general WHO

guidelines or national TB control programmes (6 ), which are currently being

updated to ensure ull consistency with recent advances in our understanding

o the programmatic management o MDR-TB.

In addition, these guidelines provide standards or registering, monitoring

and reporting the treatment outcomes o patients with DR-TB. This uniorm

inormation management system will allow systematic, consistent data collec-

tion and analysis, which will play an important role in shaping uture policiesand recommendations.

The guidelines can be adapted to suit diverse local circumstances because

they are structured around a fexible ramework, combining a consistent core

o principles and requirements with various alternatives that can be tailored to

the specic local situation.

The guidelines also detail the recommended management protocols to en-

able national TB control programmes to access concessionally-priced, quality-

assured second-line antituberculosis drugs through a mechanism known as

the Green Light Committee (GLC), hosted by WHO.1 The GLC was estab-

1 For more inormation about the services and how to contact the Green Light Committee or tech-nical support or apply or access to concessionally-priced, quality-assured second-line antituber-culosis drugs, see the GLC web page at: http://www.who.int/tb/challenges/mdr/greenlightcom-mittee/en/index.html



xix

lished in June 2000 as a partnership among ve categories o participants:

governments o resource-limited countries; academic institutions; civil-society

organizations; bilateral donors; and WHO. The GLC has successully negoti-

ated prices o drugs with producers; solicited creation o, and adopted soundpolicies or, proper management o DR-TB; established strict criteria to review

proposals or DR-TB management programmes; assisted countries in develop-

ing such proposals and ensured their proper implementation; and, nally, has

provided access to quality-assured second-line drugs at concessionary prices

to those management programmes considered technically and scientically

sound and not at risk o producing additional drug resistance. In brie, the

GLC rapidly became a model o good practice which, by providing access to

previously unaordable drugs, ensured that their use was as sae and ratio-

nal as possible. Demand or technical assistance rom the GLC grew rapidly

and in 2002, the GLC was adopted by the newly established Global Fund to

Fight AIDS, Tuberculosis and Malaria (the Global Fund) as its mechanism or

screening proposals or DR-TB programme nancing. This was a major his-

toric milestone, and today the Global Fund is the leading nancial mechanism

supporting the management o MDR-TB in resource-constrained settings.

Today, a new threat – that linked to XDR-TB – now requires even more in-

novative thinking (7 ). In October 2006, the WHO Stop TB and HIV depart-

ments organized a meeting o the Global Task Force on XDR-TB at WHOheadquarters in Geneva, Switzerland, in response to the XDR-TB emergency.

During this meeting, eight recommendations were put orward to the inter-

national TB community, outlining key areas o response, beginning with

strengthening o basic TB and HIV/AIDS control and proper management o

MDR-TB (8 ). The eight recommendations are:

• strengthening basic activities to control TB and HIV/AIDS, as detailed in

the Stop TB Strategy and the Global Plan, to avoid additional emergence

o MDR-TB and XDR-TB;

• scaling-up the programmatic management o MDR-TB and XDR-TB to

reach the targets set orth in the Global Plan;

• strengthening laboratory services or adequate and timely diagnosis o

MDR-TB and XDR-TB;

• expanding surveillance o MDR-TB and XDR-TB to better understand the

magnitude and trends o drug resistance and the links with HIV;

• ostering sound inection-control measures to avoid MDR-TB and XDR-

TB transmission to protect patients, health workers, others working in

congregate settings and the broader community, especially in high HIV prevalence settings;

• strengthening advocacy, communication and social mobilization or sus-

tained political commitment and a patient-centered approach to treat-

ment;

FOREWORD TO THE 2008 EMERGENCy UPDATED EDITION



xx


• pursuing resource mobilization at global, regional and country levels to en-

sure that necessary resources are available;

• promoting research and development into new diagnostics, drugs, vaccines,

and operational research on MDR-TB management to shorten the lengtho treatment.

The ongoing changes in the eld combined with new evidence and recom-

mendations mandate a revision o the previous guidelines. This publication

aims to underpin these recommendations with new or updated guidelines

that might provide the guidance on programmatic management necessary to

achieve many o the eight recommendations rom the Global Task Force. We

are condent that these new guidelines represent the best current knowledge

regarding the management o DR-TB and MDR-TB and oer programmesand providers options or tailoring diagnosis and care to the needs evinced

in dierent epidemiological and programmatic contexts. The recommenda-

tions, compiled by leading experts, should be ollowed by all national TB con-

trol programmes and their partners. With nearly hal a million new cases o

MDR-TB emerging every year, and an estimated global prevalence that may

be as high as one million cases, the challenge is huge. At the same time, it is

imperative to stress that the ve elements o the DOTS strategy remain the

cornerstone o TB control and the most eective tool or preventing the onset

and dissemination o drug resistance. Without the essential elements o TBcontrol ully in place, management o MDR-TB will undoubtedly ail in the

long term, as one cannot control it i the tap is not turned o. These updated

guidelines ocus on care or DR-TB patients, in the hope that the occurrence

o massive numbers o new cases can be prevented through sound TB-

control practices. While urther scientic advances are clearly needed in the

ght against DR-TB, these guidelines outline the tools we have at our disposal

to make an immediate impact on this destructive and grave epidemic.

Dr Mario Raviglione

Director

Stop TB Department World Health Organization



xxi

Reereces

1. Gandhi NR et al. Extensively drug-resistant tuberculosis as a cause o

death in patients co-inected with tuberculosis and HIV in a rural area

o South Arica. Lancet , 2006, 368(9547):1575–1580.2. Shah NS et al. Worldwide emergence o extensively drug-resistant tuber-

culosis. Emerging Inectious Diseases , 2007, 13(3):380–387.

3. Migliori GB et al. Extensively drug-resistant tuberculosis, Italy and Ger-

many. Emerging Inectious Diseases , 2007, 13(5):780–782.

4. Kim HR et al. Impact o extensive drug resistance on treatment outcomes

in non-HIV-inected patients with multidrug-resistant tuberculosis. Clin-ical Inectious Diseases , 2007, 45(10):1290–1295.

5. Guidelines or the programmatic management o drug-resistant tuberculo-sis . Geneva, World Health Organization, 2006 (WHO/HTM/TB/2006.

361).

6. Treatment o tuberculosis: guidelines or national programmes , 3rd ed. Ge-

neva, World Health Organization, 2003 (WHO/CDS/TB/2003.313).

7. Raviglione MC, Smith IM. XDR tuberculosis – Implications or global

public health. New England Journal o Medicine , 2007, 356(7):656–659.

8. The Global MDR-TB & XDR-TB Response Plan 2007–2008 . Geneva,

World Health Organization, 2007 (WHO/HTM/TB/2007.387).

FOREWORD TO THE 2008 EMERGENCy UPDATED EDITION





1

CHAPTER 1

Backgroud iormatioo DR-TB

1.1 Chapter objecties 1

1.2 The Stop TB Strateg 1

1.2.1 Pursuing high-qualit DOTS expansion and enhancement 2

1.2.2 MDR-TB, XDR-TB and other challenges 2

1.2.3 Contributing to health sstem strengthening 2

1.2.4 Engaging all care proiders 2

1.2.5 Empowering people with TB, and communities 2

1.2.6 Enabling and promoting research 2

1.3 Integration o diagnostic and treatment serices to control TB 2

1.4 Causes o DR-TB 3

1.5 Addressing the sources o DR-TB 3

1.6 Magnitude o the DR-TB problem 4

1.7 Management o DR-TB, the Green Light Committee and

the global response to DR-TB 6

Table 1.1 Causes o inadequate antituberculosis treatment 3

1.1 Cater objecties

This chapter summarizes key inormation on the emergence o drug-resistantTB (DR-TB), its public health impact, experience gained in the management

o patients and strategies or addressing drug resistance within national TB

control programmes (NTPs).

1.2 Te Sto TB Strateg

The goals o the Stop TB Strategy are to reduce dramatically the burden o

TB by 2015 in line with the Millennium Development Goals and the Stop TB

Partnership targets and to achieve major progress in the research and devel-

opment needed or TB elimination. The Stop TB Strategy continues to em-phasize the basic components o the DOTS strategy (See Chapter 2 or how

the basic DOTS strategy applies to DR-TB) while addressing additional con-

straints and challenges to TB control. The Stop TB Strategy has six principal

components:



2


1.2.1 Pursuing high-qualit DOTS expansion and enhancement

a. Political commitment with increased and sustained nancing

b. Case detection through quality-assured bacteriology

c. Standardized treatment with supervision and patient supportd. Eective drug supply and management system

e. Monitoring and evaluation system and impact measurement

1.2.2 Addressing TB/HIv, MDR-TB, XDR-TB and other challenges by

implementing collaborative TB/HIV activities, preventing and controlling

DR-TB, including XDR-TB, and addressing prisoners, reugees and other

high-risk groups and situations.

1.2.3 Contributing to health sstem strengthening by collaborating with other health-care programmes and general services, e.g. by mobilizing

the necessary human and nancial resources or implementation and im-

pact evaluation, and by sharing and applying achievements o TB control

as well as innovations rom other elds.

1.2.4 Engaging all care proiders, including public, nongovernmental

and private providers, by scaling up public–private mix (PPM) approaches

to ensure adherence to international standards o TB care, with a ocus on

providers or the poorest and most vulnerable groups.

1.2.5 Empowering people with TB, and communities by scaling up

community TB care and creating demand through context-specic advo-

cacy, communication and social mobilization.

1.2.6 Enabling and promoting research to improve programme per-

ormance and to develop new drugs, diagnostics and vaccines.

Emphasis on expanding laboratory capacity (sputum smear microscopy rst,then culture and drug susceptibility testing (DST)) and the use o quality-

assured drugs across all programmes are important aspects o this comprehen-

sive approach to TB control.

1.3 Itegratio o diagostic ad treatmet serices to

cotrol TB

Detection and treatment o all orms o TB, including drug-resistant orms,

should be integrated within NTPs. In the past, many public health authorities

reasoned that scarce resources should be used or new patients with drug-sus-ceptible TB because the cost o detecting and treating the disease was 10- to

100-old lower than or MDR-TB. However, it has now proved easible and

cost eective to treat all orms o TB, even in middle- and low-income coun-

tries. Untreated or improperly treated patients with DR-TB are a source o



3

1. BACkGROUND INFORMATION ON DRUG-RESISTANT TUBERCULOSIS

ongoing transmission o resistant strains, resulting in uture added costs and

mortality. The ramework or the management o DR-TB presented in these

guidelines can be adapted to all NTPs and integrated within the basic DOTS

strategy.

1.4 Causes o DR-TB

Although its causes are microbial, clinical and programmatic, DR-TB is essen-

tially a man-made phenomenon. From a microbiological perspective, resist-

ance is caused by a genetic mutation that makes a drug ineective against the

mutant bacilli. From a clinical and programmatic perspective, it is an inad-

equate or poorly administered treatment regimen that allows a drug-resistant

strain to become the dominant strain in a patient inected with TB. Table 1.1

summarizes the common causes o inadequate treatment.Short-course chemotherapy (SCC) or patients inected with drug-resistant

strains may create even more resistance to the drugs in use. This has been

termed the “amplier eect” o SCC.

Ongoing transmission o established drug-resistant strains in a population

is also a signicant source o new drug-resistant cases.

TABLE 1.1 Causes o iadequate atituberculosis treatmet (1)

heAlth-cAre proviDers: DruGs: inADequAte supply pAtients: inADequAteinADequAte reGimens or quAlity DruG intAKe

Inappropriate guidelines Poor qualit Poor adherence (or poor

Noncompliance with Unaailabilit o certain DOT)

guidelines drugs (stoc-outs or Lac o inormation

Absence o guidelines delier disruptions) Lac o mone (no treatment

Poor training Poor storage conditions aailable ree o charge)

No monitoring o Wrong dose or Lac o transportation

treatment combination Aderse eects

Poorl organized or unded Social barriers

TB control programmes Malabsorption

Substance dependenc

disorders

1.5 Addressig te sources o DR-TB

Any ongoing production o DR-TB should be addressed urgently beore em-

barking on any programme designed or its control. The ramework approach

described in these guidelines can help to identiy and curtail possible sources

o DR-TB. Recent outbreaks o highly resistant TB underscore the impor-

tance o preventing the development o resistance, as mortality or patientsinected with highly resistant strains is alarmingly high.

The possible contributing actors to the development o new drug-resistant

cases should be reviewed (see Table 1.1 or a list o possible actors). Well-

administered rst-line treatment or susceptible cases is the best way to pre-



4


vent acquisition o resistance. Timely identication o DR-TB and adequate

treatment regimens (Category IV regimens) administered early in the course

o the disease are essential to stop primary transmission. Integration o DOTS

with treatment o DR-TB works synergistically to eliminate all the potentialsources o TB transmission.

1.6 Magitude o te DR-TB roblem

The incidence o drug resistance has increased since the rst drug treatment or

TB was introduced in 1943. The emergence o MDR-TB ollowing the wide-

spread use o riampicin beginning in the 1970s led to the use o second-line

drugs. Improper use o these drugs has uelled the generation and subsequent

transmission o highly resistant strains o TB termed extensively DR-TB, or

XDR-TB. These strains are resistant to at least one o the fuoroquinolonedrugs and an injectable agent in addition to isoniazid and riampicin.

The WHO/IUATLD Global Project on Antituberculosis Drug Resistance

Surveillance gathers data on drug resistance using a standard methodology in

order to determine the global magnitude o resistance to our rst-line antitu-

berculosis drugs: isoniazid, riampicin, ethambutol and streptomycin ( 2 ). The

standard methodology includes representative sampling o patients with ad-

equate sample sizes, standardized data collection distinguishing between new

and previously treated patients and quality-assured laboratory DST supported

by a network o supranational TB reerence laboratories (SRLs).

Based on available inormation rom the duration o the Global Project ( 3),

the most recent data available rom 116 countries and settings were weighted

by the population in areas surveyed, representing 2 509 545 TB cases, with the

ollowing results: global population weighted proportion o resistance among

new cases: any resistance 17.0% (95% condence limits (CLs), 13.6–20.4),

isoniazid resistance 10.3% (95% CLs, 8.4–12.1) and MDR-TB 2.9% (95%

CLs, 2.2–3.6). Global population weighted proportion o resistance among

previously treated cases: any resistance 35.0% (95% CLs, 24.1–45.8), isoni-azid resistance 27.7% (95% CLs, 18.7–36.7), MDR-TB 15.3% (95% CLs,

9.6–21.1). Global population weighted proportion o resistance among all TB

cases: any resistance 20.0% (95% CLs, 16.1–23.9), isoniazid resistance 13.3%

(95% CLs, 10.9–15.8) and MDR-TB 5.3% (95% CLs, 3.9–6.6). Based on

drug resistance inormation rom these 116 countries and settings reporting

to this project, as well as nine other epidemiological actors, it is estimated

that 489 139 (95% CLs, 455 093–614 215) cases emerged in 2006. China and

India carry approximately 50% o the global burden o MDR-TB and the

Russian Federation a urther 7%.Data rom the most recent collection period showed ar greater proportions

o resistance among new cases than ound in previous reports, ranging all the

way to 16% MDR-TB among new cases in Donetsk, Ukraine, 19.4% in the

Republic o Moldova and 22.3% in Baku, Azerbaijan. Trends in MDR-TB



5

among new cases in the Baltic countries appear to have stabilized, but there

were signicant increases reported rom the two oblasts o the Russian Federa-

tion that reported data.

Prevalent cases worldwide could be two or three times higher than thenumber o incident cases (4 ), as MDR-TB patients oten live or several years

beore succumbing to the disease (5 ).Drug resistance is strongly associated with previous treatment. In previ-

ously treated patients, the probability o any resistance was over 4-old higher,

and o MDR-TB over 10-old higher, than or untreated patients. The overall

prevalence o drug resistance was oten related to the number o previously

treated cases in the country. Among countries with a high burden o TB, pre-

viously treated cases ranged rom 4.4% to 26.9% o all patients registered in

DOTS programmes. In the two largest high-TB burden countries (China and

India), re-treatment cases accounted or up to 20% o sputum smear-positive

cases (6 ).In 2006, the United States Centers or Disease Control and Prevention

(CDC) and WHO conducted a drug resistance survey to determine the extent

o resistance to second-line drugs. Surveying the WHO/IUATLD network o

SRLs, over 17 000 isolates rom 49 countries were included, all o which had

been tested or resistance to at least three classes o second- line drugs. These

are not population-based data, as second-line drug testing is not routinely car-ried out in most countries. The survey ound that o the isolates tested against

second-line drugs in the 49 contributing countries, 20% were MDR-TB and

2% were XDR-TB (7 ). Strains o XDR-TB have been reported in every region

o the world, with as many as 19% o MDR-TB strains ound to be XDR-TB,

a proportion that has more than tripled in some areas since 2000 (8 ). When

capacity allows, these guidelines recommend testing all MDR-TB isolates or

resistance to a fuoroquinolone and the second-line injectable agents to dene

the proportion XDR-TB among MDR-TB (see Chapter 5 and 6).

Despite the association with previous treatment, drug-resistant strains in-cluding XDR-TB are readily transmissible and outbreaks have been reported,

oten in populations with high HIV prevalence. In one outbreak o XDR-TB

in KwaZulu-Natal, hal o the patients had never received antituberculosis

treatment (9 ). The overlapping epidemics o HIV and TB are signicantly

worsened by XDR-TB, as outbreaks o these strains appear to cause higher

and more rapid mortality in HIV-inected patients. Such strains pose a serious

threat to global TB control, as detection is challenging in settings where labo-

ratory resources and treatment options are severely limited.

1.7 Maagemet o DR-TB, te Gree Ligt Committee ad

te global resose to DR-TB

The Working Group on DOTS-Plus or MDR-TB (currently the Work-

ing Group on MDR-TB) was established in 1999 to lead the global eort to




6


control MDR-TB. This working group, part o the Stop TB Partnership,

ormed the Green Light Committee (GLC) in 2000 to provide technical assist-

ance to DOTS programmes, promote rational use o second-line drugs world-

wide and improve access to concessionally-priced quality-assured second-linedrugs. As DR-TB has emerged as a growing threat to DOTS programmes, new

recommendations described in these updated guidelines must become a part o

routine national TB control activities.

The GLC has developed a mechanism to assist countries in adapting the

ramework described in these guidelines to country-specic contexts. Coun-

tries that meet the ramework requirements, with a strong DOTS oundation

and a solid plan to manage DR-TB, can benet rom quality-assured second-

line drugs at reduced prices. The GLC also oers technical assistance beore

implementation o programmes or control o DR-TB and monitors approved

projects.1

A well-unctioning DOTS programme is a prerequisite or GLC endorse-

ment and or continuation o GLC support. Experience has shown that im-

plementing a DR-TB control programme substantially strengthens overall TB

control or both drug-susceptible and drug-resistant cases (10 ).For control o DR-TB worldwide, WHO and its partners recommend inte-

grating management o the disease into essential services or TB control and

expanding treatment or DR-TB as rapidly as human, nancial and technicalresources will allow.

Reereces

1. Lambregts-van Wezenbeek CSB, Veen J. Control o drug-resistant tuber-

culosis. Tubercle and Lung Disease , 1995, 76:455–459.

2. Interim recommendations or the surveillance o drug resistance in tuber-culosis . Geneva, World Health Organization, 2007 (WHO/CDS/

TB/2007.385).

3. Anti-tuberculosis drug resistance in the world. Fourth global report. The WHO/IUATLD global project on anti-tuberculosis drug resistance surveil-lance, 2002–2007 . Geneva, World Health Organization, 2008 (WHO/

HTM/TB/2008.394).

4. Blower SM, Chou T. Modeling the emergence o the “hot zones”: tuber-

culosis and the amplication dynamics o drug resistance. Nature Medi-cine , 2004, 10(10):1111–1116.

5. Migliori GB et al. Frequency o recurrence among MDR-TB cases

“successully” treated with standardized short-course chemotherapy. Inter-

national Journal o Tuberculosis and Lung Disease , 2002, 6(10):858–864.

1 For more inormation about the services o the GLC and or technical support or to apply or ac-cess to concessionally-priced quality-assured second-line antituberculosis drugs, see the GLC webpage at: http://www.who.int/tb/challenges/mdr/greenlightcommittee/en/index.html



7

6. Global tuberculosis control: surveillance, planning, fnancing. WHOreport 2008 . Geneva, World Health Organization, 2008 (WHO/HTM/

TB/2008.393).

7. The Global MDR-TB and XDR-TB Response Plan 2007–2008 . Geneva, World Health Organization, 2007 (WHO/HTM/TB/2007.387).

8. Emergence o Mycobacterium tuberculosis with extensive resistance to

second-line drugs – worldwide, 2000–2004. Morbidity and Mortality Weekly Report , 2006, 55(11):301–305.


death in patients co-inected with tuberculosis and HIV in a rural area o

South Arica. Lancet , 2006, 368(9547):1575–1580.

10. Kim JY et al. From multidrug-resistant tuberculosis to DOTS expansion

and beyond: making the most o a paradigm shit. Tuberculosis , 2003,

83:59–65.




8

CHAPTER 2

Frameork or eectiecotrol o DR-TB


2.2 DOTS ramewor applied to the management o DR-TB 8

2.2.1 Sustained political commitment 9

2.2.2 A rational case-fnding strateg including accurate, timel

diagnosis through qualit-assured culture and DST 9

2.2.3 Appropriate treatment strategies that use second-line

drugs under proper case management conditions 9

2.2.4 Uninterrupted suppl o qualit-assured antituberculosis drugs 10

2.2.5 Standardized recording and reporting sstem 10

2.3 A plan or tailored integration o management o DR-TB into

national programmes 112.4 Summar 11

Box 2.1 ke steps or integrating management o DR-TB into

national TB control programmes 12

Box 2.2 List o ariables to consider when assessing needs or

integrating management o DR-TB into national TB control

programmes 12

Box 2.3 Fie components o DOTS as applied to DR-TB 13

2.1 Cater objecties

This chapter describes the ve essential components o the DOTS ramework

as they apply to the management o DR-TB. It also introduces a systematic ap-

proach or tailoring these components to the local situation, with integration

into a DOTS-based NTP.

2.2 DOTS rameork as alied to te maagemet o DR-TB

The ramework or DR-TB is organized around the ve components o the

DOTS strategy because the underlying principles are the same (1–2 ):a. Sustained political commitment

b. A rational case-nding strategy including accurate, timely diagnosis

through quality-assured culture and DST



9

2. FRAMEWORk FOR EFFECTIvE CONTROL OF DRUG-RESISTANT TUBERCULOSIS

c. Appropriate treatment strategies that use second-line drugs under proper

case management conditions

d. Uninterrupted supply o quality-assured antituberculosis drugs

e. Standardized recording and reporting system

Each o these components involves more complex and costly operations than

those or controlling drug-susceptible TB. However, addressing DR-TB usu-

ally strengthens the NTP.

2.2.1 Sustained political commitment

Sustained political commitment is essential to establish and maintain the

other our components. It requires both long-term investment and leader-

ship to ensure an appropriate environment or integrating the managemento DR-TB into NTPs. An appropriate environment includes adequate inra-

structure, development and retention o human resources, interagency cooper-

ation, enactment o necessary legislation, TB control policies enabling rational

implementation o the programme and acilitation o the procurement o qual-

ity-assured second-line drugs. In addition, the NTP must be strengthened to

prevent the emergence o more MDR-TB and XDR-TB cases.

2.2.2 A rational case-fnding strateg including accurate, timel

diagnosis through qualit-assured culture and DST Accurate, timely diagnosis is the backbone o a sound NTP. DR-TB must be

diagnosed correctly beore it can be treated eectively. Case-nding strate-

gies may vary depending on the epidemiological situation and local capacity.

In some settings, all TB patients are tested with culture and DST. However,

in most settings, only patients with an increased risk o DR-TB are tested

(strategies on which risk groups to test are discussed in Chapter 5). In areas

where XDR-TB threatens TB control, laboratories should develop the capac-

ity or DST to second-line injectable agents and the fuoroquinolones in order

to diagnose XDR-TB.Quality-assured culture and DST are indispensable. Non-viable cultures,

culture contamination and unreliable DST results have major consequences

or both individual patients and the NTP as a whole. Internal quality control

and external quality assurance should thereore be in place, including a link

or prociency testing with a recognized reerence laboratory such as one o

the WHO-recognized SRLs.

2.2.3 Appropriate treatment strategies that use second-line drugs

under proper case management conditions

An appropriate treatment strategy consists o a rational method or designing

the optimal treatment regimen, a patient-centered approach or delivering this

regimen with direct observation, and a plan or monitoring and managing



10


adverse drug reactions. Designing an optimal regimen requires proessional

expertise to consider several actors together, including:

• representative data on drug resistance surveillance (DRS) o well-dened

local groups o TB patients, distinguishing new cases and dierent types o

re-treatment cases;

• history o drug use in the country and in the individual;

• specic array o available second-line drugs;

• availability o DST to rst- and selected second-line drugs;

• reliable options or delivering directly observed therapy (DOT) or up to

two years;

• addressing patients coinected with HIV;

•

proper inection control policies implemented. A standardized regimen or certain groups o patients may be more appropri-

ate than an individualized regimen in some countries, while in others the con-

verse may be best.

The choice between hospitalization and ambulatory treatment depends on

several actors in addition to the severity o the disease. Such actors include

the availability o hospital beds with adequate inection control measures to

prevent nosocomial transmission; the availability o trained personnel at hos-

pitals and clinics to administer treatment and manage adverse drug reactions;

the availability o a social support network to acilitate adherence to ambu-

latory treatment; and the presence o other clinical or social conditions in

patients.

2.2.4 Uninterrupted suppl o qualit-assured

antituberculosis drugs

Management o second-line drugs is complex, especially when individualized

treatment regimens are used. Drugs are requently changed as a result o ad-

verse eects, delayed DST results and poor response to treatment. In addition,most second-line drugs have a short shel-lie, global production o quality-

assured drugs is limited, and drug registration may be a lengthy and costly

process that is not always attractive to drug manuacturers. Steps to ensure an

uninterrupted drug supply must begin six months or more in advance o the

anticipated need, and drug needs must be estimated as accurately as possible.

Countries should use only drugs that have been quality-assured by a stringent

drug regulatory authority recognized by WHO, a WHO prequalication pro-

gramme or that meet WHO GMP standards.

2.2.5 Standardized recording and reporting sstem

The specic characteristics o a DR-TB control programme include a record-

ing system with dierently dened categories or patient registration, culture

and DST results, and monitoring o treatment delivery and response or 24



11

months. Cohort analysis includes interim indicators and treatment outcomes

ater two or more years, as well as treatment outcomes by treatment regimen

and DST results. The set o case registration groups and treatment outcome

denitions or MDR-TB used in these guidelines (Chapter 4) were developedthrough a process that involved the Stop TB Working Group on DOTS-Plus

or MDR-TB ( 3). They can be used or conducting cohort analyses in DR-

TB control programmes. The redesigned recording and reporting system (see

Chapter 18) is essential or evaluating programme perormance and treatment

eectiveness.

2.3 A la or tailored itegratio o maagemet o DR-TB

ito atioal rogrammes

Management o DR-TB should be ully integrated into the NTP. The chal-lenge involved in this integration should not be underestimated. However, the

complexity o the process should not deter programmes rom taking the steps

necessary to allow all patients with DR-TB access to lie-saving treatment. I

many o the patients with DR-TB are treated in the private sector, integra-

tion can be acilitated through PPM approaches. Box 2.1 depicts the three key

steps o a plan or integrating the management o DR-TB into NTPs.

The most important consideration is the political will to deliver rational

treatment to patients with DR-TB as part o a sound NTP. Following conr-

mation o political will, a needs assessment should be carried out. Box 2.2 lists

the most relevant variables to consider.

The needs assessment will acilitate the design and implementation o a

plan to meet the gaps identied, in terms o both inrastructure and unction-

ing o the health-care system. Once the inrastructure is in place and the key

unctions such as a quality-assured TB laboratory are operating, a stepwise

integration o activities to control DR-TB can proceed within the NTP. Step-

wise integration means that those districts or administrative areas where the

integration is more likely to succeed should be prioritized.The design and implementation o a DR-TB control programme may vary

between and within countries, depending on the local needs and resources

available. Despite a wide range o acceptable strategies, essential requirements

such as quality-assured laboratories or diagnosis and monitoring o treat-

ment response, delivery o DOT and use o quality-assured second-line drugs

should be met under all conditions to ensure proper case management and

prevent the emergence o resistance to second-line drugs.

2.4 SummarThe DOTS ramework approach to management o DR-TB, summarized in

Box 2.3, includes ve essential components that orm the basis or every NTP

that includes detection and treatment o DR-TB.




12


Reereces

1. Treatment o tuberculosis: guidelines or national programmes , 3rd ed.

Geneva, World Health Organization, 2003 (WHO/CDS/TB/2003.

313).

2. An expanded DOTS ramework or eective tuberculosis control . Geneva, World Health Organization, 2002 (WHO/CDS/TB/2002.297).

3. Laserson KF et al. Speaking the same language: treatment outcome

denitions or multidrug-resistant tuberculosis. International Journal o Tuberculosis and Lung Disease , 2005, 9(6):640–645.

BOx 2.1

Ke stes or itegratig maagemet o DR-TB ito atioal TB

cotrol rogrammes

1. Assessment o political will to delier rational treatment to patients with

drug-resistant TB.

2. Needs assessment or drug-resistant TB control actiities.

3. Design and implementation o a plan or management o drug-resistant TB

and its stepwise integration into the national TB control programme.

BOx 2.2

List o ariables to cosider e assessig eeds or itegratig

maagemet o DR-TB ito atioal TB cotrol rogrammes

Magnitude and distribution o DR-TB

Magnitude o HIv

Preailing patterns o drug resistance

Options or case-fnding

Existing inrastructure o the health-care sstem

Aailable laborator capacit

Resources aailable or DOT oer a prolonged period

Inection control polic in place and adequate unding aailable or control

measures

Qualit standards o the laborator networ

Aailabilit o human resources

Training needs Existing legal ramewor or management o second-line drugs

Needs or external technical assistance



13


BOx 2.3 FIvE COMpOnEnTS OF DOTS AS AppLIED TO DR-TB

1. Sustaied olitical commitmet

Addressing the actors leading to the emergence o MDR-TB

Long-term inestment o sta and resources

Coordination o eorts between communities, local goernments and inter-

national agencies

A well-unctioning DOTS programme

2. Aroriate case-dig strateg icludig qualit-assured culture

ad DST

Rational triage o patients into DST and the DR-TB control programme

Relationship with supranational TB reerence laborator

3. Aroriate treatmet strategies tat use secod-lie drugs uder

roer case maagemet coditios Rational treatment design (eidence-based)

DOT

Monitoring and management o aderse eects

Properl trained human resources

4. Uiterruted sul o qualit-assured secod-lie atituberculosis

drugs

5. Recordig ad reortig sstem desiged or DR-TB cotrol

rogrammes tat eables moitorig o erormace ad ealuatio o

treatmet outcomes



14

CHAPTER 3

political commitmet adcoordiatio


3.2 General considerations 14

3.3 Political commitment 14

3.3.1 Sufcient economic support 15

3.3.2 Regulator and operational documents 15

3.4 Coordination 16

3.5 Proposed checlist 17

Box 3.1 Proposed elements o the DR-TB control programme manual 16

Box 3.2 Summar checlist or DR-TB control programme managers 18

3.1 Cater objecties

Sustained political commitment is a prerequisite or control o DR-TB. This

chapter considers how political commitment can be translated into practical

measures to support all aspects o the ramework or control o DR-TB, and

the practical implications or NTPs. The main elements are described and a

checklist or programme managers is provided.

3.2 Geeral cosideratios

Sustained political commitment and leadership are the oundation or any

sound programme to control TB. The legal and regulatory context denes

the potential as well as the structure and policies o NTPs and DR-TB control

programmes. Political commitment is expressed through adequate nancial

support and appropriate inrastructure, including acilities and trained sta.

Coordination among the dierent components o public and private health-

care programmes and organizations is essential or successul programme im-

plementation. Sucient training and retention o medical and public health

personnel depend on long-term government planning and support.

3.3 political commitmet

Political commitment must be expressed at all stages o the health intervention

process, rom planning and implementation to monitoring and evaluation.



15

3. POLITICAL COMMITMENT AND COORDINATION

Political support needs to be garnered rom sources including government

ministries and regional departments responsible or TB control, nongovern-

mental organizations and the private sector, the pharmaceutical industry,

academic and research institutions, proessional medical societies and thedonor community. This commitment takes the orm o nancial and human

resources, training, legal and regulatory documents, inrastructure and coor-

dination o all stakeholders involved in all aspects o the ramework or control

o DR-TB.

3.3.1 Sufcient economic support

The NTP budget must be sucient to develop and retain an adequate work-

orce with interest and expertise in DR-TB without weakening the workorce

o the national programme as a whole. The nancial resources needed to sup-

port the ramework should be provided. There should be no nancial barriers

to patients’ accessing appropriate care or DR-TB. Human resource needs are

discussed in Chapter 16.

3.3.2 Regulator and operational documents

Beore embarking on a DR-TB control programme, national and regional au-

thorities need to develop policies as a oundation or any subsequent legal,

administrative and technical support necessary or the initiation, implementa-tion and monitoring o the programme. Regulatory document(s) should con-

sider how the programme will be integrated into the NTP. The ollowing are

examples o the use o regulatory and operational documents:

• Legislation can be drated to ensure proper registration, availability, qual-

ity, saety and distribution o second-line drugs. (Oten, strict control o

second-line drugs is possible only ater establishment o the programme to

provide quality-assured drugs ree o charge to patients.)

•

A local steering committee or expert committee can be ormed to meetperiodically to consult on individual patients and to address programmatic

problems.

• A memorandum o understanding delineating responsibilities and unding

is oten necessary i multiple organizations are involved. In settings where

programmes involve dierent ministries or departments (including, or ex-

ample, the prison system or the social security system), an interministerial

or interdepartmental agreement should be signed that codies the mecha-

nism or coordinating services or diagnosis o TB and treatment o patients

between all authorities.

• A programme manual can be the vehicle or disseminating operational and

clinical protocols to ensure consistency. It should be ocially endorsed by

the relevant authorities. The manual describes treatment protocols, denes



16


responsibilities or dierent health-care providers and delineates the hu-

man resources that will be needed. It specically denes how disease will be

diagnosed and how patients will be registered, reported, treated and ol-

lowed up, in addition to programme monitoring and evaluation. Items tobe included in the programme manual are proposed in Box 3.1.

BOx 3.1 pROpOSED ELEMEnTS OF ThE DR-TB COnTROL

pROGRAMME MAnUAL

Bacground inormation on the DOTS programme and its integration with

treatment o patients with DR-TB

Organization and management o the DR-TB control programme

Case detection, diagnosis, classifcation o and reporting requirements or

drug-resistant TB

Organization o the laborator networ, including qualit control proceduresor laboratories proiding culture and DST

Treatment regimens or drug-resistant TB

Management o aderse eects caused b antituberculosis drugs

Management o drug-resistant TB in special populations and situations (in-

cluding children; pregnant or lactating women; diabetes mellitus; HIv; renal

or hepatic insufcienc; the elderl; alcohol and drug-dependent patients;

prisoners)

Case management sstem including DOT, transition to ambulator care,

patient assistance and deaulter tracing

Standards or ealuation and monitoring o treatment and o oerall project

perormance Plan or inection control in health acilities and other methods to preent

drug-resistant TB

3.4 Coordiatio

Coordination needs to include the contributions o all the key stakeholders,

organizations and external partners, as considered below.

• National TB control programme. The NTP is the central coordinating

body or the activities described in the strategic ramework. Commitmento the necessary resources, particularly or a strong central management

team, ensures that all elements are in place, rom the procurement o sec-

ond-line drugs to the appropriate implementation and monitoring o the

DR-TB control programme. As needed, the national programme may build

partnerships with all relevant health-care providers.

• Local health system. DR-TB control programmes should be tailored to

t the local inrastructure. The precise organizational structure o the pro-

gramme may vary greatly between dierent settings depending on how

the local health care is provided. Transer rom hospitals to outpatient set-

tings or between DOT centres requires care, advance planning and good

communication. Given the type o care required during the treatment o

DR-TB patients, a team o health workers including physicians, nurses and

social workers is oten used.



17

• Community level. Community involvement and communication with

community leaders can greatly acilitate implementation o treatment and

respond to needs that cannot be met by medical services alone. Commu-

nity education, involvement and organization around TB issues can ostercommunity ownership o control programmes and reduce stigma. In some

circumstances, communities have helped to address the interim needs o

patients, including the provision o DOT, ood and/or housing. Commu-

nity health workers oten play a critical role in ambulatory care o DR-TB

patients.

• Coordination with prisons (1). Transmission in prisons is an important

source o spread o DR-TB in some countries, and inection control meas-

ures can reduce incidence substantially. In many cases, inmates are releasedrom prison beore they nish treatment. Close coordination and commu-

nication with the civilian TB control programme, advance planning, tar-

geted social support and specic procedures or transerring care will help

ensure that patients complete treatment ater release rom prison.

• All health-care providers (both public and private) ( 2 ). In some coun-

tries, private practitioners manage most cases o DR-TB. In these settings,

it is important to involve the private sector in the design and technical as-

pects o the programme. Many PPM programmes have demonstrated eec-

tive and mutually benecial cooperation ( 3). In PPM systems, patients and

inormation move in both directions. For example, private providers can be

compensated airly through negotiated systems o reimbursement, and the

public health system may provide clinic- or community-based DOT as well

as registering patients and their treatment outcomes. Similar PPM mixes

can be established or treatment o patients with DR-TB, but they require

exceptional coordination. The public health system may also get involved

in training on national guidelines or DR-TB.

• International level. International technical support through WHO, theGLC, SRLs and other technical agencies is recommended. The NTP

should set up and lead an interagency body that ensures clear division o

tasks and responsibilities.

3.5 proosed cecklist

From the earliest planning phase, the ull range o issues encompassed in po-

litical commitment needs to be addressed. These include adequate nancial

support, an enabling regulatory environment, sucient human resources, ad-

equate physical inrastructure and good coordination. In addition, a communi-

cation strategy should be established to ensure that inormation is disseminated

eectively rom the central level to the periphery and that reports rom the peri-

pheral level are received centrally. Box 3.2 provides a checklist or programme

managers, summarizing the key aspects o a DR-TB control programme.

3. POLITICAL COMMITMENT AND COORDINATION



18


Reereces

1. Bone A et al. Tuberculosis control in prisons: a manual or programme managers . Geneva, World Health Organization, 2000 (WHO/CDS/

TB/2000.281).

2. Involving private practitioners in tuberculosis control: issues, interventions

and emerging policy ramework . Geneva, World Health Organization,2001 (WHO/CDS/TB/2001.285).

3. Towards scaling up. Report o the Third Meeting o the PPM Subgroup or DOTS Expansion. Geneva, World Health Organization, 2005 (WHO/

CDS/TB/2005.356).

BOx 3.2 SUMMARy ChECKLIST FOR DR-TB COnTROL pROGRAMME MAnAGERS

preetio Sound implementation o DOTS programme

Inection control measures taen where all DR-TB patients will be treated

Contact tracing or MDR-TB cases in place

Laborator

Testing and maintenance o equipment

Biosaet measures in place

Reagents suppl

Superision and qualit assurance sstem (relationship with SRL estab-

lished)

Sstem or reporting laborator results to the treatment centre

Laborator or monitoring o electroltes, creatinine, lipase, throid unc-

tion, lier enzmes, and hematocrit in place Point-o-care HIv testing, with counselling and reerral aailable

Pregnanc testing

patiet care Council o experts or steering committee set up

Adequate capacit and trained sta at the health centre or DOT and

patient support

DOT in place and plan to ensure case holding

Sstem to detect and treat aderse eects, including suppl o appropriate

medications

Patient and amil support to increase adherence to treatment, such as

support group, pschological counselling, transportation subsid, ood bas-ets

Patient, amil and communit health education, including stigma reduc-

tion

programme strateg Integration with DOTS programme

Sources o DR-TB identifed and corrected

Legislation or treatment protocols accepted

Project manual published and disseminated

Agreement o criteria or prioritization o patient waiting lists

Location o care defned and unctional (ambulator s hospitalization)

Integration o MDR-TB serices with HIv care Integration o all health-care proiders into the DR-TB control programme



19

CHAPTER 4

Deitios:case registratio, bacteriolog

ad treatmet outcomes


4.2 Defnitions o drug resistance and diagnostic Categor Iv 20

4.3 Site o DR-TB disease (pulmonar and extrapulmonar) 20

4.4 Bacteriolog and sputum conersion 21

4.5 Categor Iv patient registration group based on preious

antituberculosis treatment 21

4.6 Defnitions or diagnostic Categor Iv treatment outcomes 23

Box 4.1 Helpul hints on registrations and defnitions 25

4.1 Cater objectiesThis chapter establishes case denitions, patient registration categories, bac-

teriological terms, treatment outcome denitions and cohort analysis proce-

dures or patients who meet WHO Category IV diagnostic criteria.1 It is an

extension o the basic DOTS inormation system (1, 2 ).The categories, denitions and procedures dened in this chapter will

acilitate the ollowing:

• standardized patient registration and case notication;

•

assignment to appropriate treatment regimens;• case evaluation according to disease site, bacteriology and history o treat-

ment;

• cohort analysis o registered Category IV patients and Category IV treat-

ment outcomes.

1 Treatment o tuberculosis : guidelines or national programmes (1) recommends treatment regimensbased on dierent TB diagnostic categories. The diagnostic categories are:

Category I – New smear-positive patients; new smear-negative pulmonary TB (PTB) with exten-sive parenchymal involvement; severe concomitant HIV disease or severe orms o extrapulmo-

nary TB.Category II – Previously treated sputum smear-positive PTB: relapse; treatment ater interrup-tion; ailures.Category III – New smear-negative PTB (other than in Cat I) and less severe orms o extra-pulmonary TB.Category IV – Chronic cases (still sputum-positive ater supervised re-treatment) and MDR-TB.



20


4.2 Deitios o drug resistace ad diagostic Categor Iv

DR-TB is conrmed through laboratory tests that show that the inecting

isolates o Mycobacterium tuberculosis grow in vitro in the presence o one or

more antituberculosis drugs (see Chapter 6 or urther inormation on labo-ratory requirements). Four dierent categories o drug resistance have been

established:

• Mono-resistance : resistance to one antituberculosis drug.

• Poly-resistance: resistance to more than one antituberculosis drug, other

than both isoniazid and riampicin.

• Multidrug-resistance : resistance to at least isoniazid and riampicin.

• Extensive drug-resistance: resistance to any fuoroquinolone, and at leastone o three injectable second-line drugs (capreomycin, kanamycin and

amikacin), in addition to multidrug-resistance.

Diagnostic Category IV includes patients with:

• Conrmed MDR-TB.

• Suspected MDR-TB. This requires that the relevant health authority (such

as a review panel) recommends that the patient should receive Category IV

treatment. Patients may be entered in the Category IV register and startedon Category IV treatment beore MDR-TB is conrmed only i representa-

tive DST surveys or other epidemiologic data indicate a very high probabil-

ity o MDR-TB (see Chapter 5).

• Poly-resistant TB. Some cases o poly-resistant TB will require Category

IV treatments. These patients require prolonged treatment (18 months or

more) with rst-line drugs combined with two or more second-line drugs

(see Chapter 8, Table 8.1) and should be entered into the Category IV reg-

ister. (Most programmes choose to keep cases o mono- and poly-resistance

that do not require second-line drugs or require only one second-line drug,in the District TB Register).

4.3 Site o drug-resistat TB disease

(ulmoar ad etraulmoar)

In general, recommended treatment regimens or drug-resistant orms o TB

are similar, irrespective o site. The importance o dening site is primarily or

recording and reporting purposes.

• Pulmonary TB. Tuberculosis involving only the lung parenchyma.• Extrapulmonary TB. Tuberculosis o organs other than the lungs, e.g.

pleura, lymph nodes, abdomen, genitourinary tract, skin, joints and bones,

meninges. Tuberculous intrathoracic lymphadenopathy (mediastinal and/

or hilar) or tuberculous pleural eusion, without radiographic abnormali-



21

4. DEFINITIONS: CASE REGISTRATION, BACTERIOLOGy AND TREATMENT OUTCOMES

ties in the lungs, thereore constitutes a case o extrapulmonary TB. The

denition o an extrapulmonary case with several sites aected depends on

the site representing the most severe orm o disease.

Patients with both pulmonary and extrapulmonary TB should be classied as

a case o pulmonary TB.

4.4 Bacteriolog ad sutum coersio

Bacteriological examinations used in patients with DR-TB include sputum

smear microscopy and culture. Sputum smear microscopy and culture should

be perormed and results reported according to international standards ( 3).

These examinations should be done at the start o treatment to conrm TB

disease and to group the patients according to inectiousness, sputum smear-positive being most inectious.

At least one sputum sample or smear and culture should always be taken

at the time o Category IV treatment start. In order or a patient to be consid-

ered culture- or sputum smear-positive at the start o Category IV treatment,

the ollowing criteria must be met: at least one pre-treatment culture or smear

was positive; the collection date o the sample on which the culture or smear

was perormed was less than 30 days beore, or 7 days ater, initiation o Cat-

egory IV treatment.

Sputum conversion is dened as two sets o consecutive negative smearsand cultures, rom samples collected at least 30 days apart. Both bacterio-

logical techniques (smear and culture) should be used to monitor patients

throughout therapy (see Chapter 11). The date o the rst set o negative cul-

tures and smears is used as the date o conversion (and the date to determine

the length o the initial phase and treatment).

The recording and reporting system assesses the smear- and culture-status

6 months ater the start o treatment as an interim outcome. Programmes

oten use the smear and culture conversion rate at 6 months to assess pro-

gramme perormance (see Chapter 18).

4.5 Categor Iv atiet registratio grou based o istor o

reious atituberculosis treatmet

Category IV patients should be assigned a registration group based on their

treatment history, which is useul in assessing the risk or MDR-TB.

The registration groups describe the history o previous treatment and do

not purport to explain the reason(s) or drug resistance.1

1 These guidelines do not use the terms “primary” and “acquired” resistance because these types o resistance cannot be distinguished in most DR-TB control programmes. I DST is done beorethe start o the patient’s rst antituberculosis treatment, any resistance documented is primary resistance. I new resistance is ound when DST is later repeated and genetic testing conrms thatit is the same strain, only then can it be concluded that the strain has acquired resistance. Other-

wise, it may be caused by re-inection with a new strain.



22


Each Category IV patient should be classied in two dierent ways:

I. Classication according to history o previous drug use, mainly to as-

sign the appropriate treatment regimen.

• New . A patient who has received no or less than one month o antitubercu-

losis treatment. Patients are placed in this group i they had sputum collect-

ed or DST at the start o a Category I regimen and were then switched to a

Category IV regimen because MDR-TB was later conrmed. They should

be considered “new” i DST was perormed within one month o the start

o treatment (even i they had received more than one month o Category I

treatment by the time the results o DST returned and they were registered

as Category IV).

• Previously treated with rst-line drugs only . A patient who has been

treated or one month or more or TB with only rst-line drugs.

• Previously treated with second-line drugs. A patient who has been treat-

ed or one month or more or TB with one or more second-line drugs, with

or without rst-line drugs.

II. Classication according to the history o their previous treatment

(commonly reerred to as the patient’s “registration group”). The reg-

istration groups are the established groups used in the DOTS recording andreporting system, with additional subgrouping o patients treated ater ailure.

The number o groups will depend on the country policy on target groups

or DST. This grouping allows analysis o the target groups or DST, epide-

miological monitoring and projection o uture numbers o MDR-TB cases.

Again, classication is determined by treatment history at the time o collec-

tion o the sputum sample that was used to conrm MDR-TB. The groups

are as ollows:

•

New . (Same denition as in classication according to previous drug use). A patient who has received no or less than one month o antituberculosis

treatment.

• Relapse. A patient whose most recent treatment outcome was “cured” or

“treatment completed”, and who is subsequently diagnosed with bacterio-

logically positive TB by sputum smear microscopy or culture.

• Treatment ater deault . A patient who returns to treatment, bacteriologi-

cally positive by sputum smear microscopy or culture, ollowing interrup-

tion o treatment or two or more consecutive months.• Treatment ater ailure o Category I. A patient who has received Catego-

ry I treatment or TB and in whom treatment has ailed. Failure is dened

as sputum smear positive at ve months or later during treatment.



23

• Treatment ater ailure o Category II. A patient who has received Cat-

egory II treatment or TB and in whom treatment has ailed. Failure is

dened as sputum smear positive at ve months or later during treatment.

• Transer in. A patient who has transerred in rom another register or

treatment o DR-TB to continue Category IV treatment.

• Other. There are several types o patients who may not t into any o the

above categories. Programmes are encouraged to classiy these patients into

groups that are meaningul according to the local epidemiology o disease.

Examples include the ollowing: sputum smear positive patients with un-

known previous treatment outcome; sputum smear positive patients who

received treatment other than Category I or II (possibly in the private sec-

tor); previously treated patients with extrapulmonary TB; patients whohave received several unsuccessul treatments, were considered incurable

by health sta and who have lived with active TB disease with no or inad-

equate treatment or a period o time (duration depends on country situa-

tion) until Category IV treatment became available (so-called “back-log”

patients; see also Chapter 18.5).

While persistently positive smears at month ve constitute the denition o

ailure, many programmes may want to perorm culture and DST earlier based

on the overall clinical picture. Patients ound to have MDR-TB will need to beswitched to Category IV regimens beore they meet the traditional diagnosis

o ailure. When possible, these patients should be classied separately. This

will allow assessment o the value o these end-points to predict MDR-TB, and

thereby the utility o routine DST in these groups. Otherwise, they should be

classied together with the ailures o the regimens they received.

HIV status is also recorded at the start o treatment and, i unknown, point-

o-care testing is encouraged (see Chapter 18).

4.6 Deitios or diagostic Categor Iv treatmet outcomesThe ollowing are mutually exclusive Category IV outcome denitions (4 )that rely on the use o laboratory smear and culture as a monitoring tool and

will be reported in Forms 01, 02 and 07 (see Chapter 18). They have been

constructed to parallel the six DOTS outcomes or drug-susceptible TB (1, 4 ). All patients should be assigned the rst outcome they experience or the treat-

ment being evaluated or recording and reporting purposes.

• Cured . A Category IV patient who has completed treatment according to

programme protocol and has at least ve consecutive negative cultures rom

samples collected at least 30 days apart in the nal 12 months o treatment.

I only one positive culture is reported during that time, and there is no

concomitant clinical evidence o deterioration, a patient may still be con-

sidered cured, provided that this positive culture is ollowed by a minimum

o three consecutive negative cultures taken at least 30 days apart.




24


• Treatment completed . A Category IV patient who has completed treat-

ment according to programme protocol but does not meet the denition or

cure because o lack o bacteriological results (i.e. ewer than ve cultures

were perormed in the nal 12 months o treatment).

• Died . A Category IV patient who dies or any reason during the course o

MDR-TB treatment.

• Failed . Treatment will be considered to have ailed i two or more o the

ve cultures recorded in the nal 12 months o therapy are positive, or

i any one o the nal three cultures is positive. (Treatment will also be

considered to have ailed i a clinical decision has been made to terminate

treatment early because o poor clinical or radiological response or adverse

events. These latter ailures can be indicated separately in order to do sub-analysis).

• Deaulted . A Category IV patient whose treatment was interrupted or two

or more consecutive months or any reason without medical approval.

• Transerred out . A Category IV patient who has been transerred to an-

other reporting and recording unit and or whom the treatment outcome is

unknown.

Patients who have transerred in should have their outcome reported back to thetreatment centre rom which they originally were registered. The responsibility

o reporting their nal outcomes belongs to the original treatment centre.

4.7 Coort aalsis

All patients should be analysed in two dierent cohorts (groups o patients)

depending on the purpose:

• The treatment cohort includes only patients who start Category IV treat-

ment. It is dened by the date o start o Category IV treatment. The

purpose is mainly to assess result o treatment and trends over time.

• The diagnostic cohort includes patients diagnosed with MDR-TB (identi-

ed in the DST register by date o DST result) during a specic period o

time. The purpose is mainly to assess the number o patients with DR-TB,

in subgroups and over time. This allows the programme to evaluate delay

in treatment start and proportion o patents who started treatment.

The recommended timerame or Category IV treatment cohort analysis re-

fects the long duration o Category IV regimens. Cohort analyses should becarried out at 24 months and, i needed, repeated at 36 months ater the last

patient starts treatment (see Chapter 18 and Form 07). For each treatment

cohort, an interim status should be assessed at 6 months ater the start o treat-

ment to monitor programme progress (see Chapter 18 and Form 06).



25

Reereces

1. Treatment o tuberculosis: guidelines or national programmes , 3rd ed.

Geneva, World Health Organization, 2003 (WHO/CDS/TB/2003.313).

(revision 2005).

2. Revised TB recording and reporting orms and registers – version 2006 . World

Health Organization, 2006 (WHO/HTM/TB/2006.373; available at

(http://www.who.int/entity/tb/dots/r_and_r_orms/en/index.html).

3. Laboratory services in tuberculosis control [Parts I, II and III] . Geneva, World Health Organization, 1998 (WHO/TB/98.258).

4. Laserson KF et al. Speaking the same language: treatment outcome

denitions or multidrug-resistant tuberculosis. International Journal o Tuberculosis and Lung Disease , 2005, 9(6):640–645.


BOx 4.1 hELpFUL hInTS On REGISTRATIOnS AnD DEFInITIOnS

Assigig te rst outcome. All patients should be assigned the frst out-

come the experience or recording and reporting purposes. For example, a

patient deaults on a Categor Iv regimen and returns 14 months later to bere-registered and is cured with a second Categor Iv treatment. This patient

should receie a fnal outcome o “deaulted” in the cohort in which he or she

was frst registered and “cured” in the second cohort.

Traser out. A patient who is “transerred out” must be transerred out to an-

other DR-TB treatment centre. For example, a patient in a district with a good

DR-TB programme has completed 8 months o a Categor Iv regimen and is

doing well and has conerted his sputum in month two. He inorms the DR-

TB control programme that he is returning to his home district (500 m awa)

and that the district does not hae a DR-TB control programme. His uncle is

going to purchase the medicines, which he will swallow under the superison

o a local phsician. There are no culture acilities in his home district. Thispatient should be counted as a deault, because he is leaing a DR-TB control

programme that will not be able to trac him. A patient must go to another DR-

TB control programme that can report bac the fnal result to be considered

as transerred-out.

Traserred i. A patient who “transers in“ does not get counted in the cohort

o the centre in which he completes his treatment. The receiing centre must

report bac the fnal outcome o the patient to the original treatment centre.

The original centre should confrm with the receiing centre that the patient

transerred in and the fnal treatment outcome.



26

CHAPTER 5

Case-dig strategies


5.2 Bacground inormation and general considerations 27

5.3 Targeting ris groups or DST 27

5.4 Strategies or programmes with minimal access to DST and

limited resources 29

5.5 DST specimen collection 30

5.6 Case-fnding in paediatric patients 30

5.7 Case-fnding in HIv-inected patients 30

5.8 Case-fnding o patients with mono- and pol-drug resistance 31

5.9 Use o rapid drug-resistance testing 31

5.10 Use o second-line DST in case-fnding and diagnosing XDR-TB 33

Table 5.1 Target groups or DST 28

Figure 5.1 Algorithm or the use o rapid drug-resistance testing 32

Box 5.1 Countr examples o case-fnding strategies 33

5.1 Cater objecties

This chapter describes strategies or case-nding and diagnosis o patients

with either suspected or conrmed DR-TB. Several approaches to case-nd-

ing and enrolment into DR-TB control programmes are discussed, taking into

consideration that such programmes may have limited technical and nancial

capacity. The strategies range rom testing all patients with TB to testing only

a selected group o patients.

The chapter reviews case-nding o patients with DR-TB with respect to:

• risk actors or drug resistance;

• strategies or case-nding in programmes with minimal access to DST and

limited resources;

• inormation on DST collection;• the use o rapid DST methods1 to identiy drug resistance;

1 Rapid DST methods in these guidelines reer to molecular techniques that detect the genetic de-terminants o resistance. However, liquid, agar and other validated DST media that determinethe presence o resistance within 2–3 weeks can oten be substituted as rapid DST method whenmolecular methods are not available.



27

5. CASE-FINDING STRATEGIES

• the use o DST o second-line drugs and case detection o XDR-TB;

• important issues in case-nding o drug resistance in the HIV-inected

patient.

Ke recommedatios (* da dad da)

Patients at ris o DR-TB should be screened or drug resistance;

In people liing with HIv, when possible, DST should be perormed at the

start o anti-TB therap to aoid mortalit due to unrecognized DR-TB;*

For the initial screening o DR-TB, rapid DST methods should be used when-

eer possible;

Patients at increased ris o XDR-TB should be screened or resistance with

DST o isoniazid, riampicin, the second-line injectable agents and a uoro-quinolone.*

5.2 Backgroud iormatio ad geeral cosideratios

Programme strategies strive to identiy patients and initiate adequate treat-

ment or drug-resistant cases in a timely manner. Timely identication and

prompt initiation o treatment prevent the patient rom spreading the disease

to others, acquiring urther resistance and progressing to a state o permanent

lung damage.It is strongly recommended that programmes have representative DRS

data or new patients and or the dierent categories o re-treatment patients

(ailure o Category I, ailure o re-treatment, deault and relapse) as well as

other high-risk groups. Without this inormation, or when it is only partially

available, designing an eective case-nding strategy is dicult and may be

impossible. DRS data also enable a programme to estimate the number o pa-

tients who should enrol, which in turn greatly acilitates strategy planning and

drug procurement.

5.3 Targetig risk grous or DST

These guidelines assume a general understanding o case-nding and diagno-

sis o active TB. This inormation can be reviewed in reerence books on TB,

including WHO publications (1, 2 ).Routine DST at the start o treatment may be indicated or all TB pa-

tients or only in specic groups o patients at increased risk or drug resistance.

Specic elements o the history that suggest an increased risk or drug resis-

tance are listed in Table 5.1. Stronger risk actors are placed higher in the table.

Risk actors or XDR-TB are discussed in section 5.10.

The prevalence o resistance in specic risk groups can vary greatly across

dierent settings. The routine use o DST and Category IV treatment or pa-

tients with any risk actor listed in Table 5.1 is thereore not recommended.

Programmes should instead examine DRS data rom risk groups, together



28


TABLE 5.1 Target grous or DST

risK fActors for commentsDruG-resistAnt tb

Failure o re-treatment Chronic TB cases are defned as patients who are stillregimens and chronic sputum smear-positie at the end o a re-treatment

TB cases regimen. These patients hae perhaps the highest MDR-TB

rates o an group, oten exceeding 80% (1, 2).

Exposure to a nown Most studies hae shown close contacts o MDR-TB

DR-TB case patients to hae er high rates o MDR-TB. Management

o DR-TB contacts is described in Chapter 14.

Failure o Categor I Failures o Categor I are patients who while on treatment

are sputum smear-positie at month 5 or later during the

course o treatment. Not all patients in whom a regimen

ails hae DR-TB, and the percentage ma depend on anumber o actors, including whether riampicin was used

in the continuation phase and whether DOT was used

throughout treatment. More inormation on regimen

implications or Categor I ailures is gien below in this

chapter and in Chapter 7.

Failure o antituberculosis Antituberculosis regimens rom the priate sector can

treatment in the priate ar greatl. A detailed histor o drugs used is essential.

sector I both isoniazid and riampicin were used, the chances o

MDR-TB ma be high. Sometimes second-line antituber-

culosis drugs ma hae been used, and this is important

inormation or designing the re-treatment regimen.

Patients who remain Man programmes ma choose to do culture and DST on

sputum smear-positie at patients who remain sputum smear-positie at months 2

month 2 or 3 o SCC and 3. This group o patients is at ris or DR-TB, but

rates can ar considerabl.

Relapse and return ater Eidence suggests that most relapse and return ater

deault without recent deault cases do not hae DR-TB. Howeer, certain

treatment ailure histories ma point more strongl to possible DR-TB; or

example, erratic drug use or earl relapses.

Exposure in institutions Patients who requentl sta in homeless shelters,that hae DR-TB out- prisoners in man countries and health-care worers in

breas or a high DR-TB clinics, laboratories and hospitals can hae high rates o

prealence DR-TB.

Residence in areas with DR-TB rates in man areas o the world can be high enough

high DR-TB prealence to justi routine DST testing in all new cases.

Histor o using The percentage o DR-TB caused b use o poor-qualit

antituberculosis drugs drugs is unnown but considered signifcant. It is nown

o poor or unnown that poor-qualit drugs are prealent in all countries. All

qualit drugs should compl with qualit-assured WHO standards.



29

with their technical capacity and resources, to determine which groups o pa-

tients should get routine DST and/or inclusion into Category IV regimens.

5.4 Strategies or rogrammes it miimal access to DST

ad limited resources Access to DST is required in all programmes. Under exceptional circumstanc-

es, and while building the laboratory capacity to perorm DST, programmes

may use strategies to enrol patients with a very high risk o DR-TB in Cat-

egory IV regimens without individual DST. For example, the results o rep-

resentative DRS may identiy a group or groups o patients with a very high

percentage o DR-TB, which can justiy the use o Category IV regimens in

all patients in the group.

The three groups that are most likely to be considered or direct enrolment

in Category IV regimens are discussed below.

• Category II ailures (chronic TB cases) ( 3, 4 ). Patients in whom Cate-

gory II treatment has ailed in sound NTPs oten have DR-TB (1, 2 ). I the

quality o DOT is poor or unknown (i.e. i regular ingestion o the medi-

cines during Category II treatment is uncertain), patients may ail Catego-

ry II treatment or reasons other than DR-TB.

• Close contacts o DR-TB cases who develop active TB disease . Close

contacts o DR-TB patients who develop active TB disease can be enrolledor treatment with Category IV regimens. (See Chapter 14 or more detail

on the management o contacts o DR-TB patients.)

• Category I ailures. Since the prevalence o DR-TB in this group o pa-

tients may vary greatly (4–8 ), the rate in this group must be document-


TABLE 5.1 (continued)

risK fActors for commentsDruG-resistAnt tb

Treatment in programmes These are usuall non-DOTS or DOTS programmes withthat operate poorl poor drug management and distribution sstems.

(especiall recent and/or

requent drug stoc-outs)

Co-morbid conditions Malabsorption ma result in selectie low serum drug leels

associated with and ma occur in either HIv-noninected or -inected

malabsorption or rapid- patients.

transit diarrhoea

HIv in some settings Data rom the 2002–2006 Global Sureillance project

(9) suggest an association between HIv and MDR-TB in

some parts o the world, and numerous DR-TB outbreashae been documented in HIv patients (see Chapter 10).

The data are still limited and specifc actors inoled in

this association hae not been determined.



30


ed beore deciding whether enrolment in DR-TB control programmes can

take place without DST. Programmes should conduct DRS surveys is this

group to determine whether the routine use o Category II regimens pro-

vides an adequate re-treatment regimen or patients in whom Category Itreatment ailed (also see Chapter 7, Table 7.2).

The rate o DR-TB in these three groups can vary. These guidelines strongly

recommend conrming treatment ailure by culture and testing or DR-TB

through the use o DST to at least isoniazid and riampicin or all patients

who start a Category IV regimen ollowing this strategy. All programmes

should thereore have capacity or DST o at least isoniazid and riampicin.

5.5 DST secime collectio

I DST is chosen as part o the case-nding strategy, it is recommended that

two sputum specimens be obtained or culture and that DST be perormed

with the specimen that produces the best culture. DST does not routinely

need to be carried out in duplicate. Procedures or collecting and managing

specimens or culture and DST are described in Chapter 6, which also ad-

dresses dierent techniques, limitations, quality assurance requirements and

other issues o culture and DST.

Previously treated patients may have had DST in the past but it may no lon-

ger refect the resistance pattern o the strain they had at the time o enrolmentin the DR-TB control programme. Programmes that base treatment on DST

(see Chapter 7) should repeat DST in all patients who have received treatment

since the collection o their previous DST specimen.

5.6 Case-dig i aediatric atiets

Paediatric cases require adjustments in diagnostic criteria and indications or

treatment. Younger children in particular may not be able to produce spu-

tum specimens on demand. Programmes should not exclude children rom

treatment solely because sputum specimens are not available; smear- andculture-negative children with active TB who are close contacts o patients

with DR-TB can be started on Category IV regimens (see Chapter 9, section

9.5 and Chapter 14, section 14.4).

5.7 Case-dig i hIv-iected atiets

Cases o HIV inection also require adjustment in diagnostic criteria and in-

dications or treatment. The diagnosis o TB in HIV-inected people is more

dicult and may be conused with other pulmonary or systemic inections.

People living with HIV are more likely to have smear-negative TB or extrapul-monary TB. These and other WHO guidelines (10 ) recommend the use o

clinical algorithms that include the use o chest X-ray and culture to improve

the ability to diagnose TB in smear-negative patients living with HIV. Because

unrecognized MDR- and XDR-TB are associated with such high mortality



31

in these patients, many programmes perorm culture and DST testing or all

patients living with HIV and with active TB. Programmes without acilities

or resources to screen all patients living with HIV or DR-TB should put sig-

nicant eorts into obtaining them, especially i DR-TB rates are moderateor high. Some programmes may adopt a strategy o targeted DST or patients

with increased risk o DR-TB or low CD4 count (See Chapter 10, Section

10.4). Rapid diagnostic techniques or people living with HIV with active TB

can be very useul to promptly identiy those with DR-TB (see section 5.9).

I XDR-TB is prevalent, people living with HIV who have MDR-TB should

be screened or XDR-TB with the use o liquid media or another validated

rapid technique or DST o second-line injectable agents and a fuoroquinolo-

ne (see Section 5.9). In some cases (as described in Chapters 7 and 10), smear-

negative patients may need to be enrolled empirically into Category IV regi-

mens.

5.8 Case-dig o atiets it moo- ad ol-drug

resistace

Mono- and poly-drug resistant strains are strains that are resistant to antitu-

berculosis drugs but not to both isoniazid and riampicin. Most diagnos-

tic strategies used by DR-TB control programmes will also identiy cases o

mono- and poly-drug resistance, in addition to MDR-TB cases. Patients withmono- or poly-drug resistance may require modications to their SCC regi-

mens or to be moved to Category IV regimens (see Chapter 8).

5.9 Use o raid drug-resistace testig

Case-nding strategies can be greatly enhanced with rapid drug-resistance

testing, which signicantly improves the ability to identiy earlier cases o DR-

TB that can be isolated and started on treatment.

Riampicin is the most potent antituberculosis drug o the rst-line regi-

men, and riampicin resistance most commonly occurs with concomitantisoniazid resistance. A positive rapid test or riampicin resitance is a strong in-

dicator that a patient may have MDR-TB (11, 12 ), while a negative test makes

a nal diagnosis o MDR-TB highly unlikely.

Figure 5.1 is a suggested algorithm on the use o rapid drug-sensitivity

testing or identication and initial management o patients suspected o TB

who are at increased risk o DR-TB. It is based upon the important consider-

ations outlined in this chapter regarding risk actors and case-nding strate-

gies and is applicable to situations o both high and low HIV prevalence. The

algorithm relies on determining the risk o drug resistance and involves HIV testing o all TB suspects, sputum smear microscopy and results rom rapid

sensitivity testing or at least riampicin. It also includes the indications or the

use o empirical treatment regimens or DR-TB while awaiting more complete

DST results.




32


a

I m p r o v i n g t h e d i a g n o s i s a n d t r e a t m e n t o f s m e a r - n e g a t i v e p u l m o n a r y a n d e x t r a p u l m o n a r y t u b

e r c u l o s i s a m o n g a d u l t s a n d a d o l e s c e

n t s : r e c o m m e n d a t i o n s f o r H I V - p r e v a l e n t a n d

r e s o u r c e - c o n s t r a i n e d s e t t i n g s . G e n e a , W o r l d H e a l t h O

r g a n i z a t i o n , 2 0 0 7 ( W H O / H T M / T B / 2

0 0 7 . 3 7 9 ; W H O / H I v / 2 0 0 7 . 0 1 ) .

b

W h e r e r a p i d r i a m

p i c i n t e s t i n g i s n o t a a i l a b l e , t h e a l g

o r i t h m c a n b e o l l o w e d u s i n g l i q u i d m

e t h o d s .

c

B e c a u s e o t h e h i g h a n d q u i c p o s s i b i l i t o d e a t h w i t h X D R - T B i n H I v - i n e c t e d i n d i i d u a l s ,

l i q u i d m e d i a a n d o t h e r a l i d a t e d r a p i d t e c h n i q u e s o r D S T o f r s t - a n d s e

c o n d - l i n e

d r u g s ( H , R , k m ( o r A m ) , C m a n d a u o r o q u i n o l o n e ) a

r e r e c o m m e n d e d o r H I v - i n e c t e d i n d

i i d u a l s w i t h r i s a c t o r s o r X D R - T B .

d

A n t i r e t r o v i r a l T h e r

a p y f o r H I V I n f e c t i o n i n A d u l t s a n d A d

o l e s c e n t s . 2 0 0 6 r e i s i o n W H O , G e n e

a , 2 0 0 4

e

T r e a t m e n t o f t u b e

r c u l o s i s : g u i d e l i n e s f o r n a t i o n a l p r o g r a m m e s , 3 r d e d . G e n e a , W o r l d H e a l t

h O r g a n i z a t i o n , 2 0 0 3 ( W H O / C D S / T B

/ 2 0 0 3 . 3 1 3 ) .

F o l l o w W H O g u

i d e l i n e s o r

t h e d i a g n o s i s o s m e a r

n e g a t i e T B a

S m e a r n e g a t i

e a n d h i g h l

l i e l t o h a e D

R - T B m a

r e q u i r e e m p i r i c a l C a t e g o r

I v t r e a t m e n t .

I f c u l t u r e p o s i t i v e , p e r o r m

r a p i d r e s i s t a n c e t e s t i n g o r

r i a m p i c i n o n t

h e g r o w t h

r o m t

h e c u l t u r e .

F i g u r e 5 . 1

A l g o

r i t m o r t e u s e o r a i d d r u g - r e s i s t a c e t e s t i g

P A T I E N T D E T E R M I N E D

T O B E A T I N C R E A S E D R I S k o r D R - T B ( s e e T a b l e 5 . 1 )

O R P A T I E N T L I v I N G W I T H H I v

•

B e g i n S C C t r e a t m e n t a s p e r

W H O g u i d e l i n e s e

•

P e r o r m D

S T t o H

, R , k m ( o r A m ) , C m a n d

a u o r o q u i n o l o n e

c

•

D e t e r m i n e i A R T

i s i n d i c a t e d d

•

T r e a t a c c o r d i n g t o C h a p t e r s 7 , 8 a n d 1 0 .

•

P e r o r m

D S T t o H , R , k m ( o r A m ) , C m a n d

a u o r o q

u i n o l o n e c

•

T r e a t a c c

o r d i n g t o C h a p t e r 7 a n d 8 .

•

P e r o r m f r s t - l i n e D S T

•

B e g i n S C C t r e a t m e n t a s p e r W H O g u i d e l i n e s e

•

D e t e r m i n e i A R T i s i n d i c a t e d d

•

I D R - T B i d e n t i f e d , t r e a t a c c o r d i n g t o C h a

p t e r s 7 , 8 , a n d 1 0 .

H I v +

r a p i d r i a

m p i c i n t e s t +

H I v –

r a p i d r i a m p i c i n t e s t +

H I v –

r a p i d r i a m p i c i n t e s t –

H I v +

r a p i d r i a m p i c i n t e s t –

•

h I v t e s t ( o r c o f r m

r e s u l t )

•

S m e a r m i c r o s c o

S M E A R

p O S I T I v E

•

R a

i d R e s i s t a c e t e s t i g o r r i a m i c i b

E n s u r e i n e c t i o n c o n t r o l m e a s u r e s

S M E A R

n E G A T I v E





34


amycin, amikacin and capreomycin) and a fuoroquinolone. This will enable

programmes to perorm case-nding or XDR-TB and to assure proper treat-

ment.

The two strongest risk actors or XDR-TB are:

(i) Failure o an anti-TB regimen that contains second-line drugs including

an injectable agent and a fuoroquinolone.

(ii) Close contact with an individual with documented XDR-TB or with

an individual or whom treatment with a regimen including second-line

drugs is ailing or has ailed.

All suspects o XDR-TB should have DST o isoniazid and riampicin, the

second-line injectable agents and a fuoroquinolone. For people living withHIV who are at risk o XDR-TB, given the high and rapid risk o death with

coinection, liquid or other validated rapid techniques or DST o rst- and

second-line drugs is recommended.

Reereces

1. Treatment o tuberculosis: guidelines or national programmes , 3rd ed. Ge-

neva, World Health Organization, 2003 (WHO/CDS/TB/2003.313).

2. Ait-Khaled N, Enarson DA. Tuberculosis: a manual or medical students.

Geneva, World Health Organization, 2003 (WHO/CDS/TB/99.272).3. Heldal E et al. Low ailure rate in standardised retreatment o tuberculo-

sis in Nicaragua: patient category, drug resistance and survival o ‘chron-

ic’ patients. International Journal o Tuberculosis and Lung Disease , 2001,

5(2):129–136.

4. Saravia JC et al. Re-treatment management strategies when rst-line

tuberculosis therapy ails. International Journal o Tuberculosis and Lung Disease , 2005, 9(4):421–429.

5. Harries AD et al. Management and outcome o tuberculosis patients who

ail treatment under routine programme conditions in Malawi. Inter-national Journal o Tuberculosis and Lung Disease , 2003, 7(11):1040–

1044.

6. Quy HT et al. Drug resistance among ailure and relapse cases o tubercu-

losis: is the standard re-treatment regimen adequate? Interational Journal o Tuberculosis and Lung Disease , 2003, 7(7):631–636.

7. Trébucq A et al. Prevalence o primary and acquired resistance o Myco-bacterium tuberculosis to antituberculosis drugs in Benin ater 12 years o

short-course chemotherapy. International Journal o Tuberculosis and Lung Disease , 1999, 3(6):466–470.

8. Kritski AL et al. Retreatment tuberculosis cases. Factors associated with

drug resistance and adverse outcomes. Chest , 1997, 111(5):1162–1167.



35

9. Anti-tuberculosis drug resistance in the world. Fourth global report. The WHO/IUATLD global project on anti-tuberculosis drug resistance surveil-lance, 2002–2007 . Geneva, World Health Organization, 2008 (WHO/

HTM/TB/2008.394).10. Improving the diagnosis and treatment o smear-negative pulmonary and ex-

trapulmonary tuberculosis among adults and adolescents: recommendations or HIV-prevalent and resource-constrained settings . Geneva, World Health

Organization, 2007 (WHO/HTM/TB/2007.379, WHO/HIV/2007.

01).

11. Skenders G et al. Multidrug-resistant tuberculosis detection, Latvia.

Emerging Inectious Diseases , 2005, 11(9):1461–1463.

12. Abdel Aziz M et al. Epidemiology o antituberculosis drug resistance (the

Global Project on Anti-tuberculosis Drug Resistance Surveillance): an

updated analysis. Lancet , 2006, 368(9553):2142–2154.




36

CHAPTER 6

Laborator asects

6.1 Bacground 36


6.3 General defnitions or the laborator and DST 37


6.5 Essential laborator serices and structure 38

6.6 Organization o the laborator networ 39

6.7 Transport o inectious substances 41

6.8 Microscop, culture and identifcation o M. tuberculosis in

DR-TB control programmes 41

6.8.1 Microscop 41

6.8.2 Culture 426.8.3 Identifcation o M. tuberculosis 42

6.8.4 Drug susceptibilit testing 42

6.8.5 Limitations o DST 44

6.9 Rational use o DST in DR-TB control programmes 45

6.10 Time or testing and reporting: turnaround time 46

6.11 Inection control and biosaet in the laborator 46

6.12 Qualit control and qualit assurance 48

Table 6.1 Functions and responsibilities o the dierent leelso laborator serices 40

Figure 6.1 Sstematic approach to implementation o DST under

routine programmatic conditions 47

6.1 Backgroud

A denitive diagnosis o DR-TB requires that M. tuberculosis be isolated on

culture, identied and DST completed. Major challenges remain around the

capacity o laboratories to meet the demand or scaling-up DR-TB treatment

programmes within the context o routine TB control. Laboratory constraintsrelate to inrastructure, equipment, quality assurance and biosaety. Com-

pounded by an urgent need or reliable and reproducible methodologies –

especially or second-line DST – rational use o culture and DST in treatment

programmes is thereore imperative.



37

6. LABORATORy ASPECTS

6.2 Cater objecties

This chapter describes standards or laboratory services needed to diagnose

and treat DR-TB in the context o existing laboratory capacity and techno-

logical constraints.

Ke recommedatios (* indicates updated recommendation)

All patients suspected o DR-TB need access to laborator serices or

adequate and timel diagnosis o DR-TB;

Laboratories should deelop profcienc to isoniazid and riampicin as a

minimum and then consider DST o other drugs (Figure 6.1);*

Laboratories should deelop DST o the uoroquinolones and second-line

injectable agents where adequate capacit and expertise exist;* DR-TB strains can be transported sael across international borders i

international procedures and guidelines are ollowed (section 6.6);*

Laboratories should ollow all standardized protocols or inection control

and biosaet;

Qualit control and qualit assurance should be in place or microscop,

culture and DST. Lins with supranational TB reerence laboratories are

strongl encouraged.

6.3 Geeral deitios or te laborator ad DST

The ollowing are denitions o the laboratory aspects discussed in this chapter:

• Critical drug concentration. The lowest concentration o drug that will

inhibit 95% (90% or pyrazinamide) o wild strains o M. tuberculosis that

have never been exposed to drugs, while at the same time not inhibiting

clinical strains o M. tuberculosis that are considered to be resistant (e.g.

rom patients who are not responding to therapy).

• Minimum inhibitory drug concentration. The lowest concentration o

drug that will inhibit growth o the M. tuberculosis isolate in vitro.• Reproducibility. The ability o a test or experiment to be accurately repro-

duced, or replicated, under independent conditions. Reproducibility relates

to the agreement o test results across dierent laboratories and laboratory

technicians or technologists.

• Reliability. The extent to which a test result remains consistent when

repeated under identical conditions. Reliability does not imply validity. A

reliable test generates a consistent result that may not necessarily be accu-

rate, e.g. clinical ecacy may not be accurately predicted, even i a test ishighly reliable.

• Cross-resistance. Resistance mutations to one antituberculosis drug may

coner resistance to some or all o the members o the drug amily and, less

commonly, to members o dierent drug amilies.



38



Procedures or microscopy, culture and DST o rst-line antituberculosis

drugs have been standardized internationally and are well described in the

literature, with consensus on methodologies, critical drug concentrations, andreliability and reproducibility o testing.

On the other hand, surveys on practices or second-line DST in specialized

laboratories and a ew multi-centre laboratory studies have revealed important

methodological dierences. No studies have systematically evaluated all avail-

able DST methods or all available second-line drugs, established critical con-

centrations or all available second-line drugs, or evaluated a large number o

clinical isolates or microbiological and clinical end-points. Most importantly,

the correlation o in vitro DST results with clinical outcome has not been

established, and the prognostic value o in vitro resistance to second-line

antituberculosis drugs is thereore not known.

Given the urgent need or expansion o laboratory services in support o

DR-TB control programmes, WHO recently issued new policies on the ex-

panded use o liquid culture and interim policy guidance on second-line DST,

outlining the current evidence or reliability and reproducibility o DST meth-

ods, consensus agreement on critical drug concentrations to dene resistance

and providing recommendations or rational use o DST under programmatic

conditions (1).This chapter builds on existing laboratory standards outlined in guidelines

published by WHO ( 2 , 3) and the IUATLD (4 ) on laboratory services or TB

control, incorporating key points rom new WHO policies on the use o liquid

culture (5 ) and second-line DST (1). The latter constitutes current interna-

tional consensus and has gone through extensive external review by laboratory

experts, members o the GLC, members o the SRL network, members o the

WHO Stop TB Partnership Working Group on MDR-TB, and members o

the WHO Stop TB Partnership Global Laboratory Initiative.

6.5 Essetial laborator serices ad irastructure

Optimal management o DR-TB requires both mycobacterial and clinical

laboratory services. At a minimum, the mycobacteriology laboratory service

should provide culture, conrmation o M. tuberculosis and DST o isoniazid

and riampicin. Clinical laboratory services should provide basic haematology,

biochemistry, serology and urine analysis, required or the adequate evaluation

and monitoring o patients (see Chapter 11).

In addition to diagnostic services, laboratories supporting DR-TB control

programmes have a critical role in surveillance o prevailing drug resistancepatterns and trends. Surveillance o antituberculosis drug resistance is essen-

tial or providing inormation on the magnitude o and trends in drug resist-

ance, or developing appropriate treatment modalities and or evaluating the

impact o control programme interventions.



39

Adequate allocation o resources (human and nancial) to laboratory serv-

ices is essential to ensure availability o sucient, adequately qualied and

trained laboratory sta and a sae and unctioning laboratory inrastructure

with appropriate and well-maintained equipment and sucient laboratory consumables.

DR-TB control programmes should have a rapid, reliable and sae means

o collecting and transerring specimens, cultures and inormation rom the

patient and physician to appropriate levels o the laboratory service, and or

returning the results. Specimens rom patients suspected o having DR-TB

as well as cultures o M. tuberculosis pose a signicant public health risk i

not properly transported. Cultures in particular constitute enriched inectious

material containing large numbers o viable organisms, and the risk is com-

pounded when cultures o resistant strains are transported. Details on trans-

port o inectious substances are given in section 6.6.

Transmission o TB – including MDR-TB and XDR-TB – is a well-

recognized risk or laboratory workers (6 , 7 ). M. tuberculosis is classied as

a Risk Group 3 laboratory pathogen by WHO, requiring specic laboratory

containment measures (see section 6.10) (7 ). Adequately equipped laboratory

services to ensure sae handling o drug-resistant strains, especially during

aerosol-producing procedures such as mycobacterial culture and DST, are

thereore paramount. Appropriate engineering controls, maintenance o es-sential laboratory saety equipment, and laboratory sta training are equally

important.

Comprehensive systems or managing the quality o laboratory services are

mandatory, including internal quality control and external quality assurance.

6.6 Orgaizatio o te laborator etork

Conventional TB laboratory networks have a pyramidal structure based on

an appropriately large number o peripheral (Level I) laboratories accessible

to all TB suspects and patients, a moderate number o intermediate (Level II)laboratories located in mid-sized population centres and health acilities, and

a single (or more than one in large countries) central (Level III) laboratories

at the provincial, state or national levels. This chapter concentrates on the

activities o Level III laboratories as outlined in Table 6.1; the organization

and operation o Level I and II laboratories are well described in other publi-

cations ( 3, 4 ).Since 1994, the network o SRLs has been instrumental in supporting

drug resistance surveys in all regions o the world, providing quality assurance

through prociency testing and validation o DST data. The SRL network isbeing expanded to meet the challenges o scaling up the response to DR-TB.

Central reerence laboratories supporting DR-TB control programmes should

establish ormal links with one o the SRLs to ensure adequate expert input on

inrastructure development, budgeting and training. A sustained link with an




40


SRL is also strongly recommended or DR-TB control programmes in order to

maintain external quality assurance and validation o DST results, as outlined

below. Documented rst-line DST prociency o central laboratories, preer-

ably by one o the SRLs, is a prerequisite or applications by DR-TB control

programme to the GLC.

Implementation o laboratory services or culture and DST requires a rea-

sonable balance between cost and turnaround time. Such services are mostlikely to be economically aordable and provide optimal results i based on

direct delivery o specimens to a central mycobacteriology laboratory that has

large enough operational volume to ensure technical prociency, has well-

trained personnel and is properly equipped.

TABLE 6.1 Fuctios ad resosibilities o te dieret leels o laborator serices

LEvEL I

Te erieral (ote district) laborator

Receipt o specimens Preparation and staining o smears

Ziehl-Neelsen microscop and recording o results

Dispatch o results

Maintenance o laborator register

Cleaning and maintenance o equipment

Management o reagents and laborator supplies

Internal qualit control

LEvEL II

Te itermediate (ote regioal) laborator

All the unctions o a Leel I laborator

Fluorescence microscop (optional)

Digestion and decontamination o specimens

Culture and identifcation o M. tuberculosis

Training o microscopists

Support to and superision o peripheral-leel sta with respect to microscop

Preparation and distribution o reagents or microscop in peripheral laboratories

Qualit improement and profcienc testing o microscop at peripheral laboratories

LEvEL III

Te cetral (ote atioal) laborator

All the unctions o Leel I and II laboratories

DST o M. tuberculosis isolates Identifcation o mcobacteria other than M. tuberculosis

Technical control o and repair serices or laborator equipment

Updating and dissemination o laborator manuals, including guidelines on diagnos-

tic methods, on care and maintenance o equipment and on qualit assurance

Close collaboration with the central leel o the national TB control programme

Superision o intermediate laboratories regarding bacteriological methods and their

support (particularl training and superision) to the peripheral laboratories

Qualit assurance o microscop and culture perormed at intermediate laboratories

Training o intermediate-leel laborator sta

Organization o antituberculosis drug resistance sureillance

Operational and applied research relating to the laborator networ, coordinatedwith the requirements and needs o national TB control programmes





42


response to treatment is also limited. For example, even with adequate treat-

ment, specimens rom DR-TB patients may remain sputum smear-positive

ater they become culture-negative, suggesting that the bacilli are non-viable.

(Caution is nonetheless recommended or patients who are sputum smear-positive and culture-negative; they should be considered as possibly inectious

and evaluated or progression o active disease.)

6.8.2 Culture

Quality o laboratory processing is o crucial importance. Delays in speci-

men transport, excessively harsh or insucient decontamination, poor-quality

culture media or incorrect incubation temperature can adversely aect the

culture yield. Laboratory errors, such as mislabelling or cross-contamination

between specimens during aerosol-producing procedures, may lead to alse-negative or alse-positive results. In this context, laboratory ndings should

always be correlated with the patient’s clinical condition and any diagnostic

test should be repeated i necessary. Low positive culture results on solid me-

dium (<10 colonies) are not well correlated with clinical prognosis and should

be interpreted with caution, especially i a single culture with low colony

counts is reported. However, persistent positive cultures or any positive cul-

ture in the setting o clinical deterioration should be regarded as signicant.

The pros and cons o dierent culture media and techniques are discussedin other published reerences ( 3, 4 ).

6.8.3 Identifcation o M. tuberculosis

In countries with a high burden o TB, the vast majority o mycobacterial iso-

lates will be M. tuberculosis . The prevalence o non-tuberculous mycobacteria

(NTM) varies rom country to country and can be more common in patients

living with HIV. Unless the species is conrmed as M. tuberculosis , mycobac-

terial isolates appearing phenotypically resistant to rst-line drugs may rep-

resent inection with NTM and not DR-TB. Treatment o NTM is entirely dierent rom treatment o DR-TB. As a minimum, laboratories supporting

DR-TB control programmes should be able to identiy M. tuberculosis by con-

ventional biochemical identication tests or at least two other methods that

ollow international guidelines.

6.8.4 Drug susceptibilit testing

Identication and treatment o patients with, or at high risk o, DR-TB can

be based on a range o strategies (see Chapter 5 and 7). In vitro DST plays

a key role in all o these strategies, under a rational and systematic approachto implementation o the required laboratory inrastructure (see section 6.8).

These guidelines strongly recommend that NTPs develop the capacity to pro-

vide access to DST or any patient in whom resistance is considered likely.

This recommendation is consistent with international standards or TB care



43

endorsed by WHO and other partners (10 ) and resolutions on TB endorsed

by the World Health Assembly in 2007 calling or universal access to DST

by 2015 (11).

A number o dierent techniques are available or DST. Classic pheno-typic methods involve culturing o M. tuberculosis in the presence o antitu-berculosis drugs to detect inhibition o growth. Phenotypic methods allow

the detection o drug resistance regardless o mechanism or molecular basis.Phenotypic DST methods can be perormed as direct or indirect tests on solidmedia. In the direct test, a set o drug-containing and drug-ree media is inoc-

ulated directly with a concentrated specimen. An indirect test involves inocu-lation with a pure culture grown rom the specimen. Indirect phenotypic testshave been extensively validated and are currently regarded as the gold stand-

ard. Three methods are commonly used: proportion, absolute concentration,and resistance ratio. Several rounds o prociency testing in the SRL network have shown that DST results do not dier between the three methods or rst-line antituberculosis drugs. For second-line DST, broth or liquid methods and

the proportion method on solid medium have been studied; methods or theabsolute concentration or resistance ratio on solid medium have not been vali-dated. The current status o DST methodology, consensus on reliability and

reproducibility, and critical concentrations or dierent methodologies can beound in a WHO policy guidance document on rational use o second-lineDST (1).

Genotypic approaches detect the genetic determinants o resistance ratherthan the resistance phenotype. Most genotypic methods involve two steps:rst, a molecular nucleic amplication method such as polymerase chain

reaction is used to ampliy sections o the M. tuberculosis genome known to bealtered in resistant strains. In the second step, amplication products (ampli-cons) are assessed or specic mutations correlated with resistance.

Novel technologies or rapid detection o drug resistance are under devel-

opment. Most are in early development phase, undergoing laboratory vali-dation or in early stages o large-scale eld studies to assess their easibility,

cost eectiveness and cost benet. Technologies ocused on rapid riampicinresistance testing as a proxy or MDR-TB testing are most advanced. In themajority o settings, particularly where xed-dose combination (FDC) rst-

line antituberculosis drugs are used, resistance to riampicin is almost invari-ably associated with resistance to isoniazid. Detection o riampicin resistancethereore serves as a reliable (although not complete) proxy or MDR-TB. The

advantages o rapid riampicin testing include earlier identication o patients

on inappropriate rst-line regimens, prompt screening o patients at risk o MDR-TB and early interruption o MDR-TB transmission.

Several tests or rapid detection o riampicin resistance have been vali-

dated in laboratory-based studies. The use o rapid riampicin resistance test-

ing is recommended in high-risk MDR-TB settings (including high-burden




44


HIV settings); however, conrmation o MDR-TB by conventional DST is

still regarded as the gold standard, and adequate laboratory capacity to en-

sure a quality-assured diagnosis o MDR-TB thereore remains a undamental

requirement. Chapter 5 provided an algorithmic approach to using rapidriampicin tests in the setting o high HIV prevalence.

No rapid molecular tests or detection o XDR-TB are currently available;

as a result, conventional and the newer liquid DST techniques are considered

the most reliable methods or determining XDR-TB. Some o the newer liquid

and agar techniques can determine the presence o XDR-TB within 14 days.

6.8.5 Limitations o DST

The accuracy o DST (perormed under optimal circumstances) varies with

the drug tested: or the rst-line antituberculosis drugs, DST is most accurateor riampicin and isoniazid; it is less reliable and reproducible or streptomy-

cin, ethambutol and pyrazinamide (1).

Testing o in vitro susceptibility o second-line antituberculosis drugs is

much more problematic, as outlined in WHO policy guidance on second-

line DST (1): aminoglycosides, polypeptides and fuoroquinolones have been

tested in dierent laboratory environments and shown to have relatively good

reliability and reproducibility. Data on the reproducibility and reliability o

DST or the other second-line drugs are much more limited, have not been

established or the methodology or testing does not exist (1).

Susceptibility testing o second-line drugs is hampered by technical di-

culties due to in vitro drug instability, drug loss due to protein binding, heat

inactivation, incomplete dissolution, lter sterilization and/or varying drug

potency. Moreover, the critical concentration dening resistance is oten very

close to the minimal inhibitory concentration (MIC) required to achieve anti-

mycobacterial activity, increasing the probability or misclassication o sus-

ceptibility or resistance and leading to poor reproducibility o DST results.

In addition, laboratory technique, medium pH, incubation temperature andincubation time may also aect DST results.

Cross-resistance and a lack o understanding o the molecular mechanisms

underlying TB drug resistance urther compound the problem. Emerging

evidence shows a clear association between phenotypic drug resistance and

specic molecular mutations; however, not all mutations conerring resistance

to second-line drugs have been described, nor have the underlying molecular

mechanisms or the detected mutations been elucidated.

Cross-resistance between the later- generation fuoroquinolones (cipro-

foxacin and ofoxacin) is almost complete. Limited evidence suggests thatthe third-generation fuoroquinolones (notably moxifoxacin) do not have

complete cross-resistance with the older generations (12–15 ) and may have

enhanced clinical benet due to their low MICs, enhanced antimycobacte-

rial activity, and improved biochemical structure providing metabolic stabil-



45

ity and long hal-lie, theoretically reducing the selection o resistant mutants

(16 ). While the clinical benet o newer-generation fuoroquinolones has been

validated in one small retrospective study (17 ), more clinical and laboratory

research is needed to understand the extent o fuoroquinolone cross-resistanceand its clinical relevance.

Cross-resistance between the aminoglycosides and/or the polypeptides

is complex and data are very limited. The aminoglycosides kanamycin and

amikacin have very high cross-resistance. Cross-resistance between other

aminoglycoside and polypeptides appears relatively low, but more studies are

needed (1).

6.9 Ratioal use o DST i DR-TB cotrol rogrammes

Complex, incomplete and even contradictory inormation on cross-resistance,limited knowledge o the genotypes conerring resistance in second-line drugs

and the technical limitations o second-line DST have important implications

or laboratory inrastructure and design o treatment modalities in DR-TB

control programmes. Prociency in DST is a combination o laboratory tech-

nique and workload, requiring adequate numbers o specimens to be tested.

In most settings, this implies centralization o laboratory services or DST

and – particularly or DR-TB programmes with small numbers o patients –

consideration towards outsourcing such DST services, or example, to one o

the laboratories in the SRL network.

Current WHO policy guidance on DST is as ollows (1):

• Laboratory capacity to reliably detect MDR-TB through quality-assured

DST o isoniazid and riampicin resistance is a minimum prerequisite or

DR-TB control programmes.

• Formal links with one o the laboratories in the SRL network are preerable

to ensure adequate expert input on laboratory design, specimen and process

fow, biosaety, maintenance o equipment and external quality assuranceo DST result.

• Strategies or laboratory services in support o DR-TB control programmes

should ollow a systematic approach and take into account the constraints

o DST outlined above. DST should be ocused on those drugs or which a

reliable and reproducible methodology is available.

• Routine DST o second-line drugs is not recommended unless the required

laboratory inrastructure and capacity have been established, rigorous qual-

ity assurance is in place and sustainable prociency has been demonstratedor isoniazid and riampicin. In order to retain prociency and expertise,

it is recommended that second-line DST only be perormed i at least 200

specimens rom high-risk patients are expected per year.




46


• At this time, routine DST o drugs in groups 4 (ethionamide, protiona-

mide, cycloserine, terizidone, p-aminosalicylic acid) and 5 drugs (cloaz-

imine, linezolid, amoxicillin–clavulanate, thioacetazone, clarithromycin,

imipenem) is not recommended as reliability and reproducibility o labora-tory testing cannot be guaranteed.

Figure 6.1 provides an outline or systematic DST o rst- and second-line

antituberculosis drugs under routine programmatic conditions.

6.10 Time or testig ad reortig: turaroud time

Growth detection and identication o M. tuberculosis may take 3–8 weeks

on solid media and 1–2 weeks in broth media. DST o an M. tuberculosis iso-

late takes an additional 2–4 weeks in solid media and 1 week in broth media.To ensure rapid diagnosis o M. tuberculosis and DR-TB, laboratories should

dene standard turnaround times, which should be strictly ollowed.

6.11 Iectio cotrol ad biosaet i te laborator

The relative hazards o inective microorganisms handled in the laboratory

are classied by WHO according to their risk o causing human disease, the

potential or laboratory spread and whether eective treatment and prevention

measures are available (7 ). Related biosaety levels or laboratories have been

dened, taking into account the pathogenic agent, the acilities available, andthe equipment, practices and procedures required to ensure a sae laboratory

working environment (7 ). M. tuberculosis is classied by WHO as a Risk Group 3 laboratory patho-

gen (7 ). Mycobacteriological culture and DST generate high-concentration

aerosols requiring biosaety level 3 containment precautions.

Laboratory standards require the ollowing essential measures to be in place

and enorced:

•

appropriate and specic administrative controls (including good laboratory practice, standard operating procedures and accident management plans);

• appropriate engineering controls unctioning adequately as designed;

• personal protective equipment appropriate or the tasks being perormed;

• proper waste management procedures;

• proper procedures or general laboratory saety (including physical, electri-

cal and chemical saety).

Biosaety level 3 containment requires the strengthening o laboratory opera-

tions and saety programmes, specically those related to laboratory design,

the use o specialized equipment to prevent or contain aerosols and healthsurveillance o laboratory sta. Published guidelines on biosaety level 3 pre-

cautions should be rigorously ollowed and expert engineering consultation

sought when establishing laboratory inrastructure or DST (1, 7 ).





48


6.12 Qualit cotrol ad qualit assurace

A diagnosis o DR-TB has proound implications or the individual patient;

thereore, accuracy o the laboratory diagnosis is crucial, and a comprehensive

laboratory quality assurance programme must be in place to ensure the accu-racy, reliability and reproducibility o DST results. Quality control or qual-

ity assurance procedures should be perormed regularly as an integral part o

laboratory operations.

Procedures or quality assurance o microscopy, culture and DST are de-

scribed in detail in laboratory manuals and technical documents.

Central reerence laboratories involved in DR-TB control programmes

should establish ormal links with one o the laboratories in the SRL network

to help ensure the quality o laboratory services and the validation o DST

results. The SRL network consists – at the time o press – o 26 laboratories,

including a global coordinating centre in Belgium.

The SRL network ensures DST standards by a system o external quality

assurance that should preerably be established beore the implementation o

DR-TB control programmes. As a minimum, external quality assurance with

an SRL should comprise:

• an initial assessment visit;

• prociency testing with an adequate number o coded isolates;

• periodic rechecking o isolates obtained within the DR-TB control pro-gramme.

Prociency testing by the SRL involves regular distribution to national TB re-

erence laboratories o panels o coded M. tuberculosis strains with predened

drug resistance proles. The test results by the reerence laboratory are com-

pared with the coded SRL results in blinded ashion and specic perormance

indicators (sensitivity, specicity, reproducibility) calculated or each drug and

or the reerence laboratory as a whole.

As a minimum perormance indicator, prociency testing should correctly identiy resistance to isoniazid and riampicin in more than 90% in two out

o three recent rounds o panels.

The SRL network is in agreement that panels or second-line prociency

testing should not include XDR strains o M. tuberculosis ; rather, panels with

dierent permutations o mono-resistance to second-line drugs are currently

being developed, which will be compiled to allow reliable assessment o the

overall capability o national reerence laboratories to identiy XDR-TB. Pan-

els including isolates with second-line drug resistance will be made available

through the SRL network in 2008.

Reereces

1. Drug susceptibility testing o second-line anti-tuberculosis drugs: WHO policy guidance . Geneva, World Health Organization, 2008 [in press].



49

2. Guidelines or surveillance o drug resistance in tuberculosis . Geneva, World

Health Organization, 2003 (WHO/CDS/TB/2003/320; WHO/CDS/

CSR/RMD/2003.3).

3. Laboratory services in tuberculosis control. Parts I, II and III . Geneva, WorldHealth Organization, 1998 (WHO/TB/98.258).

4. The public health service national tuberculosis reerence laboratory and the national laboratory network: minimum requirements, roles, and operation inlow-income countries . Paris, International Union Against Tuberculosis and

Lung Disease, 1998.

5. http://www.who.int/tb/dots/laboratory/policy/en/index3.html

6. Joshi R et al. Tuberculosis among health-care workers in low- and mid-

dle-income countries: a systematic review. PLoS Med , 2006, December

3(12):e494.

7. Laboratory biosaety manual , 3rd ed. Geneva, World Health Organization,

2004 (WHO/CDS/CSR/LYO/2004.11).

8. Recommendations on the transport o dangerous goods: model regulations ,12th rev. ed. New York, United Nations, 2002 (ST/SG/AC.10/1/Re.12).

9. Inectious substances shipping guidelines , 3rd ed. Montreal, International

Air Transport Association, 2002.

10. International standards or tuberculosis care . The Hague, Tuberculosis Co-

alition or Technical Assistance, 2006 (available at http://www.who.int/tb/publications/2006/istc_report.pd; accessed May 2008).

11. World Health Assembly (WHA) Resolution EB120.R3. Geneva: 2007

12. Zhao BY et al. Fluoroquinolone action against clinical isolates o Mycobac-terium tuberculosis : eects o a C-8 methoxyl group on survival in liquid

media and in human macrophages. Antimicrobial Agents and Chemother-apy , 1999, 43(3):661–666.

13. Dong Y et al. Fluoroquinolone action against mycobacteria: eects o C-8

substituents on growth, survival, and resistance. Antimicrobial Agents and

Chemotherapy , 1998, 42(11):2978–2984.14. Lounis N et al. Which aminoglycoside or fuoroquinolone is more

active against Mycobacterium tuberculosis in mice? Antimicrobial Agents and Chemotherapy , 1997, 41(3):607–610.

15. Alvirez-Freites EL, Carter JL, Cynamon MH. In vitro and in vivo

activities o gatifoxacin against Mycobacterium tuberculosis. Antimicro-bial Agents and Chemotherapy , 2002, 46:1022–1025.

16. Somasundaram S, Paramasivan NC. Susceptibility o Mycobacterium

tuberculosis strains to gatifoxacin and moxifoxacin by dierent meth-

ods. Chemotherapy , 2002, 46:1022–1025.17. Yew WW et al. Comparative roles o levofoxacin and ofoxacin in the

treatment o multidrug-resistant tuberculosis: preliminary results o a ret-

rospective study rom Hong Kong. Chest , 2003, 124(4):1476–1481.






51

7. TREATMENT STRATEGIES FOR MDR-TB AND XDR-TB

Box 7.3 Examples o how to design standardized regimens 64

Box 7.4 Examples o how to design an indiidualized regimen 66

Box 7.5 Example o XDR-TB treatment 70

7.1 Cater objecties

Any patient with chronic or DR-TB requiring treatment with second-line

drugs alls under WHO diagnostic category IV and will require specialized

regimens (termed “Category IV regimens” in these guidelines). This chapter

provides guidance on the strategy options, including standardized, empirical

and individualized approaches, to treat MDR-TB as well as the more highly

resistant strains such as XDR-TB. In the absence o large-scale randomized

clinical trials, these recommendations are largely based on expert opinion

and results o cohort and case series analyses. For a complete description and

weight-based dosing o drugs used in these guidelines, see Annexes 1 and 2.


Design treatment regimens with a consistent approach based on the hier-

arch o the fe groups o antituberculosis drugs;

Promptl diagnose DR-TB and initiate appropriate therap; Use at least our drugs with either certain, or almost certain, eectie-

ness;

DST should generall be used to guide therap; howeer do not depend on

DST in indiidual regimen design or ethambutol, prazinamide, and Group

4 and 5 drugs;

Do not use ciprooxacin as an antituberculosis agent;*

Design a programme strateg that taes into consideration access to high-

qualit DST, rates o DR-TB, HIv prealence, technical capacit and fnan-

cial resources (Table 7.2);

Treat or 18 months past culture conersion;

Use adjunctie measures appropriatel, including surger and nutritional

and social support;

Aggressiel treat XDR-TB wheneer possible;

Treat aderse eects immediatel and adequatel.

7.2 Essetial assessmets beore desigig a

treatmet strateg

Programmes should design a treatment strategy when both the DRS data and

the requency o use o antituberculosis drugs in the country have been as-

sessed. Programmes that plan to introduce a treatment strategy or DR-TBshould be amiliar with the prevalence o drug resistance in new patients

as well as in dierent groups o re-treatment cases (ailures, relapse, return

ater deault, and chronic cases). It is essential to determine which, and with



52


what requency, second-line antituberculosis drugs have been used in the area

served by the DR-TB control programme. Some second-line antituberculosis

drugs may have been used only rarely and will likely be eective in DR-TB

regimens, while others may have been used extensively and thereore have ahigh probability o ineectiveness in patients with resistant strains.

It is recognized that some programmes may have to design strategies based

on limited data, as treatment or many patients cannot wait until the ull as-

sessment inormation has been obtained. In these cases, the programme can

still ollow the basic principles put orth in this chapter on how to design an

eective regimen and continue to collect the inormation described in this

section.

7.3 Deitios o terms used to describe treatmet strategiesThe ollowing are denitions o terms oten used to describe treatment strat-

egies:

• Standardized treatment. DRS data rom representative patient popula-

tions are used to base regimen design in the absence o individual DST. All

patients in a dened group or category receive the same regimen. Suspected

MDR-TB should be conrmed by DST whenever possible.

• Empirical treatment. Each regimen is individually designed based on the

patient’s previous history o antituberculosis treatment and with considera-

tion o DRS data rom the representative patient population. Commonly,

an empirical regimen is adjusted when DST results on the individual pa-

tient become available.

• Individualized treatment. Each regimen is designed based on the patient’s

previous history o antituberculosis treatment and individual DST results.

Combinations o these treatment strategies are oten used as illustrated in

Figure 7.1. These strategies are discussed in more detail in section 7.8, whichaddresses using these strategies under programmatic conditions.

7.4 Classes o atituberculosis drugs

The classes o antituberculosis drugs have traditionally been divided into rst-

and second-line drugs, with isoniazid, riampicin, pyrazinamide, ethambutol

and streptomycin being the primary rst-line drugs. These guidelines oten

reer to this classication but also use a group system based on ecacy, experi-

ence o use and drug class. These groups are reerred to in the ollowing sec-

tions and are very useul or the design o treatment regimens. The dierentgroups are shown in Table 7.1. Not all drugs in the same group have the same

ecacy or saety. For more inormation, see the individual descriptions o

each group in this section and the drug inormation sheets provided or each

individual drug in Annex 1.



53

Group 1. Group 1 drugs, the most potent and best tolerated, should be used

i there is good laboratory evidence and clinical history to suggest that a drug

rom this group is eective. I a Group 1 drug was used in a previous regimenthat ailed, its ecacy should be questioned even i the DST result suggests

susceptibility. For patients with strains resistant to low concentrations o iso-

niazid but susceptible to higher concentrations, the use o high-dose isoniazid

may have some benet (when isoniazid is used in this manner it is considered a

Group 5 drug; see below). The newer-generation riamycins, such as riabutin,

have very high cross-resistance to riampicin.

Group 2. All patients should receive a Group 2 injectable agent i susceptibil-

ity is documented or suspected. These guidelines suggest the use o kanamy-cin or amikacin as the rst choice o an injectable agent, given the high rates o

streptomycin resistance in DR-TB patients. In addition, both these agents are

low cost, have less otoxicity than streptomycin and have been used extensively

or the treatment o DR-TB throughout the world. Amikacin and kanamycin

are considered to be very similar and have a high requency o cross-resistance.

I an isolate is resistant to both streptomycin and kanamycin, or i DRS data

show high rates o resistance to amikacin and kanamycin, then capreomycin

should be used.

Group 3. All patients should receive a Group 3 medication i the strain is

susceptible or i the agent is thought to have ecacy. Ciprofoxacin is no

longer recommended to treat drug-susceptible or drug-resistant TB (1). Cur-

rently, the most potent available fuoroquinolones in descending order based


Figure 7.1 Commo treatmet strategies or DR-TB

Representatie DRS data in well-defned

patient populations are used to design theregimen. All patients in a patient group or

categor receie the same regimen.

Initiall, all patients in a certain group

receie the same regimen based on

DST sure data rom representatie

populations. The regimen is adjusted

when DST results become aailable (oten

DST is onl done to a limited number o

drugs).

Each regimen is indiiduall designed

on the basis o patient histor and then

adjusted when DST results become

aailable (oten the DST is done o both

frst- and second-line drugs)

sadadd

a

sadadd

a ollowed

b ddad

a

ea a

ollowed b

ddad

a





55

cross-resistance with isoniazid. I cost is not a constraint, PAS may be added

rst, given that the enteric-coated ormulas are relatively well tolerated and it

shares no cross-resistance to other agents. When two agents are needed, cyclo-

serine is used oten in conjunction with ethionamide or protionamide or PAS.Since the combination o ethionamide or protionamide and PAS oten causes

a high incidence o gastrointestinal adverse eects and hypothyroidism, these

agents are usually used together only when three Group 4 agents are needed:

ethionamide or protionamide, cycloserine and PAS. Terizidone contains two

molecules o cycloserine. Terizidone is being used in some countries instead o

cycloserine and is assumed tto be as ecacious; however, there are no direct

studies comparing the two drugs, and terizidone is thereore not yet recom-

mended by WHO. The approach o slowly escalating drug dosage is reerred

to as “drug ramping”. The drugs in Group 4 may be started at a low dose and

escalated over two weeks (or more on drug ramping, see section 7.7.3).

Group 5. Group 5 drugs are not recommended by WHO or routine use

in DR-TB treatment because their contribution to the ecacy o multidrug

regimens is unclear. Although they have demonstrated some activity in vitro

or in animal models, there is little or no evidence o their ecacy in humans

or the treatment o DR-TB. Most o these drugs are expensive, and in some

cases require intravenous administration. However, they can be used in cases

where adequate regimens are impossible to design with the medicines romGroups 1–4. They should be used in consultation with an expert in the treat-

ment o DR-TB. I a situation requires the use o Group 5 drugs, these guide-

lines recommend using at least two drugs rom the group, given the limited

knowledge o ecacy. While thioacetazone is a drug with known ecacy

against TB, it is placed in Group 5 because its role in DR-TB treatment is not

well established. Thioacetazone has cross-resistance with some o the other

antituberculosis agents (see Table 7.3) and overall is a weak bacteriostatic

drug. Thioacetazone is not recommended in HIV-positive individuals (6 )given the serious risk o adverse reaction that can result in Stevens-Johnson

syndrome and death. People o Asian descent also have a higher incidence o

Stevens-Johnson syndrome. Many experts eel that high-dose isoniazid can

still be used in the presence o resistance to low concentrations o isoniazid

(>1% o bacilli resistant to 0.2 µg/ml but susceptible to 1 µg/ml o isoniazid),

whereas isoniazid is not recommended or high-dose resistance (>1% o ba-

cilli resistant to 1 µg/ml o isoniazid) (7). One study rom a low-resource set-

ting where a standardized regimen is used (and DST o isoniazid at dierent

concentrations is not available) suggests that routine inclusion o high-doseisoniazid (16–20 mg/kg/day) could improve outcomes (8 ).

There is well-known cross-resistance between some o the antibiotics used in

treating TB. Cross-resistance between specic antituberculosis agents is sum-

marized in Box 7.1.






57

guidelines strongly recommend conrming treatment ailure by culture

and testing or DR-TB through the use o DST o at least isoniazid and

riampicin.

• In the era o HIV and rapid spread o highly resistant (e.g. XDR) strains,

a detailed history o previous tuberculosis treatment may not adequately

predict the resistance pattern o the inecting strain, as many patients with

DR-TB may have been inected originally with a resistant strain ( 36 ).

Even in countries where reliable DST is available, standardized regimens may

be chosen as a strategy over individualized regimens or the ollowing rea-

sons:

• Interpretation o DST to some o the rst- and second-line drugs is dicult

and could mislead regimen design. Standardized regimens can give guid-

ance to clinicians and prevent basing decisions on DST that is not reliable.

These guidelines do not recommend using DST o ethambutol, pyrazina-

mide and the drugs in Groups 4 and 5 to base individual regimen design.

• Turnaround time or many culture-based DST methods is long. In general,

patients at increased risk or DR-TB should be placed on an empirical Cat-

egory IV regimen until DST results are available.

• The laboratory may not perorm DST o certain drugs, or may perorm

them at dierent times. Results rom rapid methods (molecular) may be

available within days, but only or certain rst-line drugs such as isoni-

azid and riampicin. Many laboratories perorm second-line DST only ater

resistance to rst-line drugs is conrmed.

In summary, regular access to quality-assured DST is recommended or all

programmes, even those using a standardized regimen. Delays in treatment

while awaiting DST can result in increased morbidity and mortality, as well as


BOx 7.2 ExAMpLES OF STAnDARD DRUG CODE USED TO DESCRIBE

DRUG REGIMEnS

Eamle 7.1

6Z-Km(Cm)-O-Eto-Cs/12Z-O-Eto-Cs

The initial phase consists o fe drugs and lasts or at least six months or six

months past conersion, depending on countr protocol. In this example, the

phase without the injectable continues all the oral agents or a minimum o

12 months, or a total minimum treatment o at least 18 months. The inject-

able is anamcin, but there is an option or capreomcin. Sometimes onl

the initial treatment is written and the assumption is that either the regimen

will be adjusted with DST or the injectable will be stopped according to the

programme protocol. This tpe o notation is used without a coefcient, i.e.

Z-KM-O-Eto-Cs



58


longer periods o inectiousness. DST to many o the second-line drugs should

not be relied upon or individual regimen design (also see Chapter 6 or more

discussion on DST).

7.7 Desigig a treatmet regime

This section describes the methods or designing a treatment regimen. It

applies to standardized, empirical and individualized regimens.

7.7.1 General principles

The ollowing are the basic principles involved in any regimen design:

• Regimens should be based on the history o drugs taken by the patient.

• Drugs commonly used in the country and prevalence o resistance to rst-line and second-line drugs should be taken into consideration when design-

ing a regimen.

• Regimens should consist o at least our drugs with either certain, or almost

certain, eectiveness. I the evidence about the eectiveness o a certain

drug is unclear, the drug can be part o the regimen but it should not be

depended upon or success. Oten, more than our drugs may be started i

the susceptibility pattern is unknown, eectiveness is questionable or an

agent(s) or i extensive, bilateral pulmonary disease is present.• When possible, pyrazinamide, ethambutol and fuoroquinolones should be

given once per day as the high peaks attained in once-a-day dosing may

be more ecacious. Once-a-day dosing is permitted or other second-line

drugs depending on patient tolerance, however ethionamide/protionamide,

cycloserine and PAS have traditionally been given in split doses during the

day to reduce adverse eects.

• The drug dosage should be determined by body weight. A suggested weight-

based dosing scheme is shown in Annex 2.• Treatment o adverse drug eects should be immediate and adequate in

order to minimize the risk o treatment interruptions and prevent increased

morbidity and mortality due to serious adverse eects (see Chapter 11).

• An injectable agent (an aminoglycoside or capreomycin) is used or a mini-

mum o six months and at least our months past culture conversion (see

Section 7.9 on duration o injectable use).

• The minimum length o treatment is 18 months ater culture conversion

(see Section 7.10 on duration o treatment).

• Each dose is given as directly observed therapy (DOT) throughout the

treatment. A treatment card is marked or each observed dose.



59

• DST o drugs with high reproducibility and reliability (and rom a depend-

able laboratory) should be used to guide therapy. It should be noted that

the reliability and clinical value o DST o some rst-line and most o the

second-line antituberculosis drugs have not been determined (see Section7.6 and Chapter 6). DST does not predict with 100% certainty the eec-

tiveness or ineectiveness o a drug ( 37 ). DST o drugs such as ethambutol,

streptomycin and Group 4 and 5 drugs does not have high reproducibility

and reliability; these guidelines strongly caution against basing individual

regimens on DST o these drugs.

• Pyrazinamide can be used or the entire treatment i it is judged to be eec-

tive. Many DR-TB patients have chronically infamed lungs, which theo-

retically produce the acidic environment in which pyrazinamide is active. Alternatively, in patients doing well, pyrazinamide can be stopped with the

injectable phase i the patient can continue with at least three certain, or

almost certain, eective drugs.

• Early DR-TB detection and prompt initiation o treatment are important

actors in determining successul outcomes.

Figure 7.2 describes the steps or building a regimen or DR-TB treatment.

7.7.2 Dosing o drugsDosing o anti-tuberculosis drugs is based on the weight o the patient. Dos-

ing is described in Annexes 1 and 2. Dosing or pediatric patients is described

in Chapter 9.

7.7.3 Dose escalation (drug ramping)

Most drugs should be started at ull dose, except cycloserine, ethionamide

and PAS, in which case the dose o the drug can be increased over a two-week

period ( 38 ).

7.8 Desigig a rogramme treatmet strateg

Treatment strategies or programmes may vary depending on access to DST,

rates o DR-TB, HIV prevalence (see Chapter 10), technical capacity and -

nancial resources. Despite the variability, there are uniorm recommendations

or programme treatment strategies that the GLC has developed. Table 7.2 is

a treatment strategy guide or programmes. It is based on dierent situations

in resource-constrained areas with limited access to DST and what strategy

the GLC has generally recommended in that situation. The table attempts to

cover most situations; however, the NTP may need to adjust the strategy tomeet special circumstances. It assumes that DST o isoniazid, riampicin, the

fuoroquinolones and the injectable agents is airly reliable. It also assumes

DST o other agents is less reliable and that basing individualized treatments

on DST o these agents should be avoided.




60


Figure 7.2 ho to build a treatmet regime or MDR-TBa

a Adapted rom Drug-resistant tuberculosis: a survival guide for clinicians. San Francisco, Francis J.

Curr National Tuberculosis Center and Caliornia Department o Health Serices, 2004.b Thioacetazone is contraindicated in HIv-inected indiiduals gien the serious ris o lie-threaten-

ing aderse reaction.

STEP 1Use an aailable

Grou 1: First-lie oralagets

prazinamide

ethambutol

STEP 2Plus one o these

Grou 2: Ijectable

agets

anamcin (or amiacin)

capreomcin

streptomcin

STEP 3Plus one o these

Grou 3: Fluoroquioloes

leooxacin

moxioxacin

ooxacin

STEP 4 Pic one or more o

Grou 4: Secod-lie oral

bacteriostatic agets

p-aminosaliclic acid

ccloserine (or terizadone)

ethionamide (or

protionamide)

STEP 5Consider use o these

Grou 5: Drugs o uclearrole i DR-TB treatmet

cloazimine

linezolid

amoxacillin/claulanate

thioacetazoneb

imipenem/cilastatin

high-dose isoniazid

clarithromcin

Begin with an frst-line agents that

hae certain, or almost certain, e-

fcac. I a frst-line agent has a highlielihood o resistance, do not use it.

(For example, most Categor Iv regi-

mens used in treatment ailures o

Categor II do not include ethambu-

tol because it is liel to be resistant

based on treatment histor.)

Add an injectable agent based on

DST and treatment histor. Aoid

streptomcin, een i DST suggests

susceptibilit, because o high rateso resistance with DR-TB strains and

higher incidence o ototoxicit.

Add a uoroquinolone based on DST

and treatment histor. In cases where

resistance to ooxacin or XDR-TB is

suspected, use a higher-generation

uoroquinolone, but do not rel upon

it as one o the our core drugs.

Add Group 4 drugs until ou hae atleast our drugs liel to be eectie.

Base choice on treatment histor,

aderse eect profle and cost. DST

is not standardized or the drugs in

this group.

Consider adding Group 5 drugs in

consultation with an MDR-TB expert i

there are not our drugs that are lielto be eectie rom Groups 1–4. I

drugs are needed rom this group, it

is recommended to add at least two.

DST is not standardized or the drugs

in this group.



61


TABLE 7.2 Recommeded strategies or dieret rogrammatic situatios

pAtient Group bAcKGrounD recommenDeD strAteGy susceptibility DAtAa

ne atiet it Resistance uncommon • Start Categor I treatmet

actie TB to moderately common • Perorm DST o at least H and R in

(i.e. a countr where a patients not responsie to Categor Ic

low to moderate rate o • Rapid DST techniques are preerable

new cases hae MDR-TB)

Resistance common • Perorm DST o H and R in all patients

(i.e. a countr where a beore treatment starts

high rate o new cases • Rapid DST techniques are preerable

hae MDR-TB) • Start Categor I treatment while

awaiting DST

• Adjust regimen to a Categor Iv

regimen i DST reeals DR-TB

patiet i om Low percentage o • Perorm DST o H and R at a minimum

Categor I ailed ailures o Categor I in all patients beore treatment starts

hae MDR-TB • Rapid DST is preerable

Second-line drug • Start Categor II treatment while

resistance is rare awaiting DST

• Adjust regimen to a Categor Iv

regimen i DST reeals DR-TB

High percentage o • Perorm DST o isoniazid and riampicin

ailures o Categor I at a minimum in all patients beore

hae MDR-TB treatment starts

Second-line drug • Start Categor Iv treatment: IA-FQ- to

resistance is rare Grou 4 agets- +/– Z

High percentage o • Perorm DST o H, R, IA, FQ beore

ailures o Categor I treatment starts

hae MDR-TB • Start Categor Iv treatmet: IA-FQ-

Second-line drug tree Grou 4 agets- +/– Z while

resistance is common awaiting DST

• Adjust regimen according to DST

results i using an indiidualized

approach

patiet i om High percentage o • Perorm DST o H and R at a minimum

Categor II ailed ailures o Categor II in all patients beore treatment starts


Second-line drug to Grou 4 agets- +/– Z while

resistance is rare awaiting DST



approach

High percentage o • Perorm DST o H, R, IA, FQ beore

ailures o Categor II treatment starts


Second-line drug tree Grou 4 agets- +/– Z while

resistance is common awaiting DST



approach



62




patiet it Low to moderate rate • Perorm DST o H and R at a minimum

istor o relase o MDR-TB in this group in all patients beore treatment starts

or atiet o patients is common • Start Categor II treatmet while

returig ater awaiting DST

deault • Adjust regimen to a Categor Iv

regimen i DST returns DR-TB

Cotact o Close contact with high • Perorm rapid diagnosis and DST o H

MDR-TB atiet ris o haing the same and R at a minimum in all patients

o it actie strain beore treatment starts

TB • Start Categor Iv treatmet based on

Contact the DST pattern and treatment histor

resistance o the contact (see Chapter 14) while

pattern nown awaiting DST


results

Casual contact with low • Perorm rapid diagnosis and DST o H

ris o haing the same and R at a minimum in all patients

strain beore treatment starts

• Start Categor I treatmet while

awaiting DST


results

patiet it Documented, or almost • Start Categor Iv treatmet: IA-FQ-

documeted certain, susceptibilit to Grou 4 agets- +/– Z

MDR-TB to a FQ and IA

Documented, or almost • Start Categor Iv treatmet: IA-FQ-

certain, susceptibilit tree Grou 4 agets- +/– Z

to FQ • Use an IA with documented

Documented, or almost susceptibilit

certain, resistance to an • I the strain is resistant to all IAs, use

IA one or which resistance is relatiel

rare

Documented, or almost • Start Categor Iv treatmet: IA-FQ-

certain, resistance to tree Grou 4 agets- +/– Z

a FQ • Use a later-generation FQ

Documented, or almost

certain, susceptibilit

to IA

Documented, or almost • Start Categor Iv treatmet or XDR-

certain, resistance to a TB (see section 7.14)

FQ and IA



63

A number o principles in Table 7.2 require explanation. First, DST sur-veillance data or dierent groups o patients (new, ailures o Category I, ail-

ures o Category II, relapse and deault, and ailures o Category IV) will help

greatly in determining rates o MDR-TB and o resistance to other antituber-

culosis drugs. This is essential or developing appropriate treatment strategies

and or evaluating the impact o control programme interventions.

Screening all MDR-TB strains or second-line drug resistance is recom-

mended when capacity and resources are available. Because o the relatively

good reliability and reproducibility o DST o aminoglycosides, polypeptidesand fuoroquinolones, and since resistance to these drugs denes XDR-TB,

DST o these second-line drugs constitutes a priority or surveillance and

treatment (see Chapter 6 or a recommended hierarchy o DST).

For a standardized empirical regimen that will treat the vast majority o pa-

tients with our eective drugs, it is oten necessary to use ve or six drugs to

cover all possible resistance patterns. As Table 7.2 illustrates, or most cases, an

injectable agent and a fuoroquinolone make the core o the regimen.

I using a standardized regimen, DR-TB control programmes are strongly

encouraged to order other drugs that are not included in the standard regi-men. For example, a programme that uses a standardized regimen that does

not include PAS will still need PAS in the ollowing situations: (i) patients

intolerant to one o the core drugs; (ii) pregnant patients with DR-TB who

cannot take all the drugs in the standard regimen; (iii) as part o a “salvage




patiet i om Moderate to high rate • Perorm DST o IA and FQ (and H and R

Categor Iv ailed o XDR-TB in this group i not alread done) beore treatment

or patiet it o patients starts

documeted • Start Categor Iv treatmet or

MDR-TB ad XDR-TB (see section 7.14) while

istor o awaiting DST

etesie secod- • Adjust regimen according to DST

lie drug use results

patiet it Documented resistance • Start Categor Iv treatment or XDR-TB

documeted to H, R, IA, and FQ (see section 7.14)

xDR-TB

a All strategies in Table 7.2 assume the will be implemented in resource-constrained areas with

limited access to DST. There are no absolute thresholds or low, moderate or high resistance.

Programmes are encouraged to consult an expert on which recommended strategies in Table 7.2

are best indicated based on resistance leels and aailable resources.b Wheneer possible, perorm DST o injectable agents (IA, aminoglcosides or capreomcin) and a

uoroquinolone (FQ) i MDR-TB is documented.c Persistentl positie smears at 5 months constitute the defnition o Categor I ailure; howeer

some ma wish to consider DST earlier based on oerall clinical picture, or example i patient is

HIv-positie.



64


regimen” or those who ail the standardized regimen. In act, all programmes

are encouraged to have a “salvage regimen” or when the standardized regimen

ails. See Box 7.3 or an example o how to design a standardized regimen.

These guidelines caution against using DST o ethambutol, pyrazinamideand the drugs in Groups 4 and 5 to base the design o individual regimens.

The reliability and reproducibility o these drugs are questionable. Individu-

ally designed regimens are based on history o previous drug use and DST o

isoniazid, riampicin, the second-line injectable agents and a fuoroquinolone.

I DST results are not readily available, an empirical regimen based on the

patient’s treatment history and contact history is strongly recommended since

most DST methods have a turnaround time o several months. Placing a pa-

tient on an empirical regimen while DST results are pending is done to avoid

BOx 7.3 ExAMpLES OF hOw TO DESIGn STAnDARDIZED REGIMEnS

Eamle 1. Sure data rom 93 consecutiel enrolled relapse patients rom

a resource-constrained area show that 11% hae MDR-TB. O these MDR-TB

cases, 45% are resistant to E and 29% are resistant to S. Resistance to other

drugs is unnown; howeer, there is irtuall no use o an o the second-line

drugs in the area. What re-treatment strateg is recommended in this group

o relapse patients?

Aser: Gien the relatiel low rate o MDR-TB in this group, the ollowing

strateg is planned. All relapse patients will be started on the WHO CategorII regimen (HRZES). DST o H and R will be done at the start o treatment to

identi the 11% o MDR-TB patients who will not do well on Categor II regi-

men. Those identifed with MDR-TB will be switched to the standardized regi-

men 8Z-km-Ox-Pto-Cs/12Ox-Pto-Cs. The regimen contains our new drugs

rarel used in the area, and is also relatiel inexpensie. A small DST sure

is planned to document the prealence o resistance to the regimen’s fe

drugs in 30 relapse patients ound to hae MDR-TB. I this sure shows high

resistance to an o the proposed drugs, redesign o the regimen will be con-

sidered. (Note: the regimen proposed in this answer is onl one example o an

adequate regimen; man others based on the principles in this chapter would

be just as adequate.)Eamle 2. A programme uses a standardized Categor Iv regimen o Z-kM-

Ox-Cs-Eto in patients in whom Categor II regimen ailed. For such patients,

it is determined that 40% hae XDR-TB. The programme has limited access to

DST o uoroquinolones and injectable agents and wishes to design a stan-

dard “salage” regimen or patients in whom the standardized Categor Iv

regimen has ailed. What regimen is recommended?

Aser: Gien the high rate o XDR-TB it is best to use a regimen designed to

cure XDR-TB. An example o such a regimen is gien below:

CM-Mx-PAS-2 or 3 Group 5 agents +/– Cs

Some experts would include Cs in the regimen because the rate o deelop-

ment o resistance appears to be low. Howeer, eidence about the true rate

o deelopment o resistance in patients who are not cured with a Cs-contain-

ing regimen is er limited.



65

clinical deterioration and prevent transmission to contacts. There are a ew

exceptions. It may be convenient to wait or DST results i the laboratory uses

a rapid method with a turnaround time o 1–2 weeks. In addition, in chronic

cases who have been treated multiple times with second-line antituberculosisdrugs, waiting or DST results may be prudent even i the turnaround time is

several months, as long as the patient is clinically stable and appropriate inec-

tion control measures are in place.

Every eort should be made to supplement the patient’s memory with ob-

jective records rom previous health-care providers. A detailed clinical history

can help suggest which drugs are likely to be ineective. Although resistance

can develop in some cases in less than one month ( 39 ), as a general rule i a

patient has used a drug or over a month with persistently positive smears or

cultures, the strain should be considered as “probably resistant” to that drug,

even i by DST it is reported as susceptible.

The results o DST should complement rather than invalidate other sources

o data about the likely eectiveness o a specic drug. For example, i a his-

tory o previous antituberculosis drug use suggests that a drug is likely to be

ineective, this drug should not be relied on as one o the our core drugs

in the regimen even i the strain is susceptible by DST. Alternatively, i the

strain is resistant to a drug by DST, but the patient has never taken the drug

and resistance to it is extremely uncommon in the community, this may be acase o a laboratory error or a result o the limited specicity o DST or some

second-line drugs.

Another important constraint is that because o the turnaround time nec-

essary or DST, the patient may have already received months o a standard-

ized or empirical treatment regimen by the time DST results become available

rom the laboratory. The possibility o urther acquired resistance during this

time must be considered. I there is a high probability o acquired resistance

to a drug ater the specimen or DST was collected, this drug should not be

counted as one o the our drugs in the core regimen but can be included asan adjunctive agent.

Some laboratories may report that a strain has a low or intermediate level o

resistance to a certain drug. There is very little clinical evidence to support this

type o designation, particularly i the patient received the drug previously.

Box 7.4 gives examples o how to design individualized regimens.

7.9 Comletio o te ijectable aget (itesie ase)

The recommended duration o administration o the injectable agent, or the

intensive phase, is guided by culture conversion. The injectable agent shouldbe continued or at least six months and at least our months ater the patient

rst becomes and remains smear- or culture-negative.

The use o an individualized approach that reviews the cultures, smears,




66


X-rays and the patient’s clinical status may also help in deciding whether to

continue an injectable agent longer than the above recommendation, particu-

larly in the case o patients or whom the susceptibility pattern is unknown,eectiveness is questionable or an agent(s), or extensive or bilateral pulmo-

nary disease is present.

Intermittent therapy with the injectable agent (three times a week) can also

be considered in patients in whom the injectable has been used or a prolonged

BOx 7.4 ExAMpLES OF hOw TO DESIGn An InDIvIDUALIZED REGIMEn

Eamle 1. A atiet i om Categor I ad II treatmets ailed. DST re-

sults reeal that the inecting strain is resistant to H-R-S and susceptible to

all other medications including E-km-Cm-Ox; resistance to Z is unnown. Thepatient has receied HRE or 3 months since the date o the DST. What indi-

idualized regimen is recommended?

Aser: Since the patient receied two courses containing E and Z, and was

on unctional monotherap with E or at least 3 months, the utilit o these

drugs must be questioned despite the DST results. The same drugs can be

included in the regimen but the should not be relied on as one o the our

core drugs. The injectable choice ma depend on the prealence o resist-

ance in the communit, but since this patient neer receied km, km is low

in cost and the DST is reported to be susceptible, it ma be the frst choice

in this case:

km(Cm)-Ox-Eto(Pto)-Cs

(Man clinicians will add Z to this regimen; others ma use PAS instead o

Eto or Pto.)

Eamle 2. A atiet i om Categor I ad II treatmets ailed. A reiew

o DST results reeals that the inecting strain is resistant to H-R-Z-E-S-km

and susceptible to the medications Cm-Ox. The patient has not receied an

antituberculosis drugs since the date o the DST. What indiidualized regimen

is recommended?

Aser: Below are two possible options in this case:

1. Cm-Ox-Pto(Eto)-CsRegimen 1 ma hae the adantage o increased compliance since it re-

quires the minimum number o drugs and aoids the aderse eects o

the combination o PAS and Pto(Eto). Howeer, i one or more o the DST

results is wrong (and the reliabilit o DST o second-line drugs een to Cm

and Ox are onl moderatel reliable), the patient ma be eectiel on a

regimen o onl two or three drugs. Prealence o resistance to second-line

drugs and their aailabilit in the countr can help in the decision.

2. Cm-Ox-Pto-Cs-PAS

Regimen 2 taes into consideration the uncertaint o DST o second-line

drugs. It places the patient on an additional drug as a precaution in case

one o the DST results does not reect the efcac o an o the drugs test-

ed. Pto and PAS, while difcult to tae together, are requentl tolerated b

man patients, especiall with good patient support. A regimen with these

fe drugs is also preerred i there is extensie damage to the lungs or i

susceptibilit to an o these drugs is uncertain, gien a patient’s histor.



67


period o time and when toxicity becomes a greater risk. I the patient was on

an empirical regimen o ve or six drugs, drugs other than the injectable can

be considered or suspension once the DST results are available and the patient

continues with at least three o the most potent agents.

7.10 Duratio o treatmet

The recommended duration o treatment is guided by culture conversion.

Despite emerging evidence that shorter regimens may be ecacious, these

guidelines recommend continuing therapy or a minimum o 18 months ater

culture conversion until there is conclusive evidence to support a shorter du-

ration o treatment. Extension o therapy to 24 months may be indicated in

chronic cases with extensive pulmonary damage.

7.11 Etraulmoar DR-TB

Extrapulmonary DR-TB is treated with the same strategy and duration as

pulmonary DR-TB. I the patient has symptoms suggestive o central nerv-

ous system involvement and is inected with DR-TB, the regimen should use

drugs that have adequate penetration into the central nervous system (40 ,41). Riampicin, isoniazid, pyrazinamide, protionamide/ethionamide and

cycloserine have good penetration into the cerebrospinal fuid (CSF); kan-

amycin, amikacin and capreomycin do so only in the presence o meningeal

infammation; PAS and ethambutol have poor or no penetration. The fuo-

roquinolones have variable CSF penetration, with better penetration seen in

the later generations.

7.12 Surger i Categor Iv treatmet

The most common operative procedure in patients with pulmonary DR-TB

is resection surgery (taking out part or all o a lung). Large case-series analysis

has shown resection surgery to be eective and sae under appropriate surgi-

cal conditions (42 ). It is considered an adjunct to chemotherapy and appearsto be benecial or patients when skilled thoracic surgeons and excellent post-

operative care are available (43). It is not indicated in patients with extensive

bilateral disease.

Resection surgery should be timed to oer the patient the best possible

chances o cure with the least morbidity. Thus, the timing o surgery may be

earlier in the course o the disease when the patient’s risk o morbidity and

mortality is lower, or example, when the disease is still localized to one lung

or one lung lobe. In other words, surgery should not be considered as a last

resort. Generally, at least two months o therapy should be given beore resec-tion surgery in order to decrease the bacterial inection in the surrounding

lung tissue. Even with successul resection, an additional 12–24 months o

chemotherapy should be given.



68


Specialized surgical acilities should include stringent inection control

measures, since inectious substances and aerosols are generated in large quan-

tities during surgery and during mechanical ventilation and postoperative pul-

monary hygiene manoeuvres.Many programmes will have limited access to surgical interventions. Gen-

eral indications or resection surgery or programmes with limited access to

surgery include patients who remain smear-positive, with resistance to a large

number o drugs; and localized pulmonary disease. Computerized tomog-

raphy, pulmonary unction testing and quantitative lung perusion/ventila-

tion are recommended as part o the preoperative work-up. Programmes with

suboptimal surgical acilities and no trained thoracic surgeons should rerain

rom resection surgery, as the result may be an increase in morbidity or mor-

tality.

7.13 Adjuat teraies i DR-TB treatmet

A number o other modalities are used to lessen adverse eects and morbidity

as well as improve DR-TB treatment outcomes.

7.13.1 Nutritional support

In addition to causing malnutrition, DR-TB can be exacerbated by poor nu-

tritional status. Without nutritional support, patients, especially those already

suering rom baseline hunger, can become enmeshed in a vicious cycle o

malnutrition and disease. The second-line antituberculosis medications can

also urther decrease appetite, making adequate nutrition a greater challenge.

Vitamin B6 (pyridoxine) should also be given to all patients receiving

cycloserine or terizidone to prevent neurological adverse eects (see Chap-

ter 11 or dosing and more inormation). Vitamin (especially vitamin A) and

mineral supplements can be given in areas where a high proportion o patients

have these deciencies. I minerals are given (zinc, iron, calcium, etc.) they

should be dosed apart rom the fuoroquinolones, as they can interere withthe absorption o these drugs.

7.13.2 Corticosteroids

The adjuvant use o corticosteroids in DR-TB patients has been shown not

to increase mortality and can be benecial in conditions such as severe respi-

ratory insuciency, and central nervous system or pericardial involvement.

Prednisone is commonly used, starting at approximately 1 mg/kg and gradu-

ally decreasing the dose to 10 mg per week when a long course is indicated.

Corticosteroids may also alleviate symptoms in patients with an exacerbationo obstructive pulmonary disease. In these cases, prednisone may be given in a

short taper over 1–2 weeks, starting at approximately 1 mg/kg and decreasing

the dose by 5–10 mg per day. Injectable corticosteroids are oten used initially

when a more immediate response is needed.



69


7.14 Treatmet o xDR-TB

Since it was rst described, XDR-TB has been reported on 6 continents in at

least 37 countries, constituting up to 10% o all MDR-TB strains (44 , 45 ). It

has proven much more dicult to treat than MDR-TB and is extremely di-cult to treat in HIV-positive patients ( 36 , 45–47 ). While reports o HIV-

positive patients being promptly diagnosed with XDR-TB and placed on an

adequate regimen are non-existent to date, reports o cohorts o HIV-negative

patients have been shown to have cure rates that exceed 50% (45 , 46 ). Fig-

ure 7.3 summarizes the latest expert consensus on how to manage XDR-TB.

There are very limited data on dierent clinical approaches to XDR-TB.

Figure 7.3 Maagemet guidelies or atiets it documeted,or almost certai, xDR-TB

1. Use an Group 1 agents that ma be eectie;

2. Use an injectable agent to which the strain is susceptible and consider

an extended duration o use (12 months or possibl the whole

treatment). I resistant to all injectable agents, it is recommended to

use one the patient has neer used beore;a

3. Use a later-generation uoroquinolone such as moxioxacin;

4. Use all Group 4 agents that hae not been used extensiel in a

preious regimen or an that are liel to be eectie;

5. Use two or more agents rom Group 5;

6. Consider high-dose isoniazid treatment i low-leel resistance is

documented;

7. Consider adjuant surger i there is localized disease;

8. Ensure strong inection control measures;

9. Treat HIv (as per Chapter 10);

10. Proide comprehensie monitoring (see Chapter 11) and ull adherence

support (see Chapter 12).

a This recommendation is made because, while the reproducibilit and reliabilit o DST to inject-

ables are good, there are little data on clinical efcac o the test. Options with XDR-TB are er

limited and some strains ma be aected in io b an injectable agent een though the are

testing resistant in itro.

7.15 Coclusio

Programmatic management o DR-TB is a complex health intervention, and

no one strategy will t all situations. Programme managers need to consider

the epidemiological, nancial and operational actors when deciding which

strategy to use. Table 7.3 summarizes the principles o designing regimens.



70


BOx 7.5 ExAMpLE OF xDR-TB TREATMEnT

Eamle 1. A patient in whom a standardized regimen o Z-km-Ox-Eto ailed

remains sputum smear-positie ater 8 months o treatment. The DST done

rom a specimen taen 4 months ago reeals resistance to HRZE-km-Cm andsusceptibilit to Ox.

wat treatmet regime is recommeded?

Aser: This patient ma now be resistant to Ox. Eto and Ox cannot be relied

upon in a new regimen, limiting treatment options. A later-generation uoroqui-

nolone ma hae some eect. The recommended regimen is:

Cm-Mx-Cs-PAS plus two Group 5 drugs (Cz and Amx/Cl are perhaps the

two most common Group 5 drugs used in this circumstance).

Table 7.3 Summar o te geeral riciles or desigig treatmet regimes

bAsic summAry commentsprinciples

1. Use at least 4 drugs Eectieness is supported b a number o actors (the

certain to be eectie more present, the more liel the drug will be eectie in

I at least 4 drugs are the patient):

not certain to be • DST results show susceptibilit (or drugs in which there

eectie, use 5–7 is good laborator reliabilit).

drugs depending on • No preious histor o treatment ailure with the drug.

the specifc drugs and • No nown close contacts with resistance to the drug.leel o uncertaint. • DRS documents resistance is rare in similar patients.

• The drug is not commonl used in the area.

2. Do not use drugs or • Man antituberculosis agents exhibit cross-resistance

which there is the both within and across drug classes. knowledge o these

possibilit o cross- relationships is essential in designing regimens or DR-TB

resistance (see Box 7.1).

3. Eliminate drugs that • known seere allerg or unmanageable intolerance.

are not sae in the • High ris o seere aderse eects such as renal ailure,

patient deaness, hepatitis, depression and/or pschosis.

• Qualit o the drug is unnown.

4. Include drugs rom • Use an o the frst-line oral agents (Group 1) that are

Groups 1–5 in a liel to be eectie (see the frst section in this table as

hierarchal order based to what predicts eectieness).

on potenc • Use an eectie aminoglcoside or polpeptide b

injection (Group 2).

• Use a uoroquinolone (Group 3).

• Use the remaining Group 4 drugs to complete a regimen

o at least 4 eectie drugs.

• For regimens with ewer than 4 eectie drugs, consider

adding Group 5 drugs. The total number o drugs will

depend on the degree o uncertaint, and regimens otencontain 5–7 drugs.



71

Reereces

1. Moadebi S et al. Fluoroquinolones or the treatment o pulmonary tuber-

culosis. Drugs , 2007, 67(14):2077–2099.

2. Alvirez-Freites EJ, Carter JL, Cynamon MH. In vitro and in vivo ac-tivities o gatifoxacin against Mycobacterium tuberculosis . Antimicrobial Agents and Chemotherapy , 2002, 46(4):1022–1025.

3. Baohong JI et al. In vitro and in vivo activities o moxifoxacin and clin-

afoxacin against Mycobacterium tuberculosis . Antimicrobial Agents and Chemotherapy , 1998, 42:2006–2069.

4. Yew WW et al. Comparative roles o levofoxacin and ofoxacin in the

treatment o multidrug-resistant tuberculosis. Preliminary results o a ret-

rospective study rom Hong Kong. Chest , 2003, 124:1476–1481.

5. Yew WW et al. Comparative roles o levofoxacin and ofoxacin in the

treatment o multidrug-resistant tuberculosis: preliminary results o a ret-

rospective study rom Hong Kong. Chest , 2003, 124(4):1476–1481.

6. Nunn PP et al. Thioacetazone commonly causes cutaneous hypersensi-

tivity reactions in HIV positive patients treated or tuberculosis. Lancet ,1991, 337:627–630.

7. Rom WN, Garay S, eds. Tuberculosis . Philadelphia, Lippincott Williams

& Wilkins, 2004:751.

8. Katiyar SK et al. A randomized controlled trial o high-dose isoniazidadjuvant therapy or multidrug-reisistant tuberculosis. Internal Journal o Tuberculosis and Lung Disease , 12(2):139–145.

9. Chien HP et al. In vitro activity o riabutin and riampin against clini-

cal isolates o Mycobacterium tuberculosis in Taiwan. J Formos Med Assoc ,2000, 99(5):408–411.

10. Sintchenko V et al. Mutations in rpoB gene and riabutin susceptibility

o multidrug-resistant Mycobacterium tuberculosis strains isolated in Aus-

tralia. Pathology , 1999; 31(3):257–260.

11. Yang B et al. Relationship between antimycobacterial activities o ri-ampicin, riabutin and KRM-1648 and rpoB mutations o Mycobacteriumtuberculosis . Journal o Antimicrobial Chemotherapy , 1998, 42(5):621–

628.

12. Williams DL et al. Contribution o rpoB mutations to development o

riamycin cross-resistance in Mycobacterium tuberculosis . Antimicrobial Agents and Chemotherapy , 1998, 42(7):1853–1857.

13. Zhao BY et al. Fluoroquinolone action against clinical isolates o Mycobac-terium tuberculosis : eects o a C-8 methoxyl group on survival in liquid

media and in human macrophages. Antimicrobial Agents and Chemother-apy , 1999, 43(3):661–666.

14. Dong Y et al. Fluoroquinolone action against mycobacteria: eects o C-8

substituents on growth, survival, and resistance. Antimicrobial Agents and Chemotherapy , 1998, 42(11):2978–2984.




72


15. Lounis N et al. Which aminoglycoside or fuoroquinolone is more ac-

tive against Mycobacterium tuberculosis in mice? Antimicrobial Agents and Chemotherapy , 1997, 41(3):607–610.

16. Alangaden G et al. Mechanism o resistance to amikacin and kanamy-cin in Mycobacterium tuberculosis . Antimicrobial Agents and Chemotherapy ,1998, 42(5):1295–1297.

17. Allen BW, DA Mitchison. Amikacin in the treatment o pulmonary

tuberculosis. Tubercle , 1983, 64:111–118.

18. Morse WC et al. M. tuberculosis in vitro susceptibility and serum level ex-

periences with capreomycin. Annals o the New York Academy o Science ,1966, 135(2):983–988.

19. McClatchy JK et al. Cross-resistance in M. tuberculosis to kanamycin,

capreomycin and viomycin. Tubercle , 1977, 58:29–34.

20. Cooksey RC et al. Characterization o streptomycin resistance mecha-

nisms among Mycobacterium tuberculosis isolates rom patients in New

York City. Antimicrobial Agents and Chemotherapy , 1996, 40:1186–1188.

21. Socios En Salud database 2002.

22. Tsukamura M et al. Cross resistance relationship among capreomycin,

kanamycin, viomycin and streptomycin resistances o M. tuberculosis .Kekkaku, 1967, 42:399–404.

23. Tsukamura M. Cross-resistance relationships between capreomycin, kan-amycin and viomycin resistances in tubercle bacilli rom patients. Ameri-can Review o Respiratory Diseases , 1969, 99:780–782.

24. Tsukamura M, Mizuno S. Cross-resistant relationships among the

aminoglucoside antibiotics in Mycobacterium tuberculosis . Journal o Gen-eral and Applied Microbiology , 1975, 88(2):269–274.

25. Canetti G. Present aspects o bacterial resistance in tuberculosis. Ameri-can Review o Respiratory Diseases , 1965, 92:687–703.

26. Leord MJ. The ethionamide susceptibility o British pre-treatment

strains o Mycobacterium tuberculosis . Tubercle , 1966, 46:198–206.27. Canetti G et al. Current data on primary resistance in pulmonary tuber-

culosis in adults in France. 2d survey o the Centre d’Etudes sur la Resist-

ance Primaire: 1965–1966. Revue de tuberculose et de pneumologie , 1967,

31(4):433–474.

28. Lee H et al. Exclusive mutations related to isoniazid and ethionamide re-

sistance among Mycobacterium tuberculosis isolates rom Korea. Interna-tional Journal o Tuberculosis and Lung Disease , 2000, 4(5):441–447.

29. Banerjee A et al. inhA, a gene encoding a target or isoniazid and ethiona-

mide in Mycobacterium tuberculosis . Science, 1994, 263(5144):227–230.30. Tsukamura M. Cross-resistance o tubercle bacilli. Kekkaku, 1977,

52(2):47–49.



73

31. Leord MJ. The ethionamide susceptibility o East Arican strains o

Mycobacterium tuberculosis resistant to thiacetazone. Tubercle , 1969,

50:7–13.

32. DeBarber AE et al. Ethionamide activation and susceptibility in multid-rug-resistant Mycobacteriuim tuberculosis . Proceedings o the National Acad-emy o Sciences , 2000, 97(17):9677–9682.

33. Bartmann, K. Kreuzresistenz zwischen a-Athylthioisonicotanamid (1314

Th) und Thiosemicarbazon [Cross-resistance between ethionomide and

thioacetazone]. Tuberkuloseartz , 1960, 14:525.

34. Trnka L et al. Experimental evaluation o ecacy. In: Bartmann K, ed.

Anti-tuberculosis medications: handbook o experimental pharmacology . Ber-

lin, Springer-Verlag, 1988:56.

35. Suarez PG et al. Feasibility and cost-eectiveness o standardised second-

line drug treatment or chronic tuberculosis patients: a national cohort

study in Peru. Lancet , 2002, 359(9322):1980–1989.


death in patients co-inected with tuberculosis and HIV in a rural area o

South Arica. Lancet , 2006, 368:1575–1580.

37. Kim SJ. Drug susceptibility testing in tuberculosis: methods and reliabil-

ity o results. European Respiratory Journal , 2005, 25(3):564–569.

38. Drug-resistant tuberculosis: a survival guide or clinicians . San Francisco,Francis J. Curry National Tuberculosis Center and Caliornia Depart-

ment o Health Services, 2004.

39. Horne NW, Grant IWB. Development o drug resistance to isoniazid

during desensitization: A report o two cases. Tubercle 1963; 44: 180–2.

40. Holdiness MR. Cerebrospinal fuid pharmokinetics o antituberculoisis

drugs. Clinical Pharmacokinetics , 1985, 10:532–534.

41. Daley CL. Mycobacterium tuberculosis complex. In: Yu VL et al, eds.

Antimicrobial therapy and vaccines . Philadelphia, Williams & Wilkins,

1999:531–536.42. Francis RS, Curwen MP. Major surgery or pulmonary tuberculosis: nal

report. A national survey o 8232 patients operated on rom April 1953 to

March 1954 and ollowed up or ve years. Tubercle , 1964, supp(4)5:5–

79.

43. Pomerantz BJ et al. Pulmonary resection or multi-drug resistant tubercu-

losis. Journal o Thoracic and Cardiovascular Surgery , 2001, 121(3):448–

453.

44. XDR-TB (extensively drug-resistant tuberculosis): what, where, how and

action steps . Geneva, World Health Organization, 2007.45. Emergence o Mycobacterium tuberculosis with extensive resistance to sec-

ond-line drugs – worldwide, 2000–2004. Morbidity and Mortality Weekly Report , 2006, 55(11):301–305.








76


8.4 Treatmet o atiets it moo- ad

ol-resistat strais

Denitive randomized or controlled studies have not been perormed to de-

termine the best treatment or various patterns o drug resistance, except orstreptomycin resistance. The recommendations in these guidelines are based

on evidence rom the pre-riampicin era, observational studies, general princi-

ples o microbiology and therapeutics in TB, extrapolations rom established

evidence and expert opinion. When a decision has been made to modiy stand-

ardized SCC, the most eective regimen should be chosen rom the start to

maximize the likelihood o cure; eective drugs should not be withheld or

later use.

Table 8.1 gives suggested regimens or dierent DST patterns. When using

this table, it is essential to consider whether resistance has been acquired to any

o the drugs that will be used in the recommended regimen.

• Development o urther resistance. Further resistance should be suspect-

ed i the patient was on the unctional equivalent o only one drug or a

signicant period o time (usually considered as one month or more, but

even periods o less than one month on inadequate therapy can lead to

resistance). Sometimes resistance develops i the patient was on the unc-

tional equivalent o two drugs, depending on the drugs concerned. For

example, pyrazinamide is not considered a good companion drug to pre-vent resistance. I a patient was receiving unctionally only riampicin and

pyrazinamide in the initial phase (because o resistance to isoniazid and

ethambutol), resistance to riampicin may develop. Thus, it is crucial to

consider which unctional drugs the patient received between the time o

DST specimen collection and the time o the new regimen design (i.e. con-

sider whether resistance has developed to any o the unctional drugs).

• DST results. The DST result that prompts a change in treatment may not

accurately refect the bacterial population at the time it is reported since itrefects the bacterial population at the time the sputum was collected. The

regimens in Table 8.1 are based on the assumption that the pattern o drug

resistance has not changed during this interval. Table 8.1 should thereore

not be used i urther resistance to any o the agents in the suggested regi-

men is suspected. It is also important to note that a high level o condence

in the laboratory is needed or eective use o Table 8.1. As mentioned in

Chapters 6 and 7, DST o ethambutol and pyrazinamide is not highly re-

producible.

Table 8.1 assumes that pyrazinamide susceptibility is being tested, which is

not the case or many countries. I DST o pyrazinamide is not being car-

ried out, pyrazinamide cannot be depended upon as being an eective drug

in the regimen. In such situations, regimens rom Table 8.1 that assume the



77

8. MONO- AND POLy-RESISTANT STRAINS (DRUG-RESISTANT TUBERCULOSIS OTHER THAN MDR-TB)

TABLE 8.1 Suggested regimes or moo- ad ol-drug resistacea

(e urter acquired resistace is ot a actor ad laborator

results are igl reliable)

pAttern suGGesteD minimum commentsof DruG reGimen DurAtion ofresistAnce of treAtment

(months)

H (± S) R, Z and E 6–9 A uoroquinolone ma

strengthen the regimen or

patients with extensie

disease.

H and Z R, E and uoro- 9–12 A longer duration o treatment

quinolones should be used or patients

with extensie disease.

H and E R, Z and uoro- 9–12 A longer duration o treatment

quinolones should be used or patients

with extensie disease.

R H, E, uoroquinolones, 12–18 An injectable agent ma

plus at least 2 months strengthen the regimen or

o Z patients with extensie

disease.

R and E H, Z, uoroquinolones, 18 A longer course (6 months) o

(± S) plus an injectable agent the injectable agent ma

or at least the frst strengthen the regimen or

2–3 months patients with extensie

disease.

R and Z H, E, uoroquinolones, 18 A longer course (6 months) o

(± S) plus an injectable agent the injectable agent ma

or at least the frst strengthen the regimen or

2–3 months patients with extensie

disease.

H, E, Z R, uoroquinolones, 18 A longer course (6 months) o

(± S) plus an oral second-line the injectable agent ma

agent, plus an injectable strengthen the regimen or

agent or the frst 2–3 patients with extensiemonths disease.

H = isoniazid; R = riampicin; E = ethambutol; Z = prazinamide; S = streptomcina Adapted rom Drug-resistant tuberculosis: a survival guide for clinicians (3)

TB strain to be resistant should be used. Some clinicians would add pyrazi-

namide to those regimens because a signicant percentage o patients could

benet rom the drug; however, it would not be counted upon as a core drug

in the regimen.The design o regimens or mono- and poly-resistant cases o TB requires

experience; it is recommended or programmes with good inrastructure

that are capable o treating MDR-TB. Individually designed treatments or

mono- and poly-resistance are oten determined by a review panel that meets





79

CHAPTER 9

Treatmet o DR-TB i secialcoditios ad situatios


9.2 Pregnanc 80

9.3 Breasteeding 80

9.4 Contraception 81

9.5 Children 81

9.6 Diabetes mellitus 83

9.7 Renal insufcienc 83

9.8 Lier disorders 83

9.9 Seizure disorders 86

9.10 Pschiatric disorders 86

9.11 Substance dependence 87

9.12 HIv-inected patients 87

Table 9.1 Paediatric dosing o second-line antituberculosis drugs 82

Table 9.2 Adjustment o antituberculosis medication in renal

insufcienc 85

Box 9.1 Example o regimen design or paediatric cases 84

9.1 Cater objectiesThis chapter outlines the management o DR-TB in the ollowing special con-

ditions and situations:

• pregnancy,

• breasteeding,

• contraception,

• children,

• diabetes mellitus,

• renal insuciency,

• liver disorders,

• seizure disorders,

• psychiatric disorders,

• substance dependence.





81

9. TREATMENT OF DRUG-RESISTANT TUBERCULOSIS IN SPECIAL CONDITIONS AND SITUATIONS

Thereore, when resources and training are available, it is recommended to

provide inant ormula options as an alternative to breasteeding. When inant

ormula is provided, uel or boiling water and the necessary apparatus (stove,

heating pans and bottles) must also be provided, as well as training on how toprepare and use the inant ormula. All this should be ree o charge to poor pa-

tients, and DR-TB control programmes should thereore budget in advance or

the estimated number o patients who might need this support.

The mother and her baby should not be completely separated. However, i

the mother is sputum smear-positive, the care o the inant should be let to

amily members until she becomes sputum smear-negative, i this is easible.

When the mother and inant are together, this common time should be spent

in well-ventilated areas or outdoors. In some settings, the mother may be o-

ered the option o using a surgical mask or an N-95 respirator (see Chapter

15) until she becomes sputum smear-negative.

9.4 Cotracetio

There is no contraindication to the use o oral contraceptives with the non-

riamycin containing regimens. Patients who vomit directly ater taking an

oral contraceptive can be at risk o decreased absorption o the drug and there-

ore o decreased ecacy. These patients should be advised to take their con-

traceptives apart rom times when they may experience vomiting caused by

the antituberculosis treatment. Patients who vomit at any time directly ater,

or within the rst two hours ater, taking the contraceptive tablet, should use

a barrier method o contraception until a ull month o the contraceptive tab-

lets can be tolerated.

For patients with mono- and poly-resistant TB that is susceptible to

riampicin, the use o riampicin interacts with the contraceptive drugs result-

ing in decreased ecacy o protection against pregnancy. A woman on oral

contraception while receiving riampicin treatment may choose between two

options: ollowing consultation with a physician, use o an oral contraceptivepill containing a higher dose o estrogen (50 µg); or use o another orm o

contraception.

9.5 Cildre

Children with DR-TB generally have primary resistance transmitted rom an

index case with DR-TB. Evaluation o children who are contacts o DR-TB

patients is discussed in Chapter 14. When DST is available, it should be used

to guide therapy, although children with paucibacillary TB are oten culture-

negative. Nevertheless, every eort should be made to conrm DR-TB bac-teriologically by the use o DST and to avoid exposing children unnecessarily

to toxic drugs.

The treatment o culture-negative children with clinical evidence o active

TB disease and contact with a documented case o DR-TB should be guided





83

Anecdotal evidence suggests that adolescents are at high risk or poor treat-

ment outcomes. Early diagnosis, strong social support, individual and amily

counselling and a close relationship with the medical provider may help to im-

prove outcomes in this group.

9.6 Diabetes mellitus

Diabetic patients with MDR-TB are at risk or poor outcomes. In addition,

the presence o diabetes mellitus may potentiate the adverse eects o an-

tituberculosis drugs, especially renal dysunction and peripheral neuropathy.

Diabetes must be managed closely throughout the treatment o DR-TB. The

health-care provider should be in close communication with the physician

who manages the patient’s diabetes. Oral hypoglycaemic agents are not con-

traindicated during the treatment o DR-TB but may require the patient toincrease the dosage. Use o ethionamide or protionamide may make it more

dicult to control insulin levels. Creatinine and potassium levels should be

monitored more requently, oten weekly or the rst month and then at least

monthly thereater.

9.7 Real isuciec

Renal insuciency caused by longstanding TB inection itsel or previous

use o aminoglycosides is not uncommon. Great care should be taken in the

administration o second-line drugs in patients with renal insuciency, and

the dose and/or the interval between dosing should be adjusted according to

Table 9.2.

9.8 Lier disorders

The rst-line drugs isoniazid, riampicin and pyrazinamide are all asso-

ciated with hepatotoxicity. O the three, riampicin is least likely to cause

hepatocellular damage, although it is associated with cholestatic jaundice.

Pyrazinamide is the most hepatotoxic o the three rst-line drugs. Among thesecond-line drugs, ethionamide, protionamide and PAS can also be hepato-

toxic, although less so than any o the rst-line drugs. Hepatitis occurs rarely

with the fuoroquinolones.

Patients with a history o liver disease can receive the usual DR-TB chemo-

therapy regimens provided there is no clinical evidence o severe chronic liver

disease, hepatitis virus carriage, recent history o acute hepatitis or excessive al-

cohol consumption. However, hepatotoxic reactions to antituberculosis drugs

may be more common in these patients and should be anticipated.

In general, patients with chronic liver disease should not receive pyrazi-namide. All other drugs can be used, but close monitoring o liver enzymes

is advised. I signicant aggravation o liver infammation occurs, the drugs

responsible may have to be stopped.

Uncommonly, a patient with TB may have concurrent acute hepatitis that

9. TREATMENT OF DRUG-RESISTANT TUBERCULOSIS IN SPECIAL CONDITIONS AND SITUATIONS













89

CHAPTER 10

DR-TB ad hIv



10.3 Recommended collaboratie TB/HIv actiities 91

10.4 Clinical eatures and diagnosis o DR-TB in HIv-inected patients 94

10.5 Concomitant treatment o DR-TB and HIv 94

10.5.1 Initiating ART treatment in patients with DR-TB 95

10.5.2 DR-TB in patients alread receiing ART 95

10.5.3 Important drug–drug interactions in the treatment o HIv

and DR-TB 96

10.5.4 Potential drug toxicit in the treatment o HIv and DR-TB 97

10.5.5 Monitoring o DR-TB and HIv therap in coinected patients 97

10.5.6 Immune reconstitution inammator sndrome 102

10.6 XDR-TB and HIv 102

10.7 Implications o HIv or MDR-TB inection control 102

10.8 Coordination o HIv and TB care: inolement o the TB/HIv board 103

10.9 Summar 103

Table 10.1 WHO-recommended collaboratie TB/HIv actiities 91

Table 10.2 Timing o ART in the ART-naie patient starting

antituberculosis therap or DR-TB 95

Table 10.3 Potential oerling and additie toxicities o ART and

antituberculosis therap 98

10.1 Cater objecties

This chapter aims to illustrate where the management o DR-TB diers in the

presence o known or suspected HIV inection and to provide guidance on

recent developments in the approach to TB/HIV.1 The chapter outlines:

1 TB/HIV is the term used in the context o the overlapping o the two epidemics o TB and HIV/ AIDS, and is oten used to describe joint TB and HIV/AIDS activities. Patients with HIV-asso-ciated TB should be reerred to as such.







92


smear-negative pulmonary and extrapulmonary TB have been put orth by

WHO (16 ). Also see section 10.4 below.

• Use mycobacterial cultures and, where available, newer more rapid

methods o diagnosis. Mycobacterial cultures o sputum or other fuids

and tissues are recommended to help in the diagnosis o sputum smear-

negative and extrapulmonary TB (16 ). The heavy reliance on smear mi-

croscopy has signicant limitations and is insucient to reliably diagnose a

signicant proportion o HIV-coinected patients, especially as the degree

o immunosuppression advances (17 ). Rapid methods such as liquid cul-

ture or molecular techniques should be considered (18 ). See Chapter 6 or

more inormation on culture methods.

• Perorm DST at the start o antituberculosis therapy. UnrecognizedDR-TB carries a high risk o mortality in patients with HIV (19 ). Prompt

initiation o appropriate antituberculosis treatment (and subsequent initia-

tion o ART) can reduce mortality among HIV-inected patients inected

with DR-TB ( 29 , 21). Because unrecognized MDR-TB and XDR-TB are

associated with such high mortality in HIV-inected patients, many in-

ternational protocols dictate the perormance o DST and/or rapid drug-

resistance testing or all HIV-inected patients with established active TB.

(See Chapter 5 and section 10.4 below or more discussion on rapid tests

and diagnosing DR-TB in HIV patients.) While perorming DST or all

TB/HIV coinected patients is the standard o care or many areas, these

guidelines recognize that this may be dicult or impossible in many re-

source-limited settings. Alternative strategies are provided in section 10.4

or programmes with resource constraints. However, universal access to

DST is the long-term goal or all settings.

• Determine the extent (or prevalence) o TB drug resistance in patients

with HIV. Programmes should determine the extent o the overlap o the

DR-TB and HIV epidemics. This can be done in two ways: (i) data rompopulation-based TB DRS can be linked with HIV testing o those TB

patients included ( 22 ); and/or (ii) when implementing HIV surveillance

among TB patients (or provider-initiated testing and counselling or all

TB patients), DST can be included in all, or an unbiased sub-set o, HIV-

inected patients. The latter technique is more complex i rates o DR-TB in

HIV-inected and negative patients are to be compared, as a control group

o HIV-negative TB inected patients would also need to be established.

• Introduce ART promptly in DR-TB/HIV patients. These guidelinesrecommend the prompt initiation o ART in HIV-inected patients with

DR-TB according to WHO guidelines ( 23) (see section 10.5 and Table

10.2 on when to initiate HIV treatment in DR-TB). Where indicated, pro-



93

tocols to manage immune reconstitution infammatory syndrome (IRIS)

should be ollowed (see section 10.5.6 or more inormation on IRIS).

• Consider empirical therapy with second-line antituberculosis drugs.

Patients with a very high risk o DR-TB can be empirically started on Cat-

egory IV regimens. This strategy can be applied to all patients regardless o

HIV status but is especially important in those with HIV. (Note: empirical

use o Category IV is reserved or patients who have an extremely high rate

o MDR-TB, such as ailures o Category II or very close contacts o DR-TB.

See Chapter 5 or more inormation on the use o empirical Category IV).

• Provide CPT or patients with active TB and HIV. CPT should be pro-

vided to all patients with HIV according to WHO recommendations ( 24 ).

This therapy is not known to interact signicantly with any o the second-line antituberculosis agents. There are overlapping toxicities between ART,

antituberculosis therapy and CPT, and vigilance in terms o monitoring

adverse eects is required (see Table 10.3 below and Chapter 11).

• Arrange treatment ollow-up by a specialized team. The team o care

providers should be amiliar with the treatment o both DR-TB and HIV,

with close monitoring o potential additive adverse eects and nutritional

status as well as periodic assessments o therapeutic response or both in-

ections.

• Implement additional nutritional and socioeconomic support. Patients

with DR-TB and HIV may suer rom severe wasting, diarrhoeal diseas-

es, and malabsorption syndromes. Coinected patients oten come rom

socially marginalized groups or rom amilies with low economic resourc-

es. Additionally, DR-TB therapy with second-line antituberculosis medi-

cations may result in adverse eects that aect treatment adherence and

require more requent visits to health acilities. Wherever possible, patients

with DR-TB/HIV and limited means should be oered socioeconomic andnutritional support ( 25 ) (also see Chapter 12 or more inormation on treat-

ment support).

• Ensure eective inection control. Inection control procedures can re-

duce the risk o M. tuberculosis transmission in HIV/AIDS care acilities.

Inection control issues concerning DR-TB, including issues regarding

HIV, are discussed in Chapter 15 and in other documents published by

WHO ( 26 ).

•Involve key stakeholders in DR-TB/HIV activities. The local/nation-al TB/HIV coordinating bodies, community groups and key stakeholders

should be involved in the planning and monitoring o DR-TB/HIV activi-

ties and programmes.

10. DRUG-RESISTANT TUBERCULOSIS AND HIv



94


10.4 Cliical eatures ad diagosis o DR-TB

i hIv-iected atiets

The diagnosis o TB (including MDR-TB and XDR-TB) in HIV-inected peo-

ple is more dicult and may be conused with other pulmonary or systemicinections. The presentation is more likely to be extrapulmonary or sputum

smear-negative than in HIV-uninected TB patients, especially as immunosup-

pression advances ( 27 ). This can result in misdiagnosis or delays in diagnosis,

and in turn, higher morbidity and mortality. Algorithms have recently been

published by the WHO with the aim o improving the diagnosis o smear-neg-

ative pulmonary and extrapulmonary TB (16 ). The new algorithms emphasize

the use o clinical criteria rst and, i needed, the use o additional laborato-

ry data (culture) and radiography to diagnose TB. Clinical criteria have been

shown to have an 89–96% positive predictive value o smear-negative and

extrapulmonary TB when compared with culture ( 28 ). For patients with

advanced HIV disease, mycobacterial culture o other fuids (e.g. blood, pleural

fuid, ascitic fuid, cerebrospinal fuid and bone-marrow aspirates) and histopa-

thology (e.g. lymph node biopsies) may be helpul in diagnosis.

In many programmes and areas, all HIV patients with TB are screened or

drug- resistance with DST. Rapid drug-resistance testing is the DST tech-

nique o choice since this allows prompt diagnosis o MDR-TB, decreasing

the time the patient may be on an inadequate regimen and the period during which the patient may be spreading DR-TB.

Programmes without acilities or resources to screen all HIV-inected pa-

tients or DR-TB should put signicant eorts into obtaining them, especially

i DR-TB rates are moderate or high. Some programmes may adopt a strategy

o targeted DST or patients with increased risk o DR-TB (such as those in

whom treatment has ailed or who are contacts o DR-TB cases (see Chapter

5)). Programmes may also choose to use targeted DST or those with lower

CD4 counts (e.g. less than 200 cells/mm3) since these patents are at a very

high risk o death due to unrecognized DR-TB.

10.5 Cocomitat treatmet o DR-TB ad hIv

The treatment o DR-TB in patients with HIV is very similar to that in patients

without HIV and is described in Chapter 7, with the ollowing exceptions:

• ART plays a crucial role, as mortality in MDR-TB/HIV patients without

the use o ART is extremely high (91–100% as reported in one analysis o

MDR-TB outbreaks in 9 dierent institutions) (7 ).

• Adverse eects are more common in patients with HIV. The multiplemedicines involved in DR-TB with recognized high toxicity risks, oten

combined with ART, results in a high incidence o adverse eects. Some

toxicities are common to both antituberculosis treatment and ART, which

may result in added rates o adverse events.



95

• Monitoring needs to be more intense or both response to therapy and

adverse eects.

• The use o thioacetazone is not recommended or patients with HIV ( 29 )or or routine use in populations with high rates o HIV.

• IRIS may complicate therapy.

10.5.1 Initiating ART treatment in patients with DR-TB

The use o ART in HIV-inected patients with TB improves survival or both

drug-resistant and susceptible disease (9 , 16 , 30 ). As stated above, cohorts o

patients treated or DR-TB without the benet o ART have experienced mor-

tality rates oten exceeding 90% ( 3, 7 ). However, the likelihood o adverse

eects could compromise the treatment o either HIV or DR-TB i both treat-ments are started simultaneously. On the other hand, undue delay in the start

o ART could result in signicant risk o HIV-related death among patients

with advanced disease ( 31). The optimal timing or the introduction o ART

in patients receiving TB treatment is unknown. Table 10.2, based on WHO

guidelines or the treatment o HIV inection in adults and adolescents ( 23),

provides recommendations or initiating ART in relationship to starting ther-

apy or DR-TB.


TABLE 10.2 Timig o ART i te ART-aie atiet startig atituberculosis

tera or DR-TB

cD4 cell count Art timinG of Art in relAtionrecommenDAtions to stArt of Dr-tb treAtment

CD4 <200 cells/mm3 Recommend ART At two wees or as soon as DR-TB

treatment is tolerated

CD4 between 200 Recommend ART Ater eight weesa

and 350 cells/mm3

CD4 >350 cells/mm3 Deer ARTb Re-ealuate patient monthl orconsideration o ART start. CD4 testing

is recommended eer three months

during DR-TB treatment.

Not aailable Recommend ARTc Between two and eight wees

a Clinical ealuation ma prompt earlier initiation o ART.b ART should be started i other non-TB stage 3 or 4 eents are present.c This recognizes that some patients ma be prematurel placed on lie-long ART.

10.5.2 DR-TB in patients alread receiing ARTThere are two issues to consider in patients who are diagnosed with DR-TB

while on ART. The rst is whether modication o ART is needed due to

drug–drug interactions or to decrease the potential o overlapping toxicities.

These concerns are discussed below.



96


The second issue is whether the presentation o active DR-TB in a patient

on ART constitutes ART ailure. The principles o determining ailure in such

cases are described in other WHO documents (23). I ART ailure has been

diagnosed, it is not recommended to begin a new second-line ART regimen atthe same time as initiation o a DR-TB regimen. Instead, continue the present

ART regimen and switch to the second-line ART regimen 2–8 weeks ater the

start o DR-TB treatment.

10.5.3 Important drug–drug interactions in the treatment

o HIv and DR-TB

Currently, little is known about drug–drug interactions between second-line

antituberculosis agents and antiretroviral therapy. There are several known

interactions between drugs used to treat HIV and TB, which are summarizedbelow.

• Riamycin derivatives. While riamycin derivatives are not routinely used

in DR-TB treatment, they are used in the treatment o riampicin-sensitive

poly- and mono-resistant TB. Guidance on use o riamycin derivative-

based regimens and ART (including with PI-based regimens) is available

elsewhere ( 23, 32 ).

• Quinolones and didanosine. Buered didanosine contains an alumini-

um/magnesium-based antacid and, i given jointly with fuoroquinolones,

may result in decreased fuoroquinolone absorption ( 33); it should be avoid-

ed, but i it is necessary it should be given six hours beore or two hours ater

fuoroquinolone administration. The enteric coated (EC) ormulation o

didanosine can be used concomitantly without this precaution.

• Ethionamide/protionamide.Based on limited existing inormation o the

metabolisim o the thiamides (ethionamide and protionamide), this drug

class may have interactions with antiretroviral drugs. Ethionamide/pro-

tionamide is thought to be metabolized by the CYP450 system, althoughit is not know which o the CYP enzymes are responsible. Whether doses

o ethionamide/protionamide and/or certain antiretroviral drugs should be

modied during the concomitant treatment o DR-TB and HIV is com-

pletely unknown ( 34 ).

• Clarithromycin. Clarithromycin is a substrate and inhibitor o CYP3A

and has multiple drug interactions with protease inhibitors and NNRTIs.

I possible, the use o clarithromycin should be avoided in patients coinect-

ed with DR-TB and HIV because o both its weak ecacy against DR-TBand multiple drug interactions.



97

10.5.4 Potential drug toxicit in the treatment o HIv and DR-TB

There is limited evidence on the requency and severity o toxicities and

adverse events rom ART and second-line antituberculosis therapy. In gener-

al, HIV patients have a higher rate o adverse drug reactions to both TB andnon-TB medications, and the risk o adverse drug reactions increases with the

degree o immunosuppression ( 27 , 35 , 36 , 37 ). Identiying the source o ad-

verse eects in patients receiving concomitant therapy or DR-TB and HIV is

dicult. Many o the medications used to treat DR-TB and HIV have over-

lapping, or in some cases additive, toxicities. Oten, it may not be possible to

link adverse eects to a single drug, as the risk o resistance or ART therapy

precludes the typical medical challenge o stopping all medications and start-

ing them one by one ( 38 ). Adverse eects that are common to both antiretroviral and antituberculosis

drugs are listed in Table 10.3. It should be noted that relatively very little is

known about the rates o adverse eects in the concomitant treatment o DR-

TB and HIV. Table 10.3 is meant to alert the clinician to potentially overlap-

ping and additive toxicities, and as o the writing o these guidelines is based

on preliminary, non-published data and expert opinion.

When possible, avoid the use o agents with shared adverse eect pro-

les. Oten, however, the benet o using drugs that have overlying toxici-

ties outweighs the risk. Thereore, i two drugs with overlapping toxicities aredetermined to be essential in a patient’s regimen, these guidelines recommend

increased monitoring o adverse eects rather than disallowing a certain com-

bination. See Chapter 11 and section 10.5.5 or monitoring adverse eects in

HIV-inected patients.

10.5.5 Monitoring o DR-TB and HIv therap in coinected patients

HIV treatment must be taken daily without exception to prevent the evolution

o drug resistance. Since DOT is an important component o DR-TB therapy,

programmes would be advised to explore the provision o TB medicationsand ARVs through concomitant DOT or other methods o adherence support

(see Chapter 12). This is particularly important in the setting o second-line

antituberculosis therapy, since it can result in a large pill burden and numer-

ous adverse eects that make taking ARVs more dicult.

The complexity o antiretroviral regimens and second-line antituberculo-

sis treatment, each with its own toxicity proles and some o which may be

potentiated by concomitant therapy, demands rigorous clinical monitoring

( 39 ). Chapter 11, Table 11.1 describes the monitoring requirements while on

DR-TB therapy and indicates where any extra monitoring is required or pa-tients coinected with HIV and/or on ART.

I the patient shows signs o antituberculosis treatment ailure, the same

evaluation described in Chapter 13 is warranted. In addition, the ART regi-






99


A b d o m i n a l p a i n

A l l A R T t r e a t m e t C z , E t o /

p t o , p A S

A b d o m i n a l p a i n i s a c o m m o n a d e r s e e e c t a n d

o t e n b e n i g n ; h o w e e r , a b d o m i n

a l p a i n

a s b e e

m a b e a n e a r l s m p t o m o

s e e r e a d e r s e e e c t s s u c h a s p a n c r e a t i t i s , h e p a t i t i s o r

a s s o c i a t e d i t

l a c t i c a c i d o s i s .

a b d o m i a l a i

P a n c r e a t i t i s

D 4 T , d d I , d d C

L z d

A o i d u s e o t h e s

e a g e n t s t o g e t h e r . I a n a g e n t c a u s e s p a n c r e a t i t i s s u s p e n d i t p e r m a n e n t l

a n d d o n o t u s e a

n o t h e p a n c r e a t i t i s p r o d u c i n g

a n t i - H I v m e d i c a t i o n s ( D 4 T , d d I ,

o r d d C ) i n

t h e u t u r e .

A l s o c o n s i d e r g a l l s t o n e s o r a l c o h o l a s a p o t e n t i a l c a u s e o p a n c r e a t i t i s .

D i a r r h e a

A l l r o t e a s e

E t o / p t o , p A S ,

D i a r r h o e a i s a c o

m m o n a d e r s e e e c t . A l s o c o n s i d e r o p p o r t u n i s t i c i n e c t i o n s a s

a c a u s e o

i i b i t o r s , d d I

F l u o r o q u i n o l o n e s

d i a r r h o e a , o r c l o s t r i d i u m d

i f c i l e ( a c a u s e o p s e u d o m e m b r a n o u s c o l i t i s ) .

( b u e r e d o r m u l a )

H e p a t o t o x i c i t

n v p , E F v , a l l

h , R , E , Z , P A S ,

F o l l o w h e p a t o t o x

i c i t t r e a t m e n t r e c o m m e n d a t i o n

s i n C h a p t e r 1 1 .

r o t e a s e i i b i t o r s

E t o / P t o ,

A l s o c o n s i d e r T M

P / S M X a s a c a u s e o h e p a t o t o x i c i t i t h e p a t i e n t i s r e c e i i n g t h i s

( R T v > o t h e r

F l u o r o q u i n o l o n e s

m e d i c a t i o n .

p r o t e a s e

A l s o r u l e o u t i r a

l e t i o l o g i e s a s c a u s e o h e p a t i t i s ( H e p a t i t i s A , B , C , a n d C M v ) .

i n h i b i t o r s ) , a l l

n R T I s

S i n r a s h

A B C , n v p , E F v ,

h , R , Z , p A S ,

D o n o t r e - c h a l l e n

g e w i t h A B C ( c a n r e s u l t i n l i e - t h

r e a t e n i n g a n a p h l a x i s ) . D o n o t

D 4 T a n d o t h e r s

F l u o r o q u i n o l o n e s ,

r e - c h a l l e n g e w i t h

a n a g e n t t h a t c a u s e d S t e e n s - J

o h n s o n s n d r o m e .

a n d o t h e

r s

A l s o c o n s i d e r T M

P / S M X a s a c a u s e o s i n r a s h i t h e p a t i e n t i s r e c e i i n g t h i s m e

d i c a t i o n .

T h i o a c e t a z o n e i s

c o n t r a i n d i c a t e d i n H I v b e c a u s e

o l i e - t h r e a t e n i n g r a s h .

L a c t i c a c i d o s i s

D 4 T , d d I , A Z T ,

L z d

I a n a g e n t c a u s e

s l a c t i c a c i d o s i s , r e p l a c e i t w i t h

a n a g e n t l e s s l i e l t o c a u s e l a c t i c

3 T C

a c i d o s i s .





101

10. DRUG-RESISTANT TUBERCULOSIS AND HIv10. DRUG-RESISTANT TUBERCULOSIS AND HIv

H p e r l i p i d e m i a

p r o t e a s e

N o n e

N o o e r l a p p i n g t o

x i c i t i e s r e g a r d i n g h p e r l i p i d e m i a

h a e b e e n d o c u m e n t e d b e t w e e

n A R T a n d

i i b i t o r s , E F v

a n t i t u b e r c u l o s i s m e d i c a t i o n s . F o l l o w W H O A R T g u

i d e l i n e s o r m a n a g e m e n t o

h p e r l i p i d e m i a ( 2

3 ) .

L i p o d s t r o p h

n R T I s ( e s p e c i a l l

N o n e

N o o e r l a p p i n g t o

x i c i t i e s r e g a r d i n g l i p o d s t r o p h h a e b e e n d o c u m e n t e d b e t w e e n

A R T a n d

D 4 T a n d d d I

a n t i t u b e r c u l o s i s m e d i c a t i o n s . F o l l o w W H O A R T g u

i d e l i n e s o r m a n a g e m e n t o l i p d

s t r o p h

( 2 3 ) .

D s g l c e m i a

p r o t e a s e

G , E t o /

P t o

P r o t e a s e i n h i b i t o

r s t e n d t o c a u s e i n s u l i n r e s i s t a n

c e a n d h p e r g l c a e m i a . E t o / P t o

t e n d t o

( d i s t u r b e d b l o o d

i i b i t o r s

m a e i n s u l i n c o n

t r o l i n d i a b e t i c s m o r e d i f c u l t , a n d c a n r e s u l t i n h p o g l c a e m i a a

n d p o o r

s u g a r r e g u l a t i o n )

g l u c o s e r e g u l a t i o

n .

G a t i o x a c i n i s n o

l o n g e r r e c o m m e n d e d b t h e G L C o r u s e i n t r e a t m e n t o T B b e c a u s e o

t h i s s i d e - e e c t .

H p o t h r o i d i s m

D 4 T

E t o / p t o ,

p A S

T h e r e i s p o t e n t i a

l o r o e r l i n g t o x i c i t , b u t e i d e n

c e i s m i x e d . S e e r a l s t u d i e s s h o w

s u b c l i n i c a l h p o t h r o i d i s m a s s o c i a t e d w i t h H A A R

T , p a r t i c u l a r l s t a u d i n e . P A S a n

d E t o / P t o ,

e s p e c i a l l i n c o m

b i n a t i o n , c a n c o m m o n l c a u s e h p o t h r o i d i s m .



102


men should be evaluated or possible treatment ailure, as described in other

WHO guidelines ( 23).

Given that the regimens together are particularly dicult to take, the stig-

ma o both diseases can result in serious discrimination, and the risk o mor-tality is very high. Patients with HIV-associated DR-TB may require special

socioeconomic, nutritional and psychosocial support in order to successully

complete treatment.

10.5.6 Immune reconstitution inammator sndrome

IRIS has emerged as an important complication o ART. It is relatively com-

mon in mild to moderate orms in patients with TB started on ART (seen in

up to one third o patients in some studies (40 , 41)); however, it is relatively

rare in its severe orms. This syndrome can present as a paradoxical worseningo the patient’s clinical status, oten due a previously subclinical and unrecog-

nized opportunistic inection ( 23, 42 ). These reactions may present as ever,

enlarging lymph nodes, worsening pulmonary inltrates, respiratory distress

or exacerbation o infammatory changes at other sites. It generally presents

within three months o the initiation o ART and is more common with a low

CD4 cell count (<50 cells/mm3) (16 , 42 ).It is important to note that IRIS is a diagnosis o exclusion. Patients with

advanced AIDS may show clinical deterioration or a number o other reasons.

New opportunistic inections or previously subclinical inections may be un-

masked ollowing immune reconstitution and cause clinical worsening ( 23).

IRIS can also be conused with TB treatment ailure, and coinected patients

may be demonstrating progression o TB disease due to drug resistance.

The management o IRIS is complex and depends on the clinical status o

the patient and the site and extent o involvement. Various treatment modali-

ties have been employed, including non-steroidal anti-infammatory drugs in

mild disease and corticosteroids in moderate-severe disease. Most patients can

be treated without interruption o ART.

10.6 xDR-TB ad hIv

XDR-TB has been described in a number o countries, including settings with

a high prevalence o HIV. An algorithm to help diagnose XDR-TB in HIV-

inected individuals is provided in Chapter 5. Treatment strategies or XDR-

TB are outlined in Chapter 7.

10.7 Imlicatios o hIv or MDR-TB iectio cotrol

Delay in recognition o DR-TB, prolonged periods o inectiousness, crowded wards, and mixing TB and HIV patients all contribute to nosocomial trans-

mission. These practices have contributed to DR-TB outbreaks that aect

both HIV-inected and non-inected patients.

Implementation o adequate inection control precautions at health acili-





104


4. Anti-tuberculosis drug resistance in the world. Fourth global report. The WHO/IUATLD global project on anti-tuberculosis drug resistance surveil-lance, 2002–2007. Geneva, World Health Organization, 2008 (WHO/

HTM/TB/2008.394).5. Shah NS et al. Worldwide emergence o extensively drug-resistant tuber-

culosis. Emerging Inectious Diseases , 2007, 13(3):380–387.

6. Masjedi MR et al. Extensively drug-resistant tuberculosis: 2 years o sur-

veillance in Iran. Clinical Inectious Diseases, 2006, 43:841–847.

7. Wells CD et al. HIV inection and multidrug-resistant tuberculosis: the

perect storm. Journal o Inectious Diseases , 2007, 196 Suppl 1:S86–S107.

8. Burgos M et al. Treatment o multidrug-resistant tuberculosis in San

Francisco: an outpatient-based approach. Clinical Inectious Diseases ,2005, 40(7):968–975.

9. Waisman JL et al. [Improved prognosis in HIV/AIDS related multi-drug

resistant tuberculosis patients treated with highly active antiretroviral

therapy] Medicina (B Aires), 2001, 61(6):810–814.

10. Interim policy on collaborative TB/HIV activities . Geneva, World Health

Organization, 2004 (WHO/HTM/TB/2004.330; WHO/HTM/HIV/

2004.1).

11. Strategic ramework to decrease the burden o TB/HIV . Geneva, World

Health Organization, 2002 (WHO/CDS/TB/2002.296; WHO/HIV_ AIDS/2002.2).

12. Guidelines or implementing collaborative TB and HIV programme activities .Geneva, World Health Organization, 2003 (WHO/CDSTB/2003.319;

WHO/HIV/2003.01).

13. UNAIDS/WHO policy statement on HIV testing . Geneva, World Health

Organization and Joint United Nations Programme on HIV/AIDS, 2004

(available at http://www.who.int/hiv/pub/vct/en/hivtestingpolicy04.pd;

accessed May 2008).

14. Guidance on provider-initiated HIV testing and counseling in health acili-ties . Geneva, World Health Organization, 2007.

15. Tuberculosis care with TB-HIV co-management . Geneva, World Health

Organization, 2007 (WHO/HTM/HIV/2007.01).

16. Improving the diagnosis and treatment o smear-negative pulmonary and ex-trapulmonary tuberculosis among adults and adolescents: Recommendations or HIV-prevalent and resource-constrained settings . Geneva, World Health Or-

ganization, 2007 (WHO/HTM/TB/2007.379; WHO/HIV/2007.01).

17. Wilson D et al. Diagnosing smear-negative tuberculosis using case deni-

tions and treatment response in HIV-inected adults. International Jour-nal o Tuberculosis and Lung Disease , 2006, 10(1):31–38.

18. Moore DA et al. Microscopic-observation drug susceptibility assay or the

diagnosis o TB. New England Journal o Medicine , 2006, 355(15):1539–

1550.







107

CHAPTER 11

Iitial ealuatio, moitorigo treatmet ad maagemet

o aderse eects


11.2 Pretreatment screening and ealuation 107

11.3 Monitoring progress o treatment 108

11.4 Monitoring or aderse eects during treatment 109

11.5 Management o aderse eects 110

11.6 Summar 113

Table 11.1 Monitoring during treatment o DR-TB 111

Table 11.2 Frequenc o common aderse eects among 818

patients in fe DR-TB control programme sites 112

Table 11.3 Common aderse eects, suspected agent(s) and

management strategies 114

Table 11.4 Commonl used ancillar medications 118


This chapter provides inormation on the identication and management o

adverse eects caused by second-line antituberculosis drugs. It addresses the

ollowing:

•

monitoring requirements or the treatment o DR-TB;• monitoring actions or early detection o adverse eects;

• adverse eects associated with dierent second-line drugs;

• strategies or the treatment o adverse eects;

• adverse eects in HIV-coinected patients.

11.2 pretreatmet screeig ad ealuatio

The required initial pretreatment clinical investigation includes a thorough

medical history and physical examination. The recommended initial labora-

tory evaluations are shown in Table 11.1. The initial evaluation serves to estab-lish a baseline and may identiy patients who are at increased risk or adverse

eects or poor outcomes. The monitoring o treatment and the management

o adverse eects may have to be more intensive in patients with pre-existing

conditions or conditions identied at the initial evaluation (diabetes mellitus,



108


renal insuciency, acute or chronic liver disease, thyroid disease, mental ill-

ness, drug or alcohol dependence, HIV inection, pregnancy, lactation and

others). The management o DR-TB when these conditions exist is described

in Chapter 9. Methods o avoiding pregnancy during treatment or women o

childbearing age should be discussed.

11.3 Moitorig rogress o treatmet

Patients should be monitored closely or signs o treatment ailure. Clinically,

the most important way to monitor response to treatment is through reg-

ular history-taking and physical examination. The classic symptoms o TB– cough, sputum production, ever and weight loss – generally improve with-

in the rst ew months o treatment and should be monitored requently by

health-care providers. The recurrence o TB symptoms ater sputum conver-

sion, or example, may be the rst sign o treatment ailure. For children,

height and weight should be measured regularly to ensure that they are grow-

ing normally. A normal growth rate should resume ater a ew months o suc-

cessul treatment.

Objective laboratory evidence o improvement oten lags behind clinical

improvement. The chest radiograph may be unchanged or show only slight im-provement, especially in re-treatment patients with chronic pulmonary lesions.

Chest radiographs should be taken at least every six months, when a surgical

intervention is being considered, or whenever the patient’s clinical situation has

worsened. The most important objective evidence o improvement is conver-

sion o the sputum smear and culture to negative. While sputum smear is still

useul clinically because o its much shorter turnaround time, sputum culture

is much more sensitive and is necessary to monitor the progress o treatment.

Sputum examinations are also dependent on the quality o the sputum pro-

duced, so care should be taken to obtain adequate specimens.Persistently positive sputums and cultures or AFB should be assessed or

NTM, as overgrowth with NTM in lung damage secondary to TB is not un-

common. In such cases, although DR-TB may be adequately treated, treat-

ment may need to be directed towards the NTM as well.


Implement standard monitoring or all patients DR-TB treatment as per

Table 11.1.

Monitor both smear and culture monthl to ealuate treatment response.*

Increase monitoring or HIv coinected patients and or those on ART.*

Health-care worers in DR-TB control programmes should be amiliar with

the management o common aderse eects o MDR-TB therap.

Ancillar drugs or the management o aderse eects should be aailable

to the patient.





110


experience o several DOTS-Plus projects (1). More requent screening may be

advisable, particularly or high-risk patients. Table 11.1 includes monitoring

recommendations or HIV-inected patients.

Nephrotoxicity is a known complication o the injectable drugs, both o theaminoglycosides and o capreomycin. This adverse eect is occult in onset and

can be atal. The optimal timing or checking serum creatinine is unknown,

but most current treatment programmes or DR-TB check serum creatinine at

least monthly. In addition, patients with a history o renal disease (including

co-morbidities such as HIV and diabetes), advanced age or any renal symp-

toms should be monitored more closely, particularly at the start o treatment.

An estimate o the glomerular ltration rate may help to urther stratiy the

risk o nephrotoxicity in these patients (see Chapter 9, section 9.7).

Electrolyte wasting is a known complication o the antituberculosis in-

jectable drugs, most requently with capreomycin. It is generally a late eect

occurring ater months o treatment, and is reversible once the injectable drug

is suspended. Since electrolyte wasting is oten occult in the early stages and

can be easily managed with electrolyte replacement, serum potassium should

be checked at least monthly in high-risk patients, and in all those taking

capreomycin ( 2 ).Hypothyroidism is a late eect provoked by PAS and ethionamide. It is

suspected by clinical assessment and conrmed by testing the serum level o thyroid stimulating hormone (TSH). The use o these agents together can

produce hypothyroidism in up to 10% o patients ( 3). Since the symptoms

can be subtle, it is recommended that patients are screened or hypothyroidism

with a serum TSH at 6–9 months, and then tested again every 6 months or

sooner i symptoms arise. The dosing o thyroid replacement therapy should

be guided using serum levels o TSH. Goitres can develop due to the toxic

eects o PAS, ethionamide or protionamide. In areas where iodine-deciency

goitres are endemic, treatment with iodine is indicated, in addition to assess-

ment and treatment or hypothyroidism.

11.5 Maagemet o aderse eects

Second-line drugs have many more adverse eects than the rst-line antitu-

berculosis drugs. Management o adverse eects is possible even in resource-

poor settings ( 3). Proper management o adverse eects begins with patient

education. Beore starting treatment, the patient should be instructed in detail

about the potential adverse eects that could be produced by the prescribed

drug regimen, and i and when to notiy a health-care provider.

Table 11.2 reports the number and percentage o patients who had a par-ticular adverse event, observed in the rst ve GLC-approved projects. The

percentage o events may vary depending on the regimens used (or example,

among patients using both ethionamide and PAS, a high proportion may de-

velop a rate o hypothyroidism above 3.5%). Nonetheless, Table 11.2 provides



111

11. INITIAL EvALUATION, MONITORING OF TREATMENT AND MANAGEMENT OF ADvERSE EFFECTS

TABLE 11.1 Moitorig durig treatmet o DR-TB

monitorinG evAluAtion recommenDeD frequency

Ealuation b clinician At baseline, and at least monthl until conersion, then

eer 2–3 months

Screening b DOT worer At eer DOT encounter

Sputum smears and Monitor smears and cultures monthl throughout treatment.

cultures (Note: programmes with limited resources ma choose to

do smears monthl but cultures onl eer other month)

Weight At baseline and then monthl

Drug susceptibilit At baseline in programmes doing indiidualized treatment

testing (DST) or in programmes doing standardized treat-

ments that need to confrm MDR-TB. For patients who

remain culture-positie, it is not necessar to repeat DSTwithin less than 3 months o treatment

Chest radiograph At baseline, and then eer 6 months

Serum creatinine At baseline, then monthl i possible while receiing an

injectable drug. Eer 1–3 wees in HIv-inected patients,

diabetics and other high-ris patients

Serum potassium Monthl while receiing an injectable agent. Eer

1–3 wees in HIv-inected patients, diabetics and other

high-ris patients

Throid stimulating Eer 6 months i receiing ethionamide/protionamide

hormone (TSH) hormone and/or PAS; and monitor monthl or signs/

smptoms o hpothroidism. TSH is sufcient or screening

or hpothroidism; it is not necessar to measure hormone

throid leels

Lier serum enzmes Periodic monitoring (eer 1–3 months) in patients receiing

prazinamide or extended periods or or patients at ris or

or with smptoms o hepatitis. For HIv-inected patients,

do monthl monitoring

HIv screening At baseline, and repeat i clinicall indicated

Pregnanc tests At baseline or women o childbearing age, and repeat i

indicated

Haemoglobin and I on linezolid, monitor weel at frst, then monthl or as

white blood count needed based on smptoms; there is little clinical

experience with prolonged use

For HIv-positie patients on an ART regimen that includes

AZT, monitor monthl initiall and then as needed based on

smptoms

Lipase Indicated or wor up o abdominal pain to rule out

pancreatitis in patients on linezolid, D4T, ddI, ddc.

Lactic acidosis Indicated or wor up o lactic acidosis in patients on

linezolid or ART

Serum glucose I receiing gatioxacin, monitor glucose requentl (weel)

and educate patient on signs and smptoms o

hpoglcaemia and hperglccaemia





113

Reducing the dosage o the oending drug is another method o managing

adverse eects, but only in cases where the reduced dose is still expected to

produce adequate serum levels and not compromise the regimen. With cyclo-

serine and ethionamide, or example, a patient may be completely intolerant atone dose and completely tolerant at a slightly lower dose. Unortunately, given

the narrow therapeutic margins o these drugs, lowering the dose may also

aect ecacy, so every eort should be made to maintain an adequate dose

o the drug according to body weight. Lowering the dose by more than one

weight class should be avoided (see Annex 2 or weight classes and dosing).

Pyridoxine (vitamin B6) should be given to all patients receiving cycloserine

or terizidone to help prevent neurological adverse eects. The recommended

dose is 50 mg or every 250 mg o cycloserine (or terizidone) prescribed.

Psychosocial support is an important component o the management o

adverse eects. This is one o the most important roles played by DOT work-

ers, who educate patients about their adverse eects and encourage them to

continue treatment. Patient support groups are another means o providing

psychosocial support to patients.

Table 11.3 summarizes the common adverse eects, the likely responsible

antituberculosis agents and the suggested management strategies. Overlap-

ping toxicities or HIV-inected patients on ART and DR-TB treatment are

addressed in Chapter 10.Management oten requires the use o ancillary medications to eliminate

or lessen the adverse eects. DR-TB control programmes should, i at all pos-

sible, have a stock o ancillary medications available or health-care provid-

ers to prescribe to patients ree o charge. Table 11.4 lists the indications and

commonly used medications or the management o adverse reactions. The

list is an example o a ormulary that programmes may want to have avail-

able and will assist programmes in planning the respective drug management

and budgeting. However, programmes may choose to have available alterna-

tive medications in the same class as those in the list, or other medications notlisted here, depending on the treatment methods in a particular country.

In addition, it is recommended that all laboratory testing or the monitor-

ing o therapy, pregnancy testing, HIV screening and contraceptive methods

be oered ree o charge.

11.6 Summar

The timely and intensive monitoring or, and management o, adverse eects

caused by second-line drugs are essential components o DR-TB control pro-

grammes. Poor management o adverse eects increases the risk o deault orirregular adherence to treatment, and may result in death or permanent mor-

bidity. The health-care worker o the control programme should be amiliar

with the common adverse eects o MDR-TB therapy. Patients experiencing

adverse eects should be reerred to health-care workers who have experience














119


Reereces

1. Nathanson E et al. Adverse events in the treatment o multidrug-resistant

tuberculosis: results rom the DOTS-Plus initiative. International Journal

o Tuberculosis and Lung Disease , 2004, 8(11):1382–1384.2. Shin S et al. Hypokalaemia among patients receiving treatment or multi-

drug-resistant tuberculosis. Chest , 2004, 125:974–980.

3. Furin JJ et al. Occurrence o serious adverse eects in patients receiving

community-based therapy or multidrug-resistant tuberculosis. Interna-tional Journal o Tuberculosis and Lung Disease , 2001, 5:648–655.





121

CHAPTER 12. TREATMENT DELIvERy AND COMMUNITy-BASED DR-TB SUPPORT

12.2 Treatmet delier settigs

There are several strategies or the delivery o DR-TB treatment, including

community-based care, clinic-based treatment and hospitalization (1, 2 ).

Regardless o the mode o delivery, the management o DR-TB depends ona steady supply o medicines provided to patients ree o charge through a reli-

able network o educated providers.

• Community-based care. Although early in the history o DR-TB treat-

ment, strict hospitalization o patients was considered necessary, commu-

nity-based care provided by trained lay and community health workers

(CHWs) can achieve comparable results and, in theory, may result in de-

creased nosocomial spread o the disease (1, 2 ). In each setting, care should

be delivered by a multidisciplinary team o providers, including physicians,nurses, social workers and CHWs. The roles and responsibilities o each o

these groups o providers will vary depending on the needs and resources

available in specic settings. A more detailed description o community-

based care and support is given in section 12.10.

• Clinic-based treatment. Some DR-TB treatment strategies involve the

patient travelling to a clinic each day to receive DOT. This system works

provided there is no barrier to travel or i the patient lives near a acility o-

ering DOT o DR-TB; the patient should be given an enabler or travel insituations other than these. The patient should be smear-negative i travel-

ling on public transportation or waiting in common waiting rooms. Some

acilities have a separate area with inection control measures or smear-

positive patients. Special early morning appointments can be made or pa-

tients who need to get to work. An alternative version o this strategy is to

have the clinic act as a “day hospital” where patients can rest or get a meal

as an incentive or coming each day. Special attention must be taken in

clinic-based programmes so that HIV-inected patients are not exposed to

smear-positive patients.• Hospitalization. Hospitals should provide acceptable living conditions,

sucient activities so that patients avoid boredom, adequate ood, a heat-

ing system in cool areas, ans or cooling systems in hot climates and proper

inection control measures. Inection control requirements are described in

Chapter 15. Prisons require specic measures to improve adherence, which

are described in detail in the WHO guidelines or TB control in prisons

( 3).

12.3 Aderece to tera

Patients with DR-TB are more likely to have had problems with non-

adherence in the past (4 ). Adherence to DR-TB therapy is particularly di-

cult because o its prolonged treatment regimens with larger numbers o drugs







124


12.3.5 Earl and eectie management o aderse drug eects

Although rarely lie-threatening, the adverse eects o second-line drugs can

be debilitating or patients. Patients experiencing high rates o adverse eects

may be at increased risk o non-adherence. Thereore, early and eective man-agement o adverse eects should be part o adherence-promotion strategies in

the management o DR-TB. In most cases, management o adverse eects can

be accomplished using relatively simple and low-cost interventions without

compromising the integrity o the DR-TB treatment regimen (8 ). Manage-

ment o adverse eects is addressed in more detail in Chapter 11.

12.3.6 Monitoring and ollow-up o the non-adherent patient

A strong system o monitoring that allows the patient to be ollowed through-

out treatment must be in place. The orms in Chapter 18 are designed to assistthe care provider in ollow-up. When a patient ails to attend a DOT appoint-

ment, a system should be in place that allows prompt patient ollow-up. Most

oten, this involves a DOT worker visiting the patient’s home the same day to

nd out why the patient has missed an appointment and to ensure that treat-

ment is resumed promptly and eectively. The situation should be addressed

in a sympathetic, riendly and non-judgemental manner. Every eort should

be made to listen to reasons or the patient missing a dose(s) and to work with

patient and amily to ensure continuation o treatment. Transportation prob-lems should be addressed.

12.4 Commuit-based care ad suort

Community-based care and support is any action or help provided by, with or rom the community, including situations in which patients are receiving am-

bulatory treatment. This support contributes to, and may even be necessary to,

patient recovery. Political will rom the health and local community authori-

ties is vital to these eorts, and in settings with no tradition o community

participation, it may help to involve organizations that have expertise in socialmobilization and community organizing (9 ).

• Community care supporters. There are numerous potential supporters

who can be brought into the eort to address programmatic needs on a

local level (9–13). These include local health centre nurses, paid (and in

some cases volunteer) CHWs, ormer and current patients, aected ami-

lies, associations, cooperatives, grassroots organizations, local NGOs, com-

munity volunteers and many more.

•Function o the community care supporters. Community care support-ers can provide assistance in clinical management, DOT, contact tracing,

inection control, recording and reporting, training, advocacy and social

support.



125

— Clinical management. This can come in the orm o: (i) early detection

o potentially serious adverse reactions and prompt reerral o such reac-

tions to health workers; (ii) provision o simple, non-medical measures

to manage adverse reactions, e.g. oral hydration in mild diarrhoea, orcounselling on the avoidance o alcohol while taking drugs that have

hepatic eects, etc; and (iii) psychological encouragement. This can o-

ten be most eective when coming rom patients and ormer patients

who endured the same adverse eects while on treatment.

— DOT. Community-based support in DOT can be highly eective, es-

pecially i provided by ormer patients acting as treatment partners or

daily DOT, who are living proo that adherence to daily DOT pays and

that there is hope or cure i they persevere with their treatment. Formerpatients also show better understanding, having gone through the same

treatment themselves. Even when DOT is not provided by a ormer

patient but by a local community member, it is a powerul act o soli-

darity. This solidarity is vital to new patients, who oten eel isolated

and vulnerable.

— Contact tracing. New cases can be discovered by community-care sup-

porters through contact tracing. Early diagnosis o new cases may

improve cure rates and acts as an important inection control measure.

— Inection control. Community-based support in inection control

includes providing health education to patients on simple inection con-

trol practices that can be done in the home, such as observing cough

etiquette (covering the mouth and nose when coughing, or sneezing),

keeping one’s room well ventilated by opening windows or staying out-

doors as much as possible while visiting others.

— Recording and reporting. Data obtained within the amily and commu-

nity can contribute to better comprehensive management. This can in-clude documenting processes occurring outside the health centre and

closer to the patient’s home. Recording certain variables during a home

visit can better assess risks or the patient and amily (such as leaky

roos, insucient living space or poor sanitary conditions). Commu-

nity-based support in recording and reporting may require close super-

vision and validation by health acility sta, and should be done in a

manner that underlines “partnership”.

— Training/education. Community-based training and education can

come in the orm o peer educators (i.e. ormer patients) or trained

advocates. Topics can include general inormation on TB, how DR-TB

develops, the treatment o DR-TB and the importance o adherence and

inection control. Training and education on DR-TB will be most eec-




126


tive with the aid o materials written in lay language. WHO has issued

guidelines or the development o teaching materials under strategies re-

erred to as advocacy, communication and social mobilization (ACSM)

(14–16 ). These materials will be more eective i they contain inputrom patients. Patients can become part o a team that designs the text

and visuals o materials or DR-TB patients. Topics such as the rights

and responsibilities o patients as stated in the Patients’ charter or tuber-culosis care (17 ) should also be included. When ormer patients and care

supporters participate in this health education process, it is more cred-

ible locally and serves also to raise awareness o TB in the wider com-

munity, strengthening basic TB control and care.

— Advocacy and decreasing stigma. Community-based supporters, otenin the orm o patients, give a voice and ace to TB. The establishment

o patient peer groups (community care club) and perhaps eventually a

local organization or association can help reduce stigma and dispel in-

accurate inormation about the disease. The groups can oten infuence

decision-makers or policy change either in the clinics that they attend

or in the wider community where they live.

— Social support. Community care supporters help identiy socioeconomic

and psychosocial needs and help channel support in a timely and more

eective manner. They also help develop community resources thatmay provide useul support, and encourage patients to contribute to the

community by upholding their responsibilities (see also sections 12.3.3

and 12.3.4 above on socioeconomic and psychosocial interventions).

• The relationship o community-based support and hospitalization or

DR-TB. CHWs and community-based support can acilitate timely access

to the hospital, as hospitals and emergency services sometime reject DR-TB

patients, making advocacy necessary. During hospitalization, the commu-

nity-based network can continue to accompany patients and provide addi-tional support as needed. With an ecient network or community-based

care, the patient will be able to return to ambulatory treatment sooner,

resulting in less nosocomial transmission, reduced hospitalization costs and

more hospital beds available or other patients. Understanding and compas-

sion are oten lacking in hospitals that cater to general diseases because o

health workers’ ear o contracting DR-TB, as well as lack o experience in

dealing with DR-TB.

•

Costs and sustainability. When care is rooted in the community, owner-ship by the community supporters will make the support more sustainable.

The CHW is oten the backbone o a community-based support network.

These guidelines advocate or trained CHWs who are a certied part o

the health system and who receive a regular stipend that is a reasonable



127

compensation or the amount o time that they spend each day participat-

ing in community-based care. The added cost o a strong CHW network is

oten cost eective because it contributes to lower rates o ailure and pre-

vention o urther drug resistance.

• Monitoring the CHW. As stated, the CHW is oten the backbone o the

community-based network. Monitoring o the CHW can involve super-

visors who perorm unannounced or ad hoc visits to the patient. At these

visits, they can perorm pill counts, examinations o the treatment card and

assess how activities are being carried out. Whenever a patient is doing poor-

ly, a home visit and assessment o DOT should be perormed. It is impor-

tant to monitor the health status o CHWs and teach them how to protect

themselves against TB transmission as well to ensure that they themselvesdo not develop disease. Weekly/monthly reports rom the CHWs or those

providing care in the community should be required. A communication

network should be clear and in place, making sure that community volun-

teers have easy access to proessional health sta should there be problems

that arise in the community, e.g. adverse events or questions asked by pa-

tients that the CHWs cannot answer.

12.5 Coclusio

Treatment delivery to patients with DR-TB can be accomplished in even themost resource-poor settings. It may be carried out using a hospital-, clinic-

or community-based approach, depending on the programme’s organization

and resources. Trained community members who are closely supervised on

an ongoing basis can play an important role in the management o DR-TB in

the NTP. Thereore, NTPs should be encouraged to incorporate communi-

ty-based care and support into their national plans. Non-adherence to treat-

ment is one o the primary actors leading to poor outcomes or patients with

DR-TB. There are many reasons why patients may not adhere to therapy, and

many o these stem rom socioeconomic constraints. Higher rates o adher-

ence can be achieved i patients are oered a comprehensive package o serv-

ices, including disease education, DOT, socioeconomic support, emotional

support, management o adverse eects and monitoring systems to improve

adherence. The human resources required to deliver the proper support should

not be underestimated (see Chapter 16). Provision o the services and strate-

gies discussed in this chapter should be viewed as an essential part o DR-TB

treatment programmes worldwide, not only as a method o improving clini-

cal and epidemiological outcomes but also in solidarity with each member o the community, especially those in greatest need. The political will needed

to ensure integration o community initiatives with local and national TB

programme activities demonstrates a commitment to the right to health and

promotes participation in activities promoting the common good. Empower-






129

14. Advocacy, communication and social mobilization to fght TB: a 10-year ramework or action. Geneva, World Health Organization, 2006 (WHO/

HTM/STB/2006.37).

15. Advocacy, communication and social mobilization (ACSM) or tuberculosis control: a handbook or country programmes . Geneva, World Health Or-

ganization, 2008.

16. Advocacy, communication and social mobilization or TB control: a guide todeveloping knowledge, attitude and practice surveys . Geneva, World Health

Organization, 2008 (WHO/HTM/STB/2008.46).

17. Patients’ charter or tuberculosis care . Geneva, World Care Council, 2006

(available at http://www.who.int/tb/publications/2006/istc_report.pd;

accessed May 2008).




130

CHAPTER 13

Maagemet o atietsater MDR-TB treatmet ailure


13.2 Assessment o patients at ris or treatment ailure 130

13.3 Indications or suspending treatment 131

13.4 Suspending therap 132

13.5 Approach to suspending therap 132

13.6 Supportie care or patients in whom all the possibilities o

MDR-TB treatment hae ailed 133

13.7 Conclusion 134

Box 13.1 End-o-lie supportie measures 133


The objectives o this chapter are:

• To describe the clinical approach in suspected MDR-TB treatment ailure.

• To discuss indications or suspending treatment or patients in whom a

Category IV regimen has ailed.

• To outline the supportive care options or patients in whom all the possi-

bilities o MDR-TB treatment have ailed.

13.2 Assessmet o atiets at risk or treatmet ailure

Patients who do not show signs o improvement ater our months o treatment

are at risk or treatment ailure. All patients who show clinical, radiographi-

cal or bacteriological evidence o progressive active disease, or reappearance o

disease ater month 4 o treatment, should be considered as being at high risk

or treatment ailure.

The ollowing steps are recommended in such patients:

•

The treatment card should be reviewed to conrm that the patient hasadhered to treatment.

• The treatment regimen should be reviewed in relation to medical history,

contacts and all DST reports. I the regimen is deemed inadequate, a new

regimen should be designed.



131

13. MANAGEMENT OF PATIENTS AFTER MDR-TB TREATMENT FAILURE

• The bacteriological data should be reviewed. Oten, the smear and culture

data are the strongest evidence that a patient is not responding to therapy.

One single positive culture in the presence o an otherwise good clinical

response can be caused by a laboratory contaminant or error. In this case,subsequent cultures that are negative, or in which the number o colo-

nies is decreasing, may help prove that the apparently positive result did

not refect treatment ailure. Positive smears with negative cultures may

be caused by the presence o dead bacilli and thereore may not indicate

treatment ailure. Repeated culture- and smear-negative results in a pa-

tient with clinical and radiographical deterioration may indicate that the

patient has a disease other than MDR-TB.

•

The health-care worker should conrm that the patient has taken all theprescribed medicines. A non-conrontational interview should be under-

taken without the DOT worker present.

• A non-conrontational interview o the DOT worker alone should also be

carried out. Questions should be asked to rule out the possible manipula-

tion o the DOT worker by the patient. I manipulation is suspected, the

DOT worker should be switched to another patient, and the patient with

suspected treatment ailure should be assigned to a new DOT worker.

• Other illnesses that may decrease absorption o medicines (e.g. chronic di-arrhoea) or may result in immune suppression (e.g. HIV inection) should

be excluded.

• I surgical resection is easible, it should be considered.

MDR-TB treatment oten consists o a treatment cycle; i no response is seen,

reassessment o the regimen and treatment plan and ormulation o a new

plan o action are necessary. Patients who have persistent positive smears or

cultures at month 4 but who are doing well clinically and radiographically

may not require a regimen change. Whenever a regimen change is indicat-ed because o treatment ailure, a new regimen is started (with at least our

eective drugs) and options or adjunctive treatment – most commonly

surgery – can be considered. Adding one or two drugs to a ailing regimen

should be avoided. Changes in treatment can be made as early as 4–6 months

i conversion is not seen and i there is clinical deterioration.

13.3 Idicatios or susedig treatmet

It takes 3–4 months to evaluate whether a change in treatment plan has been

eective. I the patient continues to deteriorate despite the measures describedin the previous section, treatment ailure should be considered. There is no

single indicator to determine whether a treatment regimen is ailing. Although

there is no simple denition or treatment ailure, there oten comes a point



132


during the treatment when it becomes clear that the patient is not going to

improve. Signs indicating treatment ailure include:

• persistent positive smears or cultures past month 8–10 o treatment;

• progressive extensive and bilateral lung disease on chest X-ray, with no

option or surgery;

• high-grade resistance (oten XDR-TB), with no option to add two addi-

tional agents;

• overall deteriorating clinical condition that usually includes weight loss and

respiratory insuciency.

It is not necessary or all o these signs to be present to identiy ailure o the treatment regimen. However, a cure is highly unlikely when they are all

present.

The epidemiological denition o treatment ailure or recording outcomes

(see Chapter 4) is oten dierent rom that used in the process o suspending

therapy in a patient when the therapy is ailing. The epidemiological deni-

tion is an outcome to account or the patient in a treatment cohort analysis,

while the clinical decision to suspend therapy is made ater the clinical search

or all other options has been exhausted and cure o the patient is considered

to be highly unlikely.

13.4 Susedig tera

Treatment can be considered to have ailed and suspension o therapy is rec-

ommended in cases where the medical personnel involved are condent that

all the drugs have been ingested and there is no possibility o adding other

drugs or carrying out surgery.

There are two important considerations in suspending therapy or chang-

ing it to a supportive care regimen. The rst is the patient’s quality o lie: the

drugs used in MDR-TB treatment have signicant adverse eects, and con-tinuing them while the treatment is ailing may cause additional suering.

The second is the public health concern: continuing a treatment that is ail-

ing can ampliy resistance in the patient’s strain, resulting in highly resistant

strains such as XDR-TB that may cause subsequent inection o others.

13.5 Aroac to susedig tera

The approach to suspending therapy should start with discussions among the

clinical team, including all physicians, nurses and DOT workers involved in

the patient’s care. Once the clinical team decides that treatment should be sus-pended, a clear plan should be prepared or approaching the patient and the

amily. This process usually requires a number o visits and takes place over

several weeks. Home visits during the process oer an excellent opportunity to

talk with amily members and the patient in a amiliar environment. It is not



133

recommended to suspend therapy beore the patient understands and accepts

the reasons to do so, and agrees with the supportive care oered.

13.6 Suortie care or atiets i om all te ossibilitieso MDR-TB treatmet ae ailed

A number o supportive measures can be used once the therapy has been sus-

pended. It is very important that medical visits continue and that the patient

is not abandoned. The supportive measures are described in detail in the In-

tegrated Management o Adolescent and Adult Illness guidelines produced by

WHO in a booklet titled Palliative care: symptom management and end-o-lie care (1). The supportive measures are summarized in Box 13.1.

13. MANAGEMENT OF PATIENTS AFTER MDR-TB TREATMENT FAILURE

BOx 13.1 EnD-OF-LIFE SUppORTIvE MEASURES

pai cotrol ad smtom relie. Paracetamol, or codeine with paraceta-

mol, gies relie rom moderate pain. Codeine also helps control cough.

Other cough suppressants can be added. I possible, stronger analgesics,

including morphine, should be used when appropriate to eep the patient

adequatel comortable.

Relie o resirator isuciec. Oxgen can be used to alleiate short-

ness o breath. Morphine also proides signifcant relie rom respirator

insufcienc and should be oered i aailable.

nutritioal suort. Small and requent meals are oten best or a per-son at the end o lie. It should be accepted that the intae will reduce

as the patient’s condition deteriorates and during end-o-lie care. Nausea

and omiting or an other conditions that interere with nutritional support

should be treated.

Regular medical isits. When therap stops, regular isits b the treating

phsician and support team should not be discontinued.

Cotiuatio o acillar medicies. All necessar ancillar medications

should be continued as needed. Depression and anxiet, i present, should

be addressed.

hositalizatio, osice care or ursig ome care. Haing a patient die

at home can be difcult or the amil. Hospice-lie care should be oered

to amilies who want to eep the patient at home. Inpatient end-o- lie care

should be aailable to those or whom home care is not aailable.

preetie measures. Oral care, preention o bedsores, bathing and pre-

ention o muscle contractures are indicated in all patients. Regular sched-

uled moement o the bedridden patient is er important.

Iectio cotrol measures. The patient who is taen o antituberculosis

treatment because o ailure oten remains inectious or long periods o

time. Inection control measures should be continued (see Chapter 15).



134


13.7 Coclusio

Suspension o therapy should be considered only ater all other options or

treatment have been explored. Suspending therapy in a patient who has ailed

MDR-TB treatment is a delicate situation and dicult or amily membersand caregivers; but it is especially dicult or the patient as treatment is oten

viewed as his or her only hope. Strong support, care and sympathy must be

given to the patient and amily.

Reerece

1. Palliative care: symptom management and end-o-lie care . Geneva, World

Health Organization, 2004 (WHO/CDS/IMAI/2004.4).



135

CHAPTER 14

Maagemet o cotactso MDR-TB atiets

14.1 Chapter objectie 135


14.3 Management o smptomatic adult contacts o patients

with MDR-TB 136

14.4 Management o smptomatic paediatric contacts o patients

with MDR-TB 136

14.5 Chemoprophlaxis o contacts o MDR-TB index cases 138

14.1 Cater objectie

This chapter outlines the management o symptomatic adults and children

who have or have had a known contact with an MDR-TB patient.


DR-TB contact inestigation should be gien high priorit, and NTPs should

consider contact inestigation o XDR-TB as an emergenc situation.*

Close contacts o DR-TB patients should receie careul clinical ollow-up.

14.2 Geeral cosideratiosOpportunities to halt the transmission o resistant mycobacteria in communi-

ties and to treat MDR-TB in a timely ashion are oten squandered. The main

reasons are lack o investigation o contacts o MDR-TB patients, ailure to

ask patients presenting with active TB disease about any history o exposure

to MDR-TB, and lack o access by national treatment programmes to second-

line regimens and/or DST.

Close contacts o MDR-TB patients are dened as people living in the same

household, or spending many hours a day together with the patient in the

same indoor living space. The available data indicate that close contacts o

MDR-TB patients who develop active TB most commonly have drug-resistant

disease (1–5 ). While all contacts o TB require investigation, DR-TB requires the most





137

14. MANAGEMENT OF CONTACTS OF MDR-TB PATIENTS

to thrive and recurrent evers. Bacteriological conrmation may be dicult

to obtain because o the inability o children to generate a sputum sample, as

well as the paucibacillary nature o paediatric TB and the increased likeli-

hood o extrapulmonary TB in children. While every eort should be made toestablish a bacteriological diagnosis (and obtain DST) in a child with sus-

pected MDR-TB, in practice paediatric cases are oten not conrmed bacte-

riologically. Use o scoring systems that have been produced to aid screening

and diagnosis o active TB is strongly recommended (see Guidance or national tuberculosis programmes on the management o tuberculosis in children (6 )).

Symptomatic paediatric household contacts should receive:

• An evaluation by a physician, including history and physical examination.

• Tuberculin skin testing with puried protein derivative (PPD).

• A chest X-ray examination (computerized tomography is helpul especially

in documenting hilar adenopathy but this is oten not available in low-

resource areas).

• Sputum smear, culture and DST: every eort should be made to establish

a bacteriological diagnosis (and obtain DST) in a child with suspected DR-

TB. Bacteriological conrmation may include more aggressive measures

such as induced sputum, gastric aspirate, lymph node aspirate or other rel-

evant sample, plus culture and DST. (Note: gastric aspiration should only

be undertaken where culture acilities are available due to the low yield

rom microscopy and the distress involved or the child. Culture specimens

need to be processed within the hour because the acidic juices will kill the

bacteria relatively quickly) (6 ).

• HIV counselling and testing (in areas o high HIV prevalence or i parent(s)

known, or suspected to be, HIV-inected).When the tuberculin (PPD) skin

test result is >5 mm but the chest radiograph and gastric aspirate or sputum

smear are negative, the symptomatic child can be treated with a broad-spectrum antibiotic that is not active against TB, such as trimethoprim/

sulamethoxazole. The child should be ollowed closely, with evaluations

including smear test and culture on samples rom induced sputum or gas-

tric aspirates, or sputum samples whenever possible, as well as chest X-rays.

The optimal requency o these evaluations has not yet been determined.

It is not clear whether the requency o evaluation recommended or adults

can be applied to children. I a child’s clinical condition is highly suggestive

o TB, or progressively deteriorates, empirical therapy designed according

to the DST pattern o the strain rom the index case can be started.

Children with MDR-TB who are incorrectly entered in SCC may suer sig-

nicant and protracted morbidity as a result o ongoing active disease, with

the possibility o lielong disability or even death. Because children with TB



138


may never become sputum smear-positive, it is reasonable to initiate empiri-

cal MDR-TB therapy based on the DST pattern o the contact. I DST o the

contact is not available, therapy can be based on the common DST patterns o

resistance in the community.

14.5 Cemorolais o cotacts o MDR-TB ide cases

The only chemoprophylaxis regimens to have been studied are based on isoni-

azid and, to a lesser extent, riampicin. Since by denition MDR-TB is resist-

ant to both o these drugs, it is unlikely that use o these drugs to treat latent

inection caused by an MDR-TB strain will prevent the development o active

TB disease.1

Contacts o MDR-TB patients in whom latent inection is diagnosed may

not be inected with the same strain; some may be inected with isoniazid-susceptible strains, particularly in high-burden areas where many dierent

strains o TB may circulate in homes, schools, workplaces, etc. Studies rom

high-burden TB areas have shown that approximately one-hal to two-thirds

o household members had the same strain o TB, as determined by genetic

testing (7–9 ). (The degree o strain concordance could be higher in contacts

who are children aged under 5 years because they have less exposure to strains

circulating outside the household.)

Close contacts o DR-TB patients should receive careul clinical ollow-up

or a period o at least two years. I active disease develops, prompt initiation

o treatment with a regimen designed to treat MDR-TB is recommended. On

the basis o the currently available evidence, WHO does not recommend the

universal use o second-line drugs or chemoprophylaxis in MDR-TB con-

tacts.

More inormation on contract tracing can be ound in other WHO docu-

ments (10 ).

Reereces1. Kritski AL et al. Transmission o tuberculosis to close contacts o patients

with multidrug-resistant tuberculosis. American Journal o Respiratory and Critical Care Medicine , 1996, 153(1):331–335.

2. Schaa HS et al. Transmission o multidrug-resistant tuberculosis. Pediat-ric Inectious Disease Journal , 2000, 19(8), 695–699.

3. Teixeira L et al. Inection and disease among household contacts o

patients with multidrug-resistant tuberculosis. International Journal o Tuberculosis and Lung Disease , 2001, 5(4):321–328.

1 Tuberculin skin tests become positive in most patients inected with TB irrespective o whetherthe strain is susceptible or resistant.



139

4. Schaa HS et al. Evaluation o young children in contact with adult multi-

drug-resistant pulmonary tuberculosis: a 30-month ollow-up. Pediatrics ,2002, 109(5):765–571.

5. Bayona J et al. Contact investigations as a means o detection and timely treatment o persons with inectious multidrug-resistant tuberculosis. In-ternational Journal o Tuberculosis and Lung Disease , 2003, 7(12):S501–

509.

6. Guidance or national tuberculosis programmes on the management o tuberculosis in children. Geneva, World Health Organization 2006

(WHO/HTM/TB/2006.371; WHO/FCH/CAH/2006.7).

7. Verver S et al. Proportion o tuberculosis transmission that takes place in

households in a high-incidence area. Lancet , 2004, 363(9404):212–214.

8. Schaa HS et al. Evaluation o young children in household contact with

adult multidrug-resistant pulmonary tuberculosis cases. Pediatric Inec-tious Disease Journal , 1999, 18(6):494–500.

9. Steiner P, Rao M. Drug-resistant tuberculosis in children. Seminars inPediatric Inectious Diseases , 1993, 4:275–282.

14. MANAGEMENT OF CONTACTS OF MDR-TB PATIENTS



140

CHAPTER 15

Drug resistace adiectio cotrol


15.2 The priorities o inection control 140

15.2.1 Administratie controls 141

15.2.2 Enironmental controls 142

15.2.3 Personal respirator protection (special mass) 143

15.3 Role o rapid tests in inection control 144


This chapter addresses special considerations or reducing transmission o

DR-TB through inection control measures. Inection control practices arediscussed in more detail in other WHO documents (1). Since every instance

o transmission averted represents one less potential DR-TB case, inection

control needs to be a leading programmatic priority. It is equally important to

protect health workers in the setting o DR-TB.


Inection control, including administratie and engineering controls and

personal protection, should be made a high priorit in all DR-TB controlprogrammes.

XDR-TB patients should be placed in isolation until no longer inectious.*

DR-TB patients should receie routine care outside o normal HIv care set-

tings.*

15.2 Te riorities o iectio cotrol

DR-TB is transmitted in the same manner as drug-susceptible TB. Well-

documented outbreaks o highly drug-resistant strains o TB constitute

convincing evidence that DR-TB is transmissible, especially among highly vulnerable populations and in institutional settings. Moreover, because DR-

TB patients may respond to treatment slowly and remain sputum smear-

positive longer than other TB patients, they may inect more contacts.

The management o DR-TB does not signicantly alter the basic TB inec-



141

15. DRUG RESISTANCE AND INFECTION CONTROL

tion control strategies. However, in view o its seriousness, every programme

attempting to treat DR-TB should also undertake a systematic review o cur-

rent practices and ensure that everything possible is done to prevent transmis-

sion among patients and to sta.Recommendations or inection control to prevent DR-TB are essentially

the same as those to prevent the spread o drug-susceptible TB, with only mi-

nor dierences in emphasis. Further inormation is provided in the WHO/

CDC/IUATLD Guidelines or prevention o tuberculosis in health care acilities in resource-limited settings (1). This chapter reviews briefy the recommenda-

tions that have a specic ocus on DR-TB. (Additional recommendations or

areas with high HIV prevalence are in preparation.) TB inection control has

three components. By order o importance, they are: administrative controls,

environmental or engineering controls, and personal respiratory protection.

The administrative controls are the most eective and least expensive and

thereore have highest priority in resource-constrained settings.

15.2.1 Administratie controls

Administrative controls include policies and procedures intended to promptly

identiy inectious cases so that additional precautions can be taken. They ne-

cessitate the appointment o a director o inection control or the institution,

and an inection control committee representing key departments o the acil-

ity. The initial task o the committee is the ormulation o a comprehensive

inection control plan or the institution, including a programme or the edu-

cation o all sta on inection control policies and procedures.

An important aspect o administrative control measures is the physical

separation o patients known or suspected to have TB or DR-TB (especially

smear-positive cases) rom other patients, especially those who are immuno-

compromised. In many resource-limited settings, however, isolation rooms are

not available and patients are mixed together in open wards. A second, less

satisactory but practical, solution is to separate rather than isolate patients.In this approach, patients with TB are grouped together and apart rom those

with suspected DR-TB, who are grouped together. This separation may be di-

cult as wards are usually separated by sex, which increases the number o di-

erent areas required. The presence o a substantial number o HIV-inected

patients urther complicates separation as they are not only potentially inec-

tious but also highly vulnerable to intercurrent inection and reinection rom

others. Placing HIV-inected patients on wards with known or suspected TB

together with other TB or MDR-TB patients should always be avoided.

Inectious patients with XDR-TB, whether inected with HIV or not,should not be placed on general wards. Given the high mortality associated

with XDR-TB, isolation until the patient is no longer inectious is recom-

mended. Forced isolation and human rights are discussed more in Chapter

19 and Annex 4. Another administrative issue is the length o time patients



142


spend in the hospital. In many resource-limited countries, patients are tradi-

tionally treated or prolonged periods in the hospital, particularly when they

come rom great distances. However, this practice involves an increased risk

o nosocomial transmission. The risk o transmission to patients and health-care workers decreases when community-based ambulatory treatment is estab-

lished and hospital stays are reduced. Although most transmission is likely to

have occurred beore the diagnosis and start o treatment, ambulatory patients

should be advised to avoid contact with the general public and with particu-

larly susceptible people, such as young children or individuals with HIV inec-

tion. Health-care workers visiting TB patients at home beore treatment is well

established should wear properly tted personal respirator masks.

Attention should also be paid to outpatient clinical settings. Because o the

risk o severe morbidity and mortality in HIV-inected persons rom DR-TB,

persons with known DR-TB should receive routine care outside o normal

HIV care settings ( 2 ).

15.2.2 Enironmental controls

Environmental (or engineering) controls assume that unsuspected, untreated

TB patients will enter hospitals despite all eorts to identiy them. In addi-

tion, there are certain high-risk settings, such as sputum induction rooms,

bronchoscopy rooms and rooms or the evaluation o newly admitted patients

who may have untreated TB or DR-TB, where engineering interventions are

necessary to reduce risk. Engineering controls attempt to reduce the concen-

tration o inectious droplet nuclei in the air. They include natural and/or

mechanical ventilation, ultraviolet germicidal irradiation (UVGI) and high-

eciency particulate air ltration. Environmental methods should never

replace administrative controls; in act, they work together.

In warm climates, inection control oten depends on natural ventilation.

The ecacy o natural ventilation has not been studied, but it probably de-

pends heavily on climatic conditions. In warm climates, patients spend mucho their time outdoors where transmission is highly unlikely. However, at

night, or security and warmth, patients stay indoors with doors and windows

usually closed tightly. Thus, patients in sub-Saharan Arica (warm climate)

and in Siberia (cold climate) may endure similar high-risk conditions, at least

some o the time.

The use o extraction ans to improve ventilation in closed rooms through

wall vents can be extremely useul. Mechanical ventilation systems are un-

common in resource-poor settings and, when present, are oten poorly main-

tained. However, a little ventilation is better than none, and in acilities withmechanical ventilation systems, eorts should be made to ensure that they

unction correctly. Clinics in warm climates should be designed without inte-

rior hallways, which tend to trap air and with waiting areas that are open on

at least three sides.



143

Ventilation can be supplemented with upper-room UVGI. This has long

been known to be extremely eective in inactivating inectious particles in

the air above people’s heads, while not exposing them to skin or eye irritation,

which is the only practical saety concern. Normal convection currents or low-velocity ceiling ans usually ensure good room air mixing, thereby decontami-

nating air in the breathing zone. Upper-room UVGI is intended or use while

rooms are occupied, but not to sterilize empty rooms as is commonly done in

some parts o the world. It is much more important to decontaminate air while

the inectious source and other occupants are present, and upper-room UVGI

is designed to do so without signicant radiation risks.

A growing number o manuacturers o xtures designed or upper-room

use are established in low-income countries and can provide products at rela-

tively low cost. However, there are currently no standards or these products;

the buyer should obtain advice rom an engineer knowledgeable in the eld.

In addition to UVGI designed or upper-room use, germicidal UV is some-

times used in ventilation ducts or in an-driven air sterilizing devices mounted

on ceilings or walls, or portable units that can be moved rom room to room.

However, the ecacy o these systems is limited by the number o air turn-

overs they can produce, especially in large spaces. By irradiating large volumes

o upper-room air at one time, upper-room systems have a quantitative advan-

tage, especially when combined with low-velocity ceiling ans to ensure roomair mixing.

Laboratories that process specimens that may be DR-TB require particular-

ly strict environmental controls. These aspects are addressed in other WHO

documents ( 3) and in Chapter 6 o these guidelines.

15.2.3 Personal respirator protection (special mass)

Because administrative and engineering controls cannot provide complete

protection, the third line o deence against nosocomial TB transmission is

the use o personal respirators.Personal respirators are undamentally dierent rom, and more expensive

than, the more amiliar surgical masks which they resemble. Surgical masks

are designed to protect the operating eld rom relatively large respiratory

droplets generated by surgeons and surgical nurses. They are relatively loose-

tting and made o paper or cloth; they are not adequate or prevention o TB

inection.

Masks that prevent TB transmission are known as “particulate respira-

tors” or simply “respirators”. They are designed to protect the wearer rom tiny

(1–5 µm) airborne inectious droplets. The ltration media through which airpasses must capture these minute particles; most importantly, the respirator

must t tightly on the ace, especially around the bridge o the nose. Ideally,

respirators should be “t tested” or individual wearers. In addition to choos-

ing the proper model or each worker, this process serves to educate workers

15. DRUG RESISTANCE AND INFECTION CONTROL



144


on how to put on their respirators correctly to minimize ace-seal leakage. Men

with beards cannot be properly tted with personal respirators. Institutions

purchasing respirators are advised to look or models that are specically de-

signed to protect against TB and that meet international standards o quality.Because they are visible and relatively expensive, it is sometimes assumed

that personal respirators alone will prevent TB transmission. However, they

cannot be worn continuously and are likely not to be in use when unsuspected

TB cases, or unsuspected DR-TB, are encountered. For these reasons, admin-

istrative controls that aim to detect and separate cases, and engineering con-

trols that can reduce the risk even or unsuspected cases, are more important.

15.3 Role o raid tests i iectio cotrol

The use o a rapid test or riampicin or other drugs is an excellent methodo distinguishing those who may have DR-TB rom others. Patients who are

identied by rapid tests can be properly separated or isolated immediately (in

addition to starting proper empirical regimens). Chapters 5 and 6 provide

urther inormation on the use o rapid tests.

Reereces

1. Guidelines or the prevention o tuberculosis in health-care acilities in re-source-limited settings . Geneva, World Health Organization, 1999 (WHO/

TB/99.269).

2. Tuberculosis inection control in the era o expanding HIV care and treat-ment . Geneva, World Health Organization, 2007.

3. Laboratory services in tuberculosis control. Parts I, II and III . Geneva, World

Health Organization, 1998 (WHO/TB/98.258).



145

CHAPTER 16

huma resources:traiig ad stag



16.3 Human resource deelopment plan or DR-TB control programmes 145

Table 16.1 Human resource constraints to programme implementation 147


This chapter considers the development o human resources or DR-TB con-

trol programmes within the national programme, addressing a broad agenda

that includes the overall management o training and issues related to sta-

ing.


The development o human resources or DR-TB control programmes re-

quires specic planning within the national TB control plan. A programme

that correctly implements and manages Category IV regimens cannot simply

be added to the responsibilities o sta currently implementing the DOTS

strategy. As well as the organization o special training courses, the availabil-

ity o sucient sta in all categories o personnel involved in the programme

at all levels (clinical, laboratory, pharmaceutical and managerial) must beensured to reach a specic long-term goal or proessional competence in pro-

gramme implementation.

Ensuring competent and sucient human resources or the implementa-

tion o a DR-TB control programme o high quality requires ongoing man-

agement. As programme implementation expands, the management o human

resources will become more complex because o the continued and diversied

demands on sta at all levels.

16.3 huma resource deelomet la orDR-TB cotrol rogrammes

There are numerous constraints to the eective perormance o the health

workorce, as indicated in Table 16.1. In many instances, additional sta

with appropriate expertise have to be recruited to manage the activities o the



146


programme at the central and other levels. Central management should esti-

mate sta requirements or the implementation o all aspects o the programme.

Realistic projections, based on task analysis, revision o job descriptions and

estimation o workloads or concerned sta orm the basis o a plan or humanresource development (HRD plan) to support the programme. Issues to be

addressed include the level o eort and support systems (e.g. transportation)

required or prolonged DOT, or health-care worker visits, or social support

and or clinical and laboratory personnel.

The HRD plan or the DR-TB control programme should be part o the

national HRD plan. The plan should include all sta involved in the diagno-

sis and treatment o DR-TB, patients and national authorities responsible or

overseeing the programme, and include the proper regulatory documents.

The objectives o the human resource development component o the DR-

TB control programme are twoold:

• To ensure the availability o sucient sta (clinical and managerial) at all

levels to implement the plan without detriment to other areas o work o the

NTP.

• To ensure that all sta involved in the programme (at all service levels, and

both public or private) are competent (have the required knowledge, skills

and attitudes) and motivated or implementation.

To prepare the HRD plan or implementation by the DR-TB control pro-

gramme, the ollowing 10 steps are recommended:

1. Assign a ocal point or human resources development or the DR-TB

control programme within the NTP.

2. Assess the human resource requirements o the DR-TB control pro-

gramme and their implications or the existing workorce (clinical, mana-

gerial, laboratory, pharmaceutical):

• Dene tasks to be perormed at each level o the system to implement

the DR-TB control programme.

• Assign tasks to specic categories o health workers.

• Assess the time needed to implement those tasks, particularly at

peripheral level (where changes in the number and type o cases diag-

nosed and treated have the most impact on the workload).

• Assess how many sta o the respective categories are needed to

maintain the current service delivery level and include treatment o

DR-TB.3. Assess the current human resources situation o the NTP/health system

and determine the number o sta o the relevant categories available at

each programme level.



147

16. HUMAN RESOURCES: TRAINING AND STAFFING

4. Identiy the gaps in human resources in terms o both the numbers re-

quired (increased numbers, additional roles and responsibilities, such as a

coordinator or treatment o DR-TB or a laboratory ocal point) and thequality o sta (additional knowledge and skills needed) to implement the

DR-TB control programme.

5. Prepare short- and medium-term plans including how to ensure adequate

stang and preparation o training programmes based on the task analy-

sis. The ollowing options can be considered:

• In-service training (clinical and managerial):

— initial training in basic implementation o treatment or DR-TB,

— retraining (major perormance problems need more time than asupervisory visit to solve, e.g. a ormal training course),

— on-the-job training (reresher: small perormance problems that

can be addressed during a supervisory visit),

TABLE 16.1 huma resource costraits to rogramme imlemetatio

trAininG/competence stAffinG/motivAtion

Inadequate sills o existing sta: Imbalances in human resources or TB

— Man sta inoled in TB control control:

in general are not trained — Imbalances in oerall numbers

— Suboptimal training (in-serice — Imbalances in distribution

training): lac o specifc measur- — Urban/rural imbalance

able learning objecties, lac o — Imbalances in sills or sill-mix (a

training materials, inadequate mismatch between the tpe or leel

length o training, poor use o o training and the sills required b

adequate training methodologies, the health sstem)

lac o learning ealuation Shortages o human resources or TB

— An assumption b trainers and control

control managers that eerthing Increased demand on existing sta –

taught is learnt and will lead to not onl b national TB controlcompetent perormance programmes:

— Lac o attention to other actors — Impact o AIDS

inuencing behaiour change o — Low sta retention

health-care proiders — Low sta motiation

—Trainingisseenasatime-limited •under-skilled(inadequate/

actiit that is no longer needed inrequent training)

whenthetreatmentstrategyhas •unsupported/lackofsupervision

reached100%coverage–“allhave •poorworkenvironment

beentrained” •poorcareerstructure

— Inadequatepre-servicetraining •underpaid

•overburdened •moraleproblems

•sickorcaringforsickfamily

members

— Insufcient number o posts

— Increased “brain drain”

— High sta turnoer



148


— continuing training (to gain more skills and knowledge without

repeating previous training).

• Coordination with other in-service training programmes/training

institutions and departments (in particular, measures to retain trainedsta, interventions to stop unnecessary rotation o sta and support or

career paths).

• Pre-service training (basic training in skills needed beore entering in-

service training).

6. Develop training programmes to ensure that:

• Job descriptions are based on task analysis.

• Training courses/programmes have learning objectives based on the

task analysis and the job descriptions.• Training courses/programmes use methods and time allocation that

allow participants to meet the learning objectives.

• The participants:acilitators ratio in each course allows participants to

meet the learning objectives.

• The learning objectives have been met.

7. Consider the ollowing issues in planning and implementing evaluation:

• Evaluation during training courses:

— by participants to determine whether the course met their needs,

— o participants to determine whether their skills met the learning

objective(s).

• Evaluation in the eld:

— supervision (post-training evaluation) to identiy perormance

problems and determine whether problems are caused by “lack o

skill or lack o will”,

— specic ollow-up immediately ater training.

8. Ensure monitoring and supervision to:

• Detect perormance deciencies in newly trained sta.

• Identiy new sta in need o training (additional sta needs, sta

vacancies).

9. Carry out timely implementation o the HRD plan with regular monitor-

ing o the implementation.

10. Carry out periodic evaluation o the implementation o the HRD plan,

with revision as necessary.Note: More inormation on human resource development can be ound in

the WHO document Training or better TB control. Human resource develop-ment or TB control: a strategic approach within country support (1) and other

sources ( 2–3).



149

Reereces

1. Training or better TB control. Human resource development or TB control:a strategic approach within country support . Geneva, World Health Organi-

zation, 2002 (WHO/CDS/TB/2002.301).2. Human resources development or TB control. Report o a Consultation held

on 27 and 28 August 2003. Geneva, World Health Organization, 2003.

3. Harries AD et al. Human resources or control o tuberculosis and HIV-

associated tuberculosis. International Journal o Tuberculosis and Lung Dis-ease , 2005, 9(2):128–137.

16. HUMAN RESOURCES: TRAINING AND STAFFING



150

CHAPTER 17

Maagemet o secod-lieatituberculosis drugs


17.2 WHO Model List o Essential Medicines: second-line

antituberculosis drugs 150

17.3 Drug management ccle o second-line antituberculosis drugs 150

17.4 The WHO Green Light Committee mechanism 152

Box 17.1 Second-line antituberculosis drugs included in the

WHO Model List o Essential Medicines 151

Box 17.2 Main elements to consider when planning procurement o

second-line antituberculosis drugs 152


This chapter provides inormation on the procedures or procurement and

management o the second-line drugs used in the treatment o DR-TB. Inor-

mation is included on procurement o drugs through the GLC mechanism.

17.2 whO Model List o Essetial Medicies:

secod-lie atituberculosis drugs

Essential medicines are those that satisy the health-care needs o the majority

o the population. The drug selection is based on the development o treat-ment guidelines and on the evidence underlying the development o those

treatment guidelines. The current version o the WHO Model List o Essen-

tial Medicines, the 14th list, dates rom March 2005 and includes nine sec-

ond-line drugs (see Box 17.1). This Model List does not imply that no other

drugs could be useul or management o DR-TB, but simply that these basic

drugs, when used in accordance with appropriate therapeutic guidelines, cost-

eectively meet the needs o an important proportion o the population.

17.3 Drug maagemet ccle o secod-lieatituberculosis drugs

The management cycle o drugs comprises six elements: drug selection, quan-

titative assessment o drug requirements, management o procurement, distri-

bution, assurance o drug quality and ensuring rational drug use.



151

17. MANAGEMENT OF SECOND-LINE ANTITUBERCULOSIS DRUGS

A number o actors must be considered when selecting second-line drugs,

including the ecacy o the drugs, the treatment strategy, possible adverse

eects and the cost o the treatment (see Chapter 7). Accurate demand orecasting or second-line drugs, i.e. correct quantica-

tion o the drug needs or a specic period o time, is one o the elements that

guarantees an uninterrupted drug supply. There are two main approaches or

demand orecasting:

• The most precise method is usually the consumption-based approach, with

projections o uture needs based on records o past consumption o indi-

vidual drugs. This method assumes that the data are complete, accurate,

and properly adjusted or stock-outs and expected changes in demand anduse. However, this method is recommended only or an established pro-

gramme managing DR-TB.

• The morbidity-based approach method is recommended or new projects.

In this method, the treatment regimen (standardized, individualized or

empirical) and the number o patients to be treated with each regimen are

taken into account. Several other key actors must also be considered, in-

cluding the existing stock, lead time or delivery, saety stock needed and

the shel-lives o the drugs. Shel-lives o second-line drugs are longer thanthose o rst-line drugs, ranging rom 18 to 36 months. It is recommended

that stock should be sucient or a period o 2–3 times the delivery delay.

An inventory management system needs to be set up to ensure a saety stock

and optimal stock movement, and to provide an accurate source o inorma-

tion or drug demand orecasting.

Eective management o procurement ensures the availability o the drugs

selected, in the right quantities, at the right time, at aordable prices and o

acceptable standards o quality. For more inormation see the manual Opera-tional principles or good pharmaceutical procurement (1).

Management o drug importation and distribution requires that all port

and customs clearance orms are duly completed. The ormalities involved

depend on whether the drugs have been registered in the importing country.

BOx 17.1

Secod-lie atituberculosis drugs icluded i te

whO Model List o Essetial Mediciesa

anamcin leooxacin ooxacin

ccloserine amiacin capreomcin

ethionamide p-aminosaliclic acid

a Note. While ciprooxacin has not et been remoed rom the WHO Model List o Essential Medi-

cines and second-line antituberculosis drugs, it is no longer recommended or the treatment o

an orms o TB (see Chapter 7).



152


In many countries, it is possible to obtain an exemption on the basis o the

public health interest, allowing the NTP to import drugs that are not locally

registered.

To preserve quality, the drugs should be stored and transported by thesupplier and the NTP ollowing “good storage practices” and the recommen-

dations o the manuacturer regarding temperature and humidity.1

The quality assurance component o a drug supply system makes certain

that each drug used by a patient is sae, ecacious and o appropriate quality.

All drugs used in a regimen or DR-TB should meet the WHO recommended

standards or saety, ecacy and quality. The WHO prequalication project2

aims at producing a list o second-line drugs and manuacturers that meet

specic approved standards. The manuacturers selected to supply second-line

antituberculosis drugs should be (as a minimum) compliant with the WHO

standards o “good manuacturing practices”.3

Access to second-line drugs must be accompanied by measures to ensure

rational drug use. Misuse o the drugs will result in loss o susceptibility to the

second-line agents, producing circulating strains that will be extremely di-

cult to cure with currently available medicines. Box 17.2 lists the most impor-

tant elements to consider when preparing a plan to procure second-line drugs

or the management o MDR-TB.

BOx 17.2

Mai elemets to cosider e laig rocuremet o secod-lie

atituberculosis drugs

Drug orecast based on treatment regimen, cohort size and pace o patient

enrolment

Drug registration status o products selected

Drug labelling

Customs regulations or importing drugs

Shel-lie o the products

Lead-time or delier o the drug request Estimated size o buer stoc (2–3 times the delier dela)

17.4 Te whO Gree Ligt Committee mecaism

NTPs have had to ace several obstacles in the area o drug procurement, in-

cluding the high cost o second-line drugs, the lack o local capacity to apply a

stringent quality assessment o drug manuacturers and their products, incon-

sistent availability and the lack o guidelines on the proper use o second-line

1 For a more detailed discussion see “Guide to good storage practices or pharmaceuticals” o the WHO Expert Committee on Specications or Pharmaceutical Preparations, Annex 9 ( 2 ).

2 http://mednet3.who.int/prequal/3 As dened in “Good Manuacturing Practices or pharmaceutical products: main principles” o

the WHO Expert Committee on Specications or Pharmaceutical Preparations, Annex 4 ( 2 ).



153

drugs. In order to tackle these obstacles, the GLC mechanism was set up in

2000 by WHO and its partners in the Stop TB Working Group on DOTS-

Plus. GLC-approved projects purchase directly rom agent(s) contracted by

WHO to procure the drugs. By utilizing the GLC mechanism, a DR-TB con-trol programme benets rom access to quality-assured drugs at concessionary

prices and a continuous drug supply to the approved cohorts o patients. For

urther inormation, including details o technical assistance oered by the

GLC, see Chapter 1 and Annex 1. The most up-to-date inormation is avail-

able on the WHO web page.1 For approved projects, additional inormation

is provided on drug procurement through the Procurement manual or DOTS-Plus projects approved by the Green Light Committee ( 3).

Reereces1. Operational principles or good pharmaceutical procurement . Geneva, World

Health Organization, 1999 (WHO/EDM/PAR/99.5).

2. WHO Expert Committee on Specifcations or Pharmaceutical Preparations .Thirty-seventh report. Geneva, World Health Organization, 2003 (Tech-

nical Report Series No. 908).

3. Procurement manual or DOTS-Plus projects approved by the Green Light Committee . Geneva, World Health Organization, 2006 (WHO/HTM/

TB/2003.328 Rev.2).

17. MANAGEMENT OF SECOND-LINE ANTITUBERCULOSIS DRUGS

1 http://www.who.int/tb/challenges/mdr/greenlightcommittee/en/index.html



154

CHAPTER 18

Categor Iv recordig adreortig sstem


18.2 Aims o the inormation sstem and perormance indicators 155

18.3 Scope o the inormation sstem 156

18.4 Main orms/registers and ow o inormation 156

18.4.1 Categor Iv Treatment Card (Form 01) 157

18.4.2 Categor Iv Register (Form 02) 159

18.4.3 Request or sputum examination (Form 03) 161

18.4.4 Laborator Register or culture and DST (Form 04) 161

18.4.5 Quarterl report on MDR-TB detection and Categor Iv

treatment start (Form 05) 161

18.4.6 Six-month interim outcome assessment o confrmed

MDR-TB cases (Form 06) 162

18.4.7 Annual report o treatment result o confrmed MDR-TB

patients starting Categor Iv treatment (Form 07) 162

18.5 Addressing the baclog o patients who ailed Categor II

treatment in the past 163

18.6 Assuring the qualit o the recording and reporting sstem 163

18.7 Computerized sstems 163

18.8 International Health Regulations (IHR) 164

Box 18.1 Optional recording and reporting components 155


This chapter describes the inormation system or Category IV patients, with

the objective o recording inormation needed to monitor programme per-

ormance and treatment outcomes. It presents the instruments and minimum

variables necessary to implement and monitor Category IV treatment. Tools

are also introduced to track screening and enrolment eorts. Lastly, the chap-ter presents additional optional components (see Box 18.1) that programmes

should use when it is easible and relevant.



155

18. CATEGORy Iv RECORDING AND REPORTING SySTEM


A standardized method o recording and reporting should be implemented

in DR-TB control programmes.

DR-TB treatment cards should hae an expanded section or inormation on

patients with HIv.*

International Health Regulations should be ollowed.*

18.2 Aims o te iormatio sstem ad

erormace idicators

The aims o the inormation system are twoold:• To allow NTP managers at dierent levels to monitor overall programme

perormance (such as patients started on treatment and treatment results),

to ollow trends in the number o cases notied, to plan drug supply, and to

provide the basis or programme and policy developments.

BOx 18.1 OpTIOnAL RECORDInG AnD REpORTInG COMpOnEnTS

Some programmes ma want to include additional recording and reporting

components than those described in Chapter 18. These guidelines recom-

mend going beond basic recording and reporting wheneer it is easible andreleant.

Optional indicators and analsis include:

MDR-TB treatmet coerage: the proportion o patients started on Cat-

egor Iv treatment among the total number patients detected with MDR-TB

during a defned period. This indicator can be calculated rom the Quarterl

report on MDR-TB detection and Categor Iv treatment start (Form 05). The

same analsis can also be done or XDR-TB.

Dela betee MDR-TB detectio ad Categor Iv treatmet start. This

indicator ma be analsed separatel or each treatment histor group and

or XDR-TB. This indicator can be calculated rom the Laborator Register

or culture and DST (Form 04) and the Categor Iv Register (Form 02).

DST coerage i atiet grous targeted or DST. This assessment re-

quires comparing the number o patients in the target groups or DST. For

example, a programme ma aim at haing all patients who start Categor II

hae DST and, b comparing the names o patients who started Categor II

with the names in the laborator register or DST, determine the coerage

o obtaining DST in this patient group.

Te umber o ailures o Categor I treatmet. Routine inormation rom

the quarterl reports rom most NTP sstems.

Te umber o ailures o Categor II treatmet. Routine inormation rom

the quarterl reports rom most NTP sstems. percetage o MDR-TB i dieret atiet grous. This inormation ma

be collected rom the District TB Registers (i DST data are included), rom

the Laborator Register or culture and DST (Form 04) or through sures.

For example, the percentage o MDR-TB in ailures o Categor I s ailures

o Categor II s deault s relapse.



156


• To aid clinical providers in management o individual patients.

The perormance indicators include:

• The number o patients in whom MDR-TB is detected in the laboratory (Form 05).

• The number o MDR-TB patients started on treatment (Form 05).

• Interim treatment outcome at 6-months o MDR-TB cases (Form 06).

• Final outcome o MDR-TB treatment (Form 07).

18.3 Scoe o te iormatio sstem

The inormation system or treatment o DR-TB is based upon, and is an ex-

tension o, the basic DOTS inormation system (1–5 ). The orms have there-

ore been designed to be as similar as possible to the standard orms used inDOTS programmes.

The core inormation system should be consistent across settings to permit

comparison. The orms may be modied as necessary to suit the local context.

For instance, additional variables that are considered valuable in specic situ-

ations can be included.

The core system does not include all o the detailed inormation that treat-

ment units may need to manage individual patients; that inormation should

be contained in clinical records and other special orms used in the wards or

clinics, and depends on local requirements and practices.

18.4 Mai orms/registers ad fo o iormatio

The orms and registers include the ollowing:

• Category IV Treatment Card (Form 01);

• Category IV Register (Form 02);

• Request or sputum examination (Form 03);

• Laboratory Register or culture and DST (Form 04).

Reports include:

• Quarterly report on MDR-TB detection and Category IV treatment start

(Form 05);

• Six-month interim outcome assessment o conrmed MDR-TB cases (Form

06);

• Annual report o treatment result o conrmed MDR-TB patients starting

Category IV treatment (Form 07).

Chapter 4 denes patient registration groups and treatment outcomes useulor the completion o these orms.



157

18.4.1 Categor Iv Treatment Card (Form 01)

When the relevant health authority (such as a review panel) decides that a

patient should start Category IV treatment, the health sta in the treatment

unit should enter the patient in the Category IV Register (see section 18.4.2).The sta should complete the Category IV Treatment Card when the patient

is actually starting treatment.

This card is a key instrument or DOT workers who administer drugs to

patients on a daily basis. The card should be updated daily by ticking o the

supervised administration o drugs. The card represents the primary source

o inormation to complete and periodically update the Category IV Register.

The card, or a copy o the card, must always ollow the patient (e.g. rom a spe-

cialized hospital to an ambulatory acility). A copy o the card may be used as a

notication orm and later also to report the nal outcome o treatment.

The Category IV Treatment Card contains the ollowing sections:

Page 1• Basic demographic and clinical inormation. Records name, address,

sex, age, weight and site o disease.

• Category IV registration number. This is a new unique identication

number assigned when the patient is entered in the Category IV Register.

• Date o Category IV registration. Provides registration date in the Cat-

egory IV Register.• Previous district TB registration number and date o registration.

• Registration group according to result o previous antituberculosis

treatment. See Chapter 4, section 4.5 or denitions.

• Previous TB treatment episodes. Lists and describes any previous antitu-

berculosis treatment and outcomes. Start with the earliest treatment and

label it number 1. Use the drug abbreviations given on the ront o the treat-

ment card. Also note here the outcome o any previous treatment.

• Previous use o second-line antituberculosis drugs. Documents use o

any o the second-line drugs listed at the ront o the chart or antitubercu-

losis treatment or more than one month.

• Meetings o review panel (medical commission, selection committee,

concilium). These guidelines promote periodic meetings with the group o

caregivers involved with Category IV patients. This section provides a space

to record major decisions by the panel.

Page 2 • HIV testing inormation. This section is lled in or all patients. I test-

ed or HIV, include date o testing and results. I HIV-inected, indicate whether patient is on ART and/or CPT.

• HIV fow sheet. This section is only lled in or HIV-inected patients.

• Monitoring o weight. Weight should be recorded at least monthly.




158


• Monitoring o laboratory data including creatinine, potassium, liver

unction tests, and thyroid tests. Recommendations regarding the interval

or monitoring these indicators can be ound in Chapter 11.

Page 3• Medical diagnoses other than TB. All other important medical diag-

noses are recorded here, including diabetes, hypertension, cardiomyopathy,

HIV, opportunistic inections, etc.

• Monitoring and recording adverse eects. Record date, adverse eects

and suspected drug(s).

Page 4 •

DST results. Record the date o sputum collection and results o all DSTperormed.

• Monitoring o chest X-ray.

• Monitoring o smear and culture. Record date o sputum collection,

sample number in the laboratory register and result o smear and culture.

“Prior” reers to the sample used to indicate Category IV registration; in-

clude the date and result o that sample. Month “0” is the time o specimen

collection at the start o the Category IV regimen. Requirements or moni-

toring o smear and culture are described in Chapter 11.Pages 5 and 6 • Regimen. Record the initial Category IV regimen and later changes. Use

one line or each date on which a drug(s) is changed. I drug dosage is pro-

gressively increased (e.g. starting 250 mg o ethionamide daily and increas-

ing by 250 mg over 2–3 days until the ull dose is reached), record this in

the patient’s medical record (not on the treatment card).

• Record o daily observed administration o drugs. This is constructed

with one line per month to acilitate assessment o adherence. Mark one boxor each day the entire treatment is administered. Additionally, i dosing is

twice daily, one slash mark could be made or the A.M. dose and a second,

intersecting mark could be made or the P.M. dose; i both are received, the

box would contain an “x”. An alternative is a more detailed system contain-

ing one box or each drug prescribed daily, since there may be some incon-

sistency in administration among drugs.

• Outcome o treatment. Chapter 4, Section 4.6 provides denitions.

Record the outcome o treatment when the nal bacteriology results be-come available.



159

18.4.2 Categor Iv Register (Form 02)

The NTP should have two TB registers: a District Tuberculosis Register and

a Category IV Register. The Category IV Register is the record o all patients

who start Category IV treatment (see Chapter 4, section 4.1 or a general de-nition o Category IV patients). This register allows quick assessment o the

implementation o Category IV, acilitating quarterly reporting and analysis o

treatment start and outcomes.

The District Tuberculosis Register is the traditional register used by DOTS

programmes in which all TB patients are rst registered. In order to integrate

the treatment o Categories I, II, III and IV, this register should be modied

in three ways:

1. I culture is being done in addition to smear examination in a substantialnumber o cases, dates o collection and results should be added to both the

initial testing and the ollow-up areas.

2. Capability to record DST should be added, including the date o collection

o the sample and the drugs that are being tested.

3. Any patient who is switched to a Category IV regimen because o resistance

(without meeting the ormal criteria o ailure) should have the outcome

category “Change to Category IV” entered in the District Tuberculosis

Register.

When a patient is starting Category IV treatment, the health sta in the treat-

ment unit should enter the patient in the Category IV Register and indicate

in the District Tuberculosis Register that the patient has entered Category IV.

The date o registration should be the day when the health sta enters the

patient in the Category IV Register. In some countries, it may be the date o

the review panel meeting. The Category IV Register should be updated regu-

larly rom the Category IV Treatment Card and rom the laboratory registers.

Patients should be recorded consecutively by their date o registration. Thereshould be a clear separation (extra line) when a new quarter is started.

These guidelines recommend that patients inected with strains with rela-

tively simple resistance patterns (H, HS, HE and HZ) stay in the District

Tuberculosis Register, where adjustment o their regimen should be recorded,

including any second-line agents used (see Chapter 8). Patients inected with

more complicated mono- and poly-resistance strains (involving R or HEZ re-

sistance) or any mono- and poly-resistant strains that may have developed into

MDR-TB should be entered into the Category IV Register.

Some patients started on Category IV regimens may be ound to have drug-susceptible disease. Patient in this situation can be removed rom Category IV

treatment and placed on appropriate rst-line therapy. The patient should be

crossed out o the Category IV Register (but the name still let legible) and a

comment noted in the last column that s/he has drug-susceptible disease. All




160


patients who are switched should be registered in the District Tuberculosis Register (i they are already registered in the district register, the fnal outcome should be documented in the original line o registration (do not create a new registration).

These patients do not need to appear in Forms 05, 06 and 07 o the DR-TB report-ing orms as they do not have MDR-TB .

Any patient with mono- or poly resistance whom it has been determined

should stay in the DR-TB programme should not be crossed out o the Cat-

egory IV Register. Whether the patient continues on the same Category IV

regimen (oten done in programmes using standardized regimens) or gets an

individualized regimen based on DST can be documented on the treatment

card and the nal outcome reported in the Category IV Register. These pa-tients do not need to appear in Forms 05, 06 and 07 o the DR-TB reporting orms as they do not have MDR-TB .

The ollowing inormation is recorded in the Category IV Register (or ex-

planation see also section 18.4.1):

• Category IV registration number.

• Date o Category IV registration.

• Name, sex, date o birth, address (rom treatment card, p. 1).

• District TB registration number. All patients should have been entered

in a District Tuberculosis Register. A patient who or any reason has never

been registered in the District Tuberculosis Register should be registered

there and the number transerred to the Category IV Register.

• Site o disease (rom treatment card, p. 1). Pulmonary, extrapulmonary

or both. Patients with both pulmonary and extrapulmonary TB should be

classied as a case o pulmonary TB.

• Registration group (rom treatment card, p. 1). Described in Chapter 4,

section 4.5.• Second-line drugs received or more than one month prior to registra-

tion (rom treatment card, p. 1).

• DST (rom treatment card, p. 4). Date sample taken, date o DST result

and the results. Enter the DST that resulted in the patient being registered

as a Category IV patient. Follow-up DSTs are not recorded in the register.

I the patient has more than one DST, results are recorded on the treatment

card. I DST is perormed in a staged ashion (e.g. o riampicin and isoni-

azid rst, ollowed by other rst-line drugs, and then o second-line drugs)all results rom the same sample should be recorded in the register.

• Category IV regimen (rom treatment card, p. 5). Record the initial

Category IV regimen using the drug abbreviations. Include milligram

doses and number o tablets.



161

• Date o start o Category IV treatment (rom treatment card, p.5).

• Smear and culture monitoring results (rom treatment card, p.4).

Record all smear and culture results, even i done more oten than the rec-

ommended requency.

• Final outcome (rom treatment card, p.6). See Chapter 4, section 4.6 or

denitions.

• HIV status (rom treatment card, p.2). Testing results, CPT and ART

treatment inormation.

• Comments.

18.4.3 Request or sputum examination (Form 03)Form 03 is the same as that recommended or DOTS programmes in the

Revised TB recording and reporting orms and registers – version 2006 (5 ); the

upper portion is or requesting smear microscopy, the middle portion or cul-

ture and the lower portion or DST; the last section is used or reporting

the results. When DST is requested, the registration group should be added.

Results should be sent stepwise as they become available.

18.4.4 Laborator Register or culture and DST (Form 04)

Laboratories will have separate registers or sputum smear microscopy andculture (5 ), while reerence laboratories carrying out DST should have ad-

ditional space in the culture register or DST results (see Form 04). The

Laboratory Register or culture and DST should contain samples rom all

MDR-TB suspects, indicating the registration group (including i positive

smear at 3 or 4 months), and be lled in rom the request orm.

The Laboratory Register should be compared regularly with the Category

IV Register to ensure that all conrmed MDR-TB cases are entered in the

Category IV Register.

18.4.5 Quarterl report on MDR-TB detection and Categor Iv

treatment start (Form 05)

This report is used to assess the number o MDR-TB cases detected (distri-

bution and trends) and the number o MDR-TB cases who start treatment.

The report should be made quarterly in line with the routines o the NTP.

The report should be made by the unit managing MDR-TB. The quarterly

report includes:

•

The number o patients, with date o result showing MDR-TB during therelevant quarter taken rom the Laboratory Register (Form 04). Optionally,

the patients could be split by registration group (see Box 18.1).

• The number o MDR-TB patients started on Category IV treatment during

the quarter, taken rom the Category IV Register (Form 02).




162


I relevant, the number o XDR-TB cases registered (ater cross-checking DST

results with type o resistance) and the number o XDR-TB cases started on

XDR-TB treatment should be added.

Since there may be a considerable delay between Category IV registrationand the start o Category IV treatment, patients who start treatment during

the quarter may not be the same as those detected with DR-TB. The inor-

mation provides an approximation o treatment coverage. These guidelines

encourage programmes to calculate the average delay between detection o

DR-TB and treatment start (see Box 18.1).

18.4.6 Six-month interim outcome assessment o confrmed

MDR-TB cases (Form 06)

Since treatment takes on average two years beore nal results are known, theTB control programme needs more updated inormation on treatment out-

come. Form 06 can be used to report bacteriological status (negative, positive

or no inormation) o those still on treatment at 6 months, and or those who

have already deaulted, died or transerred out, this can be recorded as the

nal outcome. Bacteriological results are based on the smear and culture data

during months 5 and 6 o treatment. Consider the 6-month outcome assess-

ment unknown or a particular patient i a culture or smear result is unknown

or either month 5 or 6.

All cases rom the Category IV Register should be included in this report.

The orm should be completed 9 months ater the closing day o the cohort.

This allows culture inormation at month 6 o treatment to be included or all

patients in the cohort. For instance, TB patients who started treatment during

the rst quarter o a year (1 January to 31 March), should have the orm lled

in rom 1 January o the ollowing year.

18.4.7 Annual report o treatment result o confrmed MDR-TB

patients starting Categor Iv treatment (Form 07)This report is made by the central unit and shows the nal result o treat-

ment by year o treatment start. All the patients are classied by previous use

o antituberculosis drugs (none, only rst-line drugs, also second-line drugs).

I relevant, results or patients with XDR-TB could be added. All data can

be extracted rom treatment cards and Category IV Register. Form 07 is rst

completed at 24 months ater the last patient in the cohort started treatment.

Most o the patients will have nished treatment by 24 months, allowing pre-

liminary assessment o cure rates. Since a ew patients may be on treatment

or longer than 24 months, the orm may be completed again at 36 months, which will then be considered the nal result.



163

18.5 Addressig te backlog o atiets o ailed

Categor II treatmet i te ast

When Category IV treatment is being introduced, there may be a large group

o patients who are still sputum smear-positive ater supervised Category IItreatment rom previous years. There may also be patients who have received

several unsuccessul treatments, are considered incurable by health sta and

who have lived with active TB disease with no or inadequate treatment or a

period o time. While preparing or Category IV treatment, TB control pro-

grammes should keep a list o these patients. When Category IV treatment

becomes available, such cases with evidence o active disease should ollow the

national protocol or Category IV treatment start, ideally having a DST done

at the start to conrm MDR-TB.

The number o patients waiting or Category IV treatment should be

estimated in all programmes, as this will acilitate planning o drug and other

resource needs. As the Category IV treatment programme progresses, the list

o chronic cases will become smaller and eventually include only patients who

have ailed Category IV treatment.

18.6 Assurig te qualit o te recordig ad reortig

sstem

In order or the inormation system or DR-TB to unction well, adequatetraining and supervision are needed. The sta require basic knowledge o the

DOTS inormation system, with additional training on the specics o the

Category IV orms.

Regular supervisory visits by a central unit to the units using the inorma-

tion system are undamental to maintain good quality o the inormation.

Regular meetings with sta rom dierent levels may also be very helpul in

updating inormation.

The person responsible or Category IV management should regularly (at

least weekly) compare the Category IV Register with the DST register in allthe laboratories perorming DST to ensure that all patients in whom MDR-TB

is diagnosed are started on Category IV treatment. The inclusion o MDR-TB

patients rom the Laboratory Register should take into consideration the qual-

ity o the DST perormed in the laboratory. Patients diagnosed with MDR-TB

in laboratories without proper quality assurance (i.e. in many private labora-

tories, the quality o DST is completely unknown) should not be included in

the Laboratory Register or Culture and DST (Form 04) until their DST has

been conrmed in a qualied laboratory.

18.7 Comuterized sstems

The recording and reporting system can be managed by hand. However, an

electronic system is highly desirable since it acilitates better quality o in-

ormation as well as data analysis; it will also obviate the need or transcrip-




164


tion and repeated entry into dierent orms. Patient data may be entered in

a ormat similar to the Category IV Treatment Card, and lists similar to the

Category IV Register can then be generated. Print-outs o the list may be

compared with the handwritten Category IV Register to ensure completenesso the system. The corrected database may then be used to generate quarterly

and annual reports.

Even i a computerized system is in place, a handwritten Category IV Reg-

ister should be maintained, since otherwise corrections cannot be seen.

18.8 Iteratioal healt Regulatios (IhR)

The IHR (2005) entered into orce on 15 June 2007 and are legally binding

upon all WHO Member States. Their purpose and scope are “to prevent, pro-

tect against, control and provide a public health response to the internationalspread o disease in ways that are commensurate with and restricted to pub-

lic health risks, and which avoid unnecessary intererence with international

trac and trade.” The scope o diseases covered is extremely broad but can

include DR-TB. For more inormation on the IHR (2005) see the WHO web

site: http://www.who.int/ihr.

Reereces

1. Treatment o tuberculosis: guidelines or national programmes , 3rd ed. Gene-

va, World Health Organization, 2003 (WHO/CDS/TB/2003.313) (with

revision 2005).

2. Management o tuberculosis: training or district TB coordinators . Geneva,

World Health Organization, 2005 (WHO/HTM/TB/2005.347a–n).

3. Management o tuberculosis: training or district TB coordinators. How to organize training or district TB coordinators . Geneva, World Health

Organization, 2005 (WHO/HTM/TB/2005.353).

4. Enarson DA et al. Management o tuberculosis: a guide or low-income coun-

tries , 5th ed. Paris, International Union Against Tuberculosis and LungDisease, 2000.

5. Revised TB recording and reporting orms and registers – version 2006 ,Geneva, World Health Organization, 2006 (WHO/HTM/TB/2006.

373).



165

CHAPTER 19

Maagig DR-TB trougatiet-cetred care



19.3 Understanding patient-centred care 166

19.4 Dignit, rom Da One 166

19.5 Sta as staeholders, patients supporting peers 167

19.6 Communicating “cure” 168

19.7 Forced isolation and respect or human rights 168

19.8 Ciil societ 169

19.9 Conclusion 169


Any patient in whom DR-TB is suspected or diagnosed should be provided

with high-quality patient-centred care, as outlined in the International stand-ards or tuberculosis care (1) and the Patients’ charter or tuberculosis care ( 2 ).This new approach identies certain rights and responsibilities o both pro-

viders and patients, and acilitates a mutual collaboration to achieve cure with

dignity. This chapter provides guidance on how this “partnership” can be

orged, in common cause.


The programmatic management o MDR-TB is extremely challenging even in

the best o circumstances, demanding substantial eorts rom a team o health

proessionals and the patient to reach a successul outcome. The long dura-

tion o complicated treatment and oten dicult adverse eects require a joint

commitment to complete the process, and this is best practiced in an environ-

ment o mutual respect and consideration. Certain basic steps should be taken

to ensure this, and some o these are made by changing attitudes, perceptions

and behaviours while others may require rening existing management prac-

tices and service delivery systems.



166


19.3 Uderstadig atiet-cetred care

All health workers involved with the management o DR-TB should be made

amiliar with the International Standards and the Patients’ Charter. Copies o

these documents should be made available in local languages, and sta shouldreview their content as part o continuing education. Training materials are

available upon request rom WHO, the Tuberculosis Coalition or Technical

Assistance and the World Care Council, and technical assistance can also be

provided. An understanding o patient-centred care provides the basis to build

better patient–provider relations, and can contribute to improved adherence

to treatment, reduced stigmatization and better treatment outcomes. It also

sends a message to the wider eective community that DR-TB can be success-

ully treated within a dignied ramework o mutual respect, thus acilitating

case-nding and community participation.

19.4 Digit, rom Da Oe

People suspected o having DR-TB should begin what may be a long march

towards a cure in a manner to encourage their willul participation. From the

rst consultation or examination, the patient should be accorded the under-

standing o innocence, that it is not the ault o the person that bacteria are

resistant to certain drugs. Oering solidarity and compassion initially, instead

o reproach, will begin the process in a “healthy” way, which the patient willremember during the many months o treatment that ollow.

To grow this initial expression o respect into a sustained programmatic

management tool, at the rst consultation patients should be provided with a

copy o the short version o the Patients’ Charter in their local language. This

charter outlines the rights and responsibilities or patients, and its distribution

will assist the provider with educating the patient about the disease and treat-

ment as a basis or reaching better nal outcomes. It is a key element o the

Stop TB Strategy under component ve (empowering people with TB, and

communities).The socioeconomic impact o both the physical aspects o TB and o its

long-treatment can be extremely dicult or patients and their amilies. At the

onset o treatment, an assessment o the means and nancial resources o the

patient should be conducted with a view to supporting those in need o assis-

tance. Although ood packages and transport vouchers may be useul in miti-

gating some o the diculties, providing a minimum revenue or all patients

may be a worthy investment to ensure adherence and willul participation.

In settings where many months o isolation are mandated by the state or

programme, nancially supporting the patient and their amily with a mini-mum “living-allowance” would not only be a proactive step under the patient-

centred care approach and an eective incentive but also a clear sign o respect

or human dignity.



167

19. MANAGING DR-TB THROUGH PATIENT-CENTRED CARE

19.5 Sta as stakeolders, atiets suortig eers

Programmes or DR-TB control should identiy a member o sta who will

serve as the ocal point or developing patient-centred care, and to identiy a

number o patients who could be initiated in ways to encourage their peersto embrace this new approach. This lays the groundwork or the develop-

ment o a social network within the clinical acility, which can play an essen-

tial role in galvanizing adherence and decreasing deault. Working together, a

health worker and a patient can acilitate a wider participation, oster a spirit

o collaboration and take an innovative step to reduce stigma. This dynamic

relationship acilitates gaining urther support rom the community and au-

thorities to raise the standards o care.

The human resource component, specically that o health-care workers,

is an important aspect o the patient-centred approach and an essential actor

in achieving a avorable response to treatment. CHWs should be trained ap-

propriately in communicating and interacting “positively” with both patients

and amilies. The attitudes and interpersonal skills o health workers are tools

or better outcomes, as patients deault rom treatment i dissatised with the

way they are treated as human beings, and this echoes throughout the wider

aected community. Furthermore, among patients in many countries, it is

commonly understood that stigma, like water, fows downward, not upwards

rom the bottom. Health-care workers can thus play a leading role in dimin-ishing stigma by seeing the patient–provider relationship with an appreciation

o the challenges each other aces, and viewing the process to cure DR-TB as

a joint endeavour.

Providing on-site social support or patients and their amilies through peer

counselling has shown itsel to be highly eective in controlling TB in a num-

ber o communities and is a key element o scaling-up the response to HIV.

MDR-TB control programmes should develop a comprehensive component

that identies a cured patient (“community champion”), and provides train-

ing and employment to unction as a peer supporter. This worker engagesin support, treatment literacy and communicating with peers under treat-

ment. These “champion counsellors” would ollow each patient rom diagno-

sis through to cure, and act as both “riend” and educator. From the patient’s

perspective, having this companion available greatly reduces the psychologi-

cal burden o the long duration o treatment. As it proessionalizes the role o

local “MDR-TB champions”, it also serves to counter the systematic stigma

that many patients perceive accompanies TB. Training modules and materials

or the development and implementation o peer counsellor services are be-

coming available through the World Care Council and the Stop TB Partner-ship’s Working Group on MDR-TB.



168


19.6 Commuicatig “cure”

Although implementing patient-centred high-quality care, as outlined in the

International Standards, will oten require resources to scale up programmatic

inrastructure and services, part o the process requires simple adjustments inthe attitudes and language o health-care providers. Programmes that seek to

manage DR-TB should appreciate the undamental human resistance to be-

ing controlled. Although the term “TB control” is still used by many health

proessionals, people with the disease are much more responsive, and more re-

sponsible i the term “TB care” is emphasized. This seemingly small change in

language speaks volumes to the people who must struggle to “win” the chal-

lenge o a long and dicult treatment. The word “prevention” is also seen to

be more user-riendly or amilies and communities, which strengthens their

participation in supporting patients and the programme.

Programmes should adopt methods o “communicating with” and not

“talking at” patients and their amilies, in a manner that builds a positive part-

nership towards successul treatment completion. For patients with literacy

limitations, eorts should be undertaken to provide audio or visual supports,

such as inormation by recorded cassette or graphic illustrations. Sta acting

as ocal points or patient-centred care and peer supporters can also play an

important role as “communicators”.

During all phases o care, patients should be provided with appropriate andunderstandable inormation about the disease and its treatment. An inormed

patient can better assist health workers in caring or patients. Peer support

groups, champions and trained health workers can oer inormation-sharing

sessions to educate patients, and or better detecting risk actors or deault

(e.g. understanding adverse eects) and other warning signs that can aect

treatment outcome. These discussion sessions should be two-way communica-

tions, mutually deciding on interventions or problems, or example, on how

to handle drug side-eects.

19.7 Forced isolatio ad resect or uma rigts

Management o DR-TB, which can be a threat to public health, must be bal-

anced with a consideration o the human rights and dignity o the patient.

Guided by the Siracusa Principles ( 3), WHO states that orcibly isolating peo-

ple with DR-TB must be used only as the last possible resort when all other

means have ailed, and only as a temporary measure.

Health authorities and providers choosing the extreme measure o involun-

tary treatment should do so only i they can ensure it is done in a transparent

and accountable manner. I it can be proved, through evidence-based analysis,that orced isolation is temporarily required, patients must be provided with

the high-quality care that includes, among other rights, ree access to second-

line drugs, laboratory support including eective DST and social support, and

be treated with respect and dignity. Patients should be inormed clearly, in



169

their language, o the decision and its details, and o their rights and responsi-

bilities, as outlined in the Patients’ Charter, accompanied by a peer supporter

and/or amily member.

The ear o orced isolation without consideration o patients’ dignity createsa negative perception o TB control within an aected community, discourag-

ing people rom being tested or TB testing and raising the stigma attached to

the disease. I the conditions o isolation are equated with punishment, eorts

to stop transmission o the disease will be made more dicult.

Certain restrictions on liberties may be determined to be necessary on a

case-by-case basis, but these should not be prescribed unless clinically evi-

denced, and with the inormation communicated in a clear and understand-

able manner to the patient, accompanied by a peer supporter and/or a amily

member. Independent monitoring should be welcomed by the programme to

reassure amilies and the community that the human rights o the person are

being respected. In the extreme case o XDR-TB, where cure is no longer a

possibility, extra steps should be taken by programmes to ensure that pallia-

tive care is extremely patient-centred and extra measures o social support are

provided to patients and their amilies. Although inection control remains

essential and isolation may be needed, acilitating additional compassionate

human contact permits the patient and his or her amily the dignity to better

deal with the reality. For more inormation on human and patients’ rights, see Annex 4.

19.8 Ciil societ

The involvement o civil society, such as patient support groups, nongovern-

mental organizations, community or aith-based organizations, in various as-

pects o the programmatic management o DR-TB is strongly recommended.

These organizations can assist the programme through diverse but important

actions, including providing social support services, case-nding, prevention

campaigns and advocating or greater resources or local services. DR-TB isa problem or the aected community, and welcoming the participation and

building working relations with civil society organizations not only brings

new resources to conront the problem but also can serve as a dynamic link

between patient and care provider (also see Chapter 12).

19.9 Coclusio

Successul management o DR-TB requires putting the patient at the centre o

a comprehensive programme o care that includes allows patients to exercise

their rights. This, in turn, enables patients to ulll their responsibilities andassist in the treatment success. The process o adopting the patient-centred

care approach is essential both or good programmatic management practices

and or scaling up the response to the growing threat o DR-TB.

19. MANAGING DR-TB THROUGH PATIENT-CENTRED CARE



170


Reereces

1. International standards or tuberculosis care . The Hague, Tuberculosis Co-

alition or Technical Assistance, 2006 (available at http://www.who.int/

tb/publications/2006/istc_report.pd; accessed May 2008).2. The Patients’ charter or tuberculosis care . Geneva, World Care Council,

2006 (available at http://www.who.int/tb/publications/2006/istc_charter.

pd; accessed May 2008).

3. Siracusa principles on the limitation and derogation provisions in the Inter-national Covenant on civil and political rights . New York, United Nations

Economic and Social Council, 1985; available at http://www1.umn.edu/

humanrts/instree/siracusaprinciples.html; accessed May 2008).



171

Aees





ANNEX 1

Drug iormatio seets

Adapted rom Drug-resistant tuberculosis: a survival guide or clinicians . San

Francisco, Francis J. Curry National Tuberculosis Center and Caliornia

Department o Health Services, 2004.Common presentations o the drugs are described; actual preparations may

vary depending on manuacturer.

AMIKACIn (Am)

DruG clAss: AminoGlycosiDe

Actiit agaist TB, Bactericidal: aminoglcosides inhibit protein snthesis through

mecaism o actio, disruption o ribosomal unction; less eectie in acidic, intra-

ad metabolism cellular enironments; polpeptides appear to inhibit translocationo the peptidl-tRNA and the initiation o protein snthesis;

aminoglcosides are not metabolized in the lier, the are excret-ed unchanged in the urine.

prearatio ad dose Amiacin sulate, colourless solution; 250 mg/ml (2 or 4 ml ials)and 50 mg/ml (2 ml ial). The optimal dose is 15–20 mg/g

bod weight, usuall 750 mg to 1 g gien dail or 5–6 das perwee, b deep intramuscular injection. Rotation o injection sites

aoids local discomort. When necessar, it is possible to giethe drug at the same total dose 2 or 3 times weel during the

continuation phase, under close monitoring or aderse eects.

Storage Solution is stable at room temperature (15–25 °C); diluted solu-tion is stable at room temperature or at least 3 das or in the

rerigerator or at least 60 das.

Oral absortio There is no signifcant oral absorption. Intramuscular absorptionma be delaed i the same site is used consistentl.

CSF eetratio Penetrates inamed meninges onl.

Secial circumstaces pregac/breasteedig: saet class D. No reports lining

the use o amiacin to congenital deects hae been located.Ototoxicit has not been reported as an eect o in utero expo-

sure to amiacin; howeer, eighth cranial nere toxicit in theetus is well nown ollowing exposure to other aminoglcosides

(anamcin and streptomcin) and could potentiall occur withamiacin. Onl a trace amount o amiacin was ound in some

nursing inants. Gien the poor absorption o aminoglcosides,sstemic toxicit should not occur, but alteration in normal bowel

ora ma occur in nursing inants.

Real disease: use with caution. Leels should be monitored orpatients with impaired renal unction. Interal adjustment (12–

15 mg/g 2 or 3 times per wee) is recommended or creatinineclearance <30 ml/min or haemodialsis.

173







176


CApREOMyCIn (CM)

DruG clAss: cyclic polypeptiDe

Moitorig Monthl creatinine and serum potassium in low-ris patients

(oung with no co-morbidities), more requentl in high-rispatients (elderl, diabetic, or HIv-positie patients, or patientswith renal insufcienc). I potassium is low, chec magnesium

and calcium. Electrolte disturbances are more common withcapreomcin than other injectable agents. Baseline audiometr

and monthl monitoring in high-ris patients. For problems withbalance, consider increasing dosing interal.

Alertig smtoms — Rash

— Decreased urination— Feer or chills

— Trouble breathing— Bleeding or bruising

— Muscle weaness— Problems with hearing, dizziness or balance

— Bleeding or lump at IM injection site



177

CIpROFLOxACIn (C)

DRUG CLASS: fluoroquinolone

Actiit agaist TB, Bactericidal: acts b inhibiting the A subunit o DNA grase

mecaism o actio, (topoisomerase), which is essential in the reproduction o ad metabolism bacterial DNA. There is no cross-resistance with other antituber-

culosis agents, but near complete cross-resistance between

ooxacin and ciprooxacin and high in itro cross-resistancewith moxioxacin and gatioxacin. Ciprooxacin is eliminated

principall b urinar excretion, but non-renal clearance maaccount or about one-third o elimination and includes hepatic

metabolism, biliar excretion, and possibl transluminal secre-tion across the intestinal mucosa.

prearatio ad dose Tablets (250, 500, 1000 mg). vials (20 and 40 ml) or exible

containers (200 and 400 ml) with aqueous or 5% dextrose Ivsolutions equialent to 200 and 400 mg. Usual dose: 1000–

1500 mg/da.

Storage Room temperature (15–25 °C), airtight containers protectedrom light.

Oral absortio Well absorbed (70–85%) rom the gastrointestinal tract and ma

be taen with meals or on an empt stomach. Should not be ad-ministered within 2 hours o ingestion o mil-based products,

antacids, or other medications containing dialent cations (iron,magnesium, zinc, itamins, didanosine, sucralate).

Distributio, Widel distributed to most bod uids and tissues; high concen-

CSF eetratio trations are attained in idnes, gall bladder, gnaecological

tract, lier, lung, prostatic tissue, phagoctic cells, urine,sputum, and bile, sin, at, muscle, bone and cartilage. CSF

penetration is 5–10% and with inamed meninges 50–90%.

Secial circumstaces pregac/breasteedig: saet class C. Ciprooxacin leelsin amniotic uid and breast mil almost as high as in serum.

Fluoroquinolones are not recommended during breasteedingbecause o the potential or arthropath. Animal data demon-

strated arthropath in immature animals, with erosions in jointcartilage.

Real disease: doses o ciprooxacin should be reduced in pa-tients with seere renal impairment. When the creatinine clear-

ance is less than 30 ml/min, the recommended dosing is1000–1500 mg 3 times per wee.

Aderse eects Generall well tolerated.

Occasioal: gastrointestinal intolerance; CNS-headache, ma-laise, insomnia, restlessness, and dizziness.

Rare: allergic reactions; diarrhoea; photosensitiit; increasedlier unction tests (LFTs); tendon rupture; peripheral neuropath.

Drug iteractios Sucralate: decreased absorption o uoroquinolones caused b

the chelation b aluminium ions contained in the sucralate. Atacids (magnesium, aluminium, calcium, Al-Mg buer ound in

didanosine): binding to uoroquinolone antibiotics resulting in de-

creased absorption and loss o therapeutic efcac. probeecid: intereres with renal tubular secretion o cipro-

oxacin; this ma result in 50% increase in serum leel o cipro-oxacin.

Milk or dair roducts: decrease the gastrointestinal absorptiono ciprooxacin b 36–47%.

vitamis ad mierals containing dialent and trialent cationssuch as zinc and iron: ormation o uoroquinolone-ion complex

results in decreased absorption o uoroquinolones.

ANNEX 1. DRUG INFORMATION SHEETS



178


CIpROFLOxACIn (C)

DRUG CLASS: fluoroquinolone

Drug iteractios Meiletie: uoroquinolones ma inhibit ctochrome P450 1A2

resulting in increased mexiletine concentration. warari: case reports o ciprooxacin enhancing anticoagula-

tion eect o wararin.

Cotraidicatios Pregnanc, intolerance o uoroquinolones.

Moitorig No specifc laborator monitoring requirements.

Alertig smtoms — Pain, swelling or tearing o a tendon or muscle or joint pain

— Rashes, hies, bruising or blistering, trouble breathing— Diarrhoea

— yellow sin or ees— Anxiet, conusion or dizziness



179

CLOFAZIMInE (Cz)

DruG clAss: phenAzine DerivAtive

Actiit agaist TB, Bacteriostatic against M. leprae, actie in itro against M. tuber-

mecaism o actio, culosis. Clinical eectieness against M. tuberculosis not wellad metabolism established.

Cloazimine appears to bind preerentiall to mcobacterial DNA

(principall at base sequences containing guanine) and inhibitmcobacterial replication and growth.

Excreted in aeces as unabsorbed drug and ia biliar elimina-tion. Little urinar excretion.

prearatio ad dose Capsules (50 and 100 mg).

Storage Store below 30 °C, in airtight containers.

Oral absortio 20–70% absorbed rom rom gastrointestinal tract.

Distributio, Widel distributed principall to att tissue, reticuloendothelialCSF eetratio sstem and macrophages. High concentrations ound in

mesenteric lmph nodes, adipose tissue, adrenals, lier, lungs,in gall bladder, bile and spleen.

Secial circumstaces pregac/breasteedig: saet class C. Animal studies dem-

onstrated teratogenicit (retardation o etal sull ossifcation).Crosses placenta and is excreted in mil. Not recommended

during breasteeding.

Real disease: usual dose.

heatic disease: dose adjustments should be considered in pa-tients with seere hepatic insufcienc.

Aderse eects Frequet: ichthosis, and dr sin; pin to brownish-blac dis-coloration o sin, cornea, retina and urine; anorexia and abdomi-nal pain.

Drug iteractios Ma decrease absorption rate o riampicin.

Isoniazid increases cloazimine serum and urine concentrationsand decreases sin concentrations.

Ingestion o cloazimine with orange juice resulted in a modestreduction in cloazimine bioaailabilit.

Cotraidicatios Pregnanc, seere hepatic insufcienc, hpersensitiit to Cz.


Alertig smtoms — Nausea and omiting— Abdominal pain/distress (caused b crstal depositions and

can present as an acute abdomen)




180


CyCLOSERInE (Cs) [AnD TERIZIDOnE (Trd)]

DruG clAss: AnAloG of D-AlAnine

Actiit agaist TB, Bacteriostatic: competitiel blocs the enzme that incor-

mecaism o actio, porates alanine into an alanl-alanine dipeptide, an essentialad metabolism component o the mcobacterial cell wall. No cross-resistance

with other antituberculosis drugs. 60–70% excreted unchanged

in the urine ia glomerular fltration; small amount excreted inaeces; small amount metabolized.

prearatio ad dose Capsules (250 mg). 10–15 mg/g dail (max. 1000 mg), usuall

500–750 mg per da gien in two diided doses. (Some produc-ers o terizidone mae 300 mg capsule preparations, while

others mae 250 mg.)

Storage Room temperature (15–25 °C) in airtight containers.

Oral absortio Modestl decreased b ood (best to tae on an empt stom-

ach); 70–90% absorbed.

Distributio, Widel distributed into bod tissue and uids such as lung, bile,

CSF eetratio ascitic uid, pleural uid, snoial uid, lmph, sputum.

ver good CSF penetration (80–100% o serum concentration

attained in the CSF, higher leel with inamed meninges)

Secial circumstaces pregac/breasteedig: saet class C. Breasteeding withB

6supplement to the inant.

Real disease: doses o ccloserine should be reduced in patientswith seere renal impairment. When the creatinine clearance is lessthan 30 ml/minute, the recommended dosing is 250 mg/da, or

500 mg/dose 3 times per wee. The appropriateness o 250 mg/da doses has not been established. There should be careul

monitoring or eidence o neurotoxicit; i possible, measure se-rum concentrations and adjust regimen accordingl.

Aderse eects Frequet: neurological and pschiatric disturbances, including

headaches, irritabilit, sleep disturbances, aggression, and trem-ors, gum inammation, pale sin, depression, conusion, dizziness,

restlessness, anxiet, nightmares, seere headache, drowsiness. Occasioal: visual changes; sin rash; numbness, tingling or

burning in hands and eet; jaundice; ee pain.

Rare: seizures, suicidal thoughts.

Drug iteractios Etioamide: additie nerous sstem side-eects.

Isoiazid: additie nerous sstem side-eects. petoi: ma increase phentoin leels.

Toxic eect i combined with alcohol, increases ris o seizures.vitamin B

6decreases CNS eect.

Cotraidicatios Hpersensitiit to ccloserine.

Epileps.Depression, seere anxiet or pschosis.

Seere renal insufcienc.Excessie concurrent use o alcohol.

Moitorig When aailable, serum drug monitoring to establish optimal dos-ing (not higher than 30 µg/ml).

Alertig smtoms — Seizures— Shainess or trouble taling— Depression or thoughts o intentional sel-harm— Anxiet, conusion or loss o memor— Personalit changes, such as aggressie behaiour— Rash or hies— Headache



181

EThIOnAMIDE (Eto)

pROTIOnAMIDE (pto)

DruG clAss: cArbothionAmiDes Group, DerivAtives of isonicotinic AciD

Actiit agaist TB, Bacteriostatic: the mechanism o action o thionamides has notmecaism o actio, been ull elucidated, but the appear to inhibit mcolic acid sn-

ad metabolism thesis. Resistance deelops rapidl i used alone and there is

complete cross-resistance between ethionamide and protiona-mide (partial cross-resistance with thioacetazone). Ethionamide

is extensiel metabolized, probabl in the lier, to the actiesuloxide and other inactie metabolites and less than 1% o a

dose appears in the urine as unchanged drug.

prearatio ad dose Ethionamide and protionamide are normall administered in theorm o tablets containing 125 mg or 250 mg o actie drug. The

maximum optimum dail dose is 15–20 mg/g/da (max. 1 g/da), usuall 500–750 mg.

Storage Room temperature (15–25 °C), in airtight containers.

Oral absortio 100% absorbed but sometimes erratic absorption caused bgastrointestinal disturbances associated with the medication.

Distributio, Rapidl and widel distributed into bod tissues and uids, with

CSF eetratio concentrations in plasma and arious organs being approxi-matel equal. Signifcant concentrations also are present in CSF.

Secial circumstaces pregac/breasteedig: saet class C. Animal studies hae

shown ethionamide to be teratogenic. Newborns who are breast-ed b mothers who are taing ethionamide should be monitored

or aderse eects.

Real disease: doses o the thionamides are onl slightl modi-fed or patients with seere renal impairment. When the creati-nine clearance is less than 30 ml/minute, the recommended

dosing is 250–500 mg dail. heatic disease: thionamides should not be used in seere

hepatic impairment. porria: ethionamide is considered to be unsae in patients

with porphria because it has been shown to be porphrinogenicin animals and in itro sstems.

Aderse eects Frequet: seere gastrointestinal intolerance (nausea, omiting,

diarrhoea, abdominal pain, excessie saliation, metallic taste,stomatitis, anorexia and weight loss). Aderse gastrointestinal

eects appear to be dose-related, with approximatel 50% o pa-tients unable to tolerate 1 g as a single dose. Gastrointestinal

eects ma be minimized b decreasing dosage, b changing thetime o drug administration, or b the concurrent administration

o an antiemetic agent. Occasioal: allergic reactions; pschotic disturbances (including

depression), drowsiness, dizziness, restlessness, headache, andpostural hpotension. Neurotoxicit (administration o pridoxinehas been recommended to preent or reliee neurotoxic eects);

transient increases in serum bilirubin; reersible hepatitis (2%)with jaundice (1–3%); gnaecomastia; menstrual irregularit,

arthralgias, leuopenia, hpothroidism especiall when com-

bined with PAS.Rare: reports o peripheral neuritis, optic neuritis, diplopia,blurred ision, and a pellagra-lie sndrome, reactions including

rash, photosensitiit, thromboctopenia and purpura.




182


EThIOnAMIDE (Eto)

pROTIOnAMIDE (pto)

DruG clAss: cArbothionAmiDes Group, DerivAtives of isonicotinic AciD

Drug iteractios Ccloserie: potential increase incidence o neurotoxicit. Etioamide has been ound to temporaril raise serum concen-

trations o isoniazid. Thionamides ma potentiate the aderse

eects o other antituberculosis drugs administered concomi-tantl. In particular, conulsions hae been reported when

ethionamide is administered with ccloserine. Excessie ethanolingestion should be aoided because o possible pschotic reac-

tion. pAS: possible increase in lier toxicit, monitor lier enzmes;

hpothroidism in case o combined administration.

Cotraidicatios Thionamides are contraindicated in patients with seere hepaticimpairment and in patients who are hpersensitie to these

drugs.

Moitorig Ophthalmological examinations should be perormed beore andperiodicall during therap. Periodic monitoring o blood glucose

and throid unction is desirable. Diabetic patients should beparticularl alert or episodes o hpoglcaemia. Lier unction

tests should be carried out beore and during treatment withethionamide.

Alertig smtoms — An problems with ees: ee pain, blurred ision, color blind-ness, or trouble seeing

— Numbness, tingling, or pain in hands and eet— Unusual bruising or bleeding

— Personalit changes such as depression, conusion oraggression

— yellowing o sin— Dar-coloured urine

— Nausea and omiting— Dizziness





184


GATIFLOxACIn (G)

DruG clAss: fluoroquinolone

Drug iteractios Meiletie: uoroquinolones ma inhibit ctochrome P450 1A2,

resulting in increased mexiletine concentration. warari: case reports o gatioxacin enhancing anticoagulation

eect o wararin.

Cotraidicatios Pregnanc, intolerance o uoroquinolones.

Moitorig No laborator monitoring requirements.

Alertig smtoms — Pain, swelling or tearing o a tendon or muscle or joint pain

— Rashes, hies, bruising or blistering, trouble breathing— Diarrhoea

— yellow sin or ees— Anxiet, conusion or dizziness



185

KAnAMyCIn (Km)


Actiit agaist TB, Bactericidal: aminoglcosides inhibit protein snthesis b

mecaism o actio, irreersibl binding to 30S ribosomal subunit; aminoglcosidesad metabolism are not metabolized in the lier, the are excreted unchanged in

the urine.

Distributio 0.2–0.4 l/g; distributed in extracellular uid, abscesses, ascit-

ic uid, pericardial uid, pleural uid, snoial uid, lmphaticuid and peritoneal uid. Not well distributed into bile, aqueous

humour, bronchial secretions, sputum and CSF.

prearatio ad dose kanamcin sulate, sterile powder or intramuscular injection insealed ials. The powder needs to be dissoled in water or injec-

tions beore use. The optimal dose is 15 mg/g bod weight,usuall 750 mg to 1 g gien dail or 5–6 das per wee, b deep

intramuscular injection. Rotation o injection sites aoids localdiscomort. When necessar, it is possible to gie the drug at the

same total dose 2 or 3 times weel during the continuationphase, under close monitoring or aderse eects.

Storage Powder stable at room temperature (15–25 °C), diluted solutionshould be used the same da.

Oral absortio There is no signifcant oral absorption.

CSF eetratio Penetrates inamed meninges onl.

Secial circumstaces pregac/breasteedig: saet class D. Eighth cranial nere

damage has been reported ollowing in utero exposure to

anamcin. Excreted in breast mil. The American Academ o Paediatrics considers anamcin to be compatible with breast-eeding.

Real disease: use with caution. Leels should be monitored orpatients with impaired renal unction. Interal adjustment (12–

15 mg/g 2 or 3 times per wee) is recommended or creatinineclearance <30 ml/minute or haemodialsis.

heatic disease: drug leels not aected b hepatic disease(except a larger olume o distribution or alcoholic cirrhotic

patients with ascites). Presumed to be sae in seere lier dis-ease; howeer, use with caution – some patients with seere

lier disease ma progress rapidl to hepatorenal sndrome.

Aderse eects Frequet: pain at injection site, renal ailure (usuall reersible). Occasioal: estibular and auditor damage – usuall irreersi-ble; genetic predisposition possible (chec amil or aminogl-

coside ototoxicit), nephrotoxicit (dose-related to cumulatieand pea concentrations, increased ris with renal insufcienc,

oten irreersible), peripheral neuropath, rash.Ototoxicit potentiated b certain diuretics (especiall loop

diuretics), adanced age, and prolonged use. The eect o non-depolarizing muscle relaxants ma be increased.

Penicillins: in itro antagonism.

Drug iteractios Loo diuretics (bumetanide, urosemide, etacrnic acid, to-rasemide). Co-administration o aminoglcosides with loop diu-

retics ma hae an additie or snergistic auditor ototoxicit.Ototoxicit appears to be dose-dependent and ma be increased

with renal dsunction. Irreersible ototoxicit has been report-ed. Aoid concomitant administration; i used together, careul

dose adjustments in patients with renal ailure and close moni-toring or ototoxicit are required.




186


KAnAMyCIn (Km)


Drug iteractios no-deolarizig muscle relaats (atracurium, pancuronium,

tubocurarine, gallamine triethiodide): possible enhanced actiono non-depolarizing muscle relaxant resulting in possible respira-tor depression. Aoid co-administration; i concurrent adminis-

tration is needed, titrate the non-depolarizing muscle relaxantslowl and monitor neuromuscular unction closel.

nerotoic agets (amphotericin B, oscarnet, cidooir): addi-tie nephrotoxicit. Aoid co-administration; i used together,

monitor renal unction closel and discontinue i warranted. peicillis: in itro inactiation (possible). Do not mix together

beore administration.

Cotraidicatios Pregnanc (congenital deaness seen with streptomcin andanamcin use in pregnanc). Hpersensitiit to aminoglco-

sides. Caution with renal, hepatic, estibular or auditor impair-ment.

Moitorig Monthl creatinine and serum potassium in low-ris patients

(oung with no co-morbidities), more requentl in high-rispatients (elderl, diabetic, or HIv-positie patients, or patients

with renal insufcienc). I potassium is low, chec magnesiumand calcium. Baseline audiometr and monthl monitoring in

high-ris patients. For problems with balance, consider increas-ing dosing interal.

Alertig smtoms — Problems with hearing; dizziness— Rash

— Trouble breathing— Decreased urination

— Swelling, pain or redness at injection site— Muscle twitching or weaness



187

LEvOFLOxACIn (L)


Actiit agaist TB, Bactericidal: acts b inhibiting the A subunit o DNA grase

mecaism o actio, (topoisomerase), which is essential in the reproduction o bacte-ad metabolism rial DNA.

Leooxacin is generall considered to be about twice as actie

as its isomer, ooxacin.Minimal hepatic metabolism; 87% o dose excreted unchanged

in the urine within 48 h ia glomerular fltration and tubular secre-tion.

prearatio ad dose Tablets (250, 500, 750 mg).

Aqueous solution or solution in 5% dextrose or Iv administration– ials (20, 30 ml) 500 or 750 mg and exible containers (50,

100, 150 ml) 250; 500 or 750 mg.Usual dose: 750 mg/da.

Storage Tablets: room temperature (15–25 °C), airtight containers pro-

tected rom light.

Oral absortio Leooxacin is rapidl and essentiall completel absorbed ater

oral administration. Orall, should not be administered within 4 ho other medications containing dialent cations (iron, magnesi-

um, zinc, itamins, didanosine, sucralate). No interaction withmil or calcium.

Distributio, Distributes well in blister uid and lung tissues, also widel

CSF eetratio distributed (idnes, gall bladder, gnaecological tissues, lier,lung, prostatic tissue, phagoctic cells, urine, sputum and bile).

30–50% o serum concentration is attained in CSF with inamedmeninges.

Secial circumstaces pregac/breasteedig: saet class C. There are no adequate

and well-controlled studies in pregnant women. Leooxacinshould be used during pregnanc onl i the potential beneft

justifes the potential ris to the etus. Animal data demonstrat-ed arthropath in immature animals, with erosions in joint carti-

lage. Because o the potential or serious aderse eects romleooxacin in nursing inants, a decision should be made wheth-

er to discontinue nursing or to discontinue the drug, taing intoaccount the importance o the drug to the mother.

Real disease: doses o leooxacin should be reduced inpatients with seere renal impairment. When the creatinine clear-

ance is less than 30 ml/minute, the recommended dosing is750–1000 mg 3 times per wee.

heatic disease: gien the limited extent o leooxacin metabo-lism, the pharmacoinetics o leooxacin are not expected to

be aected b hepatic impairment.

Aderse eects Generall well tolerated.

Occasioal: gastrointestinal intolerance; CNS-headache; malaise;

insomnia; restlessness; dizziness; allergic reactions; diarrhoea;photosensitiit.

Rare: QT prolongation; tendon rupture; peripheral neuropath.

Drug iteractios Should not be gien to patients receiing class Ia antiarrhthmic

drugs (such as quinidine and procainamide) or Class III anti-arrhthmics (such as amiodarone and sotalol).

Sucralate: decreased absorption o uoroquinolones caused bthe chelation b aluminium ions contained in the sucralate.

Atacids (magnesium, aluminium, calcium, Al-Mg buer oundin didanosine): antacid binding to uoroquinolone antibiotics re-

sulting in decreased absorption and loss o therapeutic efcac.




188


LEvOFLOxACIn (L)


Drug iteractios probeecid: probenecid intereres with renal tubular secretion

o uoroquinolones, which ma result in 50% increase in serumleel o leooxacin.

vitamis ad mierals containing dialent and trialent cations

such as zinc and iron. Formation o uoroquinolone-ion complexresults in decreased absorption o uoroquinolones.

Meiletie: uoroquinolones ma inhibit ctochrome P450 1A2resulting in increased mexiletine concentration.

Cotraidicatios Pregnanc; hpersensitiit to uoroquinolones; prolonged QT.


Alertig smtoms — Pain, swelling or tearing o a tendon or muscle or joint pain— Rashes, hies, bruising or blistering, trouble breathing

— Diarrhoea— yellow sin or ees

— Anxiet, conusion or dizziness











193

ANNEX 2

weigt-based dosigo drugs or adults

The table below shows the suggested dosing o antituberculosis drugs or

adults based on body weight. For paediatric doses, see Chapter 9, section

9.5. While antituberculosis drugs are traditionally grouped into rst-line andsecond-line drugs, the drugs in the table are divided into ve groups based on

drug ecacy and drug properties (or drug classes). Detailed inormation on

drug groups 1–4 is given in Annex 1.

weigt-based dosig o atituberculosis drugs i te treatmet o drug-resistat TB

meDicAtion weiGht clAss(DruGAbbreviAtion), <33 KG 33–50 KG 51–70 KG >70 KG(common (Also mAximum

presentAtion) Dose)

GROUp 1: FIRST-LInE ORAL AnTITUBERCULOSIS DRUGS

Isoniazid (H) 4–6 mg/g dail 200–300 mg dail 300 mg dail 300 mg dail

(100, 300 mg) or 8–12 mg or 450–600 mg or 600 mg or 600 mg

3 x w 3 x w 3 x w 3 x w

Riampicin (R) 10–20 mg/g 450–600 mg 600 mg 600 mg

(150, 300 mg) dail

Ethambutol (E) 25 mg/g 800–1200 mg 1200– 1600–

(100, 400 mg) dail 1600 mg 2000 mg

Prazinamide (Z) 30–40 mg/g 1000–1750 mg 1750– 2000–

(500 mg) dail 2000 mg 2500 mg

GROUp 2: InJECTABLE AnTITUBERCULOSIS DRUGS

Streptomcin (S) 15–20 mg/g 500–750 mg 1000 mg 1000 mg

(1 g ial) dail

kanamcin (km) 15–20 mg/g 500–750 mg 1000 mg 1000 mg

(1 g ial) dail

Amiacin (Am) 15–20 mg/g 500–750 mg 1000 mg 1000 mg

(1 g ial) dail

Capreomcin (Cm) 15–20 mg/g 500–750 mg 1000 mg 1000 mg

(1 g ial) dail



194


meDicAtion weiGht clAss(DruGAbbreviAtion), <33 KG 33–50 KG 51–70 KG >70 KG(common (Also mAximumpresentAtion) Dose)

GROUp 3: FLUOROQUInOLOnES

Ooxacin (Ox) 15–20 mg/g 800 mg 800 mg 800–1000 mg

(200, 300, 400 mg) dail

Leooxacin (Lx) 7.5–10 mg/g 750 mg 750 mg 750–1000 mg

(250, 500 mg) dail

Moxioxacin (Mx) 7.5–10 mg/g 400 mg 400 mg 400 mg

(400 mg) dail

GROUp 4: ORAL BACTERIOSTATIC SECOnD-LInE AnTITUBERCULOSIS DRUGS

Ethionamide (Eto) 15–20 mg/g 500 mg 750 mg 750–1000 mg

(250 mg) dail

Protionamide 15–20 mg/g 500 mg 750 mg 750–1000 mg

(Pto) (250 mg) dail

Ccloserine (Cs) 15–20 mg/g 500 mg 750 mg 750–1000 mg

(250 mg) dail

Terizidone (Trd) 15–20 mg/g 600 mg 600 mg 900 mg

(300 mg) dail

P -aminosaliclic 150 mg/g 8 g 8 g 8–12 g

acid (PAS) dail

(4 g sachets)

Sodium PAS Dosing can ar with manuacture and preparation: chec dose rec-

ommended b the manuacturer.

Thioacetazone (Thz) Usual dose is 150 mg or adults

GROUp 5: AGEnTS wITh UnCLEAR ROLE In DR-TB TREATMEnT

(nOT RECOMMEnDED By whO FOR ROUTInE USE In MDR-TB pATIEnTS).

OpITMAL DOSES FOR DR-TB ARE nOT ESTABLIShED

Cloazimine (Cz) Usual adult dose is 100 mg to 300 mg dail. Some

clinicians begin at 300 mg dail and decrease to 100 mg ater4 to 6 wees.

Linezolid (Lzd) Usual adult dose is 600 mg twice dail. Most reduce the dose

to 600 mg once a da ater 4 to 6 wees to decrease aderseeects.

Amoxicillin/ Dosages or DR-TB not well defned. Normal adult dose

Claulanate (Amx/Cl) 875/125 mg twice a da or 500/125 mg three times a da.Dosages o 1000/250 hae been used but aderse side-

eects ma limit this dosing.

Thioacetazone (Thz) Usual adult dose is 150 mg

Imipenem/cilastatin Usual adult dose is 500–1000 mg Iv eer 6 hours.(Ipm/Cln)

Clarithromcin (Clr) Usual adult dose is 500 mg twice dail

High-dose isoniazid 16–20 mg/g dail(High-dose H)



195

ANNEX 3

Suggestios or urter readig

polic issues

1. Anti-tuberculosis drug resistance in the world. Third global report. The WHO/

IUATLD global project on anti-tuberculosis drug resistance surveillance,1999–2002 . Geneva, World Health Organization, 2004 (WHO/HTM/

TB/2004.343).

2. Espinal M et al. Standard short-course chemotherapy or drug-resistant

tuberculosis: treatment outcomes in six countries. Journal o the American Medical Association, 2000, 283(19), 2537–2545.

3. Program in Inectious Disease and Social Change/Open Society Insti-

tute. Global impact o drug resistant tuberculosis . Boston, Harvard Medical

School, 1999.

4. Kim JY et al. From multidrug-resistant tuberculosis to DOTS expansion

and beyond: making the most o a paradigm shit. Tuberculosis , 2003,

83:59–65.

Laborator serices

1. Laboratory services in tuberculosis control. Parts I, II and III . Geneva, World

Health Organization, 1998 (WHO/TB/98.258).

2. Guidelines or surveillance o drug resistance in tuberculosis . Geneva, World

Health Organization, 2003 (WHO/CDS/TB/2003/320; WHO/CDS/CSR/RMD/2003.3).

3. Guidelines or drug susceptibility testing or second-line anti-tuberculosis drugs or DOTS-Plus . Geneva, World Health Organization, 2001 (WHO/CDS/

TB/2001.288).

4. Laszlo A et al. Quality assurance programme or drug susceptibility testing

o Mycobacterium tuberculosis in the WHO/IUATLD Supranational Reer-

ence Laboratory Network: rst round o prociency testing. International Journal o Tuberculosis and Lung Disease , 1997, 1:231–238.

5. The public health service national tuberculosis reerence laboratory and the national laboratory network: minimum requirements, roles, and operation inlow-income countries . Paris, International Union Against Tuberculosis and

Lung Disease, 1998.







198

ANNEX 4

Legislatio, uma rigts adatiets’ rigts i tuberculosis

reetio ad cotrol

Objecties

This annex provides inormation regarding legislation, human rights and

patients’ rights in prevention and control o TB. Legislation should be placedin the context o a comprehensive strategy political, health and social action

needed to strengthen TB prevention and control.

Legislatio o commuicable diseases

Legislation is an expression o national political commitment to prevent and

control TB. Government commitment to sustained TB control is one o the

key components o the national TB prevention and control strategy. This

should be maniest in national legislation and regulations relating to all as-

pects o a national TB control strategy, and in nancial and technical support

to national TB control programmes (NTPs). The Stop TB Initiative addresses

ways o strengthening health legislation and regulations in order to better sup-

port the vital eorts to develop and expand TB prevention and control, par-

ticularly extensively drug-resistant TB (XDR-TB).

• The role o legislation and regulations in TB control. Legislation ex-

presses and ormulates health policy, supports the implementation o public

health goals and sets the oundation or executive action. Legislation also

ormulates patients’ rights and duties, helping them to realize the right tohealth in terms o health protection and access to health care.

• Scope and purpose o communicable diseases legislation. The scope

o the communicable disease acts and legislation should cover all commu-

nicable diseases. A distinction should be made between communicable

diseases that are hazardous to public health and other inections that are non-

hazardous. Its purpose should be:

— to protect the population rom communicable diseases by preventing

their occurrence or spread;

— to ensure that health authorities and other authorities implement the

measures necessary to control communicable diseases and to coordinate

their eorts;



199

— to saeguard the rights o individuals who are aected by measures to

control communicable diseases pursuant to the legislation.

The legislation should provide the legal basis or the implementation o

the various measures proven eective in combating communicable diseases

and or the continuous and systematic prevention and control o outbreaks.

These measures must:

— be necessary to prevent the transmission o a disease;

— be justiable rom a medical point o view;

— not cause needless or unreasonable harm to those aected.

huma rigts ad atiets’ rigts i resect to TB

The voluntary participation in communicable disease legislation o aectedcitizens should always be sought. I needed, participation can be made com-

pulsory to prevent the spread o a communicable disease that is hazardous to

public health. In extreme situations, measures may also be made compulsory.

Such compulsory measures should be limitedly enumerated in the law and

provisions must be made or such decisions to be appealed in court.

• The need or up-to-date legislation to support an eective national

TB prevention and control strategy. Provisions that have been in orce

or many years may need to be updated to refect current public health ap-proaches; many o the older communicable disease laws pre-date modern

methods o prevention and control. Legislation has also oten been allowed

to grow in a complex way, and thus measures on TB control appear in vari-

ous statutes but their relationship may not be clear or eective. Appropriate

legislation and regulations help ensure that policies and strategies are eec-

tive and sustainable. They must give strong backing to programmes that

produce results through a clear denition o duties and responsibilities at

local, regional and national levels. Provisions must also seriously consider

the human, technical and nancial resources necessary or TB preventionand control programmes.

• Basic values in the oundations o public action. Health policy decisions

are also considered with regard to basic human values that both motivate

and constrain our actions. The ollowing values, which serve as the corner-

stones o health-care systems, require careul consideration beore eecting

TB prevention and control legislation.

— Respect or the person. Respect or people is the most essential value in

a society proessing to adhere to the principles o human rights. It re-quires acknowledgement and protection o the dignity and autonomy o

each individual. Each individual’s interests and aspirations should be re-

garded as worthy o protection, except insoar as they violate the rights

ANNEX 4. LEGISLATION, HUMAN RIGHTS AND PATIENTS’ RIGHTS



200


o others. The right to sel-determination and privacy and the right to

inormed consent to medical treatment fow rom this principle.

— Justice. Justice mandates that, as respecting people, all people should

be respected equally. Equity in all actions is required by the value o

justice.

— Equity. Equity reers to both airness and justice. Equity in health im-

plies that everyone can attain their ull health potential and that no one

should be disadvantaged rom achieving this potential because o any so-

cially determined circumstances. Equity calls or the recognition o di-

erential needs, requiring that equal rights are recognized and that equal

needs are met. Because resources are nite, this has to be understood in

relative terms; it becomes a matter o prioritization in selecting those ac-tivities that would best reduce inequities in health. Equity involves the

air distribution o resources needed or health, air access to the oppor-

tunities available and airness in the support oered to people when ill.

A variation or dierence in health becomes a social inequity when it is

systematic and socially produced, thereore modiable and unair.

— Benefcence. Benecence is the value o doing good and o meeting the

needs and interests o others. Our constant eorts to relieve suering,

to meet human needs and to enhance the human condition are rootedin this value.

— Non-maleasance. Similarly, we seek to advance the cause o mankind

without causing harm along the way. The value o non-maleasance is

an aspect o respect or people. It permits limitations on an individual’s

liberty to pursue personal goals and choices when others will be injured

by those activities.

— Responsibility and accountability. Because people are autonomous agents

worthy o respect, they also bear responsibility or their actions, in ad-dition to enjoying undamental human rights.

This set o rights, principles and values provides the justication or the ob-

ligation placed on individuals to act in the interest o others in the control

o communicable diseases.

• Normative principles that govern public action. In order to be sound,

legislation on TB prevention and control must be based on solid scientic

and epidemiological evidence but also on the ollowing normative princi-

ples:— Equality o treatment (beore the law and public regulation). Prescriptions

cannot be imposed arbitrarily on some people and not on others. I one

is to request duties rom one group and not rom another, there must be

strong and compelling reasons.



201

— Relevance. Public action should be directly relevant to the policy ob-

jectives and the management o the problem to which the policy is

addressed.

— Proportionality and least inringement. The duty that may be imposed

must be commensurate with the benet it brings. When considering a

compulsory public health measure, it is necessary to weigh careully the

human rights and liberties limitations that it would introduce as com-

pared with the advantages it is supposed to bring and the consequential

damage o negligence or inaction.

— Eectiveness. There must be a reasonable expectation that the provisions

will result in eective action. It is not sucient that a provision appears

logical or has a scientic basis to be useul in reality.

— Feasibility. It ollows that all actions envisaged must be easible and

capable o being implemented in the real world given the actual cultur-

al, social, political and material circumstances and constraints.

— Social acceptability. The advocacy o morals is not a major role o the

State, which usually only halts what clearly oends it. When dealing

with communicable diseases, the authorities have to take into account

what is socially acceptable in the community concerned.

huma rigts i legislatio ad regulatio or

TB reetio ad cotrol

The promotion o health requires the protection o human rights o vulnerable

individuals and populations; indeed, saeguarding human rights empowers

individuals and enables them to take steps to improve their own health. This is

especially important with respect to communicable diseases and in particular

TB, or instance in encouraging sel-reporting to health services and compli-

ance with treatment.• The right to the highest attainable standard o health. The right to the

highest attainable standard o health is a claim to a set o social arrange-

ments – norms, institutions, laws, an enabling environment – that can best

secure the enjoyment o this right. Other key human rights relevant to

health include reedom rom discrimination and the right to participation,

education and inormation. Human rights are grounded in concrete gov-

ernmental obligations and generate entitlements on individuals and groups,

with a particular emphasis on those considered most vulnerable.

• The tension between public health and civil rights in communicable

disease legislation/TB regulations. Two distinct areas o human rights

are protected under international law: civil and political rights on the one

hand; and social, cultural and economic rights on the other. Civil and




202


political rights aim to protect both the individual sphere and an individ-

ual’s liberties. They saeguard individuals rom restraint, loss o reedom

and discrimination; whereas the goal o social rights is to saeguard a just

participation o people in social goods. While individual rights are inherentto the individual as a human being, social rights, among them the right to

health care, are actually conditioned by the resources o a country. In the

eld o TB control, the balance between individual civil rights and societal

obligations is crucial when drating legislation that species the circum-

stances in which it is permitted to apply involuntary measures. Communi-

cable disease legislation and TB regulations have intervened to mediate the

tension between public health and individual civil rights. In this respect,

the role o communicable disease legislation consists o both dening and

limiting government authority to constrain, on behal o public health, the

civil rights o individuals. It empowers the public health authorities to:

— test and screen;

— require notication and reporting o cases;

— mandate medical examinations, vaccinations and treatment;

— isolate patients with inectious conditions;

— trace and quarantine contacts.

For instance, communicable disease legislation can:

— limit the right to reedom o movement (in case o isolation o an inec-

tious patient or quarantine o contacts);

— limit the right to autonomy and sel-determination (in case o compul-

sory testing, screening, examination and treatment);

— limit the right to privacy (in case o compulsory contact tracing or

patient retrieval).

These are examples o restrictions on rights that may be necessary or thepublic good and thereore can be considered legitimate under international

human rights law.

• Limiting human rights on grounds o public health. In ullling its

duty to protect the public against a communicable disease hazardous to

public health such as TB, the government may impose limitations on in-

dividual liberty. Where voluntary measures do not work, public health

authorities need to be able to ensure compliance. Legislation should make

provisions or situations that can range rom voluntary to compulsory

compliance. Compulsion must always be regarded as a last resort and mustrespect the human rights o those aected. Beore resorting to compul-

sion, thereore, governments should ensure that public health measures

comport with sound science and comprise the least restrictive measures



203

necessary to prevent and control TB. Circumstances that limit human

rights or public health purposes must be:

— strictly provided by the law (hence the importance o proper legisla-

tion);

— neither arbitrary nor discriminatory;

— based on objective considerations;

— necessary to respond to a pressing public health need (such as the pre-

vention o TB transmission and the development o the disease ollow-

ing inection);

— proportional to the social aim;

— no more restrictive than necessary to achieve the intended purpose.

Even where such limitations on grounds o protecting public health arepermitted, they should be o limited duration and subject to review. In this

respect, it is important that countries develop domestic legal standards o

due process and equal protection.

patiets’ rigts i legislatio ad regulatio or

TB reetio ad cotrol

The rights o patients are central to the proper unctioning o a health system.

Sick patients are vulnerable and thereore easily subject to a violation o theirrights. The recognition o patients’ rights in turn makes people more con-

scious o their responsibilities when seeking and receiving health care.

• Common values and goals in patients’ rights. The underlying values and

goals that have supported the evolution o the rights o patients can be sum-

marized as ollows:

— To rearm undamental human rights and values in health care, and

in particular to protect the physical and mental integrity, dignity and

autonomy o the patient.

— To help patients obtain the ullest benet rom their use o health serv-

ices.

— To promote and sustain a benecial patient–physician relationship

based on trust and marked by mutual support and respect.

— To ensure high-quality o care and equity o access to scarce and costly

health-care resources.

— To promote humanization o care to the most vulnerable and, in par-ticular, to patients aected by DR-TB.

The cost o health care places an increasing burden upon national resources

and makes the equitable distribution o scarce health-care acilities a major




204


issue. Social justice and the right to health care are at stake in ensuring this

equitable distribution. Decisions made regarding this distribution directly

aect the accessibility o patients to health care. These includes issues such

as establishing a air insurance programme or other nancing system orthe costs o health care, planning health services, setting priorities, manag-

ing waiting lists and ensuring quality o care.

• The rights o patients most oten recognized in legislation. The rights

o patients most oten recognized in legislation are the rights to:

— respect or the person;

— inormation;

— inormed consent (including the right to reuse or to halt a medical

intervention);— condentiality and privacy;

— autonomy and sel-determination;

— reedom o choice within the unctioning o the health-care system;

— the protection o health as is aorded by appropriate measures or dis-

eases prevention and health care;

— care and treatment;

— be treated with dignity in relation to their diagnosis, treatment and

care, which should be rendered with respect or the person, culture and

values;

— a quality o care marked by sound proessional standards, by a humane

relationship between the patient and the health-care providers and by

the continuity o care;

— enjoy the support o their amily, and to receive spiritual support;

— relie o their suering;

— humane terminal care and to die with dignity;

— non-discrimination;

— the right and the occasion to complain.The enjoyment o these rights shall be secured without discrimination;

patients should be aware o these rights and be able to assert them.

• Complementary nature o rights and responsibilities. It is important

to remember the complementary nature o rights and responsibilities and

also to keep in mind the perspectives o both health-care providers and

patients. It is hoped that the recognition o patients’ rights will in turn

make people more conscious o their responsibilities when seeking and

receiving health care, and that this will ensure that patient–physician re-lationships are marked by mutual support and respect. Patients have re-

sponsibilities both to themselves or their own sel-care and to health-care

providers. Health-care providers enjoy the same protection o their human

rights as all other people. Patients should be aware o the practical contribu-



205

tions they can make to the optimal unctioning o the health system. Their

active participation in the diagnosis and treatment process is always desir-

able and oten indispensable. The patient has an essential role, the recipro-

cal o the physician’s, in ensuring that the dialogue between them is carriedout in good aith. Indeed, the economic and equitable use o resources

allocated to health care is an objective that can be shared together by health

proessionals and patients.

• The responsibilities o the patients. Rights and responsibilities go hand-

in-hand. In granting rights to patients, modern laws make the patient more

autonomous and thereore also more responsible. Some o the Patients’

Right Acts denes the responsibilities o patients. They may be expressed

in such terms as “A patient should:— take care o his or her health;

— undertake no action to the detriment o his or her health or the health

o others;

— in case o communicable diseases hazardous to public health, observe

precautions during contact with health-care providers and other citi-

zens;

— undertake the obligatory preventive measures such as immunization;

— give complete inormation to the physician about previous and current

diseases;

— ollow the treatment given by the physician;

— rerain rom using other medical remedies or drugs than those pre-

scribed or approved by the caring physician;

— observe the rights and dignity o other patients and other health-care

sta;

— observe the rules o the health-care establishment”.

Summar ad alicatio to te atiet it DR-TB A patient’s right to reuse treatment does not excuse that patient rom the

duty or responsibility to do nothing that may harm another person or persons.

Consequently, patients who reuse to accept that responsibility must expect

such curtailment o their liberty or reedom o action as will eectively protect

others. The restrictions imposed must be no greater than necessary to protect

others, and a patient would have a right o redress i unnecessary restrictions

are imposed. A patient who reuses to accept curtailment voluntarily must

expect a coercive response rom the responsible authorities. However, coer-

cion must always be a last resort and only when all attempts at persuasion andappropriate oers o support and other measures to encourage and acilitate

compliance have ailed to secure a positive response.

Coercive isolation must never be a substitute or treatment and medical

care. All public policies bearing on the well-being o the patient must be com-




206


patible and reinorcing to give the patient every incentive to seek and comply

with treatment. No government policy should deny or limit access to treatment

and choose isolation as a solution to decrease transmission over treatment.

No patient should be put at an economic or other disadvantage as a directconsequence o accepting treatment or o complying with curtailments or

the purpose o protecting others. Otherwise, the patient may see that the bal-

ance o personal advantage lies with reusing treatment or avoiding compli-

ance with treatment or curtailment.

A particular problem arises when DR-TB treatment has ailed and no other

options exist or treatment. The only course o action may be isolation o the

patient to prevent transmission o inection to others, and it is not certain how

long the period o isolation will be. It has not been internationally determined

what is regarded as reasonable measures to ensure that the patient has an

acceptable quality o lie, given that the reason or isolation is solely the protec-

tion o others. Such end-o-lie care must be provided in a dignied, humane

manner. Visitation with amily and riends is ully possible with inection

control measures.

The lack o economic and other resources may put in doubt the easibil-

ity o the policies proposed or implied in the oregoing. The abovementioned

descriptions and inormation are intended to serve as a guide to protect both

the health o the general population and the individual’s human rights. Allcountries should strive or the ull access to treatment or DR-TB and commu-

nicable disease legislation balanced with the ull protection o human rights

and patients’ rights.

Bibliogra

Good practice in legislation and regulations or TB control: an indicator o political will . Geneva, World Health Organization, 2001 (WHO/CDS/

TB/2001.290).

Declaration on the promotion o patients’ rights in Europe . Copenhagen, WorldHealth Organization Regional Oce or Europe, 1994 (ICP/HLE 121,

1994).

World Health Organization, Regional Oce or Europe and University o

Amsterdam, Health Law Section. Promotion o the rights o patients in Europe.Proceedings o a WHO Consultation. The Hague, University o Amsterdam,

London and Boston, Kluwer Law International, 1995.

World Medical Association Declaration on the Rights o the Patient. Adopted

by the 34th World Medical Assembly, Lisbon, Portugal, September/October

1981, and amended by the 47th WMA General Assembly, Bali, Indonesia,

September 1995, and editorially revised at the 171st Council Session, Santia-

go, Chile, October 2005.



207

Pinet G. Legislation on the rights o patients in Europe. An Overview. In:

Molven, O, ed. Health Legislation in Norway . University o Oslo, Centre or

Medical Studies, Moscow, 2002.

United Nations Committee on Economic, Social and Cultural Rights, Gener-

al Comment No. 14: The Right to the Highest Attainable Standard o Health.

Geneva, 22nd session, 2000.

International Digest o Health Legislation/Recueil international de Législationsanitaire : http://www.who.int/legislation




208

ANNEX 5

Use o eerimetal drugsoutside o cliical trials(“comassioate use”)

Objecties

This annex outlines current best practices regarding the use o experimental

drugs outside o clinical trials, oten reerred to as “compassionate use”. It aimsto encourage national health authorities o countries with a high burden o TB

to develop or update the necessary ramework (regulation, pharmacovigilance

and patient protection mechanisms) to acilitate access to the potential benet

o compassionate use programmes or patients in need and to ensure that ad-

equate precautions exist to protect them rom undue risks.

Deitios

The terms “compassionate use,” “expanded access” or “special access” pro-

grammes have essentially the same meaning. They reer to programmes that

are intended to provide potentially liesaving experimental treatments to

patients suering rom a disease or which no satisactory authorized therapy

exists and/or who cannot enter a clinical trial. For many patients, these pro-

grammes represent their last hope.

Geeral cosideratios

Both MDR- TB and XDR-TB can be lie-threatening diseases or which

approved drugs alone may be ineective. In some cases, experimental anti-tuberculosis drugs,1 used in combination with approved drugs, could poten-

tially be eective or liesaving.

Compassionate use is a well known mechanism or diseases such as cancer,

Alzheimer disease and AIDS, and can also be used or TB when other treat-

ment options have been exhausted.

To acilitate access to experimental drugs, countries can ensure that the

appropriate ramework is in place. The structures that govern compassionate

use programmes typically include the ollowing elements:

1 New drugs currently under clinical testing: diamine (SQ-109), diarylquinoline (TMC-207),nitrodihydroimidazooxazole (OPC-67683), nitroimidazole (PA-284), pyrrole (LL3858).



209

Regulator mechanisms

In most countries, only drugs or which a marketing authorization has been

granted by the national regulatory agency can be used in humans.

Regulations normally permit use o investigational new drugs (IND) in well-dened circumstances: an IND can only be used through an approved

clinical trial in accordance with protocol and inclusion criteria or through a

compassionate use programme. Usually the drug must be either the subject

o an application or a marketing authorization or the study drug in ongoing

clinical trials. The indication or the proposed use o the drug must be within

the scope o an IND application or the target label indication.

Some national regulatory agencies have developed additional mechanisms to

acilitate the access to new drugs at dierent stages o development, but beore

market approval (e.g. single patient and small group access, or continued access

to an IND at the end o a clinical trial, or patients enrolled in the trial).

Most extant regulations are based on similar modus operandi:

• The patient must be well-inormed about the drug, its intended actions

and potential adverse eects and its possible impact on other conditions or

treatments. Patients must also consent in writing to be treated with it. It is

recommended that an ethical review board (ERB)1 approve the proposed

use o the drug.

• The practitioner (usually a physician):

— is responsible or initiating a request to the regulatory agency on behal

o a single patient or a group o patients. The request must include: a

description o the conditions and circumstances necessitating treatment,

a discussion o why existing therapies are unsatisactory (including rel-

evant clinical and laboratory data) and why the probable risk o using the

IND is no greater than the probable risk rom the disease or condition;

— must agree to provide the regulatory agency with a report on the resultso the use o the drug, including any adverse reactions.

• The sponsor:2

— is willing to provide the product and has the nal word on whether the

drug will be supplied and under which conditions;

— is responsible or providing inormation, requested by relevant regula-

tory agencies, on pharmaceutical quality or requirements such as: GMP

certicate or manuacturing site, certicate o analysis, chemical and

microbial parameters, stability data, batch number and expiry date;

ANNEX 5. USE OF EXPERIMENTAL DRUGS OUTSIDE OF CLINICAL TRIALS

1 This reers to the relevant institutions in each setting that provide oversight or protection o human subjects.

2 An individual, company, institution or organization that takes responsibility or the initiation,management and/or nancing o a clinical trial.



210


— is also responsible or providing all drug inormation to requesting prac-

titioners and/or patients.

• Requests or such access are considered by the medical committee o the

regulatory agency on a case-by-case basis, taking into consideration the na-

ture o the medical condition, the availability o marketed alternatives and

the inormation provided in support o the request regarding the use, saety

and ecacy o the drug.

• The authorization o the regulatory agency to use an experimental drug

outside a clinical trial does not constitute an opinion or statement that the

drug is sae and ecacious.

Notes. In some countries, similar mechanisms are in place to give patientsaccess to drugs that are not registered by the national authorities but cannot be

considered as IND as they are registered in other countries and are recognized

as sae and eective by the international scientic community.

The use o an authorized medicinal product as part o the practice o medi-

cine or an indication dierent rom the one or which the product was ap-

proved (i.e. o-label use) is not considered compassionate use and generally

does not require the approval o regulatory authorities. This includes the use

in MDR TB treatment o drugs such as fuoroquinolones, linezolid, cloaz-

imine, and clarithromycin, imipenem. However, the institution at which theproduct will be used may require ERB approval.

Patient monitoring and pharmacoigilance

Compassionate use should only be considered i adequate clinical, biological

and bacteriological monitoring is in place, including mechanisms or collect-

ing and reporting patient data through specic case report orms. It is o the

utmost importance that adverse events are diligently reported by the practi-

tioner within the requested timelines. It is recommended that patients be pro-

vided with peer or social support when using an experimental drug to assist inthe monitoring o their psycho-social condition and adverse eects.

Patient protection

Although treating a seriously ill patient under compassionate use provisions is

motivated by humaneness and compassion, there are several ethical issues to

consider regarding the use o experimental drugs.

• Unproven efcacy. The lack o approval usually means the saety and/or e-

cacy have not been scientically proven. The possible but unproven benetso the experimental treatment must be weighed against its risks. The risks

and benets o using the experimental treatment should also be weighed

against the possible benets and risks o available alternatives.





212


Nevertheless, the experience with antiretroviral treatment has shown that

in addition to the benet to individual patients, these programmes can also

generate useul inormation on saety and eectiveness in dierent popula-

tions than those included in clinical trials.

Bibliogra

Class T. Expanded access to unapproved medical products: compassionate use

Regulatory Aairs Focus Magazine , May 2006.

Thompson L. Experimental treatments? Unapproved but not always unavail-

able. FDA Consumer magazine. January–February 2000 (available at http://

www.da.gov/dac/eatures/2000/100_exp.html; accessed June 2008).

Committee or Medicinal Products or Human Use. Drat guideline on compas-sionate use o medicinal products, pursuant to Article 83 o Regulation (EC) No726/2004 . London, European Medicines Agency, 2006 (EMEA/27170/2006/

Drat; available at http://www.emea.europa.eu/pds/human/euleg/2717006en.

pd; accessed June 2008).

U.S. Food and Drug Administration. Early/expanded access. http://www.da.

gov/cdrh/devadvice/ide/print/early.html

Health Canada. Special access programmes: drugs . http://www.hc-sc.gc.ca/dhp-

mps/acces/drugs-drogues/saps_pasd_2002_e.html

Stop TB Partnership. Working Group on New TB Drugs: strategic plan. http://

www.stoptb.org/wg/new_drugs/documents.asp

International Conerence on Harmonisation o Technical Requirements or

Registration o Pharmaceuticals or Human Use (ICH). http://www.ich.org/

cache/compo/276-254-1.html

Emergency and compassionate use o experimental drugs and devices . San Fran-

cisco, University o Caliornia, 2004, rev. August 2005.Brook I. Approval o zidovudine (AZT) or acquired immunodeciency syn-

drome: a challenge to the medical and pharmaceutical communities. Journal o the American Medical Association, 1987, 258(11):1517.

Marwick C. AZT (zidovudine ) just a step away rom FDA approval or AIDS

therapy. Journal o the American Medical Association, 1987, 257(10):1281–

1282.

Policy on the compassionate/emergency use o experimental TB Alliance drugs .New York, Global Alliance or TB Drug Development, 2006 (available at

http://www.tballiance.org/downloads/publications/Compassionate_Policy.

12.6.06.pd; accessed June 2008).



213

ANNEX 6

Metodolog

Scoig

WHO rst published guidelines that specically address DR-TB in Guide-

lines or establishing DOTS-Plus pilot projects or the management o multidrug resistant tuberculosis in 2000. As increasing evidence emerged, Guidelines or the programmatic management o drug-resistance tuberculosis was published in

2006. This publication had a wider scope and purpose and supported the im-

plementation o the new Stop TB Strategy or 2006–2015.

The recognition that there were strains o TB that had become resistant

to some second-line drugs led to the denition o extensively drug-resistant

TB (XDR-TB) in 2006, and WHO rapidly organized the rst meeting o

the Global Task Force on XDR TB in October 2006. This meeting recom-

mended that WHO TB and HIV departments should provide an emergency

update to several chapters o the 2006 guidelines in response to the emergence

o XDR-TB.

A meeting o the WHO Guidelines Steering Group, together with several

WHO advisers who had contributed to the 2006 edition, took place in April

2006. It was agreed that there was an urgent need or guidance on the best

response to XDR-TB, based on the emerging evidence. The group identied

the chapters to be reconsidered and the gaps to be addressed in this emergency

update.O the total 18 chapters, eight have been reviewed and substantially changed

in response to the emerging evidence about MDR-TB and XDR-TB (chapters

1, 4, 5, 6, 7, 10, 12 and 18). One chapter is new (Chapter 19). The remaining

chapters have undergone minor revisions to ensure consistency but have not

been rewritten or had any new evidence included.

There was also a decision that a ull review o the Guidelines will be started

ater the emergency update.

The WHO Guidelines Review Committee was in place by January 2008

and had already developed drat Guidance or Emergency Guidelines which was used to guide best practice in the nalization o this emergency update.



214


Target audiece

This document is intended to assist in the development o national policies to

improve the diagnosis and management o DR-TB. The guidelines are prima-

rily intended or:

(i) national and regional TB programme managers, managers o nongovern-

mental organizations and other programme managers who are involved

in the scaling up o integrated TB control programmes in resource-

limited settings, to be used in conjunction with HIV/AIDS control pro-

grammes.

(ii) clinicians in these settings, to enable access to comprehensive, up-to-date,

technical and clinical inormation on the prevention and management o

DR-TB and to encourage the implementation o known best practice.

Guidelies Reerece Grou

The members o the Guidelines Reerence Group are listed on pages vi–vii.

All made a signicant contribution to writing and reviewing particular updat-

ed chapters, many o them contributing to several chapters, although only the

members o the Steering Group reviewed the whole document.

The Steering Group consisted o two members o the WHO secretariat,

and three expert advisers rom partner organizations and Member States.

The Steering Group o editors and key authors were Dr Ernesto Jaramillo,Dr Salmaan Keshavjee, Dr Kitty Lambregts, Dr Michael Rich and Dr Karin

Weyer.

The rst drat o the guidelines was reviewed by the Steering Group at

meeting held in February 2008. Other advisers at this meeting were Dr Mal-

gosia Grzemska (WHO), Dr Suzanne Hill (WHO), Dr Tim Holtz (CDC,

USA) and Dr Kathrin Thomas (WHO). Any outstanding issues were then

resolved by e-mail to agree the nal version. Other members o the group were

asked to provide reviews at these later stages or particular issues.

Eidece retrieal ad stesis

The nominated lead author or each chapter used a limited evidence retrieval

consisting o:

• personal collection o publications and case reports;

• literatures searches using PubMed and other databases and search engines;

• existing guidelines, both rom WHO and rom other internationally recog-

nized organizations;• expert consensus during several group meetings or specic topics;

• unpublished data, or example data supplied to the Green Light Committee

by their approved MDR-TB management projects.



215

This evidence was synthesized by each lead author, but a ormal quality as-

sessment was not used. Given the relatively small eld o experts in managing

DR-TB, expert opinion was sought rom several o the original researchers in

the eld. The evidence was not ormally assessed or graded and there are noormal evidence summaries.

peer reie

The revised chapters were each reviewed by at least one, and usually several,

members o the Guidelines Reerence Group, rom both within the WHO

Stop TB and HIV departments and outside external experts, as appropriate.

One o the expert advisers on the Steering Group was commissioned to har-

monize and review all the updated chapters (Dr Michael Rich). The reminder

o the Steering Group also reviewed the whole document and provided exten-sive and detailed eedback.

Cofict o iterests

All contributors were asked to complete the WHO Declarations o Interest

orm. A summary is provided on page 4.

Deelomet o recommedatios

The 2006 guidelines did not present recommendations in sections separate

rom the text. The 2008 emergency update kept to this original ormat toensure consistency with the non-revised chapters.

The emergency update presents recommendations that were new or con-

sidered relevant to the response to XDR-TB or to be o an urgent nature. The

Steering Group identied, discussed and nalized the recommendations and

established the main new changes rom the 2006 guidelines at its nal meet-

ing. Key recommendations are placed at the start o each updated chapter with

new recommendations indicated by an asterisk.

Cost is not explicitly considered as part o the recommendations, althoughthe realities o human resources, socioeconomic issues and health system in-

rastructure are taken into consideration throughout the document.

Reie date

The process or scoping the Guidelines or the programmatic management o drug-resistant tuberculosis has already begun and the next edition is due or

publication in 2010, with a rigorous and evidence-based approach ollowing

the WHO guidelines or guidelines 2008 .

ANNEX 6. METHODOLOGy





Forms







220


D R - T B C o n t r o l P r o g r a m m e

F O R M 0

1

P a t i e n t n a m e :

h I v I o r m a t i o ( f l l o

r a l l p a t i e n t s )

H I v t e s t i n g d o n e : ❑ y

❑ N

❑ U n n o w n

D a t e o t e s t :

/

/

R e s u l t s :

S t a r t e d o n A R T : ❑ y

❑ N

D a t e :

/

/

S t a r t e d o n C P T : ❑ y

❑ N

D a t e :

/

/

A R T = a n t i t r e t r o i r a l t h e r a p ;

C P T = c o - t r i m o x a z o l e p r e e n t i e t h e r a p

w e i g t m o i t o r i g

M o n t h

1

2

3

4

5

6

7

8

9

1 0

1 1

1 2

1 3

1 4

1 5

1 6

1 7

1 8

1 9

2 0

2 1

2 2

2 3

2 4

D a t e

W e i g h t

L a b o r a t o r m o i t o r i g

D a t e

A L T / S G P T

A S T / S G O T

C r e a t i n i n e

k T S H

H e m o g l o b i n

W B c o u n t

C D 4

L i p a s e

H I v t e s t

P r e g n a n c t e s t

A t i r e t r o

i r a l F l o S e e t

R e g i m e n

S t a r t d a t e

S t o p d a t e

R e a s o n o r s t o p / c h a n g e

R e a s o n s

o r

1 = F a i l u r e

3 = A d e r s e e e c t s

5 = S t o c o u t

7 = P a t i e n t r e u s a l

9 = O t h e r ( s p e c i )

i n t e r r u p t i o n o

2 = T u b e r c u l o s i s /

4 = P r e g n a n c

6 = D o s e c h a n g e

8 = P M T C T e n d e d

m e d i c a t i o n s :

I n t e r a c t i o n

A b b r e i a

t i o n s :

I N R T

I N R T

I N N R T

I P

I P

3 T C = L a m i u d i n e

A B

C = A b a c a i r

N v P = N e i r a p i n e

L O P / R = L o p i n a i r /

N F v = N e l f n a i r

D 4 T = S t a u d i n e

D D

I = D i d a n o s i n e

E F v = E a i r e n z

r i t o n a i r

R = R i t o n a

i r

A Z T = Z D v = Z i d o u d i n e

T D

F = T e n o o i r



221


F O R M 0

1

P a t i e n t n

a m e :

M e d i c a l d i a g o s i s o t

e r t a t u b e r c u l o s i s

D a t e

T e ( i . e . d i a b e t e s , h p e r t e n s i o n , c a r d i o m o p a t h ,

H I v , o p

p o r t u n i s t i c i n e c t i o n s )

A d e r s e e e c t s

D a t e

T e

( i . e . n e u r o p

a t h , h e p a t i t i s , r a s h , e t c . )

S u s e c t e d d r u g

FORMS



222


F O R M 0

1

N o g r o w t h r e p o r t e d

0

F e w e r t h a n 1 0 c o l o n i e s

R e p o r t n u m b e r

o c o l o n i e s

1 0 – 1 0 0 c o l o n i e s

+

M o r e

t h a n 1 0 0 c o l o n i e s

+ +

I n n u m

e r a b l e o r c o n l u e n t g r o w t h

+ +

+

M o n t h

#

P r i o r * *

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 2 0 2 1 2 2 2 3 2 4

S u t u m

s m e a r m i c r o s c o

D a t e

*

S a m p l e N o .

R e s u l t

M o n t h

#

P r i o r * *

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 2 0 2 1 2 2 2 3 2 4

C

u l t u r e

D a t e *

S a m

p l e N o .

R e s u l t

D r u g s u s c e t i b i l i t

t e s t i g ( D S T ) r e s u l t s ( n o t a t i o n m e t h

o d o r D S T : r = r e s i s t a n t , s = s u s c e p

t i b l e , c = c o n t a m i n a t e d )

D a t e *

S

H

R

E

Z

k m

A m

C m

F q

P t o / E t o

P A S

C s

O t h e r

O t h e r

P a t i e n t n

a m e :

n o t e s :

*

A l l d

a t e s i n t h e t a b l e s t h a t r e p o r t s m e a r s , c u l t u

r e a n d D S T

a r e

d a t e s t h e s p e c i m e n w a s c o l l e c t e d r o m t

h e

p a t i e n t .

* * T h e

d a t e t h e s p u t u m w a s c o l l e c t e d t h a t l e d t o t h e p a t i e n t

b e i n

g r e g i s t e r e d w i t h M D R - T B ( i p e r o r m e d ) .

n o t a t i o m e t o d o r r e c o r d i g c u l t u r e s

n o t a t i o m e t o d o r r e c o r d i g s m e a r s

( o r o

- c e t r i u g e d s e c i m e s )

N o . A

F B

0

1 – 9 A

F B p e r 1 0 0 H P F

S c a n t ( a n d r e p o r t

n u m b e r

o A F B )

1 0 – 9 9 A F B p e r 1 0 0 H P F

+

1 – 1 0

A F B p e r H P F

+ +

> 1 0 A

F B p e r H P F

+ +

+


C e s t x

- r a

D a t e

R e s u l t





224


F O R M 0

1

P a t i e n t n a

m e :

D R - T B C o n t r o l P r o

g r a m m e

A D M I n I S T R A T I O n O F D R U G S ( c o n t i n u e d ) :

M o n t h

1

2

3

4

5

6

7

8

9

1

0

1 1

1 2

1 3

1 4

1 5

1 6

1 7

1 8

1 9

2 0

2 1

2 2

2 3

2 4

2 5

2 6

2 7

2 8

2 9

3 0

3 1

W e i g h t ( g ) , L a b , X - r a

M a r i n t h e b o x e s : O

= d i r e c t l o b s e r e d

n

= n o t s u p e r i s e d

Ø

= d r u g s n o t t a e n

C o m m e n t s

O u t c o m e

M a r k o e

D a t e

C u r e d

C o m p l e t e d

D i e d

F a i l e d

D e a u l t e d

T r a n s e r r e d o u t



225

FORMS

F O R M 0

2

C a t e g o r I v R e g i s t e r


g r a m m e

* 1 N e

w

2 R e

l a p s e

3 A t e r d e a u l t

4 A t e r a i l u r e o i r s t t r e a t m e n t

5 A t e r a i l u r e o r e - t r e a t m e n t

6 T r a n s e r i n ( r o m a n o t h e r C a t e g o r I v t r e a t m e n t s i t e )

7 O t

h e r

U n i q u e

C a t . I v

R e g i s t e r

N o .

D a t e

e n t e r e d

i n C a t .

I v

R e g i s t e r

N a m e

( i n u l l )

S e x M o

r F

A g e

D a t e o

b i r t h

d / m /

A d d r e s s

D i s t r i c t

T B

R e g i s t e r

n u m b e r

D a t e o

r e g i s -

t r a t i o n

S i t e o

d i s e a s e

( P / E P

)

R e g i s -

t r a t i o n

g r o u p *

D a t e

s a m p l e

t a e n

o r D S T

S e c o n d -

l i n e

d r u g s

a l r e a d

r e c e i e d

R e s u l t o d r u g s u s c e t i b i l i t t e s t i g ( D

S T )

( E n t e r t h e D S T t h a t r e s u l t e d i n t h e p a t i e n t b e i n g r e g i s t e r e d a s a C a t e g o r I v p a t i e n t . I

t h e D S T i s p e n d i n g i t s h o u l d b e i l l e d i n

w h e n t h e r e s u l t s a r e n o w n . S e e t r e a t m e n t c a r d

o r u l l h i s t o r o D S T d a t a )

R = r e s i s t a n t S = s u s c e p t i b l e C = c o n t a

m i n a t e d

H

R

E

S

k m

C m

F q

O t h e r

O t h e r

O t h e r

O t h e r

1 2 3 4 5 6 7 8 9 1 0

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/



226


F O R M 0

2


D a t e

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

D a t e

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

D a t e

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

D a t e

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

D a t e

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

D a t e

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

D a t e

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

D a t e

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

D a t e

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

D a t e

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

D a t e

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

M D R - T B

d o c u -

m e n t e d

M D R - T B

s u s p e c t e d

( d e t e r m i n e d b

c o u n t r p r o t o c o

l )

R e g i m e

( i d r u g i i t i a l s )

D a t e s t a r t e d

C a t e g o r I v

t r e a t m e t

R e a s o s o r

e t e r i g i

C a t e g o r I v R e g i s t e r

S t a r t o

t r e a t m e n t

M o n t h 0

M

o n t h 1

M o n t h 2

M o n t h 3

M o n t h 4

M o n t h 5

M o n t h 6

M o n t h 7

M o n t h 8

M o n t h 9

M o n t h 1 0

M o n t h 1 1

M o n t h 1 2

M o n t h 1 3

M o n t h 1 4

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

d / m /

d / m /

d / m /

d / m /

d / m /

d / m /

d / m /

d / m /

d / m /

d / m /

d / m /

d / m /

d / m /

d / m

/

d / m /

S m e a r ( S ) a d c u l t u r e ( C ) r e s

u l t s d u r i g t r e a t m e t

( i m o r e t h a n o n e s m e a r o r c u l t u r e d o n e i n a m o n

t h , e n t e r t h e m o s t r e c e n t p o s i t i e r e s u l t )



227

FORMS

F O R M 0

2


g r a m m e

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

M o n t h 1 5

M o n t h 1 6

M o n t h 1 7

M o n t h 1 8

M o n t h 1 9

M o n t h 2 0

M

o n t h 2 1

M o n t h 2 2

M o n t h 2 3

M o n t h 2 4

M o

n t h 2 5

M o n t h 2 6

M o n t h 2 7

M o n t h 2 8

M o n t h 2 9

M o n t h 3 0

M o n t h 3 1

M o n t h 3 2

M o n t h 3 3

M o n t h 3 4

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

S

C

d / m /

d / m /

d / m /

d / m /

d / m /

d / m /

d

/ m /

d / m /

d / m /

d / m /

d /

m /

d / m /

d / m /

d / m /

d / m /

d / m /

d / m /

d / m /

d / m

/

d / m /

S m e a r ( S ) a d c u l t u r e ( C ) r e s u l t s d u r i g t r e a t m e t

( i m o r e t h a n o n e s m e a r o r c u l t u r e d o n e i n a m o n

t h , e n t e r t h e m o s t r e c e n t p o s i t i e r e s u l t )



228


H P F =

h i g h - p o w e r i e l d

F O R M 0

2


O u t c o m e

C u r e d

C o m p l e t e d

F a i l e d

D i e d

D e a u l t e d

T r a n s e r r e d o u t

D a t e o u t c o m e g i e n

H I v t e s t i n g

T e s t i n g d o n e

( y / N / u n n o w n )

D a t e

o t e s t

R e s u l t

A R T y / N

S t a r t d a t e

C P T y / N

S t a r t d a t e

C o m m

e t s

T B / h I v a c t i i t i e s

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/


0

F e w e r t h a n 1 0 c o l o n i e s

R e p o r t n u m b e r

o c o l o n i e s

1 0 –

1 0 0 c o l o n i e s

+

M o r

e t h a n 1 0 0 c o l o n i e s

+ +

I n n u

m e r a b l e o r c o n l u e n t g r o w t h

+

+ +

n o t a t i o m e t o d o r r e c o r d i g c u l t u r e s

n o t a t i o m e t o d o r r e c o r d i g s m e a r s

( o r

o - c e t r i u g e d s e c i m e s )

N o .

A F B

0

1 – 9

A F B p e r 1 0 0 H P F

S c a n t ( a n d r e p o r t

n u m b e

r o A F B )

1 0 –

9 9 A F B p e r 1 0 0 H P F

+

1 – 1

0 A F B p e r H P F

+ +

> 1 0

A F B p e r H P F

+

+ +

D r u g

a b b r e i a t i o s

F i r s t - l i e d r u g s

H = I s

o n i a z i d

R = R i a m p i c i n

E = E t

h a m b u t o l

Z = P

r a z i n a m i d e

S = S t r e p t o m c i n

( T h = T h i o a c e t a z o n e )

S e c o d - l i e d r u g s

A m =

A m i a c i n

k m =

k a n a m c i n

C m =

C a p r e o m c i n

O x = O l o x a c i n

L x = L e o l o x a c i n

M x = M o x i l o x a c i n

P t o = P r o t i o n a m i d e

E t o = E t h i o n a m i d e

C s = C c l o s e r i n e

P A S = P - a m i n o s a l i c l i c

a c i d



229

FORMS

FORM 03DR-TB Control Programme

Request or sutum eamiatio (to be completed b treatment centre)

Date taen Laborator S H R E Z km Am Cm Ox Other Other

specimen no.

1

2

RESULTS (to be completed in laborator)

Smear results

Culture results

DST results

Treatment unit DatePatient name:

Age: Date o birth: Sex (mar one) M F

Address (in ull)

Reason or examination (mar one): diagnosis ollow-up examination

Test request (mar an that are needed): smear culture drug-susceptibilit testing

Signature o person requesting examination:

*isual appearance o sputum (blood-stained, mucopurulent, salia)No. AFB 0

1–9 AFB per 100 HPF Scant (and report

number o AFB)

10–99 AFB per 100 HPF +

1–10 AFB per HPF ++

>10 AFB per HPF +++

Result (mar one)

neg. 1–9 + ++ +++

Date collected Specimen Laborator Appearance*

specimen no.

1

2

3

DateExamined b (signature)

Date

Examined b (signature)

Date

Examined b (signature)

The completed orm (with results) should be sent promptl to the treatment unit

R = resistant

S = susceptible

C = contaminated

No growth reported 0

Fewer than 10 colonies Report numbero colonies

10–100 colonies +

More than 100 colonies ++

Innumerable or conluent growth +++

Date collected Specimen Laborator Result (mar one) Contaminated

specimen no. neg. 1–9 + ++ +++

1

2



230


L a b o r a t o r R e g i s t e r o

r c u l t u r e a d D S T

F O R M 0

4


g r a m m e

D a t e

s p e c i m e n

r e c e i e d

L a b o r a

t o r

s e r i a l

n u m b

e r

R e e r r i n g h e a l t h a c i l i t

P a t i e n t n a m e

D a t e o

b i r t h

T p e o

s p e c i m e n

r e c e i e d

P a t i e n t a d d r e s s i n e w

S e x

M / F

D a t e

s p e c i m e n

c o l l e c t e d

D a t e

s p e c i m e n

i n o c u l a t e d



231

FORMS



F O R M 0

4


g r a m m e


0

F e w e r t h a n 1 0 c o

l o n i e s

R e p o r t n u m b e r o c o

l o n i e s

1 0 – 1 0 0 c o l o n i e s

+

M o r e t h a n 1 0 0 c

o l o n i e s

+ +

I n n u m e r a b l e o r c

o n l u e n t g r o w t h

+ + +

S i g n a

t u r e

*

N e w p a t i e n t s o r p

a t i e n t s s t a r t i n g a r e - t r e a t m e n t r e g i m e n .

* *

P a t i e n t o n T B t r e a t m e n t , i n d i c a t e m o n t h s o t r e a t m e n t a t w h

i c h o l l o w - u p e x a m i n a t i o n i s p e r o r m e d .

* * *

O u t c o m e o c u l t u

r e r e p o r t e d a s o l l o w s :

R e a s o n o r e x a m i n a t

i o n

D i a g n o s i s *

F o l l o w - u

p * *

R e s u l t o c u l t u r e * * *

R e s u l

t o c o n i r m a t o r

t e s t o

r M .

t u b e r c u l o s i s

( p o s i t i e o r n e g a t i e )

C u l t u r e s e n t

o r D S T

( y e s o r N o )

N

a m e o p e r s o n

r e p o

r t i n g D S T r e s u l t s

C o

m m e n t s

D a t e r e s u l t s

r e p o r t e d



232




R

H

E

S

k m

C m

F q

O t h e r

O t h e r

O t h e r

D S T R e s u l t s

N a m e o p e r s o n

S i g n a t u r e

C o m m e n t s

r e p

o r t i n g D S T r e s u l t s

R e p o r t D S T r e s u l t s a s

s = s u s c e p t i b l e , r = r e s i s t a n t , c = c o n t a m

i n a t e d

F O R M 0

4



233

FORMS

Q u a r t e r l r e o r t o M D R - T B d e t e c t i o

a d C a t e g o r I v t r e a t m e t s t a r t

N a m e o a r e a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

N a m e o a

r e a c o o r d i n a t o r . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

P a t i e n t s i d e n t i f e d d u r i n g . . . . . . . . . . . . . . . . . q u a r t e r o e a r . . . . . . . . . . . . . . . . . . . . . . . . . . . .

D a t e . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 .

n u m b e r o a t i e t s d e t e c t e d i t M D R - T B / x D R - T

B i t e l a b ( b d a t e o r e s u l t o M D R - T B / x D R - T B i l a b o r t o r r e g i s t e r ) d u r i g t e q u a r t e r :

M D R - T B

x D R - T B

2 .

n u m b e r o M D

R - T B a t i e t s o s t a r t e d C a t e g o r I v t r e a t m e t d u r i g t e q u a r t e r

N e w c a s e

P r e i o u s l t r e a t e d w i t h f r s t - l i

n e d r u g s

P r e i o u s l t r e a t e d w i t h s e c o n d - l i n e d r u g

s

C o n f r m e d c a s e s

S u s p e c t e d c a s

e s

1 s t q u a r t e r :

1 s t J

a n u a r – 3 1 M a r c h

2 n d q u a r t e r :

1 e r A

p r i l – 3 0 J u n e

3 r d q u a r t e r :

1 e r J

u l – 3 0 S e p t e m b e r

4 t h q u a r t e r :

1 e r O

c t o b e r – 3 1 D e c e m b e r

S i g n a t u r e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

F O R M 0

5



234


F O R M 0

6

S i m o t i t

e r i m

o u t c o m e a s s e s s m

e t o c o f r m e d M D R - T B c a s e s

( t o

b e f l l e d o u t 9 m o t s

a t e r t r e a t m e t s t a r t )

N a m e o U n i t :

D a t e f l l e d i n :

Q u a r t e r t r e a t m e n t w a s s t a r t e d :

D a t e o t h e r e p o r t :

N u m b e r

B a c t e r i o l o g i c a l r e s u l t s a t 5 a n d 6 m o n t h s o t r e a t m e n t

N o l o n g e r o n t r e a t m e n t

s t a r t e d o n

t r e a t m e n t

N e g a t i e

P o s i t i e

C

u l t u r e a n d s m e a r u n n o w n

D i e d

D e a u l t e d

T r a n s e r r e d

( a l l s m e a r s a n d c u l t u r e s n e g a t i e

( a n s m e a r o r c u l t u r e

( C o n s i d e r u n n o w n i a c u l t u r e

o u t

d u r i n g m o n t h 5 a n d 6 , a n d

i s p o s i t i e d u r i n g

o r s m e a r r e s u l t s i s n o t d o n e

a t l e a s t a s m e a r a n d c u l t u r e

m o n t h 5 a n d 6 )

o r e i t h e r m o n t h 5 o r 6 )

d o n e e a c h m o n t h )



235

FORMS

A u a l r e o r t o t r e a t m e t r e s u l t o c o f r m e d M D R - T B a t i e t s

s t a r t i g C a t e g o r

I v t r e a t m e t

( t o b e f l l e d i 2 4

a d 3 6 m o t s a s t t

e c l o s i g d a t e o e a r o t r e a t m e t )

y e a r o t r e a t m e n t s

t a r t :

P a t i e n t g r o u p

C u r e d

T r

e a t m e n t

F a i l e d

D e a u l t e d

D i e d

T r a n s e r r e d

S t i l l o n

T o t a l

c o

m p l e t e d

o u t

t r e a t m e n t

N e w

P r e i o u s l t r e a t e

d w i t h

f r s t - l i n e d r u g s o n l

P r e i o u s l t r e a t e d w i t h b o t h

f r s t - a n d s e c o n d

- l i n e d r u g s

T o t a l

F O R M 0

7





237

Ide

A ull list o abbreviations used in the text appears on pages viii–x.

Antiretroviral therapy (ART) 92–93,94

adverse eects 97, 98–101

DR-TB in patients on 95–96

drug interactions 96

initiation in DR-TB 95

see also Immune reconstitution

infammatory syndrome

Antituberculosis drugs

abbreviations 54, 56

adverse eects see Adverse drug

eects

antiretroviral drug interactions 96

classes 52–55

dose escalation (ramping) 55, 59

dosing 59, 193–194

experimental 208–212

rst line see First-line drugs

group 1 53, 54

group 2 see Injectable antituber-culosis agents

group 3 53–54

group 4 54–55

group 5 54, 55

inormation sheets 173–192

poor or unknown quality 28

regimens see Treatment regimens

second-line see Second-line drugs

uninterrupted supply o quality-assured 10

Areas, high-prevalence 28

Arthralgias 117

Asian patients 55

Abbreviations, drug 54, 56 Abdominal pain 99

Accountability 200

Acid-ast bacilli (AFB) 41–42

Adherence to therapy 121–124

Adjuvant therapies 68

Adverse drug eects 109–118

common 114–117

concomitant HIV/TB therapy 94,

97, 98–101

requency 112

key recommendations 108

management 110–113, 114–117

medications or managing 113

monitoring or 109–110, 111

non-adherence risk 124

Advocacy 126

Advocacy, communication and social

mobilization (ACSM) strategy

126 Alcohol dependence 87

Amikacin (Am) 53, 54

inormation sheet 173–174

paediatric dosing 82

renal insuciency 85

weight-based adult dosing 193

Aminoglycosides

adverse eects 110

susceptibility testing 44, 45 see also specifc agents Amoxicillin/clavulanate (Amx/Clv)

54, 194

Annual reports (orm 07) 162, 235



238


Back-log patients 23, 163

Bacteriology

terminology 21

see also LaboratoriesBCG vaccination, laboratory workers 47

Benecence 200

Biosaety, laboratory 39, 46–47

Bone marrow suppression 100

Breasteeding 80–81

Capreomycin (Cm) 53, 54

adverse eects 110



renal insuciency 85


Case-nding strategies 9, 26–34

HIV-inected patients 30–31


mono- and poly-drug resistance 31

paediatric patients 30

Case registration 19–25

Category I ailures 22drug susceptibility testing 28, 29–

30

recording and reporting 155

treatment strategies 61

Category II ailures 23

back-log patients 163

drug susceptibility testing 29

recording and reporting 155


Category IV

denition 20

patient registration groups 21–23

Category IV recording and reporting

system 154–164

aims and perormance indicators

155–156

backlog patients 163

computerization 163–164

key recommendations 155main orms/registers and fow o

inormation 156–163, 219–235

quality assurance 163

scope 156

Category IV regimens 51

see also Treatment regimens

Category IV Register (orm 02) 159–

161, 225–228Category IV treatment

cohort analysis 24

coverage 155

delay beore starting 155

ailure see Treatment ailure

HIV coinection 93

outcome denitions 23–24

strategies 50–70

surgery 67–68

Category IV Treatment Card (orm 01)

157–158, 219–224

Central nervous system (CNS)

disease involvement 67

drug toxicity 98

Champion counsellors 167

Checklist, DR-TB control programmes

17, 18

Chemoprophylaxis, contacts o MDR-

TB cases 138Chest radiographs 108, 111, 137

Children

case-nding 30

monitoring o treatment 108

symptomatic contacts 136–138

treatment 81–83, 84

Chronic tuberculosis cases 28, 29

Ciprofoxacin 53–54, 177–178

Civil society 169

Clarithromycin (Clr) 54

adult dosing 194


Clinic-based treatment 121

Clinical trials 208, 211–212

Cloazimine (Cz) 54

adult dosing 194

inormation sheet 179

Co-trimoxazole preventive therapy

(CPT) 93Code, treatment regimen 56, 57

Cohort analysis 11, 24

Collaborative TB/HIV activities

91–93



239

Communicable diseases legislation

198–199

Communication 168

Community, role in DR-TB control 17Community-based care and support

121, 124–127

Community care supporters 124–126

Community champions 167

Community health workers (CHWs)

121, 126–127

delivery o DOT 123

monitoring 127

patient-centred care 167

Community organizations 168

Compassionate use 208–212

cost 211

drug developers 211

indications 211

monitoring and pharmacovigilance

210

patient protection 210–211

regulation 209–210

scientic benet 211–212Computerized recording and reporting

systems 163–164

Condentiality 123

Conficts o interest 215

Consent, inormed 211

Contacts, MDR-TB patient 135–144

chemoprophylaxis 138

community-based tracing 125

denition 135

drug susceptibility testing 28, 29,

136


paediatric 81–82

symptomatic adult 136

symptomatic paediatric 136–138

treatment strategy 62

Contraception 81

Coordination

DR-TB control programmes 14,16–17

HIV and TB care 103

Corticosteroids 68

Costs

community-based support 126–127

experimental drugs 211

Creatinine, serum 110, 111Critical drug concentration 37

Cross-resistance 37, 44–45, 56

Culture(s) 42

assessing treatment ailure 131

HIV-coinected patients 92

laboratory register 161, 230–232

monitoring o treatment 108–109,

111

paediatric contacts 137

quality-assured 9

requirements 21

transport 41

turnaround times 46

Cured, denition 23

Cycloserine (Cs) 54, 55


managing adverse eects 113


psychiatric patients 87renal insuciency 85

seizure disorders 86

substance dependence 87


Deault, return ater 22, 28


Deaulted (patients) 24

Denitions 19–25

Demand orecasting, second-line drugs

151

Depression 98, 115

Diabetes mellitus 83

Diagnosis, TB 36

DOTS ramework 9

HIV-coinected patients 91–92, 94

paediatric patients 136–137

turnaround times 46

Diagnostic cohort 24Diagnostic services 38–39

integration with treatment services

2–3

see also Laboratories

INDEX



240


Diamine 208

Diarrhoea 29, 99

Diarylquinolone 208

Didanosine, quinolone interaction 96Died 24

Dignity 166

Directly observed therapy (DOT) 10,

122–123

assessing adequacy 131

community based 125

condentiality 123

delivery 121, 122

HIV coinection 97

District Tuberculosis Register 159–160

DOTS ramework 8–11, 13

Drug developers 211

Drug inormation sheets 173–192

Drug ramping 55, 59

Drug resistance surveillance (DRS)

10, 27

HIV coinection 92

services 38

Drug-resistant tuberculosis (DR-TB)1–6

addressing sources 3–4

causes 3

conrmed 20

denitions 19–25

global response 5–6

magnitude o problem 4–5

management 5–6, 8–12

site 20–21

Drug susceptibility testing (DST) 9,

42–46

case-nding 26–27

contacts o MDR-TB patients 136,

137–138

coverage 155

general denitions 37

genotypic methods 43

guidance o therapy 59

HIV coinection 92, 94key recommendations 37

laboratory register 161, 230–232

limitations 44–45

minimal access to 29–30, 56

monitoring response to therapy

109, 111

mono- and poly-resistant strains

76–77phenotypic methods 43

quality control/assurance 48

rapid methods 26, 31–33, 43–44,

144

rational use 45–46, 47

role in treatment strategies 56–58,

64–65

second-line drugs see Second-line

drug susceptibility testing

service provision 38, 41

specimen collection 30

targeting risk groups 27–29

turnaround times 46, 65

Drugs, antituberculosis see Antituber-

culosis drugs

Duration o treatment 67

Dysglycaemia 101

Economic support, DR-TB controlprogramme 15

Education, disease 122, 125–126

Electrolyte disturbances 100, 110, 116

Emotional support 123

Empirical treatment 52, 53, 64–65

HIV coinection 93

Enablers 123

End-o-lie supportive measures 133

Equality o treatment 200

Equity 200

Essential Medicines, WHO Model List

150, 151

Ethambutol (E) 54

mono- and poly-resistant TB 77


renal insuciency 85


Ethical issues, experimental drugs

210–211Ethical principles 199–200

Ethical review board (ERB) 209, 211

Ethionamide (Eto) 54–55

adverse eects 110



241




paediatric dosing 82in pregnancy 80

renal insuciency 85


Evidence retrieval and synthesis 214–

215

Expanded access programmes 208

Experimental drugs, compassionate use

see Compassionate use

Extensively drug-resistant tuberculosis

(XDR-TB)

contact investigation 136

denition 20

diagnosis 31, 33–34, 44

experimental drugs 208, 211

HIV coinection 90–91, 102

inection control 141–142

magnitude o problem 5

patient-centred care 169

risk actors 34treatment 63, 69, 70

treatment strategies 50–70

Extrapulmonary drug-resistant tuber-

culosis (DR-TB) 20–21, 67

Extrapulmonary tuberculosis,

diagnosis in HIV inection 91–

92, 94

Failed treatment see Treatment ailure

Faith-based organizations 168

First-line drugs 52, 53, 54

dosing 193–194

previous treatment with 22

susceptibility testing 41

Fluoroquinolones 53–54

children 82

didanosine interaction 96


susceptibility testing 44–45weight-based adult dosing 194

see also specifc agents Follow-up

HIV coinection 93

non-adherent patients 124

Further reading 195–197

Gastritis 116Gatifoxacin 54, 183–184

Global Project on Antituberculosis

Drug Resistance Surveillance 4

Glucose, serum 111

Green Light Committee (GLC) 5–6,

59, 152–153

Guidelines Reerence Group 214

Haemoglobin 111

Headache 98

Health-care providers 17

Health system

local 16

public 17

Hearing loss 114

Hepatitis 83–86, 116

Hepatotoxicity 83, 99, 116

High-prevalence areas 28

HIV inection 89–103adverse drug reactions 94, 97, 98–

101

clinical eatures o TB 94

concomitant treatment 94–102

contraindicating thioacetazone 55,

95

coordination o care 103

diagnosis o TB 91–92, 94

DR-TB risk 29, 90–91

drug–drug interactions 96

HIV testing and counselling 91,

111, 137

inection control 93, 102–103, 141


laboratory workers 47

MDR-TB inection control and 93,

102–103

monitoring o therapy 97–102

recommended collaborative activities91–93

TB case-nding 30–31

Homeless shelters 28

Hospice care 133

INDEX



242


Hospitalization 121, 126

duration 141–142

Human resources 145–148

constraints 147development (HRD) plan 145–148

stakeholder role 167

see also Laboratory workers

Human rights 199–203

Hyperlipidaemia 101

Hypokalaemia 116

Hypomagnesaemia 116

Hypothyroidism 101, 110, 115

Imipenem/cilastatin (Ipm/Cln) 54,

194

Immune reconstitution infammatory

syndrome (IRIS) 93, 95, 102

Importation, drug 151–152

Incentives 123

Individualized treatment 52, 53, 64,

66

Inant ormula 81

Inection control 140–144administrative measures 141–142

ater treatment suspension 133

community-based support 125

environmental (engineering)

measures 142–143

implications o HIV 93, 102–103,

141


laboratories 39, 46–47

personal respiratory protection

143–144

priorities 140–141

role o rapid tests 144

Inormation systems see Recording and

reporting systems

Injectable (group 2) antituberculosis

agents 53, 54

adverse eects 110

duration o administration 65–67mono- and poly-resistant TB 77

in pregnancy 80


Institutions, exposure to 28

International Health Regulations

(IHR) 164

International standards or tuberculosis

care 165, 166International support 17

Investigational new drugs (INDs) 209

Iodine treatment 110

Isolation 141, 206

orced 168–169, 205–206

Isoniazid (H) 54


high-dose 53, 54, 55, 194


renal insuciency 85

resistance, magnitude o problem

4–5



Justice 200

Kanamycin (K) 53, 54

inormation sheet 185–186paediatric dosing 82

renal insuciency 85


Laboratories 36–48

essential services and inrastructure

38–39

general denitions 37

guidance on rational use 45–46

inection control and biosaety 39,

46–47


organization o network 39–41

quality control/assurance 48

screening or adverse eects 109–

110

Laboratory Register (orm 04) 161,

230–232

Laboratory workersBCG vaccination 47

health and medical surveillance 47

risk o transmission to 39, 46

Lactation 80–81



243

Lactic acidosis 99, 111

Latent inection 138

Legislation and regulation 198–206

experimental drugs 209–210human rights 201–203

patients’ rights 203–205

Levofoxacin (Lx) 54



renal insuciency 85


Linezolid (Lzd) 54, 194

Lipase, serum 111

Lipodystrophy 101

Liver disorders 83–86

Liver serum enzymes 111

Local health system 16

Malabsorption 29

Manual, DR-TB control programme

15–16

Masks 143–144

Methodology, WHO guidelines 213–215

Microscopy see Smear microscopy

Mineral supplements 68

Minimum inhibitory drug concen-

tration 37

Monitoring

adverse drug eects 109–110, 111

community health workers 127

compassionate use 210

DR-TB and HIV therapy 97–102


non-adherent patients 124

progress o therapy 108–109, 111

Mono-resistant tuberculosis 75–78

case-nding 31

dened 20, 75

reporting 75

treatment 76–78

Moxifoxacin (Mx) 54inormation sheet 189–190


renal insuciency 85


Multidrug-resistant tuberculosis

(MDR-TB)

denition 20

diagnosis 43–44documented, treatment strategy

62–63

experimental drugs 208, 211

HIV coinection 90–91

magnitude o problem 4–5

suspected 20

treatment strategies 50–70

Mycobacteria, non-tuberculous (NTM)

42, 108

Mycobacterium tuberculosis biosaety standards 46–47

culture see Culture(s)

drug susceptibility testing see Drug

susceptibility testing

identication 42

smear microscopy see Smear

microscopy

National tuberculosis controlprogrammes (NTPs) 16

DOTS ramework 9

economic support 15

human resources development

(HRD) plan 145–148

integrating diagnosis and treatment

services 2–3

integrating DR-TB management

11, 12

regulatory and operational

documents 15–16

see also Programmes, DR-TB control

Nausea and vomiting 98, 115

Needs assessment, DR-TB manage-

ment 11, 12

Nephrolithiasis 100

New patients 22, 61

Nitrodihydroimidazooxazole 208

Nitroimidazole 208Non-maleasance 200

Non-tuberculous mycobacteria (NTM)

42, 108

Nongovernmental organizations 168

INDEX



244


Normative principles 200–201

Nutritional support 68, 93, 133

O-label use 210Ofoxacin (Ox) 54



renal insuciency 85


Operational documents 15–16

Optic neuritis 100, 117

Oral contraceptives 81

Oral hypoglycaemic agents 83

Other patients 23

P -aminosalicylic acid (PAS) 55

adverse eects 110



renal insuciency 85

treatment regimens 63–64


Paediatric patients see ChildrenPalliative care 133

Pancreatitis 99

Patient-centred care 165–169

Patient support groups 113, 168, 169

Patients’ charter or tuberculosis care 126, 165, 166

Patients’ rights 199–201, 203–205

Peer review 215

Peer support 167

Peripheral neuropathy 98, 114

Personal respiratory protection 143–

144

Personnel see Human resources

Pharmacovigilance 210

Political commitment 9, 14–16

Poly-resistant tuberculosis 75–78

case-nding 31

dened 20, 75

reporting 75treatment 76–78

Polypeptides, susceptibility testing 44,

45

Potassium, serum 110, 111

Prednisone 68

Pregnancy 80

Pregnancy tests 111

Pretreatment screening and evaluation107–108

Prisons 17, 28

Private practitioners, role in DR-TB

control 17

Private sector, ailure o treatment in

28

Procurement, second-line drugs 151–

152

Programmes, DR-TB control

checklist 17, 18

coordination 14, 16–17

human resources development plan

145–148

poorly operated 29

see also National tuberculosis control

programmes

Proportionality 201

Protionamide (Pto) 54–55

antiretroviral drug interactions 96inormation sheet 181–182


renal insuciency 85


Psychiatric disorders 86–87

Psychosocial support 113, 123, 126

Psychotic syndromes, drug-induced

115

Public–private mix (PPM) programmes

17

Pulmonary drug-resistant tuberculosis

(DR-TB) 20, 21

surgical treatment 67–68

Pulmonary tuberculosis, diagnosis in

HIV inection 91–92, 94

Puried protein derivative (PPD) 137

Pyrazinamide (Z) 54, 59

hepatotoxicity 83

mono- and poly-resistant TB 76–77renal insuciency 85


Pyridoxine 68, 113

Pyrrole 208



245

Quality assurance

drug supply system 152

laboratory 48

recording and reporting system 163Quality control, laboratory 48

Quarterly reports (orm 05) 161–162,

233

Quinolones, didanosine interaction 96

Reading, urther 195–197

Recommendations, development 215

Recording and reporting systems

Category IV see Category IV

recording and reporting system

community-based care 125


standardized 10–11

Reusal o treatment 205

Regimens, treatment see Treatment

regimens

Registers

Category IV (orm 02) 159–161,

225–228District Tuberculosis 159–160

Laboratory (orm 04) 161, 230–232

Registration, case 19–25

Registration groups, patient 21–23

Regulation see Legislation and

regulation

Regulatory documents 15–16

Relapse

denition 22

patient with history o 28, 62

Relevance, TB control 201

Reliability 37

Renal insuciency 83, 85

Renal toxicity 100, 110, 116

Reproducibility 37

Respect or persons 199–200

Respirators, personal 143–144

Responsibilities 200, 204–205

Review date 215Riabutin (Rb) 54

Riampicin (R) 54


hepatotoxicity 83

mono- and poly-resistant TB 76, 77

oral contraceptives and 81

rapid sensitivity testing 31, 32,

43–44renal insuciency 85



Riamycins 53, 96

Risk actors

DR-TB 27–29

XDR-TB 34

Salvage regimens 63–64

Scoping, WHO guidelines 213

Screening

adverse drug eects 109–110

pretreatment 107–108

Second-line drug susceptibility testing

(DST) 38, 41

case-nding 33–34

limitations 44–45

methods 43

policy guidance 45–46, 47quality control/assurance 48

treatment strategies and 63

Second-line drugs 53–55

children 82

demand orecasting 151

GLC mechanism 152–153

hepatotoxic 83

HIV coinection 93, 97

management 150–153


previous treatment with 22


WHO Model List o Essential

Medicines 150, 151

Seizure disorders 86

Seizures, drug-induced 114

Separation, MDR-TB patients 141

Short-course chemotherapy (SCC)

amplier eect 3mono- and poly-resistant TB 75


sputum smear-positive at months 2

and 3 28

INDEX



246


Six-month interim outcome assessment

(orm 06) 162, 234

Skin rashes 99

Smear microscopy 21, 41–42assessing treatment ailure 131


111


Social acceptability, TB control 201

Social support 126, 167

Socioeconomic support 93, 123, 126,

166

Special access programmes 208

Special conditions and situations 79–

87

Specimens

sae handling 39

transport 41

Sputum conversion 21, 109

Sputum examination 41–42


111

request or (orm 03) 161, 229symptomatic contacts 136, 137

terminology 21

see also Culture(s); Smear microscopy

Sta see Human resources

Stakeholders 93, 167

Standardized treatment 52, 53, 63–64

Stevens-Johnson syndrome 55

Stigma, reducing 126, 167

Stop TB Strategy 1–2

Storage, drug 152

Streptomycin (S) 53, 54


renal insuciency 85


Substance dependence 87

Supportive care 123

adverse eects 113

community based 124–127

end-o-lie measures 133HIV coinection 93

inant eeding 81

Supranational reerence laboratories

(SRLs) 39–40, 45, 48

Surgery, resection 67–68

Suspending therapy 132

approach to 132–133

indications or 131–132Sustainability, community-based

support 126–127

Target audience, WHO guidelines 214

Terizidone (Trd) 54, 55



renal insuciency 85


Thioacetazone (Thz) 54, 55

contraindications 55, 95

dosing 194

Thyroid stimulating hormone (TSH),

serum 110, 111

Training

community-based 125–126

programmes, development 147–148

Transerred-in patients 23, 25

Transerred-out patients 24, 25Transport o inectious substances 41

Travel, or treatment 121, 122

Treatment

adherence 121–124

adjuvant 68

causes o inadequate 3

completed 24

delivery 120–128

duration 67

integration with diagnostic services

2–3

outcome denitions 23–24

patient classication by previous

21–23

reusal 205

screening and evaluation beore

107–108

suspending 131–133

Treatment cohort 24Treatment ailure 63, 130–144

assessing patients at risk 130–131

denitions 24, 132

monitoring or 108–109



supportive care 133

suspending therapy 131–133

see also Category I ailures; Category

INDEX

essential assessments beore

designing 51–52
