Management of Drug-Resistant Tuberculosis Your name Institution/organization Meeting Date International Standard 12.

Management of Drug-Resistant TuberculosisYour name Institution/organizationMeetingDate

International Standard 12

ISTC TB Training Modules 2009

Management of Drug-Resistant TB

Objectives: At the end of this presentation, participants will be able to: Describe the principles upon which treatment of

drug-resistant TB is based Understand the essential features of MDR-TB

case management Recognize the importance of patient-centered

DOT in MDR-TB treatment Become familiar with common side effects of

drugs used in the treatment of MDR-TB

International Standards 12


Overview: Definitions and predictors of

drug resistance Treatment principles Case-management principles Patient-centered directly

observed therapy Common side effects of

MDR-TB treatment


Standard 12: Management of Drug-Resistant TB

Patients with or highly likely to have tuberculosis caused by drug-resistant (especially MDR/XDR) organisms should be treated with specialized regimens containing second-line antituberculosis drugs

The regimen chosen may be standardized or based on suspected or confirmed drug susceptibility patterns

At least four drugs to which the organisms are known or presumed to be susceptible, including an injectable agent, should be used, and treatment should be given for at least 18–24 months beyond culture conversion

(1 of 2)


Standard 12: Management of Drug-Resistant TB

Patient-centered measures, including observation of treatment, are required to ensure adherence

Consultation with a provider experienced in treatment of patients with MDR/XDR tuberculosis should be obtained

(2 of 2)


Drug-Resistant TB: Definitions

Mono-resistant: Resistance to a single drug Poly-resistant: Resistance to more than one

drug, but not the combination of isoniazid and rifampicin

Multidrug-resistant (MDR): Resistance to at least isoniazid and rifampicin

Extensively drug-resistant (XDR): MDR plus resistance to fluoroquinolones and at least 1 of the 3 injectable drugs (amikacin, kanamycin, capreomycin)


Drug-Resistant TB: Definitions

Primary drug-resistance: “New Cases”Drug resistance in a patient who has never been treated for tuberculosis or received less than one month of therapy

Secondary (acquired) drug-resistance:“Previously Treated Cases”

Drug resistance in a patient who has received at least one month of anti-TB therapy


Recognizing Predictors of Drug-resistant TB

Assess drug resistance in any patient being started on treatment for tuberculosis

Nonadherence, default History of prior treatment Exposure to possible drug-resistant source

case Community prevalence of drug resistance

If drug resistance is suspected based on any of the above factors, culture and susceptibility testing should be performed for at least INH and rifampicin

ISTC TB Training Modules 2009Note: PZA does not prevent acquired resistance to companion drugs.

Predicted Resistance Pattern

Empiric Regimen (minimum duration)

INH RIF, EMB, PZA (6-9 mo)

INH, EMBRIF, PZA, Fluoroquinolone +

Injectable (9-12 mo)

RIF INH, EMB + PZA (18 mo minimum)

RIF, EMBINH, Fluoroquinolone,

PZA + Injectable (18-month minimum)

INH = Isoniazid, RIF = Rifampicin, EMB = Ethambutol, PZA = Pyrazinamide

Empiric Regimens for Drug-resistant TB


Multidrug-Resistant TB“I have been treated several times over the past five years

and I’m still coughing and can’t gain weight!”


MDR/XDR Treatment Strategies: WHO

Three approaches to treatment: Standardized regimens Empiric regimens Individualized treatment regimens

(based on DST results)

The choice among these should be based on: Availability of second-line drugs Local drug-resistance patterns, and the history of use

of second-line drugs Drug susceptibility testing of first- and second-line

drugs


Categories of Antituberculosis Drugs: WHO

Group 1 – First-line drugs: Isoniazid, rifampicin, ethambutol, pyrazinamide

Group 2 - Injectable agents: Kanamycin, amikacin, capreomycin, streptomycin

Group 3 - Fluoroquinolones: Levofloxacin, moxifloxacin, ofloxacin

Group 4 - Oral bacteriostatic agents: Ethionamide, cycloserine, para-aminosalicylic acid (PAS), prothionamide, terizadone

Group 5 – Unclear role: Clofazamine, linezolid, amoxicillin/clavulanate, Imipenem/cilastatin, thioacetazone, high-dose isoniazid, clarithromycin,


Designing an MDR/XDR Treatment Regimen

General Principles, WHO Use of at least four drugs highly likely to be

effective Do not use drugs for which there is

cross-resistance Eliminate drugs that are unsafe for the patient. Include drugs from groups 1-5 in a hierarchical

order based on potency Be prepared to prevent, monitor and manage

adverse effects from the drugs selected


Additional Important Principles: WHO

Use direct observation of treatment (DOT) with a patient-centered approach to care

Use daily, not intermittent, administration Treatment duration of a minimum of 18-24

months after culture conversion When possible, continue injectable for

minimum six months (at least 4 months post-culture conversion)

Continue at least three oral drugs for full treatment duration


Potential Effectiveness: WHO

Effectiveness is supported by a number of factors: Demonstrated susceptibility No history of treatment failure with the drug No contacts with resistance to the drug Resistance rare in similar patients (surveys) Drug is not commonly used in the area

If at least four drugs are not certain to be effective, use five to seven drugs, depending on specific drugs and degree of certainty.


Cross-Resistance: WHO

All rifamycins: high level cross-resistance Fluoroquinolones: variable, but probably

should be assumed to be cross-resistant Amikacin and kanamycin: generally highly

cross-resistant, but both should be tested Capreomycin and aminoglycosides:

occasional cross-resistance, susceptibilities should be tested


Drug Contraindications: WHO

Known severe drug allergy Unmanageable drug intolerance Risk of severe toxicity, with symptoms

such as renal failure, hepatitis, hearing loss, depression, and psychosis

Drugs of unknown quality (lack of quality assurance exposes patient to risks with unknown benefits)


Determining Drugs to Use: WHO

Use any first-line drug likely to be effective (Group1)

Include aminoglycoside or capreomycin (Group 2)

A fluoroquinolone should always be used if deemed likely to be effective (Group 3)

Use remaining Group 4 drugs to make a regimen of at least four effective agents

Use Group 5 drugs as needed to make a regimen of at least four effective agents


Predicted Resistance Pattern Empiric Regimen

INH, RIF Fluoroquinolone, PZA, EMB, Injectable

INH, RIF, EMB Fluoroquinolone, PZA, Injectable, CS, + PAS or ETH

INH, RIF, PZA Fluoroquinolone, EMB, Injectable, CS, + PAS or ETH

INH, RIF, PZA, EMB Fluoroquinolone, Injectable, CS, PAS or ETH, + one more drug

INH = Isoniazid, RIF = Rifampicin, EMB = Ethambutol, PZA = PyrazinamideCS = Cycloserine, PAS = P-aminosalicylic acid, ETH = Ethionamide

Empiric Regimens for MDR-TB


Use any available

One of these

One of these

First-line drugs Fluoroquinolones Injectable

agents

Pyrazinamide

Ethambutol

Levofloxacin

Moxifloxacin

Ofloxacin

Amikacin

Capreomycin

Streptomycin

Kanamycin

Building a Regimen for MDR-TB STEP 1

Begin with any first-line agents to which the isolate is susceptible

Add a fluoroquinolone and an injectable drug based on susceptibilities

PLUS PLUS


Pick one or more of these

Oral second-line drugs

CycloserineEthionamidePAS

Building a Regimen for MDR-TB STEP 2

If 4 drugs are not identified in Step 1:Add second-line drugs until you have four to six drugs to which the isolate is susceptible (and preferably which have not been used to treat the patient previously)


Consider use of these

Third-line drugs

Clofazimine

Linezolid

Amoxicillin/Clavulanate

Imipenem

Clarithromycin

STEP 3

Building a Regimen for MDR-TB

If there are not four to six drugs available in the abovecategories, consider third-line drugs in consultation with an expert.


Building a Regimen for XDR-TB STEP 1

Begin with any first-line agents to which the isolate is susceptible

Add a fluoroquinolone and an injectable drug based on susceptibilities

Use any available

One of these

One of these

First-line drugs Fluoroquinolones Injectable

agents

Pyrazinamide

Ethambutol

Levofloxacin

Moxifloxacin

Ofloxacin

Amikacin ?

Capreomycin ?

Streptomycin ?

Kanamycin ?

Commonly not susceptible

By definition there is fluoroquinolone resistance

Select agent based on historyand susceptibility testing

PLUS PLUS


STEP 2

Building a Regimen for XDR-TB

Add second-line drugs until you have four to six drugs to which the isolate is susceptible (and preferably which have not been used to treat the patient previously)

Pick one or more of these

Oral second-line drugs

CycloserineEthionamidePAS

With XDR-TB, often all three of these agents are necessary


STEP 3

Building a Regimen for XDR-TB

If there are not four–six drugs available in the above categories, consider third-line drugs in consultation with an expert.

Consider use of these

Third-line drugs

Clofazimine

Linezolid

Amoxicillin/Clavulanate

Imipenem

Clarithromycin


Ensure laboratory services for hematology, biochemistry and audiometry are available

Establish a clinical and laboratory baseline before starting the regimen

Initiate treatment gradually when using drugs that cause gastro-intestinal intolerance

Ensure availability of ancillary drugs to manage adverse effects

Use DOT for all doses

Initiating Treatment: WHO


Isolate until three consecutive sputum AFB smears (or documented culture conversion) are negative and there has been a good clinical response to treatment

Initiate MDR-TB treatment under close supervision to provide patient education and monitoring and to treat drug toxicity

Tailor toxicity monitoring to specific drugs employed

Seek consultation with an expert as soon as drug resistance is known

MDR/XDR-TB: Management Principles


Use daily patient-centered DOT throughout entire treatment course

Record drugs given, bacteriological results, chest radiographic findings, and the occurrence of toxicities

Optimize management of underlying medical conditions (example: diabetes) and nutritional status

MDR/XDR-TB: Management Principles


MDR/XDR-TB: Monitoring

Collect sputum specimens for smear and culture periodically during treatment once culture negative

Obtain end-of-treatment sputum specimen for smear and culture

Perform chest radiograph periodically during treatment and at end of treatment

Resources permitting, monitor minimum of two years following treatment (quarterly during first year, every six months during second year)


As soon as rifampicin resistance is known, order second-line drug susceptibility testing

Repeat susceptibility testing on cultures that remain positive after two–three months of treatment

MDR/XDR-TB: Laboratory Testing


More Than Watching PatientsSwallow Their Pills DOT is a support system that enables

the completion of the long, difficult course of MDR-TB treatment

A patient requires respect and dignity regardless of social class, educational level or unhealthy behaviors

The whole patient, lifestyle and support system are assessed and routinely addressed in the delivery of care

Goal: Inspire and empower patient via a relationship of trust and support

Patient-centered DOT


Weis SE, et al. NEJM 1994; 330(17): 1179-84* P < 0.001

Self-RX N=407 (pre 1987)

DOTN=581 (1987 +)

Primary R 13.0% 6.7%

Secondary R 10.3% 1.4%

Relapse 20.9% 5.5%

MDR relapse 6.1% 0.9%

Directly Observed TreatmentEffect on Resistance and Relapse


Common Adverse Effects

G.I. complaints

Ethionamide CycloserinePAS Fluoroquinolones Clofazimine Rifabutin

Hepatotoxicity

(early symptoms are anorexia and malaise, then abdominal pain, vomiting, jaundice)

INH Rifampicin/rifabutin Ethionamide PZA PAS Fluoroquinolones



Peripheral neuropathy

INH Ethionamide Cycloserine LinezolidEthambutol

Rash All

Headache

Fluoroquinolones Isoniazid Cycloserine Ethionamide Ethambutol

Seizures Cycloserine



Hypothyroidism Ethionamide, PAS

Hearing loss, Vestibular toxicity

Aminoglycosides, Capreomycin

Behavioral changes Cycloserine, Ethionamide, Isoniazid, Fluoroquinolones

Visual changes Ethambutol, Rifabutin, Isoniazid, Linezolid

Renal failureHypokalemia, Hypomagnesemia

Aminoglycosides, Capreomycin



Summary:

Treatment of MDR-TB is complex and costly. It is much easier to prevent than to treat. XDR-TB is even more difficult!

Expert consultation should be obtained whenever possible when MDR- or XDR-TB is suspected.



Summary (cont.):

Patients can be treated with a standardized or an empiric regimen. Ideally the regimen should be guided by drug-susceptibility tests.

There are sound principles that can be used to guide the design of a treatment regimen.



Summary (cont.):

Considerable attention must be paid to treatment supervision and support.

A patient-centered approach to DOT is an important element of successful care.

Adverse effects of second-line drugs are common and may be severe. Monitoring for these effects is essential.


Standard 12: Patients with TB caused by drug-resistant

(especially MDR) organisms should be treated with specialized regimens containing second-line antituberculosis drugs.

At least four drugs to which the organisms are known or presumed to be susceptible should be used (treatment for at least 18 months).

Summary: ISTC Standard Covered*

*[Abbreviated version]


Standard 12 (cont.):

Patient-centered measures are required to ensure adherence.

Consultation with a provider experienced in treatment of patients with MDR-TB should be obtained.

Summary: ISTC Standard Covered*

*[Abbreviated version]


Alternate Slides


Resources

WHO: Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis, Emergency Update 2008 www.who.int/tb

Drug-Resistant Tuberculosis, A Survival Guide for Clinicians, 2nd edition 2008 www.nationaltbcenter.ucsf.edu

The PIH guide to the Medical Management of Multidrug-Resistant Tuberculosis, International Edition. Partners in Health 2003. www.pih.org


Purpose of ISTC


ISTC: Key Points

21 Standards (revised/renumbered in 2009) Differ from existing guidelines: standards

present what should be done, whereas, guidelines describe how the action is to be accomplished

Evidence-based, living document Developed in tandem with Patients’ Charter

for Tuberculosis Care Handbook for using the International

Standards for Tuberculosis Care


Audience: all health care practitioners, public and private

Scope: diagnosis, treatment, and public health responsibilities; intended to complement local and national guidelines

Rationale: sound tuberculosis control requires the effective engagement of all providers in providing high quality care and in collaborating with TB control programs

ISTC: Key Points


Questions



1. The 5 year-old son of a woman you are currently treating for known isoniazid and rifampicin resistant tuberculosis presents with cough and malaise for three weeks and an abnormal chest film. Of the following available regimens, choose the one best option:

A. Begin empiric treatment with at least four drugs that the mother’s organism is known to be susceptible to

B. Begin empiric treatment with the standard initial regimen of isoniazid, rifampicin, ethambutol, and pyrazinamide with the addition of a fluoroquinolone

C. Begin empiric treatment with the standard initial regimen of isoniazid, rifampicin, ethambutol, and pyrazinamide

D. Treat first for a potential community-acquired pneumonia with a fluoroquinolone



2. Reasonable steps for building a regimen for multidrug-resistant tuberculosis after drug-sensitivities results are known include all of the following except:

A. Always start by choosing any available first-line drug that the isolate remains susceptible to

B. Aim for a total of four to six drugs that the isolate is known to be sensitive to (preferably not drugs used previously by the patient)

C. Second-line agents (like cycloserine, ethionimide, and PAS) would be preferred over injectable agents to minimize healthcare resources used in association with injections and improve patient comfort

D. If there are not four to six drugs available among the first- and second-line agents, third-line agents could be considered, preferably in consultation with an expert



3. Clinical management and monitoring plans for the care of MDR/XDR-TB should include (as resources permit) all of the following except:

A. Daily patient-centered directly observed treatment (DOT) throughout the entire treatment course

B. Diligent recording of drugs given, bacteriological results, chest film findings and any occurrence of medication toxicity

C. Periodic sputum specimens for smear and culture, both to document culture conversion and monitor for signs of treatment failure

D. Monthly sputum for drug-sensitivity testing throughout the entire course of treatment

Management of Drug-Resistant Tuberculosis Your name Institution/organization Meeting Date International Standard 12.

Documents

drugresistant tb slide

treatment of drug

tb treatment slide

management of drug

mdrtb treatment

istc tb training modules

multidrugresistant tb

resistant tb patients