Management of Drug-Resistant TBglobaltb.njms.rutgers.edu/downloads/courses/tbintensive...MDR TB defined as resistance to at least isoniazid and rifampin. Primary MDR TB United States,

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Management of Drug-Resistant TB

Dana G. Kissner, M.D.Wayne State University

Detroit Department of Health & Wellness Promotion: TB Services

2010

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DefinitionsHistoryEpidemiologyOrigins of drug resistanceDiagnosing drug resistanceDiagnosing drug resistanceTreatment of MDR -TBContacts of MDR -TB cases

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MDR (Multiple Drug-Resistant) TB◦ Resistant to AT LEAST INH & RIF◦ INCLUDESINCLUDESXDR (Extensively Drug-Resistant) TB*◦ MDR-TB that is also resistant to:MDR TB that is also resistant to:

ANY fluoroquinolone plusANY ONE OF THE FOLLOWING INJECTABLES:

AmikacinCapreomycinKanamycin

*Case definition 10/06 by WHO Emergency Global Task Force on XDR-TB

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Pre-XDR◦ MDR TB◦ Resistant to a fluoroquinolone OR an injectable*,

but not bothTDR (Total Drug-Resistant) TB( g )

*Amikacin, Capreomycin, Kanamycin

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ODR (Other Drug Resistant) TB◦ Resistant to INH, but not to RIF ◦ Resistant to RIF, but not to INH◦ Resistant to EMB, PZA*, &/or streptomycin, but not

to INH or RIF (also known as polyresistant)

*RIF & PZA are essential for 6 month regimens

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Drug Resistance in New Case◦ Patients with <1 month prior TB treatment◦ implies recent transmission of drug resistant TB◦ Older term: Primary resistance

Drug Resistance in Previously Treated Case◦ Patients previously treated for TB > 1 month◦ May include acquired resistance or re-infection*◦ Older term: Secondary resistance

*If DST is not available for first isolate, may also include primary resistance with failed therapy

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Drug resistance can develop in a patient treated inappropriately for more than 1 month.

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Resistance 1st

recognized with Streptomycin 1940s1980s multiple

b k f MDR240002600028000

Reported Cases MDR TB in USA

outbreaks of MDR-TB◦ NY, FL◦ Beijing strain W in NY

Highly transmissible, virulent

10000120001400016000180002000022000

83 85 87 89 91 93 95 97 99 2001

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1987 – Advisory Council for the Elimination of TB (ACET) established

1992 – National Action Plan to Combat MDR-TBpublished (MMWR)

1994 WHO and IUATLD established Global Project On1994 WHO and IUATLD established Global Project On Anti-TB Drug Resistance Surveillance, including a supranational laboratory network◦ Reports

1997, 2000, 2004February 2008 – reporting for 2002-20072010 “Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on surveillance and response”

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Supranational Reference Laboratories 2009

1994 – Supranational Reference Laboratory Network was formed to assure quality of laboratories participating in Global Project

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2000 – Stop TB Partnership’s Green Light Green Light CommitteeCommittee was formed to improve access to 2nd-line drugs

Soon theSoon the Green Light CommitteeGreen Light Committee encounteredSoon the Soon the Green Light Committee Green Light Committee encountered cases resistant to 2nd-line drugs

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11/05 – 1st report of findings on XDR-TB

2000-2004 – Of 17,690 TB isolates world-wide (convenience sample) 20% MDR, 2% XDR TB*XDR-TB*

10/06 – Case definition revised

*Definition used: Res INH, RIF, & 3/6 main classes of 2nd line drugs. Shah, et al. Emerging Inf Dis 2007;13:380-387

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2006 – Tugela Ferry, KwaZulu-Natal Province, South Africa*◦ 53 patients with XDR-TBp◦ 52 died within an average of 25 days from time drug

resistance first suspected◦ All 44 patients tested for HIV were +

*Gandhi, et al. XDR TB…Lancet 2006;368:1575-80 **Basu, et al. Prevention of nosocomial trans…Lancet 2007;370: 1500-07

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2007: Global Laboratory Initiative◦ Strengthen laboratory availability, capabilitiesMay, 2009: World Health Assembly Resolution 62.15◦ Urges member states to achieve universal access to◦ Urges member states to achieve universal access to

diagnosis and treatment of MDR TB, including XDR

440,000 incident cases of TB were MDR TB3.6% of all TB cases were MDR TBAlmost 50% were from I di & Chi 9%India & China, 9% Russia150,000 deaths from MDR TBProportion of MDR & XDR cases highest in Central Asia, Russian Federation <2% MDR TB cases reported to WHO

Small PM, Pai M. NEJM.org Sep 1 2010

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19Proportion of MDRProportion of MDR--TB Among New TB Among New

TB Cases: 1994TB Cases: 1994--20092009

20Proportion of MDRProportion of MDR--TB Among Previously TB Among Previously

Treated TB Cases:1994Treated TB Cases:1994--20092009

ChinaIndiaRussian FederationSouth AfricaIndonesia

KazakhstanEstoniaGeorgiaRepublic of MoldovaAzerbaijanUzbekistan

Highest # of Cases Highest Proportion of MDR Cases

PakistanNigeriaUkraineBangladesh

UzbekistanRussian FederationLithuaniaUkraineLatvia

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DURBAN, South Africa — “Most patients in the hulking, seven-story tuberculosis hospital here — all infected with potentially lethal, drug-resistant strains of the disease — have gone home

since a majority of nurses, orderlies and janitors went on strike a week and a half ago.” By CELIA W. DUGGER

August 27, 2010

Joao Silva for The New York Times

King George V Hospital

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INH Resistant 782 cases (8.4% )MDR TB 107 cases (1.1% cases)Primary MDR** 86 cases (1.1%)◦ 77% were foreign bornXDR TB 4 casesXDR TB 4 cases

◦ California, NY, Texas – Highest # DR cases

*CDC. Reported Tuberculosis in the United States 2008. Published Sept, 2009

**No prior history of TB

Primary Anti-TB Drug Resistance United States, 1993–2008*

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esis

tant

01993 1996 1999 2002 2005 2008

Isoniazid MDR TB

% R

e

*Updated as of May 20, 2009.

Note: Based on initial isolates from persons with no prior history of TB.Multidrug resistant TB (MDR TB) is defined as resistance to at least isoniazid and rifampin.

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Primary MDR TB inU.S.-born vs. Foreign-born Persons,

United States, 1993–2008*

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3

esista

nt

0

1

1993 1996 1999 2002 2005 2008

U.S.-born Foreign-born

% R

e

*Updated as of May 20, 2009.

Note: Based on initial isolates from persons with no prior history of TB.MDR TB defined as resistance to at least isoniazid and rifampin.

Primary MDR TBUnited States, 1993–2008*

200300400500

2

3No. of Cases Percentage

0100200

1993 1996 1999 2002 2005 20080

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No. of Cases Percentage

*Updated as of May 20, 2009.

Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least isoniazid and rifampin.

XDR TB Case Count defined on Initial DST† by Year, 1993–2008*

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Coun

t

0

2

4

6

1993 1996 1999 2002 2005 2008

Case

C

Year of Diagnosis†Drug susceptibility test.*Reported incident cases as of May 20, 2009.Extensively drug-resistant TB (XDR TB) is defined as resistance to isoniazid and rifampin, plus resistance to any fluoroquinolone and at least one of three injectable second-line anti-TB drugs.

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Drug costs 50-200 times higherOverall costs 10 times higherDuration of treatment 3-4 times longerDrug toxicity much higherB 70%Best cure rate < 70%2010-2015 ◦ Cost to treat 1.3 million MDR TB cases in 27 high

burden countries is estimated to be 16.2 billion US dollars

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Genetic mutations◦ Single nucleotide substitutions ◦ No horizontal gene transferSelective pressure◦ Inappropriate treatment

or

Nucleotides

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SM (aminocyclitol glycoside)◦ rrs◦ rpsL◦ strAQuinolones (CIP, OFX)

INH ◦ KatG◦ inhA◦ kasA◦ ahpC

85% of 85% of resistanceresistance

◦ gyrAKanamycin, Amikacin◦ rrsCycloserine◦ ?alrAEthionamide (analog INH)◦ inhA

◦ oxyRRIF◦ rpoBPZA (analog nicotinamide)◦ pncAEMB◦ embB

>95% of >95% of resistanceresistance

32Spontaneous mutationsdevelop as bacilliproliferate to >108

Drug Mutation RateRifampin 10-8

Isoniazid 10-6

Pyrazinamide 10-6

Thomas Shinnick, PhD, Mycobacteriology

Lab Branch, DTBE CDC

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Spontaneous mutations are more likely in cavitary disease with many rapidly growing organisms

Mutations occur at a rate that makes it impossible f l bfor a single organism to become resistant to more than one antibiotic without selective pressure

◦ The likelihood is the product of the probabilities for each: INH & RIF (1 in 10-14). This # does not occur

Antibiotics select resistant organisms to survive

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A mutation occurs in an INH-R organism that makes it resistant to RIF. Only the

MDR-TB organisms can survive.

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Phenotypically◦ Culture growth in the presence of drugGenotypically◦ Identify resistance-conferring mutations

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Culture-based◦ Proportion Method (GOLD GOLD standard) - Resistance

present when >1% of # of control colonies grow when exposed to drug

Solid Medium (Middlebrook 7H10 agar) ControlSolid Medium (Middlebrook 7H10 agar) Broth – Manual & Automated

Bactec 460TB (radiometric) (G0LD G0LD standard for PZA)Measures 14CO2 produced)

Bactec MGIT 960 (fluorescent marker) ◦ Absolute Concentration - ~MIC◦ Relative Ratio

Control

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AFB smear: ≤ 24 hNucleic acid amplification assay: ≤ 48 h◦ Confirms M.tb complexGrowth detection by culture: ≤ 14 days (broth)(broth)TB identification: ≤ 21 days (DNA, broth)Susceptibility testing (DST): < 30 days (directly on broth) – 1o drugsDST of 2o drugs: ≤ 4 weeks from request

*CDC. Controlling TB in the US…MMWR 2005; 54:1-79 Wisconsin has laws/regs mandating essential lab services

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EMB – to work, drug needs to enter cell. Growth continues until the drug is incorporated into the organism. Can be interpreted falsely as resistant.

PZA – different method is used; drug is only active at lower pH. Organism is allowed to start growth at normal pH; then pH is lowered to 6 and continued growth is compared with & without PZA.

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The following 3 tables are adapted from Ghandi NR, et al. Lancet 2010;375:830-43PATH=Program for Appropriate Technology in Healthin HealthFIND=Foundation for Innovative New Diagnostics

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43Culture Description Manufacturer

Microscopic Observation Drug Susceptibility Assay(MODS)More D, et al. NEJM 2006;355:1539-50

Broth culture, inverted light microscope to detect cord formation, with & without drugs

Standardized version being developed by PATH

Thin la er agar Earl gro th detection on selecti e Standardi ed ersion

www.upch.edu

Thin-layer agar Early growth detection on selective thin-layer agar, detect with light microscopy or colorimetric method

Standardized version being developed by FIND

Nitrate reductase assay

Early growth detected via color change caused by ability of MTB to reduce nitrate to nitrite (Griess reaction), selective media

None, endorsed by WHO to detect drug resistance

Colorimetric redox indicator assays

Growth detected by reduction of a colored indicator added to selective media

None, endorsed by WHO to detect drug resistance

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Nucleic Acid Amplification Test

Description Manufacturer / Availability

Line Probe Assays

Endorsed by WHO to detect drug resistance

PCR amplification of a segment of rpoB (& InhA, KatG for INH) with hybridization of the biotin-labeled amplicons

Hain Lifscience: Geno Type® MTBDR plus detects RIF & INH res;

MTBDRsl detects to oligonucleotide probes on a membrane strip (line probe)

fluoroquinolones, aminoglycosides, capreomycin & EMB res.

Innogenetics: INNO-LiPA® Rif.TB

XpertMTB/RIF Multiplex PCR amplification of rpoB with real-time detection with a fluorescent signal (molecular beacons

Cepheid

Funded by FIND

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Line Probe Assays - Commercial products–approved in EuropeDetect MTB complex and resistance mutations on clinical specimen

INNO-LiPA ® Rif TB (Innogenetics)Tests RIF R; 91% RIF R isolates are INH R

GenoType® MTBDR plus (Hain Lifescience)Tests for RIF & INH resistance -katG, inhA, & rpoB * **

* Piloted in NY **Barnard, et al. Am J Respir Crit Care 2008;177:787-792 – SA -done on sputum with ≥ 1+ AFB

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Public-Private partnership◦ GeneXpert, Cepheid and FINDFully automated molecular test ◦ For TB case detection◦ For Rifampin - resistance testingFor Rifampin resistance testing

Assay Procedure for the MTB/RIF Test.

Boehme CC et al. N Engl J Med 2010. DOI: 10.1056/NEJMoa0907847

Beacon, Unhybridized oligonucleotide QuencherFFluorophore

HybridFluorophore

Diagram adapted from: http://www.cellscience.com

Loop containsLoop contains probe sequence complementary to target sequence. When the target sequence is present, a hybrid is formed and fluorescence occurs. Beacons are highly specific & can discriminate sequences that differ by a single nucleotide.

No resistance mutations

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5 sites in Peru, Azerbaijan, S Africa (Capetown & Durham), IndiaJuly, 2008 – March, 2009Funded by Cepheid, FIND, NIH, Bill & Melinda Gates Foundation551/561 (98 2%) f l551/561 (98.2%) of culture +, smear + cases detected124/171 (72%) culture +, smear – cases detected◦ 90% detected after 3rd test200/2005 (97%) RIF-resistant cases identified504/514 (98.1%) Rif-sensitive cases identified

Boehme CC et al. N Engl J Med 2010. DOI: 10.1056/NEJMoa0907847

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Technology Description ManufacturerBacteriophage assays Mycobacteriophages

infect MTb, replicate, are released, & detected as plaques on “lawn” of M. smegmatis

BIOTEC Laboratories Ltd: FASTPlaque TB-Response

smegmatis

High Resolution Melt Assays

Uses DNA melting temperature during PCR to scan for mutations

Experimental

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Prior treatment, especially with inappropriate regimen◦ Wrong drugs, doses, regimens

Rifabutin in HIV – useful when protease inhibitors are needed. When used twice a week, has been associated with relapse treatment failure & acquired resistance When CD4relapse, treatment failure, & acquired resistance. When CD4 <100/mm3 use daily or tiwRifapentine – should not be used in patients with cavitary disease, + AFB after 2 months of therapy, HIV/AIDS

◦ Interruptions◦ Noncompliance◦ Malabsorption

Burman, et al. Acquired rifamycin res with twice weekly Rx HIV-related TB Am J Respir Crit Care Med 2006; 173

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Extensive cavitary disease (more organisms)Poor clinical response to therapy after 2 monthsPositive cultures after 3 months ofPositive cultures after 3 months of therapyContact with person with resistant diseaseEmigration from or travel to high prevalence/incidence region

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All new isolates – test 1st line drugs+ cultures after 3 months of therapy+ cultures after period of negative ones2o drugs should be tested for all cases of RIF

i tresistance◦ Should only be done in reference laboratoriesCOMMUNICATE WITH LAB

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IsoniazidRifampinPyrazinamideEthambutol

StreptomycinAmikacin or kanamycin*Capreomycin

First Line Drugs Second Line Drugs

Rifabutin*Rifapentine

Cycloserinep-Aminosalicylic acidEthionamideLevofloxacin*Moxifloxacin*

*Not approved by U.S. Food & Drug Administration for

use in treatment of TB

Linezolid*Imepenim*Ampicillin/Clavulanate*Clarithromycin*

Gatifloxacin is off the market Cipro is notrecommended – it has resulted in

Third Line Drugs

Clofazimine*has resulted in relapses and longer time to cure when substituted into 1st-line regimensLinezolid – good invitro sensitivity

*Not approved by U.S. Food & Drug Administration for use in

treatment of TB

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Initial DSTs will be sufficient if:◦ 1. The patient has not been on TB Rx between the time

the sputum was obtained & the results become availableStandard is <30 days for primary drugs< 4 weeks from REQUEST for secondary ones

2 Th i h b ffi i # f d◦ 2. The patient has been on a sufficient # of drugs to which the TB is sensitive to prevent further resistance

DSTs will be outdated if:◦ The patient has been on an insufficient # of drugs to

prevent the development of new resistance between the time the sputum was collected & the DSTs are available

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TB is diagnosed; patient started on RIPE5 weeks later DST shows R to INH, RIF, PZADuring the 5 weeks the patient has been receiving only 1 effective drug – EMBA embB mutation may have occurred, causing e b utat o ay a e occu ed, caus gEMB-RYou need a new DST to determine if this is the case in addition to DST for secondary drugsIf DST only shows INH-R, you can assume that there is no further resistance

R=resistance

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Take a very careful history of prior TB therapy

Try to determine source case

Ob i h l if h h dObtain expert help if you have not had experience treating drug resistant TB

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Select at least 3 drugs (4 for MDR-TB) that the patient has never taken before (or that the TB is sensitive to if DSTs can be considered sufficient). Add other previously unused drugs likely to be active.

Continue drugs to which the TB was sensitive◦ Obtain a new specimen for DST to confirm that

sensitivity persists◦ In our example you would continue EMB in addition

to the 3-4 new drugs

Consider initial inpatient management

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All rifamycinsAll quinolonesAmikacin and kanamycin (usually) (deoxystreptamine aminoglycosides)

Capreomycin is a polypeptide & may be cross◦ Capreomycin is a polypeptide & may be cross-resistant to amikacin & kanamycin

INH & Ethionamide when there is resistance to low levels of INH only (inhA mutation)

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Step 1Use any available

Begin with anyFirst line agents toWhich the isolate is Susceptible

Add aFluoroquinoloneAnd an injectable

Fluoroquinolones

Levofloxacin

Injectable agentsAmikacin Capreomycin

PLUSOne of these

One of these

First-line drugs

Pyrazinamide

Eth b t l

PLUS

And an injectableDrug based onsusceptibilities

Moxifloxacinp y

Streptomycin Kanamycin

Ethambutol

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Step 1Use any available

Begin with anyFirst line agents toWhich the isolate is Susceptible

Add a

Fluoroquinolones Injectable agents

PLUSOne of these

One of these

First-line drugs

PLUS

Add aFluoroquinoloneAnd an injectableDrug based onsusceptibilities

Levofloxacin Moxifloxacin

Amikacin Capreomycin Streptomycin Kanamycin

Pyrazinamide

Ethambutol

Step 2 Pick one or more of these

Oral second line drugsCycloserine Ethionamide PAS

Add 2nd line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously)

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Step 1Use any available

Begin with anyFirst line agents toWhich the isolate is Susceptible

Add aFluoroquinoloneAnd an injectableDrug based onsusceptibilities

Fluoroquinolones

Levofloxacin Moxifloxacin

Injectable agentsAmikacin Capreomycin Streptomycin Kanamycin

PLUSOne of these

One of these

First-line drugs

Pyrazinamide

Ethambutol

PLUS

Step 2 Pick one or more of these

Step 3

Third line drugsImipenem Linezolid Macrolides Amoxicillin/Clavulanate Clofazimine

Consider use of these

If there are not 4-6 drugs available consider 3rd line in consult with MDRTB experts

Oral second line drugsCycloserine Ethionamide PAS

Add 2nd line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously)

For strain W with resistance only to low level of INH, consider

INH 900 mg intermittently

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NEVER ADD A SINGLE AGENT TO A FAILING NEVER ADD A SINGLE AGENT TO A FAILING REGIMENREGIMEN

SEEK ADVICE FROM AN EXPERT EXPERIENCED SEEK ADVICE FROM AN EXPERT EXPERIENCED IN THE MANAGEMENT OF MDR OR XDRIN THE MANAGEMENT OF MDR OR XDR TBTBIN THE MANAGEMENT OF MDR OR XDRIN THE MANAGEMENT OF MDR OR XDR--TBTB

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Aminoglycosides: concentration-dependent killers◦ The higher the peak the more effective the drug◦ ATS recommended dose for community-acquired

pneumonia is 20 mg/kg dailyp g g y◦ Higher doses, shorter periods of time, or

intermittent dosing probably more effective and safer◦ Amikacin

Peak 60-80, trough <1 mcg/mL

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Persistent + cultures @ 4-6 monthsExtensive drug resistanceLocalized cavity necrotic tissueLocalized cavity, necrotic tissueAdequate reserve

Alice Neel (1900-1984), T.B. Harlem, 1940 JAMA cover, volume 293, June 8, 2005

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Monthly culturesFor some patients consider isolation until cultures negativeContinue injectable for 6-12 months

D il 3 ti k◦ Daily, 3 times a weekDaily DOTTreat for 18-24 months after culture conversionFollow for 2 years OBTAIN EXPERT CONSULTATION

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First determine if LTBI is due to contact to MDR-TB caseEMB + PZAMoxifloxacin or Levofloxacin + PZA ◦ May be poorly toleratedMay be poorly toleratedMoxifloxacin or Levofloxacin + EMB6-12 monthsObserve for 2 yearsInsufficient data

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Nitroimidazoles ◦ Metronidazol◦ PA824 – Phase 2◦ OPC-67683 – Phase 2Diarylquinolones◦ TMC 207 – Phase 2

Funding shortfall for

drug research & development ◦ TMC 207 Phase 2

Oxazolidinones◦ Linezolid◦ PNU 100480 – Phase 1◦ AZD5847 – Phase 1Ethylenediamines◦ SQ 109, derivative of Ethambutol – Phase 1

Ma Z, et al. Lancet 2010;375:2100-09

development 75%75%

Global Tuberculosis Control 2009 EPIDEMIOLOGY STRATEGY FINANCING