Multi-drug Resistant Tuberculosis

Dr Shahid PervaizNishtar Hospital Mutlan.

Presentation OutlineDefinition of MDR TBDefinition of MDR TBEpidemiology of MDR TBEpidemiology of MDR TBGenesis of MDRGenesis of MDRMechanism of resistanceMechanism of resistanceTreatmentTreatmentChemoprophylaxis for MDR TB exposureChemoprophylaxis for MDR TB exposure

Definition of MDR TB

1950s-1970s: 1950s-1970s: M. TB resistant to INH, streptomycin M. TB resistant to INH, streptomycin

and/or PASand/or PAS1980s-current: 1980s-current:

M. TB resistant to at least INH and M. TB resistant to at least INH and RifampinRifampin

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

Why INH and Rifampin• Most potent and bacteriocidalMost potent and bacteriocidal• Tb can be treated effectively with INH+Rif Tb can be treated effectively with INH+Rif

alonealone• Mono-resistance to one of them can be Mono-resistance to one of them can be

treated effectively with a regimen treated effectively with a regimen containing the other agent with very low containing the other agent with very low failure rate (2.5-5%)failure rate (2.5-5%)

• Failure rate when INH+Rif resistant is 44% Failure rate when INH+Rif resistant is 44% in non-HIV and 70% in HIV patientsin non-HIV and 70% in HIV patients

• Duration required for cure doubles to Duration required for cure doubles to triples.triples.

Genesis of MDR TB

• Resistance is a man-made amplification of a natural Resistance is a man-made amplification of a natural phenomenon.phenomenon.

• Inadequate drug delivery is main cause of Inadequate drug delivery is main cause of secondary drug resistance.secondary drug resistance.

• Secondary drug resistance is the main cause of Secondary drug resistance is the main cause of primary drug resistance due to transmission of primary drug resistance due to transmission of resistant strains.resistant strains.

• MDR due to spontaneous mutations is not possible MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are as the genes encoding resistance for anti TB are unlinked.unlinked.

Strains with genetic drug resistance

Wild M. TB strain

Acquired drug resistance

Primary drug resistance

Spontaneous mutationSpontaneous mutation

Selection: inadequate treatmentSelection: inadequate treatment

TransmissionTransmission

Development of anti-tuberculosis drug resistanceDevelopment of anti-tuberculosis drug resistance

Clinical Factors Promoting Resistance• Delayed diagnosis and isolationDelayed diagnosis and isolation• Inappropriate drug regimen.Inappropriate drug regimen.

– Inadequate initial therapyInadequate initial therapy– Incomplete course of treatmentIncomplete course of treatment– Inappropriate treatment modificationsInappropriate treatment modifications– Adding single drug to a failing regimenAdding single drug to a failing regimen– Inappropriate use of chemoprophylaxisInappropriate use of chemoprophylaxis

• Poor adherence and incomplete F/UPoor adherence and incomplete F/U• Failure to isolate MDR TB patientsFailure to isolate MDR TB patients• Failure to employ DOTFailure to employ DOT• Over the counter anti TBOver the counter anti TB• Faked drugsFaked drugs

Household contacts of MDR-TB patients almost always have MDR-TB

• A Peru study looked at 4503 household contacts of 693 MDR-TB and XDR-TB index patients:– 117 (2.6%) had active TB at the time the index

patient began MDR-TB treatment– 242 contacts developed TB during 4-year follow-

up– Of the 359 cases of active TB, 142 had DST, of

whom 129 (91%) had MDR-TBBecerra MC, Appleton SC, Franke MF, et al. Tuberculosis burden in households of patients with multidrug-resistant and extensively drug-resistant tuberculosis: a

retrospective cohort study. Lancet 2011; 377: 147-52.

MDR-TB: Epidemiology

• In 2012, an estimated 450,000 new cases of MDR-TB emerged globally[1]

• Among all new cases of TB, 3.6% are estimated to have MDR-TB[1]

• An estimated 20% of persons with previously treated TB have MDR-TB[1,2]

• More than one half of the new MDR-TB cases occur in China, India, and the Russian Federation[1]

• Mortality in MDR-TB patients usually exceeds 10%[3]

• In 2012, MDR-TB caused an estimated 170,000 deaths[1]

1. WHO. 2013. Update on MDR-TB. 2. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12. 3. Wells CD. Curr Infect Dis Rep. 2010;12:192-197.

DiagnosisChallenges Way forward

1. Culture and DST test reimbursement - Number of tests (throughout the treatment course) to be reimbursed is in discussion

2. Use of GeneXpert to diagnose MDR-TB beyond at-risk populations

Diagnosis of MDR-TB• Gold-standard test: Culture of patient specimen (sputum) to assess

inhibition of M tuberculosis growth in the presence of antibiotics (phenotypic assay)

• Solid-media assays: Result may not be available for 3-6 wks• Automated liquid culture systems: Faster and more sensitive than solid-

media cultures; results available in 1-2 wks• Rapid molecular tests can identify genotypic resistance in 1-2 days

– Xpert TB/RIF identifies M tuberculosis and rifampin resistance using cartridge-based real-time PCR

– Line-probe assays (eg, Hain GenoType) identify genotypic resistance to both isoniazid and rifampin

1-2 days 1-2 wks 3-6 wks 4-12 wks

Average Turnaround Time for Diagnostic Tests

How Do We Know If A Patient Has MDRTB?

• The diagnosis of MDRTB can only be made in a laboratory that can test sputum specimens for the presence of M.tuberculosis (the TB germ isolated by culture) and then test those TB isolates for drug resistance.

• Patients who report interrupted treatment for TB, or failure to have symptoms improve after one to two months of TB treatment, may have drug-resistant TB, and should be separated from persons with HIV infection until their condition is evaluated.

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Who needs DST?

• Cat I, II failures, chronics• Failure anti-TB TX in the private sector• Contacts of DR-/MDR-TB• HCW at risk, prisoners, homeless, etc.• No SS/C conversion Month 2,3• Residence in very high DR-prevalence settings• Exposure to poor quality drugs• Previous treatment by poor programmes• Co-morbidities favouring rapid transit/ malabsorbtion• HIV+

• ALL CASES??

Compared culture

• Sensitivity for AFB+/culture+ 98.2%• Sensitivity for AFB-/culture+ 72.5%• Specificity 99.2%

Rifampicin resistance detection

• Sensitivity – 98%• Specificity – 99%

Xpert MTB/RIF assay & GeneXpert instrument Sensitivity and specificity

New WHO recommendations

• "In settings where rapid molecular-based DST results are not routinely available to guide the management of individual patients, empiric treatment should be started as follows:– TB patients whose treatment has failed or other patient

groups with high likelihood of multidrug-resistant TB (MDR) should be started on an empirical MDR regimen;

– TB patients returning after defaulting or relapsing from their first treatment course may receive the retreatment regimen containing first-line drugs 2HRZES/1HRZE/5HRE if country-specific data show low or medium levels of MDR in these patients or if such data are not available."

Management of MDR TB

Prolonged Hospitalization Significant psycho-social issues Requires increased number of drugs Poor tolerance to the drugs Increased drug- associated toxicity Long term Follow-Up is necessary Increased health care costs

Care and TreatmentChallenges Way forward

1. Promote treatment adherence and success

- Side effect management- Provide socio-economic support to

patients

2. Stigmatization - Public/community education

3. Information sharing - Improve communication and record tracking and keeping system

4. Quality DOT provision for MDR-TB patients

- Community engagement

MDR TB Management Treatment should be individualized and based on drug

susceptibility studies Patient to receive all the drugs to which the infecting

M.TB is susceptible. When available drugs need to be given iv

If there is past history of TB and drugs previously received are known, give at least 3 drugs (bactericidal) never used before

If drug susceptibility still unknown give at least 3 bactericidal drugs, but no Rifampin or Isoniazid

Treatment for 2 years following bacteriologic conversion DOT mandatory Well structured and strict follow-up Surgery in selected cases

Building a Treatment Regimen for MDR-TB

Adapted from: Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for clinicians. Chang KC, et al. Respirology. 2013;18:8-21.

Step 1: Include any first-line drugs to which the isolate is

susceptibleInjectables

Kanamycin Amikacin

Capreomycin Streptomycin

Step 2: Add a fluoroquinolone

Fluoroquinolone

LevofloxacinMoxifloxacin Gatifloxacin

First-line Drugs

Ethambutol Pyrazinamide

Step 3: Include an injectable agent

Oral Second-line Drugs

Ethionamide Prothionamide

Cycloserine/terizidone Para-aminosalicylic acid

Third-line Drugs

Clofazimine Clarithromycin

Amoxicillin-clavulanate Linezolid

Thiacetazone Meropenem-clavulanate

ThioridazineOther new drugs

Step 4: Include second-line drugs until you have 4-6 drugs

to which the isolate is susceptible

Consider third-line drugs if there are not 4-6 drugs to

which the isolate is susceptible

Potency and Tolerability of Existing TB Drugs

Dorman SE, et al. Nat Med. 2007;13:295-298.

Increasing potency, reliability,

reproducibility of susceptibility testing

Decreasing tolerability

Firs

t-lin

e

Dru

gs

Seco

nd-l

ine

Dru

gs

RifampinIsoniazid

PyrazinamideEthambutol

Fluoroquinolones(moxifloxacin, gatifloxacin,

levofloxacin)

Injectable agentsAminoglycosides (streptomycin,

amikacin, kanamycin)Polypeptides (capreomycin)

Oral bacteriostatic agents(ethionamide, protionamide, cycloserine/

terizidone, p-aminosalicylic acid, thiacetazone)

Agents with unclear efficacy (clofazimine, amoxicillin-clavulanate, clarithromycin, linezolid)

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

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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 agents

Amikacin Capreomycin Streptomycin Kanamycin

PLUSOne of these

One of these

First-line drugs

Pyrazinamide

Ethambutol

PLUS

BS

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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 agents

Amikacin Capreomycin Streptomycin Kanamycin

PLUSOne of these

One of these

First-line drugs

Pyrazinamide

Ethambutol

PLUS

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 3

Third line drugs

Imipenem Linezolid Macrolides Amoxicillin/Clavulanate

Consider use of these

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

Step 1Use any available

Begin with anyFirst line agents toWhich the isolate is Susceptible

Add aFluoroquinoloneAnd an injectableDrug based onsusceptibilities

Fluoroquinolones

Levofloxacin Moxifloxacin

Injectable agents

Amikacin Capreomycin Streptomycin Kanamycin

PLUSOne of these

One of these

First-line drugs

Pyrazinamide

Ethambutol

PLUS

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)

BS

Treatment of MDR TB• Factors determining SuccessFactors determining Success

–Culture of MDR TBCulture of MDR TB–Reliable susceptibilityReliable susceptibility–Reliable history of previous drug regimensReliable history of previous drug regimens–Program to assure delivery of prescribed Program to assure delivery of prescribed

drugs (DOT)drugs (DOT)–Correct choice of modified treatment Correct choice of modified treatment

regimenregimen–Reliable follow upReliable follow up

Why is MDRTB a problem?

• Because the two most important anti-TB drugs are not effective in treating MDR-TB, treatment requires drugs which are more toxic, more expensive, take longer to work and that do not work as well (called “second line” drugs). Also, these second line drugs are not widely available in resource-limited settings.

How is MDRTB prevented?• MDRTB is a condition that can be prevented by following

the international TB control strategy called DOTS, which stands for Directly Observed Treatment, Short-course.

• Health care providers should always adhere to the National

Tuberculosis Program Guidelines and use only the recommended anti-TB treatment regiments, drug combinations and drug dosages.Anti-TB drugs, preferably Fixed Dose Combinations of high quality should be available in regular and sufficient quantities.

• Adherence to anti-TB treatment must be ensured with

support, encouragement and monitoring of adherence by a relative, community volunteer, or a clinic nurse.

MDR TB ControlExtraordinary measures are needed in

countries with the highest rates of TB and MDR TB: rapid detection, access to drugs and steady drugs supply and effective and expert care.

The only reasonable approach is strengthening TB Control worldwide to prevent MDR TB and XDR TB

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The message

Any person at high risk of MDR-TB should

Undergo rapid testing

to start an appropriate treatment

immediately

While an additional sputum specimen

undergoes conventional culture and DST

Tuberculosis anywhere is Tuberculosis everywhere