DRUG RESISTANT

TUBERCULOSIS
MDR-TB, XMDR-TB
Dr.T.V.Rao MD

DR.T.V.RAO MD

Table of drugs used for the treatment of

Tuberculosis.
First line drugs
Essential Other Pyrazinamide Ethambutol Streptomycin Old Capreomycin Amikacin Kanamycin Cycloserine Ethionamide PAS Thioacetazone

Second line drugs

New Quinolones ofloxacin ciprofloxacin moxifloxacin Macrolides clarithromycin Clofazimine Amoxycillin & Clavulanic acid Lanizolid

Isoniazid Rifampicin

New rifamycins DR.T.V.RAO Rifabutin MD Rifapentine

WHY INH AND RIFAMPIN ARE IMPORTANT

Most potent and bactericidal Tb can be treated effectively with INH+Rif alone Mono-resistance to one of them can be treated effectively with a regimen containing the other agent with very low failure rate (2.5-5%) Failure rate when INH+Rif resistant is 44% in non-HIV and 70% in HIV patients Duration required for cure doubles to triples.
DR.T.V.RAO MD

DEFINITIONS
Multidrug-resistant tuberculosis (MDRTB) Resistance to Isoniazid and Rifampicin Extensively (extremely) drug-resistant (XDRTB) MDR-TB plus resistance to a second line injectable drug such as Amikacin plus a quinolone.

DR.T.V.RAO MD

DRUGRESISTANT M. TUBERCULOSIS Epidemiology

Primary drug resistance

initial drug resistance

Secondary drug resistance

acquire drug resistance

Treatment of tuberculosis: guidelines for national programmes, 3rd ed. Geneva, (World Health Organization, 2003(WHO/CDS/TB/2003.313).

DR.T.V.RAO MD

DR.T.V.RAO MD

WHAT IS MULTIDRUG-RESISTANT TUBERCULOSIS (MDR TB)? Multidrug-resistant TB (MDR TB) is TB that is resistant to at least two of the best anti-TB drugs, isoniazid and rifampicin. These drugs are considered first-line drugs and are used to treat all persons with TB disease.
DR.T.V.RAO MD

CHALLENGES:
1. Accurately diagnose infections 2. Prevent transmission 3. Provide appropriate treatment 4. Correctly classify the organism

GENESIS OF MDR TB
Resistance is a man-made amplification of a natural phenomenon. Inadequate drug delivery is main cause of secondary drug resistance. Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains. MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked.

DR.T.V.RAO MD

Development of anti-tuberculosis drug resistance

Wild M. TB strain
Spontaneous mutation

Strains with genetic drug resistance

Selection: inadequate treatment

Acquired drug resistance

Transmission

Primary drug resistance

DR.T.V.RAO MD

Pablo'sPablo's-Mendez et al. WHO, 1997

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Does Microbes, will travel faster With Migrating populations increasing ?

Compared to 1960-75, four-fold increase in migration -75 4 x increase in volume as compared to 1960
Source: Population Action International 1994 DR.T.V.RAO MD
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Definition of MTB drug resistance

Mono-drug-resistence

Resistance against one (first-line) drug, INH, RMP, EMB, PZA

Uncomplicated treatment. Duration of treatment may be prolonged

Poly-drug-resistance

Resistance against > 1 (first-line) drugs, but sensitivity to INH and/or RMP Resistance against at least INH and RMP

Usually uncomplicated treatment. Duration of treatment is is prolonged Complicated treatment. Duration of treatment is prolonged to > 18 months Outcome depends on level of drug resistance Complicated treatment. Duration of treatment is prolonged to > 24 months Outcome depends on level of drug resistance
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Multi-drug-resistance MDR

Extensively-drug-resistance XDR

MDR plus resistance to - any fluoroquinolone - amikacin, capreomycin or kanamycin

DR.T.V.RAO MD

MECHANISM OF RESISTANCE
INH
Chromosomally mediated Loss of catalase/peroxidase Mutation in my colic acid synthesis Regulators of peroxide response

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MECHANISM OF RESISTANCE
Rifampin
Reduced binding to RNA polymerase Clusters of mutations at Rifampin Resistance Determining Region (RRDR)

Reduced Cell wall permeability permeability

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Spontaneous mutations develop as bacilli proliferate to >108

Drug Rifampin Isoniazid Pyrazinamide
DR.T.V.RAO MD

Mutation Rate 10-8 10-6 10-6

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Drug-resistant mutants in large bacterial population

Multidrug therapy: No bacteria resistant to all 3 drugs

INH RIF
PZA

Monotherapy: INH-resistant bacteria proliferate

INH

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Spontaneous mutations develop as bacilli proliferate to >108 INH resistant bacteria multiply to large numbers

INH RIF INH

DR.T.V.RAO MD

INH mono-resist. mutants killed, RIF-resist. mutants proliferate MDR TB

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MULTIDRUG-RESISTANT TUBERCULOSIS (MDR-TB)

Multidrug-resistant tuberculosis (MDR-TB) is an increasing global problem, with most cases arising from a mixture of physician error and patient non-compliance during treatment of susceptible TB. The extent and burden of MDR-TB varies significantly from country to country and region to region. As with TB itself, the overwhelming burden of MDR-TB is in high-burden resource-poor countries. The diagnosis depends on confirming the drug susceptibility pattern of isolated organisms, which is often only possible in resource-rich settings
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XDR-TB A GLOBAL THREAT

Between 2000-2004, of 17,690 TB isolates in the world were MDR-TB 20% and XDR-TB 2%
(Lancet2006;368:964)

Between 2003-2005, of 1,284 TB isolates in Iran were MDR-TB 9.3% and XDR-TB 1%
(CID2006;316:216)
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MDR- and XDR- tuberculosis

DR.T.V.RAO MD

Donald et al. NEJM 2009

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WHO IS AT RISK FOR GETTING MDR TB?

Drug resistance is more common in people who:
do not take their TB medicine regularly do not take all of their TB medicine as told by their doctor or nurse develop active TB disease again, after having taken TB medicine in the past come from areas of the world where drug-resistant TB is common have spent time with someone known to have drug-resistant TB disease

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ROLE OF THE LABORATORY

Detect drug resistance to enable clinician to design effective multidrug regimen Initial M. tuberculosis isolate should be tested against primary drugs
INH, RIF, PZA, EMB

For Rif-R isolates, test secondary drugs as needed

FQ, AMI, KAN, CAP
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DR.T.V.RAO MD

METHODS
Drug susceptibility testing performed on all cultures positive for M. tuberculosis Isoniazid, rifampicin, Ethambutol, streptomycin, ciprofloxacin, kanamycin Chart review performed for patients with strains resistant to all tested drugs (XDR TB cases) Demographics, prior TB treatment, prior hospital admissions, HIV status, survival Molecular fingerprinting by Spoligotyping on all XDR TB isolates
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DRUG SUSCEPTIBILITY TESTING Culture-based methods

Proportion method Solid media Liquid media Absolute concentration method Relative ratio method

Molecular methods
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DR.T.V.RAO MD

AGAR PROPORTION METHOD

Plate bacteria on media containing
No drugs Critical concentrations of a drug Incubate for 3 weeks Count colonies Isolate is resistant if the number of colonies on drug-containing media is >1% of the colonies on drug-free media
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DR.T.V.RAO MD

DRUG RESISTANCE TESTING

Antimycobacterial Susceptibility Tests (ASTs) Two methods Agar based Broth based Creighton University does NE surveillance

ASTS BY AGAR PROPORTION METHOD

Gold standard Dilutions of standardized inoculum onto control and drug containing agar Compare growth in absence or presence of drug >1% colony growing on the drug containing agar suggests resistance

2. PREVENT

TRANSMISSION

Identifying suspected sources Genotyping provides tool

Understanding transmission patterns

GENOTYPING ANALYSIS
Isolate A Isolate B

Likely Related

GENOTYPING ANALYSIS
Isolate A Isolate B

Not Related

GENOTYPING METHODS
Two PCR-based methods: Spoligotyping MIRU-VNTR Results converted to numeric code Matches can be further investigated by other technologies

SPOLIGOTYPING
Spacer Oligonucleotide Typing Presence or absence of 43 spacer regions found in the Direct Repeat region of M. tb genome. Results converted to 15 digit code

SPOLIGOTYPING
Original banding pattern Binary code 14 + 1 grouping Designation (15 digits)
1

1 1 1 0 0 1 1 0 0 1 1 1
111-100-110-011-1..

7 4 6 3

DRUG RESISTANT GENES IN TUBERCULOSIS

Drug Rifampicin Streptomycin Isoniazid
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Gene rpoB rpsL No: base pairs katG inhA

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PROBLEMS WITH DRUG RESISTANCE SURVEILLANCE

Quality of laboratory sensitivity testing Maintenance of standards over time Selection of specimens Only 1% of patients surveyed
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EPIDEMIOLOGY INFORMATION OF MDR-TB

Incidence varies according to reported sites. High incidence is located in some geographic area and not evenly distribution. Data of sensitivity can not be directly compared because of different methodology. No seperation of previously treated and untreated cases. High incidence is associated with poor compliance previous treatment history, HIV infection, contact with drug resistant case, inborn country.
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RISK FACTORS FOR INFECTION WITH DRUG-RESISTANT TUBERCULOSIS (1) Expose to person who has known drug-resistant tuberculosis Exposure to a person with active tuberculosis who has prior treatment for tuberculosis (treatment failure or relapse) and whose susceptibility test results are not known Expose to persons with active tuberculosis from areas in which there is a high prevalence of drug resistance
From Centers for Disease Control and Prevention. Treatment of tuberculosis. American Thoracic Society of America. MMWR Morb Mortal Wkly Rep.2003;52(RR-11):1-88.
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WHAT IS EXTENSIVELY DRUG RESISTANT TUBERCULOSIS (XDR TB)?

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB. XDR TB is defined as TB which is resistant to isoniazid and rifampin, plus resistant to any fluoroquinolones and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or Capreomycin). Because XDR TB is resistant to first-line and second line drugs, patients are left with treatment options that are much less effective. XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system. These persons are more likely to develop TB disease once they are infected, and also have a higher risk of death once they develop TB.

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WHO REPORT
The report, "Antituberculosis drug resistance in the world", is based on data collected between 2002 and 2006 on 90,000 TB patients in 81 countries. It found that extensively drug-resistant tuberculosis (XDR-TB), a virtually untreatable form of the respiratory disease, has been recorded in 45 countries
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HOW CAN MDR TB BE PREVENTED?

The most important thing a person can do to prevent the spread of MDR TB is to take all of their medications exactly as prescribed by their health care provider. No doses should be missed and treatment should not be stopped early. Patients should tell their health care provider if they are having trouble taking the medications. If patients plan to travel, they should talk to their health care providers and make sure they have enough medicine to last while away.

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ROLE OF HEALTH CARE WORKERS

Health care providers can help prevent MDR TB by quickly diagnosing cases, following recommended treatment guidelines, monitoring patients response to treatment, and making sure therapy is completed.
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REDUCTION OF EXPOSURE TO INFECTED CASES

Another way to prevent getting MDR TB is to avoid exposure to known MDR TB patients in closed or crowded places such as hospitals, prisons, or homeless shelters. If you work in hospitals or healthcare settings where TB patients are likely to be seen, you should consult infection control or occupational health experts. Ask about administrative and environmental procedures for preventing exposure to TB. Once those procedures are implemented, additional measures could include using personal respiratory protective devices.
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THE GLOBAL SPREAD OF MDR- AND XDR- TB - CONCLUSIONS

MDR and XDRTB is increasing There is little likelihood of new drugs being available within the next ten years We will have to mange with what we have Reduction in drug resistance has been achieved in some settings Lessons form successful areas must be adapted and deployed in problem areas.
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Better Understaning of Disease

Drug resistant strains of MTB are increasing worldwide Causes for the emergence of MTB drug resistance are variable (healthcare mismanagement, unavailability of drugs, direct transmission of MTB resistant strains in vulnerable populations) The treatment prognosis is dependent upon the level of drug resistance and the availability of second line drugs Therapy of MDR/XDR TB is long-lasting (> 18 months) and frequently requires modifications due to adverse effects of the drugs There is a need for biomarkers to predict the duration of therapy in individual patients There is a need for the development of new drugs against MTB but not much is changing for now
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MDR TB is a manmade problem..It is costly, deadly, debilitating, and the biggest threat to our current TB control strategies.
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SHOULD WE TREAT OR FOLLOW CONTACTS TO MDR/XDR?

The answer is.yes. Guidelines for MDR and drug resistance recommend following the contact for at least two years. Data to support strategies for managing contacts is very sparse.
MMWR June 19, 1992 / 41(RR-11);59-71

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BE UNITED ELIMINATE TUBERCULOSIS

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 Programme created by Dr. T.V.Rao MD for Medical , Paramedical , and Health care Workers in the Developing World
Email doctortvrao@gmail.com

DR.T.V.RAO MD

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