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Multidrug Resistant Tuberculosis

Multidrug Resistant Tuberculosis

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Multidrug Resistant Tuberculosis
Multidrug Resistant Tuberculosis

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DRUG RESISTANT

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

DR.T.V.RAO MD

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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

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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

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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

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DRUG²RESISTANT 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

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DR.T.V.RAO MD

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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

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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

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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

DR.T.V.RAO MD

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MECHANISM OF RESISTANCE
‡ Rifampin
‡ Reduced binding to RNA polymerase ‡ Clusters of mutations at ³Rifampin Resistance Determining Region´ (RRDR)

‡ Reduced Cell wall permeability permeability

DR.T.V.RAO MD

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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

DR.T.V.RAO MD

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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
DR.T.V.RAO MD

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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)
DR.T.V.RAO MD

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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

DR.T.V.RAO MD

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DR.T.V.RAO MD

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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
23
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
DR.T.V.RAO MD

24

DRUG SUSCEPTIBILITY TESTING ‡ Culture-based methods
‡ Proportion method ‡ Solid media ‡ Liquid media ‡ Absolute concentration method ‡ Relative ratio method

‡ Molecular methods
25
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
26
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 ‡ ‡ ‡
DR.T.V.RAO MD

Gene rpoB rpsL No: base pairs katG inhA

35

PROBLEMS WITH DRUG RESISTANCE SURVEILLANCE

‡ Quality of laboratory sensitivity testing ‡ Maintenance of standards over time ‡ Selection of specimens ‡ Only 1% of patients surveyed
DR.T.V.RAO MD

36

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.
DR.T.V.RAO MD

37

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.
DR.T.V.RAO MD

38

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.

DR.T.V.RAO MD

39

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
DR.T.V.RAO MD

40

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.

DR.T.V.RAO MD

41

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.
DR.T.V.RAO MD

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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.
DR.T.V.RAO MD

43

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.
DR.T.V.RAO MD

44

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
DR.T.V.RAO MD

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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.
DR.T.V.RAO MD

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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

DR.T.V.RAO MD

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BE UNITED ELIMINATE TUBERCULOSIS

DR.T.V.RAO MD

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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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