short talk MDR TB sheetu

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Presentation on MDR, TDR & XDR TB.


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MULTI-DRUG AND TOTAL –DRUG RESISTANT TUBERCULOSIS Dr.Sheetu Jailkhani M.D.Community Medicine GMC, Miraj , Maharashtra


INDEX Types of Drugs Resistance Causes of Drug Resistant TB Genes associated with Drug-Resistant TB MDR TB– Definitions Magnitude, Distribution Mechanism of spread & Development Diagnosis & treatment XDR TB -Definitions Magnitude, Distribution Treatment options TDR TB Newer drugs under development Preventive measures

Types of Drugs Resistance:

Types of Drugs Resistance Primary Drug Resistance patients with no history of previous Tuberculosis treatment Secondary/Acquired Drugs Resistance History of previous episode of susceptible TB Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains.

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A patient is confirmed to have drug resistant TB only by an RNTCP quality assured Culture & DST Laboratory. Such patients are classified according to the following definition: 1.Drug-resistant case: A patient whose TB is due to tubercle bacilli that are resistant in vitro to at least one anti-TB drug according to accepted laboratory methods in an RNTCP accredited laboratory.

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2.Mono-resistance: A patient whose TB is due to tubercle bacilli that are resistant in vitro to exactly one anti-TB drug in an RNTCP accredited laboratory. 3. Poly-resistance: A patient whose TB is due to tubercle bacilli that are resistant in-vitro to more than one anti-TB drug, except not both isoniazid and rifampicin in an RNTCP accredited laboratory. 4. MDR TB 5. XDR TB

Causes of Drug Resistant TB:

Causes of Drug Resistant TB Microbiological cause : Resistance by genetic mutation – makes drug ineffective against mutant bacilli. Clinical & programmatic : Inadequate or poorly administered treatment – allows drug resistant mutants to become dominant strain in TB infected patient. Use of standardised short course chemotherapy in MDR TB cases – fails to cure a significant proportion of such cases - create even more resistance to drugs in use “ amplifier effect of short course chemotherapy “

Causes of inadequate treatment:

Causes of inadequate treatment

Genes associated with Drug-Resistant M.tuberculosis:

Genes associated with Drug-Resistant M.tuberculosis Drug Gene Isoniazid Kat G, Inh A, Kas A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A Dubaniewicz A, et al. Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis. Int J Infect Dis2000;4:129-33.

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Emergence of Resistance to Drugs Particularly Multi Drug RESISTANT TB ( MDR-TB) Has become a Significant Public Health Problem


DEFINITION OF MDR TB 1950s-1970s: M. tuberculosis resistant to INH, streptomycin and/or PAS 1980s-current: M. tuberculosis resistant to at least INH and Rifampin

Who is an MDR TB Suspect?:

Who is an MDR TB Suspect? MDR-TB Suspect can be any of the following: Any TB patient who fails an RNTCP Category I treatment regimen i.e. has sputum smear positive at the end of the fifth month of treatment or later; Any RNTCP Category II patient who is sputum smear positive at the end of the fourth month of treatment or later; or Close contacts of MDR-TB patients who are found to have smear positive pulmonary TB (PTB) disease

MDR TB Case:

MDR TB Case MDR-TB Case: An MDR-TB suspect who is sputum culture positive and has M. tuberculosis resistant to isoniazid and rifampicin , with or without resistance to other anti-tubercular drugs based on DST results from an RNTCP accredited laboratory. Single Isoniazid or Rifampicin resistance is not MDR TB. MDR TB is a laboratory diagnosis.

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Genetic probes which detect drug resistance to rifampicin with >95% accuracy are very suggestive of MDR-TB; <10% of rifampicin resistance is monoresistant , and so rifampicin resistance is a marker for MDR-TB in >90% of cases. MDR-TB is now subdivided into ‘basic’ MDR-TB, with resistance only to rifampicin and isoniazid , and ‘MDR-TB-plus’, with a similar resistance pattern but with resistance to one or more additional first- and/or second-line drugs. L. P. Ormerod , British Medical Bulletin 2005; 73 and 74

Why INH and Rifampin:

Why INH and Rifampin Most potent and bacteriocidal . 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.


MAGNITUDE Presence of MDR TB has been known virtually from the time anti-tuberculosis drugs were introduced for the treatment of TB. Though the Rate of MDR-TB is low in India However Absolute No. of cases is large ( Ongoing transmission of established MDR Pts in Pop.)

Magnitude of MDR TB:

Magnitude of MDR TB Magnitude of Problem :Among all incident TB cases globally, 3.6% (95% confidence interval (CI): 3.0–4.4) are estimated to have MDR-TB In the past 1 to 3 % in New Cases ˜ 12 % in re-treatment cases ( Study by TRC & NTI in past ) Recent studies in Gujarat & Maharashtra By RNTCP - New Cases - 3% - Re-treatment - 12-17 %

Distribution of MDR TB:

Distribution of MDR TB

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How is MDR/XDR/TDR-TB spread? Spread occurs in 2 ways TB bacilli with different levels of resistance spread in the same way and with the same risk of infection as fully drug susceptible strains. 1.In a patient who is receiving treatment for active TB -when anti-TB drugs are misused or mismanaged, -inadequate clinical care or drug management. -wrong treatment, -wrong dose, -treatment for too short period of time -erratic drug supply -poor quality drugs 2. by becoming infected from a patient who is already ill with the condition ( by coughing, sneezing)

Development of anti-tuberculosis drug resistance:

Development of anti-tuberculosis drug resistance Primary drug resistance Spontaneous mutation Selection: inadequate treatment Transmission Pablos -Mendez et al. WHO, 1997

Mechanism of resistance:

Mechanism of resistance INH Chromosomally mediated Loss of catalase / peroxidase Mutation in mycolic acid synthesis Regulators of peroxide response. Rifampin Reduced binding to RNA polymerase Clusters of mutations at “ Rifampin Resistance Determining Region” (RRDR) Reduced Cell wall permeability

MDR TB & Possible effective Treatment:

MDR TB & Possible effective Treatment

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MDR TB is a man made phenomenon due to - poor treatment - poor drugs - poor adherence

Development of MDRTB:

Development of MDRTB Inappropriate chemotherapy Interrupted drug supply Poor patient management Poor patient adherence Abuse of TB drugs Poor TB control programme



Patient flow…………..Diagnosis:

Patient flow…………..Diagnosis MDR-TB suspect referred by MO PHI to DTO -Copy of Treatment Card ( Cat I / II ) -Request for Culture and DST form -Drug –o-gram DTO has to - Confirm Suspect -Send Sputum Sample to IRL along with -Request for C/DST form & drug-o-gram - C/DST reports communicated to DTO by Mail Non MDR-TB MDR-TB DTO to -Trace the pt -Counsel -Refer to DOTS Plus Site Continue Cat II Pt. Continues Cat II

Diagnosis of MDR-TB:

Diagnosis of MDR-TB ● Primary Culture By Solid or Liquid media ● DST By Solid/Liquid/Line Probe Assay ( LPA)

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Solid Culture: gives results in 3-4 mths Liquid Culture: in 3-4 wks Line probe Assay: in 3-4 assay In Maharashtra, Line probe Assay facility is available at- 1. STDC, Nagpur 2. STDC, Pune 3. J.J.Hospital , Mumbai But at the 4 th IRL, Hinduja hospital only Liquid culture is done.

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Pt is kept continued on Cat II regimen till C&DST results are obtained. This will keep pt in touch with & will not loose faith in the programme . After counselling,Confirmed MDR-TB patients and those with any rifampicin resistance are referred to the RNTCP designated DOTS-Plus site, with their DST result and request for Category IV treatment form. pre-treatment evaluation and initiation of Category IV treatment.



Treatment of MDR TB:

Treatment of MDR TB Factors determining Success Culture of MDR TB Reliable susceptibility Reliable history of previous drug regimens Program to assure delivery of prescribed drugs (DOT) Correct choice of modified treatment regimen Reliable follow up

Category IV regimen:

Category IV regimen RNTCP will be using a Standardised Treatment Regimen (Cat IV) for the treatment of MDR-TB cases (and those with rifampicin resistance) under the programme . Cat IV regimen comprises of 6 drugs- kanamycin , ofloxacin ( levofloxacin ), ethionamide , pyrazinamide , ethambutol and cycloserine during 6-9 months of the Intensive Phase and 4 drugs- ofloxacin ( levofloxacin ), ethionamide , ethambutol and cycloserine during the 18 months of the Continuation Phase. p- aminosalicylic acid (PAS) is included in the regimen as a substitute drug if any bactericidal drug (K, Ofl , Z and Eto ) or 2 bacteriostatic (E and Cs) drugs are not tolerated.

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After starting Cat IV treatment, Ist culture is sent 3mths after starting treatment, from 3-7 th mth , sputum is sent for culture monthly, Then from 9 th mth up to end of treatment, every 3 mthly. Sputum is sent in phalcon tubes & should reach IRL in 24-48 hrs. Patient is declared cured if last 5 culture reports are negative. If 2 or more culture are positive- failure of treatment. If culture is positive at 6 th mth or after completion of treatment, their culture isolate are sent to NTC, Bangalore for testing of XDR TB.


DOTS PLUS Launched by WHO in 2000, by RNTCP in India in 2007. Refers to DOTS Programme With Addition of MDR -TB - Diagnosis - Management & - Treatment

Status of DOTS PLUS:

Status of DOTS PLUS DOTS Plus In 2007 Services in selected districts Gujarat & Maharashtra ( Ist in Nagpur) By end of 2009 : in 125 districts across 10 States 2010 to 2012 all over Country ( Complete geographical coverage) By 2012, : it is aimed to extend services to all retreatment cases & New cases failed an initial line of treatment . By 2015 , : services will be made available to all Sm + ve Pulm TB Intended to cover 30,000 MDR cases annually in 2012-13


FIVE COMPONENTS OF DOTS-PLUS 1. Sustained political and administrative commitment A well functioning DOTS programme Long term investment of staff and resources Coordination efforts between community, local governments, and international agencies Addressing the factors leading to the emergence of MDR-TB

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2. Diagnosis of MDR-TB through quality-assured culture and drug susceptibility testing:- Proper triage of patients for Culture & DST testing and management under DOTS-Plus. Co-ordination with National and Supra-National Reference Laboratories.

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3. Appropriate treatment strategies that utilize second-line drugs under proper management conditions Rational standardized treatment design (evidence-based) Directly observed therapy (DOT) ensuring long-term adherence Monitoring and management of adverse drug reactions Adequate human resources.

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4. Uninterrupted supply of quality assured anti-TB drugs. 5. Recording and reporting system designed for DOTS-Plus programmes that enable performance monitoring and evaluation of treatment outcome.

What is XDR TB?:

What is XDR TB? Extensively drug-resistant tuberculosis (XDR TB) is a relatively rare type of MDR TB. It is resistant to - two best first-line drugs: isoniazid and rifampin also known as MDR-TB, in addition to the best second-line medications: fluoroquinolones (such as Ofloxacin or moxifloxacin ) and at least one of three injectable drugs (i.e., amikacin , kanamycin , or capreomycin ). (World Health Organization [WHO] definition) In 2006, the first reports of extensively drug-resistant tuberculosis (XDR-TB) began to appear.

Magnitude of XDR TB:

Magnitude of XDR TB XDR-TB is rare, however 77 countries worldwide had reported at least one case by the end of 2011. Information from countries with reliable data suggests that about 9% of MDR TB cases worldwide have XDR TB. Results of second-line drug susceptibility testing for MDR-TB patients from DOTS (Directly Observed Treatment Short) and the samples collected from Gujarat and Maharashtra drug resistance survey shows – no new cases of XDR-TB 0.5 percent are among re-treatment cases (Central TB division)

Distribution of XDR TB:

Distribution of XDR TB

XDR TB & Diminishing treatment options:

XDR TB & Diminishing treatment options

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Can XDR TB be treated and cured? Some TB control programs have shown that cure is possible for an estimated 30% of affected people. For such cases additional drugs will need to be procured These include clofazimine , linezolid , amoxicillin/ clavulanate , thioacetazone , imipenem / cilastatin , clarithromycin . Efficacy is not assured, however, and both toxicity and cost for some of these compounds are high. Successful outcomes depend greatly on the extent of the drug resistance, the severity of the disease, whether the patient’s immune system is weakened, and adherence to treatment.


TDR TB TDR-TB (Super XDR-TB) Resistant to all 2nd line class drugs In all TDR-TB cases, culture & smear remained (+) after 18 months of therapy with 2nd line drugs. The emergence of TDR-TB in India has made headlines across the globe. India is the home to a fifth of the world's TB patients misuse and abuse of the anti-TB drugs has changed the easily manageable TB germ into a monstrous, totally resistant variety.

Some reports on TDR TB:

Some reports on TDR TB TDR isolated in the fluid samples of 12 TB patients in the past three months at Hinduja Hospital alone, the Indian Times reported. According to the press release, the Hinduja Hospital laboratory is not accredited by the RNTCP for culture and sensitivity test for second line drugs to diagnose extreme drug resistant (XDR)/Total Drug Resistant (TDR) cases. It is only accredited for conducting Drug Susceptibility Testing (DST) by liquid culture and sensitivity for first line drug only.

More Reports:

More Reports The two earliest recorded cases of TDR tuberculosis were in Italy in 1995 and 1998. (The scientific journal Eurosurveillance ) Despite protracted treatment, they both died in 2003. In 2009, doctors registered 15 cases of TDR tuberculosis in Iran.

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“The term TDR-TB is neither recognised by the WHO nor by RNTCP. For now, these cases are defined as Extensively Drug Resistant Tuberculosis (XDR-TB), according to WHO definitions, and accordingly can be managed by national XDR-TB treatment guidelines,

Why is TDR TB not recognised by WHO? :

Why is TDR TB not recognised by WHO? In vitro drug susceptibility testing (DST) is technically challenging and limitations on the use of results remain: conventional DST for the drugs that define MDR and XDR-TB has been thoroughly studied. Data on the reproducibility and reliability of DST for the remaining SLDs are either much more limited or have not been established, or the methodology for testing does not exist. Most importantly, correlation of DST results with clinical response to treatment has not yet been adequately established. Thus, a strain of TB with in vitro DST results showing resistance could in fact, in the patient, be susceptible to these drugs.

New TB drugs under development:

New TB drugs under development




PREVENTION By Health Care providers quickly diagnosing cases, following recommended treatment guidelines, monitoring patients’ response to treatment, and making sure therapy is completed, proper implementation of infection control procedures to prevent exposure to TB in hospitals.

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By International agencies like WHO/CDC : to raise awareness and enhance strategies for TB prevention worldwide by Strengthening TB services for people living with HIV/AIDS Assembling outbreak response teams Improving access to TB drugs Developing international TB testing standards Building capacity of health care providers to diagnose and treat TB Reconvening the Federal TB Task Force Providing technical assistance to expand TB program capacity Supporting TB communication and education efforts

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Right Drugs Right Doses Right Interval Right Duration TDRTB has not reached epidemic proportions. We need to launch a massive public health response that will trace patients and help not only them but also their relatives, who could at greatest risk of developing the disease.


References Towards universal access to diagnosis and treatment of multidrug-resistant and extensively drug-resistant tuberculosis by 2015; WHO PROGRESS REPORT 2011 Global tuberculosis control: WHO report 2010. Geneva, World Health Organization, 2010 (WHO/HTM/TB/2010.7) and TB data available at: RNTCP-DOTS plus guidelines; Central TB Division, Directorate General of Health Services, Ministry of Health & Family Welfare, Nirman Bhavan , New Delhi: Jan 2010. World Health Organization. The WHO/IUATLD. Global Project on Antituberculosis Drug Resistance Surveillance: Antituberculosis drug resistance in the world. Report No.3.Geneva: Switzerland; 2004. WHO/CDS/TB/2004. Treatment of tuberculosis: guidelines – 4th ed. WHO/HTM/TB/2009.420 THE GLOBAL PLAN TO STOP TB 2006-2015: PROGRESS REPORT 2006-2008 Tuberculosis in the South-East Asia Region; The Regional Report: 2012 ;WHO SEARO 2012.

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