MDR Tuberculosis

MDR TuberculosisJune, 2011Dept of medicineBMC, burdwansubhraprakash pramanik : 

MDR TuberculosisJune, 2011Dept of medicineBMC, burdwansubhraprakash pramanik

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Presentation Outline Definition Epidemiology Genesis of MDR Mechanism of resistance Management Monitoring

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Multi-drug resistant tuberculosis (MDR TB) is defined as resistance to isoniazid and Rifampicin whether there is resistance to other drugs or not (a laboratory diagnosis). Extensively drug resistant TB (XDR-TB) is MDR + resistance to any fluoroquinolone + resistance to at least one 2nd-line injectable drug (amikacin, kanamycin, or capreomycin)

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Why INH and Rifampicin …. 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.

Estimated MDR TB Cases by Regions : 

Estimated MDR TB Cases by Regions

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Czech Rep. The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.  WHO 2005. All rights reserved Ecuador Georgia Argentina Bangladesh Germany Rep of Korea Armenia Russian Fed. South Africa Portugal Latvia Mexico Peru USA Brazil UK Sweden Thailand Chile Based on information provided to WHO Stop TB Department - June 2008 Spain China, Hong Kong SAR France Japan Norway Canada Italy Netherlands Estonia Lithuania Ireland Romania Israel Azerbaijan Poland Slovenia India Australia Mozambique Vietnam Countries with XDR-TB confirmed cases as of June 2008 Ukraine Moldova Philippines Botswana Nepal Islamic Rep. of Iran Lesotho Swaziland Namibia

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Impact of Drug Resistance

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Several reasons identified for resistance (i)Deficient or deteriorating TB control programmes resulting in inadequate administration of effective treatment; (ii) poor case holding, administration of sub-standard drugs, inadequate or irregular drug supply and lack of supervision; (iii) ignorance of health care workers in epidemiology, treatment and control; iv) improper prescription of regimens; (v) interruption of chemotherapy due to side effects; (vi) non-adherence of patients to the prescribed drug therapy;

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(vii) availability of anti-TB drugs across the counter, without prescription; viii) massive bacillary load; (ix) illiteracy and low socio-economic status of the patients; (x) the epidemic of HIV infection; (xi) laboratory delays in identification and susceptibility testing of M. tuberculosis isolates; (xii) use of non standardized laboratory techniques, poor quality drug providers and lack of quality control measures; and (xiii) use of anti-TB drugs for indications other than tuberculosis.

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DR-TB raises concerns of a future TB epidemic with restricted treatment options, and jeopardizes the major gains made in TB control and progress on reducing TB deaths among people living with HIV/AIDS. It is therefore vital that TB control is to be managed properly and new tools to be developed to prevent, treat and diagnose the disease.

Several Drugs becoming resistant : 

Several Drugs becoming resistant

Mechanisims of Drug Resistance in Tuberculosis : 

Mechanisims of Drug Resistance in Tuberculosis

Development of Drug Resistancefrom the perspective of the patient : 

Development of Drug Resistancefrom the perspective of the patient Multiple drug resistant strains result from the step-wise accumulation of individual resistance elements therefore MDR-TB is MAN-MADE Types of drug resistance Drug resistance in TB may be broadly classified as primary and acquired.

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When drug resistance is demonstrated in a patient who has never received anti-TB treatment previously, it is termed primary resitance. Acquired resistance is that which occurs as a result of specific previous treatment. The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past, while the level of acquired resistance is a measure of on-going TB control measures.

CLASSIFIACATION OF ATD : 

CLASSIFIACATION OF ATD 1.GROUP-1 (1st line oral ATD) Isoniazid Rifampicin Ethambutol Pyrazinamide 2.GROUP-2 (injectable ATD) Streptomycin Kanamycin Amikacin Capreomycin 3.GROUP-3 (fluoroquinolones) Ciprofloxacin Ofloxacin

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Levofloxacin Moxifloxacin Gatifloxacin 4.GROUP-4 (oral bacteriostatic 2nd line ATD) Ethionamide Prothionamide Cycloserine Terizidone PAS Thioacetazone 5. Newer ATDs Oxazolidinones : linezolid. Imidazole derivatives : PA824. Diaryquinolone : TMC207. Ketolides : telithromycin. Drug on latency stage : Glyoxylate.

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When to suspect MDR TB Re-treatment patients who’s sputum smear remains positive after three months’ of intensive therapy Treatment failure and interruption cases Close contacts of MDR tuberculosis cases Positive diagnoses with; TB culture and susceptibility testing

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Designing MDR-TB Treatment Regimens Minimum of four drugs necessary during intensive phase At least three drugs not administered previously for more than three months One drug option per category due to crossresistance Drugs selected from highest ranking categories Aminoglycoside must be included during the intensive phase Fluoroquinolone must be included throughout

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General Treatment Principles Provide 18-24 months’ treatment, always with intensive phase of at least 4 months PROVIDE DOT THROUGHOUT Warn patients about side-effects Manage side-effects appropriately Perform cultures monthly

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Second Line Drug Treatment (SLD’s) Less effective, more costly and more toxic, 50% cure rate Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol 18 month continuation phase (3 drugs) Ethionamide Ofloxacin Cycloserine or Ethambutol Treatment should last for at least 18 months after culture conversion

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Drugs for MDRTB Drug Doses in mg (usual adult doses) Kanamycin 1000 Ofloxacin 400 – 600 Ethionamide 500 Cycloserine 500 Amikacin 500 Ethambutol 600 – 1200 PAS 10 gms Thioacetazone 150 Isoniazid 600 All the drugs need Physician’s approval

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What to do with non converters at 9 months? Value of second-line testing (suspect XDR-TB). 1. Continue treating up to month 22. 2. Restart intensive phase. 3. Terminate treatment at month 9 and re-evaluate.

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WHO Guidelines for treatment of MDR-TB Strengthen basic TB care to prevent the emergence of drug-resistance Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients Increase investment in laboratory infrastructures to enable better detection and management of resistant cases.

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DOTS-Plus A comprehensive strategy of the WHO Stop TB Partnership, developed by the DOTS-Plus Working Group, for the diagnosis and management of MDR-TB and other forms of drug resistant TB.

MDR TB and HIV : 

MDR TB and HIV MDR TB occurs with the same frequency in HIV patients as in TB patients who are smear negative Transmission of drug-resistant strains among HIV-infected patients in congregate settings occurs leading to ‘outbreaks’ of MDR TB in such settings Infection control measures absolutely essential in settings where large number of HIV TB patients stay together.

XDR-TB and HIV : 

XDR-TB and HIV It can also be contracted without a patient receiving any previous treatment for TB. People infected with HIV are particularly susceptible as their immune systems are already weakened. HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic.

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Universal guidelines for prevention of Tuberculosis Prevention of transmission - Simple measures more effective Early diagnosis and treatment Isolation of different patient categories Cure of most of TB cases However Unknown TB cases are major source of transmission

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monitoring & evaluation of treatment

The careful monitoring of patients with drug resistant TB is essential to their safe and successful completion of therapy : 

The careful monitoring of patients with drug resistant TB is essential to their safe and successful completion of therapy Monitoring includes Initial evaluation General monitoring Clinical response monitoring Bacteriological response Drug side effects monitoring To monitor adherence to treatment

Monitoring strategy can depends on... : 

Monitoring strategy can depends on... Patient factors Clinical conditions: age, HIV, baseline CXR, DST results Social, economic, geographic circumstances: home/family vs. homeless, employed vs. unemployed, urban/rural Provider factors training and expertise availability of consultants, specialists

Pre-treatment evaluation : 

Pre-treatment evaluation Medical history Demographics History of TB Social history MDR TB contacts Patient complaints Physical examinations Laboratory data Chest radiography Additional examinations

Evaluation by physician : 

Evaluation by physician At baseline Daily in hospital At least monthly until conversion on ambulatory treatment Then every 2-3 months Evaluation include: Clinical signs (especially weight changes) Bacteriological results Laboratory results Appearance of side effects Radiographic response

Evaluation by DOT worker : 

Evaluation by DOT worker At every DOT encounter: Conversation with patient about possible side effects or another problems Ensuring that patient take their medications daily as prescribed Patients should be observed swallowing each dose of medication Standard medical record-keeping Perform frequent patient visits, collect data, and triage significant findings to physicians

Sputum smear and culture : 

Sputum smear and culture At least monthly until conversion. If the patient remains smear and/or culture positive at the end of 4 months of treatment, or the patient again becomes smear/culture positive after having been previously negative, DST should repeat to decide further treatment possibilities

Chest x- ray : 

Chest x- ray At baseline Every 3 month until conversion Then every 6 month Also: If consider surgical intervention Never accept MDR-TB or a Failure based only on X-ray examination criteria

Validation of DOT : 

Validation of DOT Most important part of monitoring Record all necessary information on the treatment card and the patient card Valid DOT Give all tablets and observe the patient taking his medicines and ask him to return the next day. Patients observed swallowing of each dose, Check mouth Examine the patient for side effects like: Nausea, headache, jaundice, anaemia, dry itchy skin, and other complications etc.

Best options to diagnoseX-MDR tuberculosis : 

Best options to diagnoseX-MDR tuberculosis Successful diagnosis of XDR-TB depends on the patient’s access to quality health-care services. If TB bacteria are found in the sputum, the diagnosis of TB can be made in a day or two, but this finding will not be able to distinguish between drug-susceptible and drug-resistant TB. To evaluate drug susceptibility, the bacteria need to be cultivated and tested in a suitable laboratory. Final diagnosis in this way for TB, and especially for XDR-TB, may take from 6 to 16 weeks To reduce the time needed for diagnosis, new tools for rapid TB diagnosis are urgently needed.

Seven point action plan.(WHO) : 

Seven point action plan.(WHO) Conduct rapid surveys to detect cases of XDR-TB Enhance laboratory capacity for detection of drug resistance Improve technical capacity of clinical and public health managers to effectively respond to XDR-TB outbreaks Implement infection control precautions, especially in facilities where HIV-positive individuals are receiving care Increase research support for anti-TB drug development Increase research support for rapid diagnostic test development Promote universal access to antiretroviral drugs under joint TB-HIV activities

24 March : 

24 March