MNG MDR TB

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MANAGEMENT OF MDR TB – AN UPDATE Presented by Dr. Md. Hasib Iskandar FCPS part 2 Student Respiratory wing Dept of Medicine, BSMMU : 

MANAGEMENT OF MDR TB – AN UPDATE Presented by Dr. Md. Hasib Iskandar FCPS part 2 Student Respiratory wing Dept of Medicine, BSMMU

DEFINITIONS : 

DEFINITIONS Multidrug-resistant tuberculosis (MDR TB )– is defined as TB resistant to at lest Isoniazid and Rifampicin, the two most potent anti-TB drugs. Extensively drug-resistant tuberculosis (XDR-TB) : this is a subcategory of MDR TB, is defined as MDR TB plus resistance to a quinolone and an injectable 2nd line drug (kanamycin,capreomycin etc. )

TYPES OF DRUG RESISTANCE : 

TYPES OF DRUG RESISTANCE Mono resistance : Resistance to one type of drugs (e.g. isoniazid). Poly-resistance : Resistance to more than one type of drugs , other than both isoniazid and rifampicin Primary Resistance: The presence of resistant strains of M. tuberculosis in patients , who have been infected with resistant bacilli by another patient and subsequently develop the disease.

TYPES OF DRUG RESISTANCE : 

TYPES OF DRUG RESISTANCE Acquired or secondary resistance : Resistance to one or more anti- TB drugs , which arises during the course of treatment , usually due to non- adherence to the recommended regimen or due to incorrect drug prescription and intake.

TYPES OF DRUG RESISTANCE : 

TYPES OF DRUG RESISTANCE Depending on the treatment history, 2 types of resistance are distinguished: Resistance among new patients, i.e. Patients who were never treated before or were treated for maximum one month. Resistance among retreatment patients.

Distribution of multidrug-resistant tuberculosis rates among previously treated cases. (Source: World Health Organization, 2006) : 

Distribution of multidrug-resistant tuberculosis rates among previously treated cases. (Source: World Health Organization, 2006)

Slide 10: 

GLOBAL BURDEN OF MDR TB The WHO/IUATLD Global Project on Antituberculosis Drug Resistance Surveillance gathers data on drug resistance using a standard methodology in order to determine the global magnitude of resistance to four first-line antituberculosis drugs: isoniazid, rifampicin, ethambutol and streptomycin Based on available information from the duration of the Global Project ,the most recent data available from 116 countries and settings were weighted by the population in areas surveyed, representing 2 509 545 TB cases, with the following results:

Slide 11: 

Global population weighted proportion of resistance among previously treated cases: any resistance 35.0% isoniazid resistance 27.7% MDR-TB 15.3% Global population weighted proportion of resistance among new cases: any resistance 17.0% isoniazid resistance 10.3% MDR-TB 2.9%

Slide 12: 

Global population weighted proportion of resistance among all TBcases: any resistance 20.0% (95% CLs, 16.1–23.9), isoniazid resistance 13.3%(95% CLs, 10.9–15.8) MDR-TB 5.3% (95% CLs, 3.9–6.6). Based on drug resistance information from these 116 countries and settings reporting to this project, it is estimated that 489 139 cases emerged in 2006. China and India carry approximately 50% of the global burden of MDR-TB and the Russian Federation a further 7%.

Magnitude of MDR-TB in Bangladesh : 

Magnitude of MDR-TB in Bangladesh

SITES OF MDR-TB : 

SITES OF MDR-TB While MDR-TB is a disease involving the lungs predominantly , there have been a substantial number of reports on its occurrence in extrapulmonary sites, such as skin and soft tissues, bone, lymph nodes, central nervous system and other organs. Extrapulmonary involvement is more common among HIV-infected subjects but is not entirely restricted to that patient population

Risk Factors for MDR-TB : 

Risk Factors for MDR-TB Failure of retreatment regimens and chronic TB cases, 80% of MDR-TB MDR-TB contacts Cat-1 failure Smear +ve at 2/3 m of SCC High MDR-TB prevalent centre/areas Treatment failure at private centres Use of poor/unknown quality drugs Co-morbid conditions with malabsorption/rapid transit diarrohea, HIV+ve

Drug Resistance Mechanism : 

Drug Resistance Mechanism Natural drug resistance is due to- 1. the unusual multi-layer cell envelope and active multidrug efflux pumps. 2. neutralize the toxicity of antibiotics in the cytoplasm. Acquired resistance is caused by Mutations in chromosomal genes. The MDR phenotype is caused by sequential accumulation of mutations in different genes involved in resistance to individual drugs, due to inappropriate treatment or poor adherence to treatment. Colony of MTB Resistant Mutant Secondary DRTB Primary DR-TB More Primary DR-TB Natural mutations Seletion of resistant strains by inadequate treat Transmission in droplets Further transmission

TB DIAGNOSTIC CATEGORIES : 

TB DIAGNOSTIC CATEGORIES Treatment of tuberculosis: guidelines for national programmes (1) recommends treatment regimens based on different TB diagnostic categories. The diagnostic categories are: Category I – New smear-positive patients; new smear-negative pulmonary TB (PTB) with extensive parenchymal involvement; severe concomitant HIV disease or severe forms of extrapulmonary TB. Category II – Previously treated sputum smear-positive PTB: relapse; treatment after interruption;failures. Category III – New smear-negative PTB (other than in Cat I) and less severe forms of extrapulmonary TB. Category IV – Chronic cases (still sputum-positive after supervised re-treatment) and MDRTB

Each Category IV patient should be classified in two different ways: : 

Each Category IV patient should be classified in two different ways: I. Classification according to history of previous drug use, mainly to assign the appropriate treatment regimen. • New. A patient who has received no or less than one month of antituberculosis treatment. Patients are placed in this group if they had sputum collected for DST at the start of a Category I regimen and were then switched to a Category IV regimen because MDR-TB was later confirmed. • Previously treated with first-line drugs only. A patient who has been treated for one month or more for TB with only first-line drugs. • Previously treated with second-line drugs. A patient who has been treated for one month or more for TB with one or more second-line drugs, with or without first-line drugs.

Slide 21: 

II. Classification according to the history of their previous treatment (commonly referred to as the patient’s “registration group”). The registration groups are the established groups used in the DOTS recording and reporting system, with additional subgrouping of patients treated after failure. • New. (Same definition as in previous classification).A patient who has received no or less than one month of antituberculosis treatment. • Relapse. A patient whose most recent treatment outcome was “cured” or “treatment completed”, and who is subsequently diagnosed with bacteriologically positive TB by sputum smear microscopy or culture. • Treatment after default. A patient who returns to treatment, bacteriologically positive by sputum smear microscopy or culture, following interruption of treatment for two or more consecutive months. • Treatment after failure of Category I. A patient who has received Category I treatment for TB and in whom treatment has failed. Failure is defined as sputum smear positive at five months or later during treatment. • Treatment after failure of Category II. A patient who has received Category II treatment for TB and in whom treatment has failed. Failure is defined as sputum smear positive at five months or later during treatment.

Slide 22: 

• Transfer in. A patient who has transferred in from another register for treatment of DR-TB to continue Category IV treatment. • Other. There are several types of patients who may not fit into any of the above categories.

Category IV treatment outcomes : 

Category IV treatment outcomes • Cured. A Category IV patient who has completed treatment according to programme protocol and has at least five consecutive negative cultures from samples collected at least 30 days apart in the final 12 months of treatment. If only one positive culture is reported during that time, and there is no concomitant clinical evidence of deterioration, a patient may still be considered cured, provided that this positive culture is followed by a minimum of three consecutive negative cultures taken at least 30 days apart.

Category IV treatment outcomes (cont) : 

Category IV treatment outcomes (cont) Treatment completed. A Category IV patient who has completed treatment according to programme protocol but does not meet the definition for cure because of lack of bacteriological results (i.e. fewer than five cultures were performed in the final 12 months of treatment). Died. A Category IV patient who dies for any reason during the course of MDR-TB treatment.

Category IV treatment outcomes (cont) : 

Category IV treatment outcomes (cont) • Failed. if two or more of the five cultures recorded in the final 12 months of therapy are positive, or if any one of the final three cultures is positive • Defaulted. A Category IV patient whose treatment was interrupted for two or more consecutive months for any reason without medical approval. • Transferred out. A Category IV patient who has been transferred to another reporting and recording unit and for whom the treatment outcome is unknown.

REFERRAL FLOW CHART : 

REFERRAL FLOW CHART Category 2 failures referred from various health facilities with brief history (with DOTS registration No.) signed by referring doctors NIDCH OPD Received by the resident physician Referred to focal point/ member secretary DOTS PLUS clinical management committee Decision about Hospitalization Arrange sputum sample collection and send to NTRL Inform clinical management committee

Slide 27: 

Category 2 Regimen Smear +ve after 4 months Failures(Smear +ve at the end of treatment) Culture & DST DST proven MDR Standardized 2nd line treatment regimen Clinical and smear result review by Clinical Management Committee INCLUTION CRITERIA FOR CASE FINDING AND TREATMENT

Dx of MDR TB : 

Dx of MDR TB Sputum Smear microscopy Sputum Culture Drug Susceptibility Testing

Key recommendations regarding DST : 

Key recommendations regarding DST Patients at risk of DR-TB should be screened for drug resistance; In people living with HIV, when possible, DST should be performed at the start of anti-TB therapy to avoid mortality due to unrecognized DR-TB; For the initial screening of DR-TB, rapid DST methods should be used whenever possible; Patients at increased risk of XDR-TB should be screened for resistance with DST of isoniazid, rifampicin, the second-line injectable agents and a fluoroquinolone.

Target groups for Drug susceptibility Testing(DST) : 

Target groups for Drug susceptibility Testing(DST) Failure of retreatment regimens and chronic TB cases, 80% of MDR-TB MDR-TB contacts Cat-1 failure Smear +ve at 2/3 m of SCC High MDR-TB prevalent centre/areas Treatment failure at private centres Use of poor/unknown quality drugs Co-morbid conditions with malabsorption/rapid transit diarrohea, HIV+ve

Types of DST : 

Types of DST Phenotypic Method Direct: a set of drug-containing and drug-free media is inoculated directly with a concentrated specimen Indirect: inoculation with a pure culture grown from the specimen. Indirect phenotypic tests have been extensively validated and are currently regarded as the gold standard.

Types of DST(cont) : 

Types of DST(cont) Genotypic method 1st Step- a molecular nucleic acid amplification method such as PCR is used to amplify sections of the M. tuberculosis genome known to be altered in resistant strains 2nd step- amplification products are assessed for specific mutations correlated with resistance.

DOT/DOTS-Plus : 

DOT/DOTS-Plus DOTS-Plus strategy for DR TB Sustained government commitment; Accurate, timely diagnosis through quality assured culture and drug susceptibility testing; Appropriate treatment utilizing second-line drugs under strict supervision; Uninterrupted supply of quality assured anti-TB drugs; and Standardized recording and reporting system.

Standard code for antituberculosis treatment regimens : 

Standard code for antituberculosis treatment regimens Each drug has an abbreviation . A DR-TB regimen consists of two phases: the first phase is the period in which the injectable agent is used and the second phase is after it has been stopped. The number shown before each phase stands for phase duration in months and is the minimum amount of time that stage should last. The number in subscript (e.g., 3) after a letter is the number of drug doses per week. If there is no number in subscript, treatment is daily. An alternative drug(s) appears as a letter(s) in parentheses. The drugs in the higher groups are written first followed by the others in descending order of potency.

Monitoring of sputum : 

Monitoring of sputum Sputum smears and cultures should be monitored closely throughout treatment. The tests shoud be performed monthly before smear and culture conversion, with conversion defined as two consecutive negative smears and cultures taken 30 days apart. After conversion, the minimum period recommended is monthly for smears and quarterly for cultures

Intensive phase : 

Intensive phase The recommended duration of administration of the injectable agent, or the intensive phase, is guided by culture conversion. The injectable agent should be continued for at least six months and at least four months after the patient first becomes and remains smear- or culture-negative.

Duration of treatment : 

Duration of treatment The recommended duration of treatment is guided by culture conversion. Despite emerging evidence that shorter regimens may be efficacious, these guidelines recommend continuing therapy for a minimum of 18 months after culture conversion until there is conclusive evidence to support a shorter duration of treatment. Extension of therapy to 24 months may be indicated in chronic cases with extensive pulmonary damage.

Extrapulmonary DR-TB : 

Extrapulmonary DR-TB Extrapulmonary DR-TB is treated with the same strategy and duration as pulmonary DR-TB. If the patient has symptoms suggestive of central nervous system involvement and is infected with DR-TB, the regimen should use drugs that have adequate penetration into the central nervous system . Rifampicin, isoniazid, pyrazinamide, protionamide/ethionamide and cycloserine have good penetration into the cerebrospinal fluid (CSF); kanamycin,amikacin and capreomycin do so only in the presence of meningeal inflammation; PAS and ethambutol have poor or no penetration. The fluoroquinolones have variable CSF penetration, with better penetration seen in the later generations.

The adjuvant use of corticosteroids in DR-TB : 

The adjuvant use of corticosteroids in DR-TB has been shown not to increase mortality and can be beneficial in conditions such as severe respiratory insufficiency, and central nervous system or pericardial involvement. Prednisone is commonly used, starting at approximately 1 mg/kg and gradually decreasing the dose to 10 mg per week when a long course is indicated. Corticosteroids may also alleviate symptoms in patients with an exacerbation of obstructive pulmonary disease. In these cases, prednisone may be given in a short taper over 1–2 weeks, starting at approximately 1 mg/kg and decreasing the dose by 5–10 mg per day. Injectable corticosteroids are often used initially when a more immediate response is needed.

Surgery in Category IV treatment : 

Surgery in Category IV treatment The most common operative procedure is resection surgery (taking out part or all of a lung). It is considered an adjunct to chemotherapy It is not indicated in patients with extensive bilateral disease. Resection surgery should be timed to offer the patient the best possible chances of cure with the least morbidity. Thus, the timing of surgery may be earlier in the course of the disease when the patient’s risk of morbidity and mortality is lower, for example, when the disease is still localized to one lung or one lung lobe. In other words, surgery should not be considered as a last resort. Generally, at least two months of therapy should be given before resection surgery in order to decrease the bacterial infection in the surrounding lung tissue. Even with successful resection, an additional 12–24 months of chemotherapy should be given.

Compassionate use of drugs : 

Compassionate use of drugs The terms “compassionate use,” “expanded access” or “special access” programmes have essentially the same meaning. They refer to programmes that are intended to provide potentially lifesaving experimental treatments to patients suffering from a disease for which no satisfactory authorized therapy exists and/or who cannot enter a clinical trial. For many patients, these programmes represent their last hope. Compassionate use is a well known mechanism for diseases such as cancer, Alzheimer disease and AIDS, and can also be used for TB when other treatment options have been exhausted.

New drugs currently under clinical testing: : 

New drugs currently under clinical testing: diamine (SQ-109), diarylquinoline (TMC-207), nitrodihydroimidazooxazole (OPC-67683), nitroimidazole (PA-284), pyrrole (LL3858).

Special Situations : 

Special Situations Pregnancy: Avoid pregnancy. If treament is needed withheld until 2nd trimester if not severe. Avoid ethionamide and injectable drugs esp aminoglycoside, if really needed then Cm is the drug of choice. Breast feeding: Drug conc in the breast milk is not harmful, however infant formula may be an option. In smear +ve mother baby may be separated till mother becomes –ve, N95 mask may be used. Contraception: Barrier method or OC pill of high oestrogen 50 µgm. DM: poor outcome. Oral hypoglycaemic can be used but doses need to be increased. Ethionamide, protionamide may increase insulin dose needed. Renal insufficiency: needs adjustment

Special Situations : 

Special Situations Liver disorders: Among 2nd line drugs ethionamide, protionamide, PAS and fluroquinolines are hepatoxic but less then 1st line drugs. However hepatotoxic effect is more common in drug-resistant TB. Seizure disorder: Cs cause seizure disorder. R,H have interaction with anti-convulsant, so dose may need to be adjusted. Psychiatric disorders: Majority DR-TB suffer from anxiety and depression. Cs also cause psychiatric problem, so benefit should outweigh the risk. Substance abuse: should be avoided. Alcohol increase risk of seizure if Cs is used.

MDR-TB contact : 

MDR-TB contact

THANK YOU : 

THANK YOU

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