Definitions: Drug Resistant Tuberculosis Cases of T.B. caused by an isolate of TB resistant to one of the first line anti TB drugs PRIMARY DRUG RESISTANCE (P.D.R) PDR is defined as resistance to one of the frontline drugs in person with TB who is not known to have previous treatment with ATT NATURAL DRUG RESISTANCE IN WILD STRAINS (Spontaneous Mutation) SECONDARY (ACQUIRED) DRUG RESISTANCE (A.D.R) ADR is defined as acquiring increasing level of resistance to one or more drugs in a strain recovered from a patient undergoing ineffective therapy. TRANSMITTED DRUG RESISTANCE (T.D.R) TDR is said to have occurred when a single or multi drug resistant strain is recovered from patient who is high risk contact of other individual known to be shedding strain with comparable patterns of drug resistance MULTI DRUG RESISTANCE (M.D.R) MDR defined as resistance to two or more first line drugs. Now usually used when resistance to Rifampicin & INH is seen with or without resistance to other drugs. Cross Resistance: Capreomycin & Viomycin Thiacetazone & Ethionamide Epidemiology US: Prevalence decreasing in US b/c of effective measures. 1991 National survey of all TB cases revealed PDR to 1 or more drugs in 13.4% PDR to RH in 3.2 % of Isolates New York highest incidence 33 % of isolates 1 drug 26% to INH 19 % to RH Epidemiology US: In 1997 decreased to 10% INH most common 8% R1.7% S5.9% E1.6% RH2.5% Epidemiology UK: GRANGES & YATES 1993 In South East ENGLAND 8.5% of Immigrant Indian subcontinent population with tuberculosis had drug resistance Epidemiology World Wide: Epidemiology Local: Rifampicin 10/1258% INH 32/18417.3% Ethambutol 11/1248.8% Strep 8/5913.5% Sensitive to all drugs137/18474.4% Resistant to 1 drug 35/18419.8% Resistant to 2 drugs 9/1844.8% Resistant to 3 drugs 3/1841.6% Institue Of Chest Disease Kotri: 16.4 % Pts did not convert to 5 drugs suggesting high prevalence of resistance At Ash 100 Isolates Of Patients In Relapse / Retreatment Group: No of resistance cases6060% Resistance to single drug3838%63% Resistance to two drugs1818%30% Resistance to three drugs22%3.3% Resistance to four drugs22%3.3 % INH Resistance1428%46.6% Rates of Primary MDR are generally low; median 1.4% Secondary MDR TB much more common median 13.0% Highest proportion Latvia 54% South Korea28% Russia27.7% Predisposing Factors: Type of bacterial Population Insufficient Concentration of Drug Patients Drug inactivation status Patient Factors: Contact with resistant case Irregular drug intake Premature drug stoppage Poor absorption (Intestinal TB Excessive vomiting). Economic reasons. Disease Factors: In Cavitatory TB Drug concentration fluctuates Higher no. of bacteria. PH Factor Thickened Pleura Barrier to effective drug penetration Iatrogenic Factors: Treatment with one effective drug Inadequate dosage Inadequate duration Use of cross resistant drugs Inadequate Prescribing Practice: In 1995 25% of new cases of TB were initially treated with 2-3 drugs regimen 2 Surveys by AKUH among GP & Interns Once resistance develops, prescribing errors, usually by inexperienced physicians can exacerbate situation. Review of patients referred to National Jewish Hospital (Denver) for management of complex MDR-TB documented an average of 3.93 prescribing errors per patient. Erratic Compliance: New York study by Brudrey showed that out of 178 patient only 11 % compliant Drug often taken erratically and often singly Nosocomial Transmission: In Prisons In Hospitals In Nursing Homes HIV Infection is often associated with a high prevalence of drug resistance Patient fails to improve Patient improves initially but has recurrence of symptoms Patient fails to become smear negative Patients who have taken treatment previously Previously treated patients who have been non compliant. Implication Of MDR: Prolonged hospital stay & Isolation Loss of benefit of short course chemotherapy High cost of treatment Low success rate High relapse rate Diagnosis: Once suspected it is easy to diagnose Diagnosis follows same lines as standard TB AFB culture and sensitivity should be sent Treatment: General Principles Isolation to prevent spread of disease prolonged hospital admission. D.O.T with effective drugs. If already taking treatment add at least two new drugs. Adjust treatment according to sensitivities when available. Treatment: General Principles Never add one drug at a time. Treatment to be continued for longer period (12-24 months) INH is often useful even if the sensitivities don't favour it. Isoniazid Monoresistance: Rifamycin, Pyrazinamide and Ethambutol for 6 to 9 months or 4 months after culture conversion. Rifampicin Monorisestancae: Most often seen in HIV positive patients. Uncommon but increasingly frequent. Because Rifampicin is corner stone of all six months regime, resistance requires prolongation of treatment. Streptomycin, Isoniazid, Pyrazinamide for 9 months. (12 months for HIV +ve) SHE for 3 months followed by HE for 18 months. Pyrazinamide Monoresistance Requires 9 months of Isoniazid and Rifampicin. Monoresistance To Other Agents: Single drug resistance to Ethambutol, Streptomycin, or second line agents is of little clinical significance. Patient can still be treated with 2 RHZ followed by 4 to 6 months of RH. Suggested Treatment regimens for multidrug resistant tuberculosis Suggested Treatment regimens for multidrug resistant tuberculosis Prevention Of MDR: Educate the prescriber. Educate the patient. DOTS Availability of drugs. Using 4 drugs in initial phase, 3 in continuation & giving treatment for 9 months. More frequent use of Microbiology services. Drug levels. Reference Lab.
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