EPTBMDR - DM SEMINAR JULY 29, 2005 MDR TB AT EXTRAPULMONARY...

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MDR TB AT EXTRAPULMONARY SITES – Current Concepts & Literature Review Navneet Singh Department of Pulmonary Medicine DM SEMINAR JULY 29, 2005
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HEADINGS • Salient features of EPTB • Salient features of MDR TB • Prevalence & Epidemiology of MDR EPTB • Diagnosis of MDR in EPTB • MDR at specific sites in EPTB • Treatment of MDR EPTB
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Overview of EPTB
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EPTB - Overview • From the initial phase of invasion of human lung, M. tuberculosis can disseminate through lymph vessels or bloodstream to any organ or tissue in the body • Extrapul inv can occur in isolation or along with a pul focus (latter classified as PTB under NTP conditions) • Term EPTB used to describe isolated occurrence of TB at sites other than lung
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EPTB - Overview • EPTB constitutes about: ± 15-20 % of all TB cases in immunocompetent pts ± >50 % of TB cases in immunosupressed pts • M.C. sites of involvement : • LN > Pl eff > Others • S/S depend on area inv – often nonspecific • Dx often delayed: • Atypical clinical presentation • No pathognomonic radiographic signs for any site • Poor diagnostic yield of conventional methods • Tissue samples for Dx often difficult to obtain
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EPTB - Overview TYPE OF LESION APPROX BACTERIAL LOAD Smear-positive TB 10 7 -10 9 bacilli Cavitary 10 7 -10 9 bacilli Infiltrating 10 4 -10 7 bacilli Nodules 10 4 -10 6 bacilli Adenopathies 10 4 -10 6 bacilli Renal TB 10 7 -10 9 bacilli Extrapulmonary TB 10 4 -10 6 bacilli
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EPTB - Overview ATS/CDC/IDSA: Treatment of Tuberculosis Am J Respir Crit Care Med 2003; 167: 603–662. EPTB usually responds to std ATT
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EPTB - Overview • Some authors & scientific societies recommend extending duration of Rx to 9 m in meningeal, osteoarticular, and lymphatic TB BUT there is no firm evidence supporting this recommendation • Treatment trials conducted for EPTB have not been as thorough as those for PTB • Under NTP conditions, there should be no diff in Rx of EPTB and PTB
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Overview of MDR TB
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MDR TB - Overview • MDR-TB caused by MTB resistant to both H & R ± resistance to other drugs • Normally resistance to anti- TB drugs occur due to spon chromosomally borne mutations in MTB • Mutations occur at predictable rates & unlinked • Spon mutations causing resistance to INH & RIF occur in ~ 1/10 6 & ~ 1/10 8 replications Æ bacilli reqd for resistance to both INH & RIF ~1 /(10 6 x 10 8 ) = 1/10 14
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MDR TB - Overview • Bacilli in extensive cavitatory PTB ~ 10 7- 10 9 Æ negligible chances of spontaneous occurrence of dual resistance to INH & RIF (i.e. spontaneous occurrence of MDR ) • 1° mechanism of MDR due to accumulation of altered target genes of individual drugs by: • Mutation of target genes • Overproduction of target genes
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MDR TB - Overview DRUG GENE(s) FOR DRUG RESISTANCE Isoniazid Catalase-peroxidase (katG) Enoyl acp reductase (inhA) Alkyl hydroperoxide reductase (ahpC) Oxidative stress regulator (oxyR) Rifampicin RNA polymerase subunit B (rpoB) Pyrazinamide Pyrazinamidase (pncA) Streptomycin Ribosomal protein subunit 12 (rpsL) 16s ribosomal RNA (rrs) Aminoglycoside phosphotransferase gene (strA) Ethambutol Arabinosyl transferase (emb A,B and C) Fluoroquinolones DNA gyrase (gyr A and B)
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EPTBMDR - DM SEMINAR JULY 29, 2005 MDR TB AT EXTRAPULMONARY...

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