Direct susceptibility testing for multi drug resistant tuberculosis: A meta-analysis

Abstract

BackgroundOne of the challenges facing the tuberculosis (TB) control programmes in resource-limited settings is lack of rapid techniques for detection of drug resistant TB, particularly multi drug resistant tuberculosis (MDR TB). Results obtained with the conventional indirect susceptibility testing methods come too late to influence a timely decision on patient management. More rapid tests directly applied on sputum samples are needed. This study compared the sensitivity, specificity and time to results of four direct drug susceptibility testing tests with the conventional indirect testing for detection of resistance to rifampicin and isoniazid in M. tuberculosis. The four direct tests included two in-house phenotypic assays – Nitrate Reductase Assay (NRA) and Microscopic Observation Drug Susceptibility (MODS), and two commercially available tests – Genotype® MTBDR and Genotype® MTBDRplus (Hain Life Sciences, Nehren, Germany).MethodsA literature review and meta-analysis of study reports was performed. The Meta-Disc software was used to analyse the reports and tests for sensitivity, specificity, and area under the summary receiver operating characteristic (sROC) curves. Heterogeneity in accuracy estimates was tested with the Spearman correlation coefficient and Chi-square.ResultsEighteen direct DST reports were analysed: NRA – 4, MODS- 6, Genotype MTBDR® – 3 and Genotype® MTBDRplus – 5. The pooled sensitivity and specificity for detection of resistance to rifampicin were 99% and 100% with NRA, 96% and 96% with MODS, 99% and 98% with Genotype® MTBDR, and 99% and 99% with the new Genotype® MTBDRplus, respectively. For isoniazid it was 94% and 100% for NRA, 92% and 96% for MODS, 71% and 100% for Genotype® MTBDR, and 96% and 100% with the Genotype® MTBDRplus, respectively. The area under the summary receiver operating characteristic (sROC) curves was in ranges of 0.98 to 1.00 for all the four tests. Molecular tests were completed in 1 – 2 days and also the phenotypic assays were much more rapid than conventional testing.ConclusionDirect testing of rifampicin and isoniazid resistance in M. tuberculosis was found to be highly sensitive and specific, and allows prompt detection of MDR TB.

Cost-effectiveness in the diagnosis of tuberculosis: choices in developing countries

“…Chaiyasirinroje et al analyzed 202 sputum samples of clinically diagnosed TB patients with MODS assay in relation to gold standard BACTECT MGIT 960 and Ogawa solid culture. The median time to culture positivity by MODS, solid, and liquid culture were 12, 30, and 6 days, respectively [15]. In another study conducted in Egypt, 115 smearpositive TB patients were simultaneously tested using MODS and the BACTECT MGIT 960.…”

Boronic-aurone Derivatives as Anti-Tubercular Agents: Design, Synthesis and Biological Evaluation

“…The utility of Alamar Blue as a phenotypic high-throughput cell viability screen for identification of potentially new TB leads for screening of clinical isolates of MTB has been demonstrated [23,24], among others. In addition, several studies have also shown the reliability of Alamar blue cell viability assay for detection of drug resistant MTB [25,30].…”

“…The resazurin microtiter assay (REMA) was performed in 7H9 medium containing Middlebrook broth and 0.5% glycerol and supplemented with oleic acid, albumin, dextrose, and catalase (Difco TM ) as previously reported [23][24][25]. Clear 96-well plates were inoculated with 100 μL of drug diluted with 90 µl of 7H9 medium and 10 µL DMSO (giving essentially 50 µL of drug).…”

Rapid Diagnosis of Mycobacterium tuberculosis Infection and Drug Susceptibility Testing

“…For detecting rifampin resistance, the Genotype MTBDRplus assay shows a diagnostic sensitivity of approximately 98% with a specificity of approximately 99%. 41 In contrast, for detecting isoniazid resistance the diagnostic sensitivity is only approximately 84% with about the same specificity (approximately 100%). 41 The reason for the lower sensitivity in detecting isoniazid resistance compared with detecting rifampin resistance isn't completely understood, but may, in part, be that the assay tests for fewer genes conferring resistance to isoniazid resistance compared with the number of genes that can be detected conferring resistance to rifampin.…”

“…[32][33][34][35][36][37][38][39][40][41][42] Conceptually similar to the INNO-Lipa Rif.tb assay, the MTBDRplus assay has been reported to have a diagnostic sensitivity of approximately 94% for detecting M tuberculosis DNA in smear-positive respiratory specimens. 33 It is of interest that most clinical evaluations of this device have focused on its use for susceptibility testing, not detection of M tuberculosis, so the performance characteristics for the latter use are less well defined.…”