Pyrazinamide Susceptibility Testing in Mycobacterium tuberculosis: a Systematic Review with Meta-Analyses

Abstract

ABSTRACTStandard culture-based testing of the susceptibility ofMycobacterium tuberculosisto pyrazinamide is difficult to perform. This systematic review with meta-analyses evaluated the roles of molecular assays targetingpncAand of pyrazinamidase assays. PubMed and Embase were searched for relevant publications in English. Sensitivity and specificity were estimated in bivariate random-effects models. Of 128 articles identified, 73 sets of data involving culture isolates were initially included in meta-analyses. Summary estimates of sensitivity and specificity, respectively, were 87% and 93% for PCR-DNA sequencing (n= 29), 75% and 95% for PCR-single-stranded conformation polymorphism (SSCP) (n= 5), 96% and 97% for a mixture of other molecular assays (n= 6), and 89% and 97% for pyrazinamidase assays using the Wayne method (n= 33). The median prevalence (range) of pyrazinamide resistance was 51% (31% to 89%) in multidrug-resistantM. tuberculosisisolates and 5% (0% to 9%) in non-multidrug-resistant isolates. Excluding studies with possibly considerable false resistance in the reference assay gave the following estimates of sensitivity and specificity, respectively: 92% and 93% for PCR-DNA sequencing (n= 20), 98% and 96% for other molecular assays (n= 5), and 91% and 97% for the Wayne assay (n= 27). The Wayne assay had significant funnel plot asymmetry, so the test performance might have been overestimated. Considering the prevalence of pyrazinamide resistance in different clinical settings, PCR-DNA sequencing, and possibly other molecular assays targetingpncA, can detect pyrazinamide resistance in multidrug-resistantM. tuberculosisisolates, with predictive values largely exceeding 90%, and rule out pyrazinamide resistance in non-multidrug-resistant isolates, with predictive values exceeding 99%. Molecular assays are probably the way forward for detecting pyrazinamide resistance.