Diagnostic Accuracy of a Molecular Drug Susceptibility Testing Method for the Antituberculosis Drug Ethambutol: a Systematic Review and Meta-analysis

Ethambutol (EMB) is a first-line antituberculosis drug; however, drug resistance to EMB has been increasing. Molecular drug susceptibility testing (DST), based on the embB gene, has recently been used for rapid identification of EMB resistance. The aim of this meta-analysis was to establish the accuracy of molecular assay for detecting drug resistance to EMB. PubMed, Embase, and Web of Science were searched according to a written protocol and explicit study selection criteria. Measures of diagnostic accuracy were pooled using a random effects model. A total of 34 studies were included in the meta-analysis. The respective pooled sensitivities and specificities were 0.57 and 0.93 for PCR-DNA sequencing that targeted the embB 306 codon, 0.76 and 0.89 for PCR-DNA sequencing that targeted the embB 306, 406, and 497 codons, 0.64 and 0.70 for detecting Mycobacterium tuberculosis isolates, 0.55 and 0.78 for detecting M. tuberculosis sputum specimens using the GenoType MTBDRsl test, 0.57 and 0.87 for pyrosequencing, and 0.35 and 0.98 for PCR-restriction fragment length polymorphism. The respective pooled sensitivities and specificities were 0.55 and 0.92 when using a lower EMB concentration as the reference standard, 0.67 and 0.73 when using a higher EMB concentration as the reference standard, and 0.60 and 1.0 when using multiple reference standards. PCR-DNA sequencing using multiple sites of the embB gene as detection targets, including embB 306, 406, and 497, can be a rapid method for preliminarily screening for EMB resistance, but it does not fully replace phenotypic DST. Of the reference DST methods examined, the agreement rates were the best using MGIT 960 for molecular DST and using the proportion method on Middlebrook 7H10 media.