Comparative Performance of Genomic Methods for the Detection of Pyrazinamide Resistance and Heteroresistance in Mycobacterium tuberculosis

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dc.contributor.authorWhitfield, Michael G.en_ZA
dc.contributor.authorEngelthaler, David M.en_Za
dc.contributor.authorAllender, Christopheren_ZA
dc.contributor.authorFolkerts, Meganen_ZA
dc.contributor.authorHeupink, Tim H.en_ZA
dc.contributor.authorLimberis, Jasonen_ZA
dc.contributor.authorWarren, Robin M.en_ZA
dc.contributor.authorVan Rie, Anneliesen_ZA
dc.contributor.authorMetcalfe, John Z.en_ZA
dc.date.accessioned2023-03-27T06:26:28Zen_ZA
dc.date.available2023-03-27T06:26:28Zen_ZA
dc.date.issued2021en_ZA
dc.descriptionCITATION: Whitfield, M. G. et al. 2021. Comparative Performance of Genomic Methods for the Detection of Pyrazinamide Resistance and Heteroresistance in Mycobacterium tuberculosis. Journal of Clinical Microbiology 60(1):10 pages.doi.10.1128/JCM.01907-21en_ZA
dc.descriptionThe original publication is available at: .asm.orgen_ZA
dc.description.abstractPyrazinamide is an important component of both drug-susceptible and drug-resistant tuberculosis treatment regimens. Although approximately 50% of rifampin- resistant isolates are also resistant to pyrazinamide, pyrazinamide susceptibility testing is not routinely performed due to the challenging nature of the assay. We investigated the diagnostic accuracy of genotypic and phenotypic methods and explored the occurrence of pyrazinamide heteroresistance. We assessed pyrazinamide susceptibility among 358 individuals enrolled in the South African EXIT-RIF cohort using Sanger and targeted deep sequencing (TDS) of the pncA gene, whole-genome sequencing (WGS), and phenotypic drug susceptibility testing. We calculated the diagnostic accuracy of the different methods and investigated the prevalence and clinical impact of pncA heteroresistance. True pyrazinamide susceptibility status was assigned to each isolate using the Köser classification and expert rules. We observed 100% agreement across genotypic methods for detection of pncA fixed mutations; only TDS confidently identified three isolates (0.8%) with minor variants. For the 355 (99.2%) isolates that could be assigned true pyrazinamide status with confidence, phenotypic DST had a sensitivity of 96.5% (95% confidence interval [CI], 93.8 to 99.3%) and specificity of 100% (95% CI, 100 to 100%), both Sanger sequencing and WGS had a sensitivity of 97.1% (95% CI, 94.6 to 99.6%) and specificity of 97.8% (95% CI, 95.7 to 99.9%), and TDS had sensitivity of 98.8% (95% CI, 97.2 to 100%) and specificity of 97.8% (95% CI, 95.7 to 99.9%). We demonstrate high sensitivity and specificity for pyrazinamide susceptibility testing among all assessed genotypic methods. The prevalence of pyrazinamide heteroresistance in Mycobacterium tuberculosis isolates was lower than that identified for other first-line drugs.en_ZA
dc.description.versionPublisher’s versionen_ZA
dc.format.extent10 pagesen_ZA
dc.identifier.citationWhitfield, M. G. et al. 2021. Comparative Performance of Genomic Methods for the Detection of Pyrazinamide Resistance and Heteroresistance in Mycobacterium tuberculosis. Journal of Clinical Microbiology 60(1):10 pages.doi.10.1128/JCM.01907-21en_ZA
dc.identifier.issn0095-1137 (print)en_ZA
dc.identifier.issn1098-660X (online)en_ZA
dc.identifier.otherdoi.10.1128/JCM.01907-21en_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/126713en_ZA
dc.language.isoen_ZAen_ZA
dc.publisherAmerican Society for Microbiologyen_ZA
dc.rights.holderAuthors retain copyrighten_ZA
dc.subjectMultidrug-resistant tuberculosisen_ZA
dc.subjectPyrazinamideen_ZA
dc.subjectMycobacterium tuberculosisen_ZA
dc.subjectRifampinen_ZA
dc.subjectDrug resistanceen_ZA
dc.titleComparative Performance of Genomic Methods for the Detection of Pyrazinamide Resistance and Heteroresistance in Mycobacterium tuberculosisen_ZA
dc.typeArticleen_ZA
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