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Pyrazinamide (PZA) is an important first-line drug in all existing and new tuberculosis (TB) treatment regimens. PZA-resistance in  M. tuberculosis  is increasing, especially among M/XDR cases. Noted issues with PZA Drug Susceptibility Testing (DST) have driven the search for alternative tests. This study provides a comprehensive assessment of PZA molecular diagnostics in M/XDR TB cases. A set of 296, mostly XDR, clinical  M. tuberculosis  isolates from four countries were subjected to DST for eight drugs, confirmatory Wayne’s assay, and whole-genome sequencing. Three genes implicated in PZA resistance,  pncA ,  rpsA , and  panD  were investigated. Assuming all non-synonymous mutations cause resistance, we report 90% sensitivity and 65% specificity for a  pncA -based molecular test. The addition of  rpsA  and  panD  potentially provides 2% increase in sensitivity. Molecular heterogeneity in  pncA  was associated with resistance and should be evaluated as a diagnostic tool. Mutations near the N-terminus and C-terminus of PZase were associated with East-Asian and Euro-American lineages, respectively. Finally, Euro-American isolates are most likely to have a wild-type PZase and escape molecular detection. Overall, the 8–10% resistance without markers may point to alternative mechanisms of resistance. Confirmatory mutagenesis may improve the disconcertingly low specificity but reduce sensitivity since not all mutations may cause resistance.

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A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis