Systematic Review of Mutations in Pyrazinamidase Associated with Pyrazinamide Resistance in Mycobacterium tuberculosis Clinical Isolates

Pyrazinamide (PZA) is an important first-line drug in the treatment of tuberculosis (TB) and of significant interest to the HIV-infected community due to the prevalence of TB-HIV coinfection in some regions of the world. The mechanism of resistance to PZA is unlike that of any other anti-TB drug. The gene pncA, encoding pyrazinamidase (PZase), is associated with resistance to PZA. However, because single mutations in PZase have a low prevalence, the individual sensitivities are low. Hundreds of distinct mutations in the enzyme have been associated with resistance, while some only appear in susceptible isolates. This makes interpretation of molecular testing difficult and often leads to the simplification that any PZase mutation causes resistance. This systematic review reports a comprehensive global list of mutations observed in PZase and its promoter region in clinical strains, their phenotypic association, their global frequencies and diversity, the method of phenotypic determination, their MIC values when given, and the method of MIC determination and assesses the strength of the association between mutations and phenotypic resistance to PZA. In this systematic review, we report global statistics for 641 mutations in 171 (of 187) codons from 2,760 resistant strains and 96 mutations from 3,329 susceptible strains reported in 61 studies. For diagnostics, individual mutations (or any subset) were not sufficiently sensitive. Assuming similar error profiles of the 5 phenotyping platforms included in this study, the entire enzyme and its promoter provide a combined estimated sensitivity of 83%. This review highlights the need for identification of an alternative mechanism(s) of resistance, at least for the unexplained 17% of cases.