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Updated: Apr 6, 2026
Amplicon Sequencing using the Long-Read Sequencing Technologies
Published on: August 29, 2025
A Global Perspective on Pyrazinamide Resistance: Systematic Review and Meta-Analysis
Michael G Whitfield1, Heidi M Soeters2, Robin M Warren1
1SA MRC Centre for TB Research, Stellenbosch University, South Africa; DST/NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, South Africa; Division of Molecular Biology and Human Genetics, Stellenbosch University, South Africa; Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.
Background:
Pyrazinamide (PZA) is crucial for tuberculosis (TB) treatment, given its unique ability to eradicate persister bacilli. The worldwide burden of PZA resistance remains poorly described.
Methods:
Systematic PubMed, Science Direct and Scopus searches for articles reporting phenotypic (liquid culture drug susceptibility testing or pyrazinamidase activity assays) and/or genotypic (polymerase chain reaction or DNA sequencing) PZA resistance. Global and regional summary estimates were obtained from random-effects meta-analysis, stratified by presence or risk of multidrug resistant TB (MDR-TB). Regional summary estimates were combined with regional WHO TB incidence estimates to determine the annual burden of PZA resistance. Information on single nucleotide polymorphisms (SNPs) in the pncA gene was aggregated to obtain a global summary.
Results:
Pooled PZA resistance prevalence estimate was 16.2% (95% CI 11.2-21.2) among all TB cases, 41.3% (29.0-53.7) among patients at high MDR-TB risk, and 60.5% (52.3-68.6) among MDR-TB cases. The estimated global burden is 1.4 million new PZA resistant TB cases annually, about 270,000 in MDR-TB patients. Among 1,815 phenotypically resistant isolates, 608 unique SNPs occurred at 397 distinct positions throughout the pncA gene.
Interpretation:
PZA resistance is ubiquitous, with an estimated one in six incident TB cases and more than half of all MDR-TB cases resistant to PZA globally. The diversity of SNPs across the pncA gene complicates the development of rapid molecular diagnostics. These findings caution against relying on PZA in current and future TB drug regimens, especially in MDR-TB patients.
