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Meta-Analysis
. 2015 Jul 28;10(7):e0133869.
doi: 10.1371/journal.pone.0133869. eCollection 2015.

A Global Perspective on Pyrazinamide Resistance: Systematic Review and Meta-Analysis

Michael G Whitfield  1 , Heidi M Soeters  2 , Robin M Warren  1 , Talita York  1 , Samantha L Sampson  1 , Elizabeth M Streicher  1 , Paul D van Helden  1 , Annelies van Rie  3
Affiliations
Meta-Analysis

A Global Perspective on Pyrazinamide Resistance: Systematic Review and Meta-Analysis

Michael G Whitfield et al. PLoS One. .

Abstract

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Flow diagram describing article selection.
Fig 2
Fig 2. Global distribution of included studies.
Countries are shaded if a study was included in this review.
Fig 3
Fig 3. Forest plot for the summary estimates of pyrazinamide prevalence by WHO region and presence or risk of MDR-TB.
Abbreviations: CI, confidence interval; DST, drug susceptibility test; MDR-TB, multi-drug resistant tuberculosis; N/A, not applicable; WHO, world health organization. MDR-TB was defined as an isolate being resistant to RIF and INH. High risk of MDR-TB was defined as an isolate being resistant to at least one anti-TB drug. *Any TB was defined as the inclusion of patients independent of drug resistance profile.
Fig 4
Fig 4. Distribution of reported single nucleotide polymorphisms (SNPs) throughout the pncA gene.
Dashed lines indicate the open reading frame for the pncA gene.
See this image and copyright information in PMC

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