title: A Global Perspective on Pyrazinamide Resistance: Systematic Review and Meta-Analysis.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: SA 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.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Whitfield
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Soeters
authors.affiliation: SA 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.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Warren
authors.affiliation: SA 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.
authors.forename: Talita
authors.initials: T
authors.lastname: York
authors.affiliation: SA 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.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Sampson
authors.affiliation: SA 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.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Streicher
authors.affiliation: SA 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.
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Helden
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; International Health Unit, Epidemiology and Social Medicine, Faculty of Medicine, University of Antwerp, Antwerp, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: van Rie
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use*; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011718:Pyrazinamide / Q000627:therapeutic use*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide