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

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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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Most cited references 103

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Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance.

Martin P Grobusch, R. Van Der Leeuw, A Pym … (2012)

The 2-year follow-up results for a randomized placebo-controlled study of 47 patients with multidrug-resistant pulmonary tuberculosis treated with either the new diarylquinoline TMC207, recently renamed bedaquiline, or placebo, added to the first 8 weeks of a background regimen, are presented. Bedaquiline significantly reduced the time to culture conversion over 24 weeks (hazard ratio, 2.253; 95% confidence interval, 1.08 to 4.71; P = 0.031). With the exception of nausea reported in 26% of patients receiving bedaquiline and none receiving placebo, adverse events occurred at similar frequencies in both groups of patients: bilateral hearing impairment, extremity pain, acne, and noncardiac chest pain occurred in 13 and 21%, 17 and 13%, 9 and 17%, and 4 and 17% of patients, respectively, receiving bedaquiline or placebo. Excluding resistance to ethambutol and ethionamide, only one patient receiving bedaquiline acquired resistance to companion drugs, but five patients receiving placebo (4.8% versus 21.7%; P = 0.18) acquired resistance to companion drugs, and resistance to ofloxacin was acquired in four patients receiving placebo and none receiving bedaquiline (0% versus 22%; 0 = 0.066). In all, 23 patients (49%), including 13 receiving placebo (54%) and 10 receiving bedaquiline (44%), discontinued the study prior to its completion, 12 during the first 24 weeks of treatment. Eight subjects were withdrawn for noncompliance or default, and seven withdrew consent, citing the rigorous program of investigations for safety and pharmacokinetic monitoring. Bedaquiline may contribute to the management of multidrug-resistant tuberculosis by effecting more rapid sputum culture negativity and by preventing acquired resistance to companion drugs.

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The action of antituberculosis drugs in short-course chemotherapy.

D A Mitchison (1985)

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The curious characteristics of pyrazinamide: a review.

Y. Zhang, D. Mitchison (2003)

Pyrazinamide (PZA) is an important sterilising tuberculosis drug that helps to shorten the duration of current chemotherapy regimens for tuberculosis. When first discovered, it had activity in murine tuberculosis but no apparent in vitro activity, and its subsequent use in treatment depended largely on classic experiments at Cornell University, which showed its requirement for an acid pH for activity and its sterilising activity in the mouse. Recent studies have shown that PZA enters Mycobacterium tuberculosis by passive diffusion, is converted to pyrazinoic acid (POA) by nicotinamidase/pyrazinamidase (PZase) and is then excreted by a weak efflux pump. Protonated POA (HPOA) is reabsorbed into the bacilli under acid conditions and accumulates because the efflux pump is inefficient, causing cellular damage. Unlike other antibacterials, PZA has no defined target of action. PZA is more active against old than against actively growing cultures, probably because the energy production and efflux pump would be slowed down by low bacterial metabolism. This review deals with the activity of PZA in vitro, in macrophages and in animal models. It describes the evidence from clinical trials that it is an effective sterilising drug that acts synergistically with rifampicin. The highly diverse mutations in the PZase gene (pncA) that lead to loss of PZase activity cause PZA resistance. Methods for susceptibility determination either as tests against PZA or nicotinamide in liquid and solid media, as tests for PZase activity or for mutations in pncA, are reviewed.

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Author and article information

Contributors

Igor Mokrousov: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 28 July 2015

Publication date Collection: 2015

Volume: 10

Issue: 7

Electronic Location Identifier: e0133869

Affiliations

[1 ]SA MRC Centre for TB Research, Stellenbosch University, South Africa

[2 ]DST/NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, South Africa

[3 ]Division of Molecular Biology and Human Genetics, Stellenbosch University, South Africa

[4 ]Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa

[5 ]Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America

[6 ]International Health Unit, Epidemiology and Social Medicine, Faculty of Medicine, University of Antwerp, Antwerp, Belgium

St. Petersburg Pasteur Institute, RUSSIAN FEDERATION

Author notes

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

Conceived and designed the experiments: MGW RMW AVR. Analyzed the data: HMS AVR. Wrote the paper: MGW HMS. Literature search: MGW TY. Figures and Tables: MGW TY HMS AVR RMW. Data abstraction: MGW HMS TY. Data interpretation: MGW HMS EMS AVR RMW. Critical revision for important content and final approval of article: MGW HMS SLS PDVH AVR RMW.

* E-mail: rw1@ 123456sun.ac.za

Article

Publisher ID: PONE-D-15-19212

DOI: 10.1371/journal.pone.0133869

PMC ID: 4517823

PubMed ID: 26218737

SO-VID: ed6c2046-e1b5-4f22-b985-8cee71fd0975

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 4 May 2015

Date accepted : 3 July 2015

Page count

Figures: 4, Tables: 1, Pages: 16

Funding

AVR and MGW are partially funded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), grant R01AI099026. HMS was partially supported by the NIH training grant 2T32AI070114. SLS is funded by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa, award number UID 86539. MGW funded by the NRF of South Africa and the Medical Research Council of South Africa, grant UID 89519. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability All relevant data are within the paper and its Supporting Information files.

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

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Abstract

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Most cited references 103

Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance.

The action of antituberculosis drugs in short-course chemotherapy.

The curious characteristics of pyrazinamide: a review.

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