{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T13:35:09Z","timestamp":1751376909709,"version":"3.40.5"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T00:00:00Z","timestamp":1663718400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004695","name":"University of KwaZulu-Natal","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004695","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p><jats:italic>Mycobacterium tuberculosis<\/jats:italic> strains with phenotypically susceptible <jats:italic>rpoB<\/jats:italic> mutations (rifampicin discordant) have emerged following implementation of rapid molecular drug resistance testing for tuberculosis. Whilst rifampicin resistance is known to be associated with resistance to other rifamycins (rifapentine and rifabutin) as well as isoniazid and pyrazinamide, rifampicin discordant strains have shown high rates of susceptibility to isoniazid and rifabutin. However, pyrazinamide susceptibly testing results have not been reported.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Materials and methods<\/jats:title>\n<jats:p>We evaluated pyrazinamide resistance in 80 rifampicin discordant and 25 rifampicin and isoniazid susceptible isolates from KwaZulu-Natal in South Africa using Mycobacteria Growth Indicator Tube method and sequencing of the <jats:italic>pncA<\/jats:italic>. We also compared susceptibility of pyrazinamide with that of isoniazid.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Pyrazinamide resistance was found in 6\/80 (7.5%) rifampicin discordant isolates. All pyrazinamide resistant isolates were also resistant to isoniazid and pyrazinamide resistance was found to be associated with isoniazid resistance. No pyrazinamide resistance was found among the isoniazid susceptible isolates.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Given the low prevalence of pyrazinamide resistance in rifampicin discordant TB, this anti-TB drug still has a significant role in the treatment of these patients. Performing pyrazinamide susceptibility testing remains a challenge, our findings show that isoniazid susceptible isolates are unlikely to be resistant to pyrazinamide among the discordant TB isolates.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0274688","type":"journal-article","created":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T17:42:44Z","timestamp":1663782164000},"page":"e0274688","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pyrazinamide resistance in rifampicin discordant tuberculosis"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5298-5556","authenticated-orcid":true,"given":"Nomonde Ritta","family":"Mvelase","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ravesh","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khine","family":"Swe Swe-Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koleka Patience","family":"Mlisana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,9,21]]},"reference":[{"key":"pone.0274688.ref001","doi-asserted-by":"crossref","first-page":"3501","DOI":"10.1128\/JCM.01209-09","article-title":"Mycobacterium tuberculosis strains with highly discordant rifampin susceptibility test results","volume":"47","author":"A Van Deun","year":"2009","journal-title":"Journal of clinical microbiology"},{"key":"pone.0274688.ref002","doi-asserted-by":"crossref","first-page":"216","DOI":"10.5588\/ijtld.11.0178","article-title":"Clinical failures associated with rpoB mutations in phenotypically occult multidrug-resistant Mycobacterium tuberculosis","volume":"16","author":"DA Williamson","year":"2012","journal-title":"Int J Tuberc Lung Dis"},{"key":"pone.0274688.ref003","doi-asserted-by":"crossref","first-page":"e90569","DOI":"10.1371\/journal.pone.0090569","article-title":"Correlation between Genotypic and Phenotypic Testing for Resistance to Rifampin in Mycobacterium tuberculosis Clinical Isolates in Haiti: Investigation of Cases with Discrepant Susceptibility Results","volume":"9","author":"O Ocheretina","year":"2014","journal-title":"PLoS ONE"},{"key":"pone.0274688.ref004","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1128\/JCM.00553-13","article-title":"Rifampin drug resistance tests for tuberculosis: challenging the gold standard","volume":"51","author":"A Van Deun","year":"2013","journal-title":"Journal of clinical microbiology"},{"key":"pone.0274688.ref005","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1128\/JCM.00691-14","article-title":"Profiling of rpoB mutations and MICs for rifampin and rifabutin in Mycobacterium tuberculosis","volume":"52","author":"FB Jamieson","year":"2014","journal-title":"Journal of clinical microbiology"},{"key":"pone.0274688.ref006","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1128\/JCM.02741-12","article-title":"Rifampin resistance missed in automated liquid culture system for Mycobacterium tuberculosis isolates with specific rpoB mutations","volume":"51","author":"L Rigouts","year":"2013","journal-title":"Journal of clinical microbiology"},{"key":"pone.0274688.ref007","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1093\/jac\/dkt284","article-title":"Phenotypically occult multidrug-resistant Mycobacterium tuberculosis: dilemmas in diagnosis and treatment","volume":"68","author":"J Ho","year":"2013","journal-title":"J Antimicrob Chemother"},{"key":"pone.0274688.ref008","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.3389\/fmicb.2016.01947","article-title":"Correlation of rpoB Mutations with Minimal Inhibitory Concentration of Rifampin and Rifabutin in Mycobacterium tuberculosis in an HIV\/AIDS Endemic Setting, South Africa","volume":"7","author":"I Rukasha","year":"2016","journal-title":"Frontiers in microbiology"},{"key":"pone.0274688.ref009","first-page":"1641","article-title":"Global surveillance for antituberculosis-drug resistance, 1994\u20131997. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance","volume":"338","author":"A Pablos-M\u00e9ndez","year":"1998","journal-title":"The New England journal of medicine"},{"key":"pone.0274688.ref010","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/S1473-3099(18)30073-2","article-title":"Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance study","volume":"18","author":"M Zignol","year":"2018","journal-title":"Lancet Infectious Diseases"},{"key":"pone.0274688.ref011","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.diagmicrobio.2016.01.019","article-title":"Rifabutin and rifampin resistance levels and associated rpoB mutations in clinical isolates of Mycobacterium tuberculosis complex","volume":"85","author":"ZL Berrada","year":"2016","journal-title":"Diagnostic microbiology and infectious disease"},{"key":"pone.0274688.ref012","doi-asserted-by":"crossref","first-page":"ofz065","DOI":"10.1093\/ofid\/ofz065","article-title":"rpoB Mutations Causing Discordant Rifampicin Susceptibility in Mycobacterium tuberculosis: Retrospective Analysis of Prevalence, Phenotypic, Genotypic, and Treatment Outcomes","volume":"6","author":"NR Mvelase","year":"2019","journal-title":"Open forum infectious diseases"},{"key":"pone.0274688.ref013","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1038\/nm0696-662","article-title":"Mutations in pncA, a gene encoding pyrazinamidase\/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus","volume":"2","author":"A Scorpio","year":"1996","journal-title":"Nature medicine"},{"key":"pone.0274688.ref014","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1093\/jac\/dkg446","article-title":"Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid","volume":"52","author":"Y Zhang","year":"2003","journal-title":"The Journal of antimicrobial chemotherapy"},{"key":"pone.0274688.ref015","doi-asserted-by":"crossref","first-page":"1016.e1","DOI":"10.1016\/j.cmi.2017.12.012","article-title":"Phenotypic and genotypic characterization of pyrazinamide resistance among multidrug-resistant Mycobacterium tuberculosis clinical isolates in Hangzhou, China","volume":"24","author":"W Liu","year":"2018","journal-title":"Clinical microbiology and infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases"},{"issue":"6","key":"pone.0274688.ref016","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/0041-3879(85)90040-6","article-title":"The action of antituberculosis drugs in short-course chemotherapy","volume":"6","author":"DA Mitchison","year":"1985","journal-title":"Tubercle"},{"key":"pone.0274688.ref017","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1099\/0022-1317-51-1-42","article-title":"Conditions that may affect the results of susceptibility testing of Mycobacterium tuberculosis to pyrazinamide","volume":"51","author":"Y Zhang","year":"2002","journal-title":"Journal of medical microbiology"},{"volume-title":"Technical report on critical concentrations for drug susceptibility testing of isoniazid and the rifamycins (rifampicin, rifabutin and rifapentine)","year":"2021","author":"WHO","key":"pone.0274688.ref018"},{"journal-title":"MGIT Procedure Manual Foundation for Innovative New Diagnostics","year":"2006","author":"R-GS Siddiqi SH","key":"pone.0274688.ref019"},{"key":"pone.0274688.ref020","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1128\/JCM.41.3.1235-1239.2003","article-title":"Susceptibility testing with the manual mycobacteria growth indicator tube (MGIT) and the MGIT 960 system provides rapid and reliable verification of multidrug-resistant tuberculosis","volume":"41","author":"K Adjers-Koskela","year":"2003","journal-title":"Journal of clinical microbiology"},{"key":"pone.0274688.ref021","doi-asserted-by":"crossref","first-page":"4056","DOI":"10.1128\/JCM.02438-14","article-title":"Mendel CM, Bosman ME, Hepple JA, Pym AS, Warren RM, van Helden PD. Rapid sequencing of the Mycobacterium tuberculosis pncA gene for detection of pyrazinamide susceptibility","volume":"52","author":"EM Streicher","year":"2014","journal-title":"J Clin Microbiol"},{"volume-title":"Catalogue of mutations in Mycobacterium tuberculosis complex and their association with drug resistance","year":"2021","author":"WHO","key":"pone.0274688.ref022"},{"key":"pone.0274688.ref023","doi-asserted-by":"crossref","first-page":"4499","DOI":"10.1128\/AAC.00630-11","article-title":"Pyrazinamide susceptibility testing in Mycobacterium tuberculosis: a systematic review with meta-analyses","volume":"55","author":"KC Chang","year":"2011","journal-title":"Antimicrobial agents and chemotherapy"},{"key":"pone.0274688.ref024","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.tube.2016.05.003","article-title":"Prevalence of pyrazinamide resistance across the spectrum of drug resistant phenotypes of Mycobacterium tuberculosis","volume":"99","author":"MG Whitfield","year":"2016","journal-title":"Tuberculosis"},{"key":"pone.0274688.ref025","doi-asserted-by":"crossref","first-page":"491","DOI":"10.3201\/eid2303.161034","article-title":"pncA Gene Mutations Associated with Pyrazinamide Resistance in Drug-Resistant Tuberculosis, South Africa and Georgia","volume":"23","author":"S Allana","year":"2017","journal-title":"Emerging infectious diseases"},{"key":"pone.0274688.ref026","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/S1473-3099(18)30222-6","article-title":"Prevalence of drug-resistant tuberculosis and imputed burden in South Africa: a national and sub-national cross-sectional survey","volume":"18","author":"NA Ismail","year":"2018","journal-title":"The Lancet Infectious diseases"},{"issue":"10","key":"pone.0274688.ref027","doi-asserted-by":"crossref","first-page":"3459","DOI":"10.1128\/JCM.00973-08","article-title":"Pyrazinamide resistance among South African multidrug-resistant Mycobacterium tuberculosis isolates","volume":"46","author":"M Mphahlele","year":"2008","journal-title":"Journal of clinical microbiology"},{"key":"pone.0274688.ref028","doi-asserted-by":"crossref","first-page":"ofw150","DOI":"10.1093\/ofid\/ofw150","article-title":"Clinical Impact on Tuberculosis Treatment Outcomes of Discordance Between Molecular and Growth-Based Assays for Rifampin Resistance, California 2003\u20132013","volume":"3","author":"NS Shah","year":"2016","journal-title":"Open Forum Infect Dis"},{"key":"pone.0274688.ref029","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1093\/jac\/dky248","article-title":"The potential use of rifabutin for treatment of patients diagnosed with rifampicin-resistant tuberculosis","volume":"73","author":"MG Whitfield","year":"2018","journal-title":"J Antimicrob Chemother"},{"volume-title":"Technical manual for drug susceptibility testing of medicines used in the treatment of tuberculosis","year":"2018","author":"WHO","key":"pone.0274688.ref030"},{"key":"pone.0274688.ref031","doi-asserted-by":"crossref","first-page":"e01819","DOI":"10.1128\/mBio.01819-14","article-title":"Mycobacterium tuberculosis pyrazinamide resistance determinants: a multicenter study","volume":"5","author":"P Miotto","year":"2014","journal-title":"MBio"},{"volume-title":"Module 3: diagnosis\u2014rapid diagnostics for tuberculosis detention, 2021 update","year":"2021","author":"WHO","key":"pone.0274688.ref032"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0274688","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T17:43:43Z","timestamp":1663782223000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0274688"}},"subtitle":[],"editor":[{"given":"Frederick","family":"Quinn","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,9,21]]},"references-count":32,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9,21]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0274688","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2022,9,21]]}}}