{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T09:05:01Z","timestamp":1769072701273,"version":"3.49.0"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T00:00:00Z","timestamp":1691107200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-74-10090"],"award-info":[{"award-number":["21-74-10090"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-74-10090"],"award-info":[{"award-number":["21-74-10090"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-74-10090"],"award-info":[{"award-number":["21-74-10090"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-74-10090"],"award-info":[{"award-number":["21-74-10090"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-74-10090"],"award-info":[{"award-number":["21-74-10090"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>OXA-48 carbapenemases are frequently expressed by <jats:italic>Klebsiella pneumoniae<\/jats:italic> clinical isolates; they decrease the effectiveness of carbapenem therapy, particularly with meropenem. Among these isolates, meropenem-susceptible carbapenemase-producers may show decreased meropenem effectiveness. However, the probability of the emergence of resistance in susceptible carbapenemase-producing isolates and its dependence on specific <jats:italic>K<\/jats:italic>. <jats:italic>pneumoniae<\/jats:italic> meropenem MICs is not completely known. It is also not completely clear what resistance patterns will be exhibited by these bacteria exposed to meropenem, if they would follow the patterns of non-beta-lactamase-producing bacteria and other than beta-lactams antibiotics. These issues might be clarified if patterns of meropenem resistance related to the mutant selection window (MSW) hypothesis. To test the applicability of the MSW hypothesis to meropenem, OXA-48-carbapenemase-producing <jats:italic>K<\/jats:italic>. <jats:italic>pneumoniae<\/jats:italic> clinical isolates with MICs in a 64-fold range (from susceptible to resistant) were exposed to meropenem in a hollow-fiber infection model; epithelial lining fluid meropenem pharmacokinetics were simulated following administration of 2 grams every 8 hours in a 3-hour infusion. Strong bell-shaped relationships between the meropenem daily dose infused to the model as related to the specific isolate MIC and both the antimicrobial effect and the emergence of resistance were observed. The applicability of the MSW hypothesis to meropenem and carbapenemase producing <jats:italic>K<\/jats:italic>. <jats:italic>pneumoniae<\/jats:italic> was confirmed. Low meropenem efficacy indicates very careful prescribing of meropenem to treat <jats:italic>K<\/jats:italic>. <jats:italic>pneumoniae<\/jats:italic> infections when the causative isolate is confirmed as an OXA-48-carbapenemase producer.<\/jats:p>","DOI":"10.1371\/journal.pone.0288660","type":"journal-article","created":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T17:29:58Z","timestamp":1691170198000},"page":"e0288660","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Testing the mutant selection window hypothesis with meropenem: In vitro model study with OXA-48-producing Klebsiella pneumoniae"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2107-8259","authenticated-orcid":true,"given":"Kamilla 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Ther"},{"key":"pone.0288660.ref022","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1093\/jac\/dkab160","article-title":"Application of the hollow fibre infection model (HFIM) in antimicrobial development: a systematic review and recommendations of reporting.","volume":"76","author":"Z Sadouki","year":"2021","journal-title":"J Antimicrob Chemother"},{"key":"pone.0288660.ref023","unstructured":"European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/use-pharmacokinetics-pharmacodynamics-development-antibacterial-medicinal-products-scientific#current-effective-version-section [accessed on 22.03.2023]."},{"key":"pone.0288660.ref024","doi-asserted-by":"crossref","first-page":"e00139","DOI":"10.1128\/mBio.00139-10","article-title":"The combination of rifampin plus moxifloxacin is synergistic for suppression of resistance but antagonistic for cell kill of Mycobacterium tuberculosis as determined in a hollow-fiber infection model","volume":"1","author":"GL Drusano","year":"2010","journal-title":"mBio"},{"key":"pone.0288660.ref025","volume-title":"Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: eleventh edition M07","author":"Clinical and Laboratory Standards Institute","year":"2019"},{"key":"pone.0288660.ref026","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1111\/j.1365-3164.2009.00856.x","article-title":"New concepts in antimicrobial susceptibility testing: the mutant prevention concentration and mutant selection window approach.","volume":"20","author":"JM Blondeau","year":"2009","journal-title":"Vet Dermatol"},{"key":"pone.0288660.ref027","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.ijantimicag.2014.06.013","article-title":"Predicting bacterial resistance using the time inside the mutant selection window: possibilities and limitations.","volume":"44","author":"AA Firsov","year":"2014","journal-title":"Int J Antimicrob Agents"},{"key":"pone.0288660.ref028","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.1093\/jac\/dkx249","article-title":"Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to linezolid in an in vitro dynamic model","volume":"72","author":"AA Firsov","year":"2017","journal-title":"J Antimicrob Chemother"},{"key":"pone.0288660.ref029","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/S0924-8579(01)00299-0","article-title":"Evaluation of two in vitro pharmacodynamic simulation models: microfiltration versus centrifugation-filtration.","volume":"17","author":"L Alou","year":"2001","journal-title":"Int J Antimicrob Agents"},{"key":"pone.0288660.ref030","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1128\/AAC.45.3.927-931.2001","article-title":"Relationships of the area under the curve\/MIC ratio to different integral endpoints of the antimicrobial effect: gemifloxacin pharmacodynamics in an in vitro dynamic model","volume":"45","author":"AA Firsov","year":"2001","journal-title":"Antimicrob Agents Chemother"},{"key":"pone.0288660.ref031","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1099\/jmm.0.000214","article-title":"Pharmacokinetic-pharmacodynamic modelling of meropenem against VIM-producing Klebsiella pneumoniae isolates: clinical implications","volume":"65","author":"M Tsala","year":"2016","journal-title":"J Med Microbiol"},{"key":"pone.0288660.ref032","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1128\/AAC.01190-09","article-title":"Comparison of the activity of a human simulated, high-dose, prolonged infusion of meropenem against Klebsiella pneumoniae producing the KPC carbapenemase versus that against Pseudomonas aeruginosa in an in vitro pharmacodynamic model","volume":"54","author":"CC Bulik","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"key":"pone.0288660.ref033","doi-asserted-by":"crossref","first-page":"2638","DOI":"10.1128\/AAC.01721-09","article-title":"Impact of different carbapenems and regimens of administration on resistance emergence for three isogenic Pseudomonas aeruginosa isolates with differing mechanisms of resistance","volume":"54","author":"A Louie","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"key":"pone.0288660.ref034","doi-asserted-by":"crossref","first-page":"e0052522","DOI":"10.1128\/spectrum.00525-22","article-title":"Evaluating mono- and combination therapy of meropenem and amikacin against Pseudomonas aeruginosa bacteremia in the hollow-fiber infection model.","volume":"10","author":"ML Avent","year":"2022","journal-title":"Microbiol Spectr"},{"key":"pone.0288660.ref035","doi-asserted-by":"crossref","first-page":"e02055","DOI":"10.1128\/AAC.02055-17","article-title":"Optimization of a meropenem-tobramycin combination dosage regimen against hypermutable and nonhypermutable Pseudomonas aeruginosa via mechanism-based modeling and the hollow-fiber infection model","volume":"62","author":"CB Landersdorfer","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"pone.0288660.ref036","doi-asserted-by":"crossref","first-page":"e00026","DOI":"10.1128\/AAC.00026-18","article-title":"Evaluation of Ceftolozane-Tazobactam in combination with meropenem against Pseudomonas aeruginosa sequence type 175 in a hollow-fiber infection model","volume":"62","author":"M Montero","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"pone.0288660.ref037","doi-asserted-by":"crossref","first-page":"e01679","DOI":"10.1128\/AAC.01679-19","article-title":"Meropenem-tobramycin combination regimens combat carbapenem-resistant Pseudomonas aeruginosa in the hollow-fiber infection model simulating augmented renal clearance in critically ill patients","volume":"64","author":"R Yadav","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"pone.0288660.ref038","doi-asserted-by":"crossref","first-page":"2646","DOI":"10.1128\/AAC.00065-10","article-title":"The combination of meropenem and levofloxacin is synergistic with respect to both Pseudomonas aeruginosa kill rate and resistance suppression","volume":"54","author":"A Louie","year":"2010","journal-title":"Antimicrob Agents 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