{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T12:12:02Z","timestamp":1754482322391,"version":"3.41.2"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T00:00:00Z","timestamp":1689033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Society of Infectious Diseases Pharmacists"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Cystic fibrosis (CF) patients are often colonized with Pseudomonas aeruginosa. During treatment, P. aeruginosa can develop subpopulations exhibiting variable in vitro antimicrobial (ABX) susceptibility patterns. Heteroresistance (HR) may underlie reported discrepancies between in vitro susceptibility results and clinical responses to various ABXs. Here, we sought to examine the presence and nature of P. aeruginosa polyclonal HR (PHR) and monoclonal HR (MHR) to ceftolozane\/tazobactam in isolates originating from CF pulmonary exacerbations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This was a single-centre, non-controlled study. Two hundred and forty-six P. aeruginosa isolates from 26 adult CF patients were included. PHR was defined as the presence of different ceftolozane\/tazobactam minimum inhibitory concentration (MIC) values among P. aeruginosa isolates originating from a single patient specimen. Population analysis profiles (PAPs) were performed to assess the presence of MHR, defined as \u22654-fold change in the ceftolozane\/tazobactam MIC from a single P. aeruginosa colony.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sixteen of 26 patient specimens (62%) contained PHR P. aeruginosa populations. Of these 16 patients, 6 (23%) had specimens in which PHR P. aeruginosa isolates exhibited ceftolozane\/tazobactam MICs with categorical differences (i.e. susceptible versus resistant) compared to results reported as part of routine care. One isolate, PSA 1311, demonstrated MHR. Canonical ceftolozane\/tazobactam resistance genes were not found in the MHR isolates (MHR PSA 1311 or PHR PSA 6130).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Ceftolozane\/tazobactam PHR exists among P. aeruginosa isolates in this work, and approximately a quarter of these populations contained isolates with ceftolozane\/tazobactam susceptibiilty interpretations different from what was reported clinically, supporting concerns surrounding the utility of traditional susceptibility testing methodology in the setting of CF specimens. Genome sequencing of isolates with acquired MHR to ceftolozane\/tazobactam revealed variants of unknown significance. Future work will be centred on determining the significance of these mutations to better understand these data in clinical context.<\/jats:p><\/jats:sec>","DOI":"10.1093\/jacamr\/dlad083","type":"journal-article","created":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T06:06:26Z","timestamp":1689055586000},"source":"Crossref","is-referenced-by-count":4,"title":["Ceftolozane\/tazobactam heteroresistance in cystic fibrosis-related<i>Pseudomonas aeruginosa<\/i>infections"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8251-458X","authenticated-orcid":false,"given":"Marguerite L","family":"Monogue","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Texas Southwestern Medical Center , Dallas, TX 75390 , USA"},{"name":"Department of Internal Medicine, Infectious Diseases and Geographic Medicine, University of Texas Southwestern Medical Center , Dallas, TX 75390 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James M","family":"Sanders","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Texas Southwestern Medical Center , Dallas, TX 75390 , USA"},{"name":"Department of Internal Medicine, Infectious Diseases and Geographic Medicine, University of Texas Southwestern Medical Center , Dallas, TX 75390 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine A","family":"Pybus","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Texas Southwestern Medical Center , Dallas, TX 75390 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiwoong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Population and Data Sciences, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center , Dallas, TX 75390 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6249-7193","authenticated-orcid":false,"given":"Xiaowei","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Population and Data Sciences, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center , Dallas, TX 75390 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew E","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center , Dallas, TX 75390 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David E","family":"Greenberg","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Infectious Diseases and Geographic Medicine, University of Texas Southwestern Medical Center , Dallas, TX 75390 , USA"},{"name":"Department of Microbiology, University of Texas Southwestern Medical Center , Dallas, TX 75390 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,7,11]]},"reference":[{"article-title":"Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations\/the Review on Antimicrobial Resistance","year":"2014.","author":"O\u2019Neill J.","key":"2023071106061588800_dlad083-B1"},{"issue":"Suppl 9","key":"2023071106061588800_dlad083-B2","first-page":"S11","article-title":"The clinical predictive value (or lack thereof) of the results of in vitro antimicrobial susceptibility tests","volume":"49","author":"Doern","year":"2011","journal-title":"J Clin Microbiol"},{"key":"2023071106061588800_dlad083-B3","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.jcf.2019.01.008","article-title":"Antimicrobial susceptibility testing (AST) and associated clinical outcomes in individuals with cystic fibrosis: a systematic review","volume":"18","author":"Somayaji","year":"2019","journal-title":"J Cyst Fibros"},{"key":"2023071106061588800_dlad083-B4","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/s41579-019-0218-1","article-title":"Mechanisms and clinical relevance of bacterial heteroresistance","volume":"17","author":"Andersson","year":"2019","journal-title":"Nat Rev Microbiol"},{"key":"2023071106061588800_dlad083-B5","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1038\/s41564-019-0480-z","article-title":"Antibiotic combinations that exploit heteroresistance to multiple drugs effectively control infection","volume":"4","author":"Band","year":"2019","journal-title":"Nat Microbiol"},{"key":"2023071106061588800_dlad083-B6","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1128\/CMR.00058-14","article-title":"Antimicrobial heteroresistance: an emerging field in need of clarity","volume":"28","author":"El-Halfawy","year":"2015","journal-title":"Clin Microbiol Rev"},{"key":"2023071106061588800_dlad083-B7","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1093\/cid\/ciz364","article-title":"Reconciling antimicrobial susceptibility testing and clinical response in antimicrobial treatment of chronic cystic fibrosis lung infections","volume":"69","author":"Waters","year":"2019","journal-title":"Clin Infect Dis"},{"key":"2023071106061588800_dlad083-B8","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.molcel.2019.09.028","article-title":"Bacterial heterogeneity and antibiotic survival: understanding and combatting persistence and heteroresistance","volume":"76","author":"Dewachter","year":"2019","journal-title":"Mol Cell"},{"key":"2023071106061588800_dlad083-B9","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/s41564-018-0342-0","article-title":"The high prevalence of antibiotic heteroresistance in pathogenic bacteria is mainly caused by gene amplification","volume":"4","author":"Nicoloff","year":"2019","journal-title":"Nat Microbiol"},{"key":"2023071106061588800_dlad083-B10","doi-asserted-by":"crossref","DOI":"10.1128\/mSphere.00615-17","article-title":"Heterogeneous antimicrobial susceptibility characteristics in Pseudomonas aeruginosa isolates from cystic fibrosis patients","volume":"3","author":"Qin","year":"2018","journal-title":"mSphere"},{"key":"2023071106061588800_dlad083-B11","doi-asserted-by":"crossref","first-page":"3321","DOI":"10.1093\/jac\/dkac320","article-title":"Clinically undetected polyclonal heteroresistance among Pseudomonas aeruginosa isolated from cystic fibrosis respiratory specimens","volume":"77","author":"Maxwell","year":"2022","journal-title":"J Antimicrob Chemother"},{"key":"2023071106061588800_dlad083-B12","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.02538-18","article-title":"Characterization of hypermutator Pseudomonas aeruginosa isolates from patients with cystic fibrosis in Australia","volume":"63","author":"Rees","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2023071106061588800_dlad083-B13","doi-asserted-by":"crossref","DOI":"10.1128\/CMR.00031-19","article-title":"Epidemiology and treatment of multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa infections","volume":"32","author":"Horcajada","year":"2019","journal-title":"Clin Microbiol Rev"},{"key":"2023071106061588800_dlad083-B14","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1099\/jmm.0.46816-0","article-title":"Characterization of clinical isolates of Pseudomonas aeruginosa heterogeneously resistant to carbapenems","volume":"56","author":"Pournaras","year":"2007","journal-title":"J Med Microbiol"},{"key":"2023071106061588800_dlad083-B15","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1099\/jmm.0.032276-0","article-title":"Investigation of carbapenem heteroresistance among different sequence types of Pseudomonas aeruginosa clinical isolates reveals further diversity","volume":"60","author":"Oikonomou","year":"2011","journal-title":"J Med Microbiol"},{"key":"2023071106061588800_dlad083-B16","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.ijantimicag.2017.10.014","article-title":"Heteroresistance to carbapenems in invasive Pseudomonas aeruginosa infections","volume":"51","author":"He","year":"2018","journal-title":"Int J Antimicrob Agents"},{"key":"2023071106061588800_dlad083-B17","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1093\/jac\/dkab461","article-title":"Prevalence of colistin heteroresistance in carbapenem-resistant Pseudomonas aeruginosa and association with clinical outcomes in patients: an observational study","volume":"77","author":"Howard-Anderson","year":"2022","journal-title":"J Antimicrob Chemother"},{"key":"2023071106061588800_dlad083-B18","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S1473-3099(21)00194-8","article-title":"Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens","volume":"21","author":"Choby","year":"2021","journal-title":"Lancet Infect Dis"},{"volume-title":"Performance Standards for Antimicrobial Susceptibility Testing\u2014Thirty-Third Edition:","year":"2023","author":"CLSI","key":"2023071106061588800_dlad083-B19"},{"key":"2023071106061588800_dlad083-B20","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.cmi.2022.10.018","article-title":"Antibiotic heteroresistance in ESKAPE pathogens, from bench to bedside","volume":"29","author":"Roch","year":"2023","journal-title":"Clin Microbiol Infect"},{"key":"2023071106061588800_dlad083-B21","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1093\/jac\/dkx483","article-title":"Antibacterial activity of ceftolozane\/tazobactam alone and in combination with other antimicrobial agents against MDR Pseudomonas aeruginosa","volume":"73","author":"Monogue","year":"2018","journal-title":"J Antimicrob 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heteroresistance to polymyxin B among carbapenem-susceptible and -resistant Pseudomonas aeruginosa","volume":"62","author":"Hermes","year":"2013","journal-title":"J Med Microbiol"},{"key":"2023071106061588800_dlad083-B32","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.jgar.2017.08.002","article-title":"Colistin resistance among blood culture isolates at a tertiary care centre in Hungary","volume":"11","author":"Juh\u00e1sz","year":"2017","journal-title":"J Glob Antimicrob Resist"},{"key":"2023071106061588800_dlad083-B33","doi-asserted-by":"crossref","DOI":"10.1128\/Spectrum.00152-21","article-title":"Combined effect of polymyxin B and tigecycline to overcome heteroresistance in carbapenem-resistant Klebsiella pneumoniae","volume":"9","author":"Tian","year":"2021","journal-title":"Microbiol Spectr"}],"container-title":["JAC-Antimicrobial 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