{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T02:46:59Z","timestamp":1781232419824,"version":"3.54.1"},"reference-count":24,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2016,1,1]],"date-time":"2016-01-01T00:00:00Z","timestamp":1451606400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Cubist Pharmaceuticals, Inc."}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2016,1]]},"abstract":"ABSTRACT<\/jats:title>\n \n Ceftolozane plus tazobactam is an antipseudomonal cephalosporin combined with tazobactam, an established beta-lactamase inhibitor, and has\n in vitro<\/jats:italic>\n potency against a range of clinically important \u03b2-lactamase-producing bacteria, including most extended-spectrum-\u03b2-lactamase (ESBL)-positive\n Enterobacteriaceae<\/jats:named-content>\n . The pharmacodynamics of \u03b2-lactam\u2013\u03b2-lactamase inhibitor combinations presents a number of theoretical and practical challenges, including modeling different half-lives of the compounds. In this study, we studied the pharmacodynamics of ceftolozane plus tazobactam against\n Escherichia coli<\/jats:named-content>\n and\n Pseudomonas aeruginosa<\/jats:named-content>\n using an\n in vitro<\/jats:italic>\n pharmacokinetic model of infection. Five strains of\n E. coli<\/jats:named-content>\n , including three clinical strains plus two CTX-M-15 (one high and one moderate) producers, and five strains of\n P. aeruginosa<\/jats:named-content>\n , including two with OprD overexpression and AmpC \u03b2-lactamases, were employed. Ceftolozane MICs (\n E. coli<\/jats:named-content>\n , 0.12 to 0.25 mg\/liter, and\n P. aeruginosa<\/jats:named-content>\n , 0.38 to 8 mg\/liter) were determined in the presence of 4 mg\/liter tazobactam. Dose ranging of ceftolozane (percentage of time in which the free-drug concentration exceeds the MIC [\n fT<\/jats:italic>\n >MIC], 0 to 100%) plus tazobactam (human pharmacokinetics) was simulated every 8 hours, with half-lives (\n t<\/jats:italic>\n 1\/2<\/jats:sub>\n ) of 2.5 and 1 h, respectively. Ceftolozane and tazobactam concentrations were confirmed by high-performance liquid chromatography (HPLC). The ceftolozane-plus-tazobactam\n fT<\/jats:italic>\n >MIC values at 24 h for a static effect and a 1-log and 2-log drop in initial inoculum for\n E. coli<\/jats:named-content>\n were 27.8% \u00b1 5.6%, 33.0% \u00b1 5.6%, and 39.6% \u00b1 8.5%, respectively. CTX-M-15 production did not affect the 24-h\n fT<\/jats:italic>\n >MIC for\n E. coli<\/jats:named-content>\n strains. The ceftolozane-plus-tazobactam\n fT<\/jats:italic>\n >MIC values for a 24-h static effect and a 1-log and 2-log drop for\n P. aeruginosa<\/jats:named-content>\n were 24.9% \u00b1 3.0%, 26.6% \u00b1 3.9%, and 31.2% \u00b1 3.6%. Despite a wide range of absolute MICs, the killing remained predictable as long as the MICs were normalized to the corresponding\n fT<\/jats:italic>\n >MIC. Emergence of resistance on 4\u00d7 MIC plates and 8\u00d7 MIC plates occurred maximally at an\n f<\/jats:italic>\n T<\/jats:italic>\n >MIC of 10 to 30% and increased as time of exposure increased. The\n fT<\/jats:italic>\n >MIC for a static effect for ceftolozane plus tazobactam is less than that observed with other cephalosporins against\n E. coli<\/jats:named-content>\n and\n P. aeruginosa<\/jats:named-content>\n and is more similar to the\n fT<\/jats:italic>\n >MIC reported for carbapenems.\n <\/jats:p>","DOI":"10.1128\/aac.00727-15","type":"journal-article","created":{"date-parts":[[2015,11,10]],"date-time":"2015-11-10T04:09:28Z","timestamp":1447128568000},"page":"515-521","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":20,"title":["Pharmacodynamics of Ceftolozane plus Tazobactam Studied in an\n In Vitro<\/i>\n Pharmacokinetic Model of Infection"],"prefix":"10.1128","volume":"60","author":[{"given":"Alasdair P.","family":"MacGowan","sequence":"first","affiliation":[{"name":"Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R.","family":"Noel","sequence":"additional","affiliation":[{"name":"Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon G.","family":"Tomaselli","sequence":"additional","affiliation":[{"name":"Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Nicholls","sequence":"additional","affiliation":[{"name":"Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen E.","family":"Bowker","sequence":"additional","affiliation":[{"name":"Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_1_2_2","volume-title":"53rd Intersci Conf Antimicrob Agents Chemother","author":"Lucasti C","year":"2013","unstructured":"Lucasti C, Hershberger E, Miller B, Yankelev S, Steenbergen J, Friedland I, Solomkin J. 2013 A multicenter, double-blind, randomized, phase 2 study to assess the safety and efficacy of ceftolozane\/tazobactam (TOL\/TAZ) plus metronidazole (MTZ) compared with meropenem (MER) in adult patients with complicated intra-abdominal infections (cIAI), abstr K-1709. 53rd Intersci Conf Antimicrob Agents Chemother."},{"key":"e_1_3_1_3_2","unstructured":"ClinicalTrials.gov. 2010. Safety and Efficacy of IV CXA-101 and IV Ceftazidime in Patients with Complicated Urinary Tract Infections study NCT00921024. www.clinicaltrials.gov."},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2014.01.032"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01737-10"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkq252"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku184"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkp193"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00912-09"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01590-12"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01153-07"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01753-09"},{"key":"e_1_3_1_13_2","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1093\/jac\/31.suppl_A.39","article-title":"The chemistry, pharmacokinetics and tissue distribution of piperacillin\/tazobactam","volume":"31","author":"Sorgel F","year":"1993","unstructured":"Sorgel F, Kinzig M. 1993. The chemistry, pharmacokinetics and tissue distribution of piperacillin\/tazobactam. J Antimicrob Chemother 31(Suppl A):39\u201360.","journal-title":"J Antimicrob Chemother"},{"key":"e_1_3_1_14_2","volume-title":"Approved standard","author":"Clinical and Laboratory Standards Institute","year":"2009","unstructured":"Clinical and Laboratory Standards Institute. 2009. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard, 8th ed, MO7-A8. Clinical and Laboratory Standards Institute, Wayne, PA.","edition":"8"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/158.4.831"},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5520(03)00065-5"},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1086\/510079"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00936-10"},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03572-14"},{"key":"e_1_3_1_20_2","volume-title":"Abstr 52nd Intersci Conf Antimicrob Agents Chemother, San Francisco, CA","author":"Bowker KE","year":"2012","unstructured":"Bowker KE, Noel AR, Tomaselli SE, Nicholls DL, MacGowan AP. 2012. Pharmacodynamics of piperacillin-tazobactam (P\/T) against Pseudomonas aeruginosa: antibacterial effect and risk of emergence of resistance, abstr A642. Abstr 52nd Intersci Conf Antimicrob Agents Chemother, San Francisco, CA. American Society for Microbiology, Washington, DC."},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02513-12"},{"key":"e_1_3_1_22_2","volume-title":"Abstr 52nd Intersci Conf Antimicrob Agents Chemother","author":"Bowker KE","unstructured":"Bowker KE, Noel AR, Tomaselli SE, Nicholls DL, MacGowan AP. Pharmacodynamics of ceftaroline against Enterobacteriaceae, abstr A629. Abstr 52nd Intersci Conf Antimicrob Agents Chemother, San Francisco, CA. American Society for Microbiology, Washington, DC."},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.06111-11"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01752-10"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.47.3.1088-1095.2003"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00727-15","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00727-15","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:29:00Z","timestamp":1645475340000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00727-15"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1]]},"references-count":24,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2016,1]]}},"alternative-id":["10.1128\/AAC.00727-15"],"URL":"https:\/\/doi.org\/10.1128\/aac.00727-15","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,1]]},"assertion":[{"value":"2015-03-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-11-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-12-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}