{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:08:07Z","timestamp":1790644087578,"version":"4.1.0"},"reference-count":9,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2013,12,1]],"date-time":"2013-12-01T00:00:00Z","timestamp":1385856000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2013,12]]},"abstract":"ABSTRACT<\/jats:title>\n \n We recently investigated the pharmacokinetics-pharmacodynamics (PK-PD) of tazobactam in combination with ceftolozane against an isogenic CTX-M-15-producing\n Escherichia coli<\/jats:named-content>\n triplet set, genetically engineered to transcribe different levels of\n bla<\/jats:italic>\n CTX-M-15<\/jats:sub>\n . The percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold) was identified as the PK-PD exposure measure that was most closely associated with efficacy. Moreover, the tazobactam concentration was dependent upon the enzyme transcription level. Given that the aforementioned strains were genetically engineered to transcribe a single \u03b2-lactamase enzyme and that clinical isolates typically produce multiple \u03b2-lactamase enzymes with various transcription levels, it is likely that the tazobactam threshold concentration is isolate\/enzyme dependent. Our first objective was to characterize the relationship between the tazobactam %Time>threshold in combination with ceftolozane and efficacy using clinical isolates in an\n in vitro<\/jats:italic>\n PK-PD infection model. Our second objective was to identify a translational relationship that would allow for the comodeling across clinical isolates. The initial challenge panel included four well-characterized \u03b2-lactamase-producing\n E. coli<\/jats:named-content>\n strains with variable enzyme expression and other resistance determinants. As evidenced by\n r<\/jats:italic>\n 2<\/jats:sup>\n values of ranging from 0.90 to 0.99 for each clinical isolate, the observed data were well described by fitted functions describing the relationship between the tazobactam %Time>threshold and change in log\n 10<\/jats:sub>\n CFU from baseline; however, the data from the four isolates did not comodel well. The threshold concentration identified for each isolate ranged from 0.5 to 4 mg\/liter. We identified an enabling translational relationship for the tazobactam threshold that allowed comodeling of all four clinical isolates, which was the product of the individual isolate's ceftolozane-tazobactam MIC value and 0.5. As evidenced by an\n r<\/jats:italic>\n 2<\/jats:sup>\n value of 0.90, the transformed data were well described by a fitted function describing the relationship between tazobactam %Time>threshold and change in log\n 10<\/jats:sub>\n CFU from baseline. Due to these findings, the challenge panel was expanded to include three well-characterized \u03b2-lactamase-producing\n Klebsiella pneumoniae<\/jats:named-content>\n strains with variable enzyme expression and other resistance determinants. The translational relationship for the tazobactam threshold that allowed for the comodeling of the four\n E. coli<\/jats:named-content>\n isolates performed well for the expanded data set (seven isolates in total; four\n E. coli<\/jats:named-content>\n and three\n K. pneumoniae<\/jats:named-content>\n ), as evidenced by an\n r<\/jats:italic>\n 2<\/jats:sup>\n value of 0.84. This simple translational relationship is especially useful as it is directly linked to\n in vitro<\/jats:italic>\n susceptibility test results, which are used to guide the clinician's choice of drug and dosing regimen.\n <\/jats:p>","DOI":"10.1128\/aac.00656-13","type":"journal-article","created":{"date-parts":[[2013,9,17]],"date-time":"2013-09-17T03:45:54Z","timestamp":1379389554000},"page":"5924-5930","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":67,"title":["Pharmacological Basis of \u03b2-Lactamase Inhibitor Therapeutics: Tazobactam in Combination with Ceftolozane"],"prefix":"10.1128","volume":"57","author":[{"given":"Brian","family":"VanScoy","sequence":"first","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Latham, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo E.","family":"Mendes","sequence":"additional","affiliation":[{"name":"JMI Laboratories, North Liberty, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"McCauley","sequence":"additional","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Latham, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujata M.","family":"Bhavnani","sequence":"additional","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Latham, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catharine C.","family":"Bulik","sequence":"additional","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Latham, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olanrewaju O.","family":"Okusanya","sequence":"additional","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Latham, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Forrest","sequence":"additional","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Latham, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald N.","family":"Jones","sequence":"additional","affiliation":[{"name":"JMI Laboratories, North Liberty, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence V.","family":"Friedrich","sequence":"additional","affiliation":[{"name":"Cubist Pharmaceuticals, Lexington, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith N.","family":"Steenbergen","sequence":"additional","affiliation":[{"name":"Cubist Pharmaceuticals, Lexington, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul G.","family":"Ambrose","sequence":"additional","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Latham, New York, USA"},{"name":"University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"187","article-title":"Piperacillin\/tazobactam in the treatment of serious acute soft tissue infection","volume":"17","author":"Gould IM","year":"1991","unstructured":"GouldIM AnsariA HarveyG DouglasJG SmithCC ReidTM. 1991. Piperacillin\/tazobactam in the treatment of serious acute soft tissue infection. Drugs Exp. Clin. 17:187\u2013190.","journal-title":"Drugs Exp. Clin."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dks246"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.38.10.2351"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05005-11"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02513-12"},{"key":"e_1_3_2_7_2","volume-title":"CLSI document M07-A9","author":"Clinical and Laboratory Standards Institute","year":"2012","unstructured":"Clinical and Laboratory Standards Institute. 2012. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard, 9th ed. CLSI document M07-A9. Clinical and Laboratory Standards Institute, Wayne, PA.","edition":"9"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.34.10.1925"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/66.2.237"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01590-12"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00656-13","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00656-13","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T22:27:28Z","timestamp":1645482448000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00656-13"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,12]]},"references-count":9,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2013,12]]}},"alternative-id":["10.1128\/AAC.00656-13"],"URL":"https:\/\/doi.org\/10.1128\/aac.00656-13","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,12]]},"assertion":[{"value":"2013-04-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-09-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-11-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}