{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T09:42:22Z","timestamp":1771234942608,"version":"3.50.1"},"reference-count":30,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2017,9,1]],"date-time":"2017-09-01T00:00:00Z","timestamp":1504224000000},"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":[[2017,9]]},"abstract":"ABSTRACT<\/jats:title>\n \n The lack of new antibiotics has prompted investigation of the combination of two existing agents\u2014cefepime, a broad-spectrum cephalosporin, and tazobactam\u2014to broaden their efficacy against extended-spectrum beta-lactamase (ESBL)-producing\n Enterobacteriaceae<\/jats:named-content>\n . We determined the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the combination in a murine neutropenic thigh model in order to establish its exposure-response relationships (ERRs). The PK of cefepime were determined for five doses; that of tazobactam was determined in earlier studies (Melchers et al., Antimicrob Agents Chemother 59:3373\u20133376, 2015,\n https:\/\/doi.org\/10.1128\/AAC.04402-14<\/jats:ext-link>\n ). The PK were linear for both compounds. The estimated mean (standard deviation [SD]) half-life of cefepime was 0.33 (0.12) h, and that of tazobactam was 0.176 (0.026) h; the volumes of distribution (\n V<\/jats:italic>\n ) were 0.73 liters\/kg and 1.14 liters\/kg, respectively. PD studies of cefepime administered every 2 h (q2h) with or without tazobactam, including dose fractionation studies of tazobactam, were performed against six ESBL-producing isolates. A sigmoidal maximum-effect (\n E<\/jats:italic>\n max<\/jats:sub>\n ) model was fitted to the data. In the dose fractionation study, the q2h regimen was more efficacious than the q4h and q6h regimens, indicating time-dependent activity of tazobactam. The threshold concentration (\n \n C\n T<\/jats:sub>\n <\/jats:italic>\n ) best correlating with tazobactam efficacy was 0.25 mg\/liter, as evidenced by the best fit of the percentage of time above the threshold concentration (%\n fT<\/jats:italic>\n >\n \n C\n T<\/jats:sub>\n <\/jats:italic>\n ) and response. A mean %\n fT<\/jats:italic>\n >\n \n C\n T<\/jats:sub>\n <\/jats:italic>\n of 24.6% (range, 11.4 to 36.3%) for a\n \n C\n T<\/jats:sub>\n <\/jats:italic>\n of 0.25 mg\/liter was required to obtain a bacteriostatic effect. We conclude that tazobactam enhanced the effect of cefepime in otherwise resistant isolates of\n Enterobacteriaceae<\/jats:named-content>\n and that the %\n fT<\/jats:italic>\n >\n \n C\n T<\/jats:sub>\n <\/jats:italic>\n of 0.25 mg\/liter best correlated with efficacy. These studies provide the basis for the development of human dosing regimens for this combination.\n <\/jats:p>","DOI":"10.1128\/aac.00267-17","type":"journal-article","created":{"date-parts":[[2017,6,20]],"date-time":"2017-06-20T00:30:28Z","timestamp":1497918628000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["Pharmacodynamics of Cefepime Combined with Tazobactam against Clinically Relevant Enterobacteriaceae in a Neutropenic Mouse Thigh Model"],"prefix":"10.1128","volume":"61","author":[{"given":"Maria J.","family":"Melchers","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands"},{"name":"Department of Medical Microbiology & Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita C.","family":"van Mil","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands"},{"name":"Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Lagarde","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"den Hartigh","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6736-4149","authenticated-orcid":false,"given":"Johan W.","family":"Mouton","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands"},{"name":"Department of Medical Microbiology & Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.34.10.1932"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.36.11.2439"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.40.2.325"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/43.9.1570"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/40.5.679"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.7860\/JCDR\/2013\/4564.2733"},{"key":"e_1_3_2_8_2","unstructured":"Mouton\nJ\nMelchersMvan MilA. 2010. In vitro activity of cefepime alone and in combination with tazobactam against ESBL producers. Abstr 50th Intersci Conf Antimicrob Agents Chemother poster E-809 p A-2251."},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.10.2473"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkm073"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5520(03)00065-5"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01586-06"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00033-15"},{"key":"e_1_3_2_14_2","volume-title":"Fourteenth Eur Cong Clin Microbiol Infect Dis","author":"Melchers MJ","year":"2014","unstructured":"Melchers MJ van MilACLagardeCMoutonJW. 2014. Pharmacodynamics of tazobactam combined with cefepime in a neutropenic mouse thigh model,poster P-1736. Fourteenth Eur Cong Clin Microbiol Infect Dis,Barcelona, Spain,10 to 13 May 2014."},{"key":"e_1_3_2_15_2","volume-title":"Abstr 54th Intersci Conf Antimicrob Agents Chemother","author":"Melchers MJ","year":"2014","unstructured":"Melchers MJ van MilACLagardeCMoutonJW. 2014. Pharmacodynamic interaction between cefepime and tazobactam in a neutropenic mouse thigh model,poster A-1340. Abstr 54th Intersci Conf Antimicrob Agents Chemother,Washington, DC,5 to 9 September 2014."},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.33.8.1268"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01580-16"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01269-15"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.2.378-383.2004"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03706-14"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.6.1941-1947.2004"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01590-12"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00656-13"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/ajhp\/52.6_Suppl_2.S23"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00851-12"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01989-12"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02513-12"},{"key":"e_1_3_2_28_2","volume-title":"Abstr 51st Intersci Conf Antimicrob Agents Chemother","author":"Mouton J","year":"2011","unstructured":"Mouton J MavridouMDonnellyRvan MilA. 2011. PK\/PD of beta-lactam\u2014beta-lactamase inhibitors: correlation of in vitro susceptibility testing with in vivo efficacy. Abstr 51st Intersci Conf Antimicrob Agents Chemother,abstr A-1687."},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-6-55"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04402-14"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02662-14"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00267-17","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00267-17","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:53:51Z","timestamp":1645476831000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00267-17"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9]]},"references-count":30,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2017,9]]}},"alternative-id":["10.1128\/AAC.00267-17"],"URL":"https:\/\/doi.org\/10.1128\/aac.00267-17","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9]]},"assertion":[{"value":"2017-02-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-06-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-08-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00267-17"}}