{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T12:19:11Z","timestamp":1789820351777,"version":"4.0.1"},"reference-count":10,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2012,1,1]],"date-time":"2012-01-01T00:00:00Z","timestamp":1325376000000},"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":[[2012,1]]},"abstract":"ABSTRACT<\/jats:title>\n \n New broad-spectrum \u03b2-lactamases such as KPC enzymes and CTX-M-15 enzymes threaten to markedly reduce the utility of our armamentarium of \u03b2-lactam agents, even our most potent drugs, such as carbapenems. NXL104 is a broad-spectrum non-\u03b2-lactam \u03b2-lactamase inhibitor. In this evaluation, we examined organisms carrying defined \u03b2-lactamases and identified doses and schedules of NXL104 in combination with the new cephalosporin ceftaroline, which would maintain good bacterial cell kill and suppress resistance emergence for a clinically relevant period of 10 days in our hollow-fiber infection model. We examined three strains of\n Klebsiella pneumoniae<\/jats:named-content>\n and one isolate of\n Enterobacter cloacae. K. pneumoniae<\/jats:named-content>\n 27-908M carried KPC-2, SHV-27, and TEM-1 \u03b2-lactamases. Its isogenic mutant,\n K. pneumoniae<\/jats:named-content>\n 4207J, was \u201ccured\u201d of the plasmid expressing the KPC-2 enzyme.\n K. pneumoniae<\/jats:named-content>\n 24-1318A carried a CTX-M-15 enzyme, and\n E. cloacae<\/jats:named-content>\n 2-77C expressed a stably derepressed AmpC chromosomal \u03b2-lactamase. Dose-ranging experiments for NXL104 administered as a continuous infusion with ceftaroline at 600 mg every 8 h allowed identification of a 24-h area under the concentration-time curve (AUC) for NXL104 that mediated bactericidal activity and resistance suppression. Dose fractionation experiments identified that \u201ctime > threshold\u201d was the pharmacodynamic index linked to cell kill and resistance suppression. Given these results, we conclude that NXL104 combined with ceftaroline on an 8-hourly administration schedule would be optimal for circumstances in which highly resistant pathogens are likely to be encountered. This combination dosing regimen should allow for optimal bacterial cell kill (highest likelihood of successful clinical outcome) and the suppression of resistance emergence.\n <\/jats:p>","DOI":"10.1128\/aac.05005-11","type":"journal-article","created":{"date-parts":[[2011,10,25]],"date-time":"2011-10-25T05:44:10Z","timestamp":1319521450000},"page":"258-270","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":69,"title":["Pharmacodynamics of \u03b2-Lactamase Inhibition by NXL104 in Combination with Ceftaroline: Examining Organisms with Multiple Types of \u03b2-Lactamases"],"prefix":"10.1128","volume":"56","author":[{"given":"Arnold","family":"Louie","sequence":"first","affiliation":[{"name":"Ordway Research Institute, Emerging Infections Pharmacodynamics Laboratory, Albany, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Castanheira","sequence":"additional","affiliation":[{"name":"JMI Laboratories, North Liberty, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiguo","family":"Liu","sequence":"additional","affiliation":[{"name":"Ordway Research Institute, Emerging Infections Pharmacodynamics Laboratory, Albany, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Grasso","sequence":"additional","affiliation":[{"name":"Ordway Research Institute, Emerging Infections Pharmacodynamics Laboratory, Albany, 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":"Gregory","family":"Williams","sequence":"additional","affiliation":[{"name":"Cerexa, Inc., Oakland, California, a wholly owned subsidiary of Forest Laboratories, Inc., New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Critchley","sequence":"additional","affiliation":[{"name":"Cerexa, Inc., Oakland, California, a wholly owned subsidiary of Forest Laboratories, Inc., New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Thye","sequence":"additional","affiliation":[{"name":"Cerexa, Inc., Oakland, California, a wholly owned subsidiary of Forest Laboratories, Inc., New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Brown","sequence":"additional","affiliation":[{"name":"Ordway Research Institute, Emerging Infections Pharmacodynamics Laboratory, Albany, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"VanScoy","sequence":"additional","affiliation":[{"name":"Ordway Research Institute, Emerging Infections Pharmacodynamics Laboratory, Albany, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Kulawy","sequence":"additional","affiliation":[{"name":"Ordway Research Institute, Emerging Infections Pharmacodynamics Laboratory, Albany, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. L.","family":"Drusano","sequence":"additional","affiliation":[{"name":"Ordway Research Institute, Emerging Infections Pharmacodynamics Laboratory, Albany, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.38.6.1386"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.31.7.1054"},{"key":"e_1_3_2_4_2","volume-title":"Abstr. 48th Intersci. Conf. Antimicrob. Agents Chemother.\/46th Meet. Infect. Dis. Soc. Am","author":"Borgonovi M","year":"2008","unstructured":"BorgonoviM. 2008. Importance of NXL104 pharmacokinetics (PK) in the pharmacodynamics (PD) of ceftazidime+NXL104 combinations in an in vitro hollow fiber infection model, abstr. A-023. Abstr. 48th Intersci. Conf. Antimicrob. Agents Chemother.\/46th Meet. Infect. Dis. Soc. Am."},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1086\/319281","article-title":"Hollow fiber unit evaluation of a new human immunodeficiency virus type 1 protease inhibitor, BMS-232632, for determination of the linked pharmacodynamic variable","volume":"183","author":"Drusano GL","year":"2001","unstructured":"DrusanoGL. 2001. Hollow fiber unit evaluation of a new human immunodeficiency virus type 1 protease inhibitor, BMS-232632, for determination of the linked pharmacodynamic variable. J. Infect. Dis. 183:1126\u20131129.","journal-title":"J. Infect. Dis"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.2.464-470.2002"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1086\/424849"},{"key":"e_1_3_2_8_2","first-page":"664","article-title":"2009. AmpC \u03b2-lactamases","volume":"22","author":"Jacoby G","year":"2009","unstructured":"JacobyG. 2009. 2009. AmpC \u03b2-lactamases. Clin. Microbiol. Rev. 22:664\u2013689.","journal-title":"Clin. Microbiol. Rev"},{"key":"e_1_3_2_9_2","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1128\/AAC.01412-06","article-title":"Spread of extended-spectrum beta-lactamase CTX-M-producing Escherichia coli clinical isolates in community and nosocomial environments in Portugal","volume":"51","author":"Mendona\u0327 N","year":"2007","unstructured":"Mendona\u0327N Leit\u00e3oJ ManageiroV FerreiraE Cani\u00e7aM. 2007. Spread of extended-spectrum beta-lactamase CTX-M-producing Escherichia coli clinical isolates in community and nosocomial environments in Portugal. Antimicrob. Agents Chemother. 51:1946\u20131955.","journal-title":"Antimicrob. Agents Chemother"},{"key":"e_1_3_2_10_2","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1093\/jac\/dkg124","article-title":"Plasmid-mediated, carbapenem-hydrolyzing beta-lactamase, KPC-2, in Klebsiella pneumoniae isolates","volume":"51","author":"Smith Moland E","year":"2003","unstructured":"Smith MolandE. 2003. Plasmid-mediated, carbapenem-hydrolyzing beta-lactamase, KPC-2, in Klebsiella pneumoniae isolates. J. Antimicrob. Chemother. 51:711\u2013714.","journal-title":"J. Antimicrob. 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