title: In vitro activity of doripenem alone and in multi-agent combinations against extensively drug-resistant Acinetobacter baumannii and Klebsiella pneumoniae.
abstract: Carbapenems are increasingly needed to treat infections caused by drug-resistant gram-negative bacilli (GNB), but carbapenem resistance is increasing. We evaluated the activity of doripenem by broth microdilution against 96 extensively drug-resistant (XDR) Acinetobacter baumannii and Klebsiella pneumoniae isolates from patients with hospital-associated infections. All isolates were non-susceptible to doripenem, but ≥ 1 doripenem combination demonstrated synergy (fractional inhibitory concentration index: ≤ 0.5 for 2 agents, ≤ 0.75 for 3 agents) against 7 (15%) A. baumannii and 23 (48%) K. pneumoniae isolates; doripenem with rifampin and/or polymyxin B were most active. As doripenem has unique potential for use in prolonged infusions, suggested pharmacodynamic (PD) breakpoints range from 2-8 μg/mL; synergistic activity was found for higher proportions of XDR-GNB at higher PD breakpoints with doripenem with amikacin or with rifampin. The clinical utility of these observations requires further study, as treatment options for XDR-GNB infections are limited.
authors.affiliation: Columbia University, New York, NY 10032, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Clock
authors.forename: Setareh
authors.initials: S
authors.lastname: Tabibi
authors.forename: Luis
authors.initials: L
authors.lastname: Alba
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Kubin
authors.forename: Susan
authors.initials: S
authors.lastname: Whittier
authors.forename: Lisa
authors.initials: L
authors.lastname: Saiman
mesh_terms: D000151:Acinetobacter Infections / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000583:Amikacin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology*; D003428:Cross Infection / Q000382:microbiology; D000077726:Doripenem; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D006801:Humans; D007710:Klebsiella Infections / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D011112:Polymyxin B / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000583:Amikacin; D000077726:Doripenem; D011112:Polymyxin B; D012293:Rifampin