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Efficacy and Pharmacokinetics of the Combination of OP0595 and Cefepime in a Mouse Model of Pneumonia Caused by Extended-Spectrum-Beta-Lactamase-Producing Klebsiella pneumoniae


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Title: Efficacy and Pharmacokinetics of the Combination of OP0595 and Cefepime in a Mouse Model of Pneumonia Caused by Extended-Spectrum-Beta-Lactamase-Producing Klebsiella pneumoniae
Authors: Kaku, Norihito / Kosai, Kosuke / Takeda, Kazuaki / Uno, Naoki / Morinaga, Yoshitomo / Hasegawa, Hiroo / Miyazaki, Taiga / Izumikawa, Koichi / Mukae, Hiroshi / Yanagihara, Katsunori
Issue Date: Jul-2017
Publisher: American Society for Microbiology
Citation: Antimicrobial Agents and Chemotherapy, 61(7), e00828-17; 2017
Abstract: OP0595 (RG6080) is a novel diazabicyclooctane that inhibits class A and C serine beta-lactamases. Although the combination of OP0595 and cefepime (FEP) showed good in vitro activity against extended-spectrum-beta-lactamase (ESBL)-producing pathogens, the effect of the combination therapy against severe infections, such as pneumonia or bacteremia, remains unknown in vivo. In this study, we investigated the efficacy and pharmacokinetics of the combination therapy of OP0595 and FEP in a mouse model of pneumonia caused by Klebsiella pneumoniae harboring SHV- and CTX-M-9-type ESBLs. The infected BALB/c mice were intraperitoneally administered saline (control), 100 mg/kg of body weight of FEP, 20 mg/kg of OP0595, or both FEP and OP0595, twice a day. The MIC of FEP against the bacteria was 8 mg/liter and markedly improved to 0.06 mg/liter with the addition of 0.5 mg/ml of OP0595. In the survival study, the combination of FEP and OP0595 significantly improved the survival rate compared with that reported with either OP0595 or FEP alone (P < 0.001). The number of bacteria in the lungs and blood significantly decreased in the combination therapy group compared to that reported for the monotherapy groups (P < 0.001). In addition, the in vivo effect depended on the dose of FEP. However, pharmacokinetic analysis revealed that the percentage of time above MIC remained constant when increasing the dose of FEP in combination with 20 mg/kg of OP0595. The results of our study demonstrated the in vivo effectiveness of the combination of OP0595 and FEP.
Keywords: ESBLs / Klebsiella pneumoniae / serine-beta-lactamase inhibitor / diazabicyclooctane
URI: http://hdl.handle.net/10069/37699
ISSN: 00664804
DOI: 10.1128/AAC.00828-17
Rights: © 2017 American Society for Microbiology
Type: Journal Article
Text Version: author
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/37699

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