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.

Antimicrobial Agents and Chemotherapy
Norihito KakuKatsunori Yanagihara

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 vi...Continue Reading

References

May 16, 1980·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·R P Ambler
Jun 19, 2004·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·David L PatersonVictor L Yu
Dec 10, 2009·Antimicrobial Agents and Chemotherapy·Karen Bush, George A Jacoby
May 13, 2014·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·Y HaradaK Yanagihara
Jun 20, 2015·The Journal of Antimicrobial Chemotherapy·Akihiro MorinakaDavid M Livermore

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Citations

Jun 12, 2019·Antimicrobial Agents and Chemotherapy·Melissa D BarnesRobert A Bonomo
Apr 4, 2018·Expert Opinion on Investigational Drugs·Lindsay M Avery, David P Nicolau

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