Efficacy and pharmacokinetics of the combination of OP0595 and cefepime in a mouse model of pneumonia caused by ESBL-producing Klebsiella pneumoniae [PublishAheadOfPrint]

Background: OP0595 (RG6080) is a novel diazobicyclooctane 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 bacteraemia, remains unknown in vivo.

Objectives: 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 harbouring SHV and CTX-M-9-type ESBLs.

Methods: The infected BALB/c mice were intraperitoneally administered saline (control), 100 mg/kg of FEP, 20 mg/kg of OP0595, or both FEP and OP0595, twice a day.

Results: The minimum inhibitory concentration (MIC) of FEP against the bacteria was 8 mg/L and markedly improved to 0.06 mg/L 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 to 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.

Conclusions: The results of our study demonstrated the in vivo effectiveness of the combination of OP0595 and FEP.

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