The pharmacodynamics of fosfomycin in combination with meropenem against Klebsiella pneumoniae studied in an in vitro model of infection

Abstract

Background: Intravenous fosfomycin is used in combination with other antimicrobials for the management of severe and/or multidrug resistant Gram-negative infection. We used an in vitro pharmacokinetic model to study the combination of fosfomycin plus meropenem.

Methods: Six Klebsiella pneumoniae fosfomycin MICs 8-1024 mg/L, meropenem MICs 0.06->1024 mg/L were employed. A dilutional pharmacokinetic model was used to generate fosfomycin exposure ranges up to a fAUC/MIC 500. Exposure-ranging experiments were repeated in the presence of meropenem at exposures associated with 2 g 8-hourly human dosing for strains with meropenem MICs ≥32 mg/L and at half the bacteriostatic fT > MIC for strains with MICs <32 mg/L. The log change in bacterial burden from the initial inoculum after 24 h drug exposure was taken as the primary endpoint and fAUC/MIC ratios for antibacterial effects were calculated. The risk of emergence of resistance was assessed by measurement of the population profiles.

Results: Fosfomycin fAUC/MIC for bacteriostatic effect at 24 h were >500 for 5/6 K. pneumoniae strains. Meropenem fT > MIC for static effect were 16.6%-77.9% for the strains with meropenem MIC ≤ 64 mg/L. Strains with MICs of >1024 mg/L were not tested. Fosfomycin fAUC/MICs in the presence of meropenem were all reduced and for 5/6 strains the fAUC/MIC for static effect was <10 and <30 for a 2 log drop. Addition of meropenem suppressed changes in fosfomycin population profiles. There were no changes in meropenem population profiles exposed to the combination.

Conclusion: Addition of meropenem to fosfomycin had a dramatic impact on the fosfomycin fAUC/MIC exposures required for bacteriostatic and bactericidal effects and suppressed emergence of fosfomycin resistance.