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

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.