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.
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.
| Original language | English |
|---|---|
| Article number | dkaf020 |
| Pages (from-to) | 967-975 |
| Number of pages | 9 |
| Journal | Journal of Antimicrobial Chemotherapy |
| Volume | 80 |
| Issue number | 4 |
| Early online date | 31 Jan 2025 |
| DOIs | |
| Publication status | Published - 4 Apr 2025 |
Bibliographical note
Publisher Copyright:© The Author(s) 2025. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved.