Background: MDR Gram-negative bacteria, such as ESBL-producing and carbapenemase-producing Klebsiella pneumoniae, represent major global health threats. Treatment options are limited due to increasing resistance and slowed development of novel antimicrobials, making it necessary to apply effective combination therapies based on approved antibiotics.
Objectives: To quantitatively evaluate the synergistic potential of meropenem and fosfomycin against carbapenem-resistant K. pneumoniae strains isolated from clinics.
Methods: We evaluated four MDR K. pneumoniae strains, each expressing KPC-2 or KPC-3, using static time-kill assays that accounted for measured meropenem degradation. This was followed by pharmacokinetic/pharmacodynamic (PK/PD) interaction modelling, which estimated meropenem degradation rate constants and identified perpetrator-victim relationships in PD interactions. Dynamic hollow-fibre infection model (HFIM) experiments were used to confirm synergy.
Results: Static time-kill assays demonstrated high killing effects and suppressed regrowth for the combination of meropenem and fosfomycin, compared with the failure of monotherapy. Meropenem degradation was significantly higher in the presence of bacteria, attributable to carbapenemase activity. Pharmacometric models indicated a synergistic interaction primarily driven by meropenem as the perpetrator, enhancing the potency of fosfomycin. HFIM experiments confirmed in vitro synergy, demonstrating continuous bacterial suppression of the combination therapy.
Conclusions: Meropenem and fosfomycin exhibited additive or synergistic potential against carbapenemase-expressing single- or double-resistant K. pneumoniae at clinically achievable concentrations. This combination therapy may offer a strategy against MDR infections, possibly improving clinical treatment outcomes. Further in vivo research is needed to translate these findings into clinical practice, emphasizing the importance of PK/PD modelling in rationalizing antibiotic use.
© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].