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Updated: Jan 20, 2026
Author Spotlight: Advancing Research on Candida albicans Biofilm-Associated Prosthetic Joint Infections
Published on: February 2, 2024
Cefepime/enmetazobactam for Gram-negative periprosthetic joint infections? A randomized porcine study on target
M B D Nielsen1,2, M K D Mikkelsen1,2, H C Rasmussen1,2
1Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.
Background:
Periprosthetic joint infections pose clinical and socioeconomic challenges. Gram-negative pathogens are associated with poorer outcomes compared with Gram-positive organisms. Rising antimicrobial resistance limits treatment options. The new combination of cefepime/enmetazobactam offers a promising carbapenem-sparing therapy.
Objectives:
To investigate the distribution and the time above the minimum inhibitory concentration for cefepime and the time above the threshold concentration for enmetazobactam during the first and third dosing intervals in tissues relevant to periprosthetic joint infection, following either intermittent short-term infusion or continuous infusion in a preclinical, randomized porcine model.
Materials And Methods:
Sixteen pigs were randomized to receive cefepime/enmetazobactam either as a short-term infusion (2 g/0.5 g over 2 h) or continuous infusion (initial dosage of 1 g/0.25 g administered over 15 min followed by 2 g/0.5 g over 7 h and 45 min) in three dosing intervals of 8 h. Microdialysis was used to dynamically sample interstitial fluid concentrations of cefepime and enmetazobactam from cancellous bone, subcutaneous tissue and synovial fluid. Plasma samples were collected as reference. The following dosing interval targets were applied: for cefepime, 60% T > MIC of 8 mg/L and for enmetazobactam, 45% of T > Ct of 2 mg/L.
Results:
All pigs reached the predetermined targets in all investigated compartments following both administration forms. For all targets, compartments, dosing intervals and administration forms, the mean T > MIC for cefepime was ≥92% and mean T > Ct for enmetazobactam was ≥99%.
Conclusion:
Cefepime/enmetazobactam demonstrated robust tissue distribution, reaching the applied pharmacokinetic/pharmacodynamic targets in all investigated tissue compartments, regardless of the mode of administration. From a pharmacokinetic view, cefepime/enmetazobactam may prove useful in future Gram-negative periprosthetic joint infection settings.
Insights
Cefepime/enmetazobactam effectively reached therapeutic concentrations in relevant tissues for periprosthetic joint infections. This combination therapy shows promise for treating Gram-negative infections, regardless of administration method.
Area of Science:
- Pharmacology
- Infectious Diseases
- Biomedical Engineering
Background:
- Periprosthetic joint infections (PJIs) present significant clinical and economic burdens.
- Gram-negative pathogens in PJIs are linked to worse patient outcomes.
- Increasing antimicrobial resistance necessitates novel treatment strategies, such as cefepime/enmetazobactam.
Purpose of the Study:
- To evaluate cefepime and enmetazobactam tissue distribution in a preclinical PJI model.
- To determine time above minimum inhibitory concentration (MIC) and threshold concentration (Ct) for both drugs.
- To compare intermittent short-term infusion versus continuous infusion of cefepime/enmetazobactam.
Main Methods:
- A randomized porcine model was used to simulate PJI.
- Cefepime/enmetazobactam was administered via short-term or continuous infusion.
- Microdialysis sampled drug concentrations in cancellous bone, subcutaneous tissue, and synovial fluid.
Main Results:
- Both cefepime/enmetazobactam administration methods achieved pharmacokinetic/pharmacodynamic targets in all tissues.
- Mean cefepime time above MIC was ≥92% across all conditions.
- Mean enmetazobactam time above Ct was ≥99% across all conditions.
Conclusions:
- Cefepime/enmetazobactam exhibits excellent tissue penetration for PJI-relevant sites.
- The drug combination meets established targets regardless of infusion method.
- Cefepime/enmetazobactam is a potential therapeutic option for Gram-negative PJIs.
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