Cefepime/enmetazobactam for Gram-negative periprosthetic joint infections? A randomized porcine study on target tissue pharmacokinetics

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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.

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