CEFEPIME/ENMETAZOBACTAM FOR GRAM-NEGATIVE PERIPROSTHETIC JOINT INFECTIONS? A PORCINE STUDY EVALUATING TARGET TISSUE CONCENTRATIONS FOLLOWING INTERMITTENT SHORT-TERM INFUSION AND CONTINUOUS INFUSION OF A NOVEL ANTIBIOTIC COMBINATION

Aim To investigate the distribution and the time above the minimum inhibitory concentration (T>MIC) for cefepime and the time above the threshold concentration (T>C t ) for enmetazobactam during the first and third dosing intervals in tissues relevant to PJI treatment following intermittent short-term infusion (STI) and continuous infusion. Method Sixteen pigs were randomised to receive either STI of cefepime/enmetazobactam (2g/0.5g over 2 h) or continuous infusion (initial dosage of 1g/0.25g administered over 15 min followed by 2g/0.5g over 7 h and 45 min) in three dosing intervals of 8 h. Microdialysis was employed to dynamically sample interstitial fluid concentrations of cefepime and enmetazobactam from cancellous bone, subcutaneous tissue (SCT) 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>C t of 2 mg/L. Results All pigs reached the predetermined targets of 60% T>MIC 8 mg/L for cefepime and 45% T>C t 2 mg/L for enmetazobactam in all investigated compartments following both administration forms. Conclusions 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 PJI settings.