Cefepime/enmetazobactam steady-state concentrations in spondylodiscitis-relevant tissues: an experimental porcine study

BACKGROUND: Spondylodiscitis is a severe infection associated with considerable morbidity and mortality. The prevalence of gram-negative infections is on the rise, posing significant therapeutic challenges. Cefepime/enmetazobactam constitutes a novel antibiotic combination that offers broad-spectrum activity against resistant gram-negative organisms. However, its pharmacokinetic profile within spinal tissues remains unknown. OBJECTIVES: To dynamically assess unbound steady-state concentrations of cefepime/enmetazobactam in healthy vertebral cancellous bone, intervertebral disc, and paravertebral muscle after both short-term and continuous infusions. METHODS: 16 pigs were randomised to receive either short-term infusion (3 doses of 2 g/0.5 g cefepime/enmetazobactam administered over 2 h, repeated every 8 h) or continuous infusion (1 g/0.25 g loading dose administered over 15 min, followed by 6 g/1.5 g administered over 15 h and 45 min). Steady state was assumed during the third dosing interval (16-24 h). Microdialysis was employed to sample interstitial fluid from spondylodiscitis-relevant tissues: vertebral cancellous bone, intervertebral disc and paravertebral muscle, at steady state for 8 h. The unbound concentrations of cefepime and enmetazobactam were quantified by LC-MS/MS. The primary endpoint was to determine the time above relevant MIC (T > MIC) for cefepime (0.125, 4, 8, and 32 mg/L) and the time above relevant concentration threshold (T > Ct) for enmetazobactam (2 and 8 mg/L). RESULTS: For both cefepime and enmetazobactam, there were no differences in T > MIC and T > Ct when comparing dosing regimens, applying the conventional targets of MIC 0.125, 4, and 8 mg/L, and Ct of 2 mg/L. Only when applying the aggressive targets of MIC 32 mg/L and Ct 8 mg/L did continuous infusion yield longer T > MIC and T > Ct compared with short-term infusion in both the vertebral cancellous bone and intervertebral disc. CONCLUSION: Both cefepime and enmetazobactam consistently reached theoretically effective unbound steady-state tissue levels in relevant target tissues for spondylodiscitis, irrespective of the dosing regimen.