Pharmacokinetics of ampicillin, sulbactam and combined ampicillin/sulbactam in subcutis, muscle and plasma: A microdialysis trial in healthy volunteers

Background This study aimed to investigate pharmacokinetics (PK)/pharmacodynamic (PD) target attainment, tissue and plasma PK, and PK interactions of ampicillin/sulbactam. Methods Thirty healthy volunteers received a single intravenous 30-minute infusion of ampicillin 2000mg (n=10), sulbactam 1000mg (n=10), or ampicillin 2000mg/sulbactam 1000mg (n=10). Drug concentrations were determined in the interstitial fluid of subcutis and muscle using microdialysis and in plasma over 8h. A non-compartmental analysis and an adjustment to the plasma protein binding determined by ultrafiltration were performed to calculate PK parameters and the proportion of participants achieving PK/PD targets. The PK/PD targets selected for ampicillin were f T >MIC >50% and f T >MIC >70%, reflecting established efficacy thresholds for β-lactam antibiotics across varying degrees of disease severity. Results Fewer than 90% of participants reached the PK/PD target of ampicillin f T >MIC >50% at MICs ≥4 mg/L and the target of f T >MIC >70% at MICs ≥0.5mg/L in plasma, muscle and subcutis, assuming three times daily dosing. In the pooled analysis, the mean f AUC 0-8 of ampicillin was 80 (SD 25), 84 (SD 29), and 80 (SD 20) mg/L × h in subcutis, muscle, and plasma. The mean f AUC 0-8 of sulbactam was 49 (SD 13), 54 (SD 15), and 60 (SD 17) mg/L × h in subcutis, muscle, and plasma. While ampicillin concentrations were similar between the groups, sulbactam showed higher concentrations in the combined group than in the sulbactam alone group, including an increased plasma f AUC 0-8 (68 [SD 12] versus 51 [SD 18] mg/L × h, p=0.027). Conclusion Although tissue concentrations almost reached plasma levels, the target attainment of ampicillin may be suboptimal when administered three times daily. Sulbactam tissue and plasma levels were slightly higher after combined administration with ampicillin than after administration of sulbactam alone.