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 pharmacokinetic (PK)/pharmacodynamic (PD) target attainment, tissue and plasma PK and PK interactions of ampicillin/sulbactam.

METHODS

Thirty healthy volunteers received a single intravenous 30-min infusion of ampicillin 2000 mg (n = 10), sulbactam 1000 mg (n = 10) or ampicillin 2000 mg/sulbactam 1000 mg (n = 10). Drug concentrations were determined in the interstitial fluid of subcutis and muscle using microdialysis and in plasma over 8 h. 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 fT>MIC >50% and fT>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 fT>MIC > 50% at MICs ≥4 mg/L and the target of fT>MIC > 70% at MICs ≥0.5 mg/L in plasma, muscle and subcutis, assuming three times daily dosing. In the pooled analysis, the mean fAUC0-8 of ampicillin was 80 (S.D. 25), 84 (S.D. 29) and 80 (S.D. 20) mg/L × h in subcutis, muscle and plasma. The mean fAUC0-8 of sulbactam was 49 (S.D. 13), 54 (S.D. 15) and 60 (S.D. 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 fAUC0-8 (68 [S.D. 12] vs. 51 [S.D. 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.