Pharmacokinetic/pharmacodynamic analysis of sulbactam against pneumonia: establishing efficacy targets in the epithelial lining fluid.

Background: Sulbactam is an effective therapy for infections. Previous sulbactam pharmacokinetics/pharmacodynamics (PK/PD) analyses established exposure efficacy targets in plasma against pneumonia. Herein, we established sulbactam efficacy targets in epithelial lining fluid (ELF). The PTA following clinical sulbactam regimens was estimated.

Methods: Sulbactam (dosed as ampicillin-sulbactam) bronchopulmonary PK was assessed in the neutropenic murine pneumonia model. The percentage of the dosing interval during which the free drug concentration remained above the MIC (%T > MIC) required to achieve different efficacy endpoints was estimated in 21 clinical isolates. PTA was assessed using Monte Carlo Simulations and utilizing previously published healthy volunteers sulbactam ELF pharmacokinetics.

Results: Median (IQR) %T > MIC required to achieve 1-log kill in isolates resistant to both sulbactam and meropenem was 47.51 (39.7-54.2). This target was much higher than isolates with other phenotypes (i.e. sulbactam-susceptible/intermediate and sulbactam-resistant but meropenem susceptible) that required 16.62 (5.3-22.0). The PTA following sulbactam 1 g q6h 0.5h infusion regimen was >90% up to MIC of 2 mg/L while the PTA for MIC 4 mg/L (susceptibility breakpoint) was 81%. Conversely, previous assessment in plasma demonstrated the same regimen exceeded 90% PTA up to MIC of 4 mg/L. Sulbactam 3 g q8h 4h infusion provided PTA >90% for MIC 8 mg/L (sulbactam-intermediate), similar to previous assessment in plasma.

Conclusion: Based on the ELF assessment, the maximum FDA approved dose of sulbactam (1 g q6h 0.5h infusion) provided >90% PTA for isolates with sulbactam MIC only up to 2 mg/L. Nevertheless, sulbactam 3 g q8h for 4 hours of infusion achieved higher PTA and conferred additional benefit against sulbactam-susceptible/intermediate isolates.