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

Abstract

Background: Sulbactam is an effective therapy for Acinetobacter baumannii infections. Previous sulbactam pharmacokinetics/pharmacodynamics (PK/PD) analyses established exposure efficacy targets in plasma against A. baumannii 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 (%fT > MIC) required to achieve different efficacy endpoints was estimated in 21 clinical A. baumannii isolates. PTA was assessed using Monte Carlo Simulations and utilizing previously published healthy volunteers sulbactam ELF pharmacokinetics.

Results: Median (IQR) %fT > 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.