Pharmacokinetics and pharmacodynamics of cefoperazone/sulbactam in neutropenic murine lung and thigh infection models against Gram-negative organisms.

OBJECTIVES

Cefoperazone-sulbactam, a β-lactam/β-lactamase inhibitor combination, is widely used against ESBL-producing Gram-negative pathogens. This study investigated the in vivo pharmacokinetics/pharmacodynamics (PK/PD) of 1:1 and 2:1 cefoperazone-sulbactam formulations in neutropenic murine thigh and lung infection models.

METHODS

Eleven ESBL-producing Gram-negative isolates with varying MICs were used to establish murine thigh and lung infection models. The plasma and epithelial lining fluid (ELF) pharmacokinetics of cefoperazone and sulbactam were evaluated over a wide dose range. Five dose-fractionation experiments were conducted to identify the PK/PD index most correlated with efficacy, and dose-escalation to determine PK/PD targets.

RESULTS

All isolates exhibited cefoperazone MICs ≥ 64 mg/L, reduced by 8- to 16-fold by sulbactam at a 1:1 or 2:1 ratio. Cefoperazone and sulbactam showed linear pharmacokinetics across the dose range, well described by a two-compartmental model. Plasma protein binding was 57% for cefoperazone and 3% for sulbactam. ELF penetration was 0.12 for cefoperazone and 0.21 for sulbactam, which were used to determine the ELF-based targets. PK/PD targets reflecting the primary active component against each pathogen were reported. Cefoperazone %fT > MIC was used as the PK/PD index for E. coli and K. pneumoniae, the magnitude for 1-log10 cfu bacterial reduction was 50.3% (1:1) and 51.3% (2:1) in the thigh infection model, 52.4% (1:1) and 75.6% (2:1) in the lung infection model. For A. baumannii, sulbactam was identified as the primary active component, and the 1-log10 cfu %fT > MIC target for sulbactam was 68.7%.

CONCLUSIONS

Cefoperazone-sulbactam demonstrated strong in vivo antibacterial activity against the 11 tested isolates. This study established PK/PD targets under varied conditions, providing a valuable foundation for optimizing the clinical application of cefoperazone-sulbactam.