In vitro pharmacokinetics/pharmacodynamics of the β-lactamase inhibitor, durlobactam, in combination with sulbactam against Acinetobacter baumannii-calcoaceticus complex

Infections caused by Acinetobacter baumannii are increasingly multidrug resistant and associated with high rates of morbidity and mortality. Sulbactam is a beta-lactamase inhibitor with intrinsic antibacterial activity against A. baumannii. Durlobactam is a non-beta-lactam beta-lactamase inhibitor with an extended spectrum of activity compared to other inhibitors of its class. In vitro pharmacodynamic infection models were undertaken to establish the pharmacokinetic/pharmacodynamic (PK/PD) index and magnitudes associated with sulbactam and durlobactam efficacy and to simulate epithelial lining fluid (ELF) exposures at clinical doses to understand sulbactam-durlobactam activity with and without co-administration of a carbapenem. Hollow fiber infection models (HFIMs) and one-compartment systems were used to identify the PK/PD indices and exposure magnitudes associated of 1-log(10) and 2-log(10) colony-forming unit (CFU)/mL reductions. Sulbactam and durlobactam demonstrated PK/PD drivers of % time above the minimum inhibition concentration (%T > MIC) and area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-24))/MIC, respectively. Against a sulbactam-susceptible strain, sulbactam %T > MIC of 71.5 and 82.0 were associated with 1-log(10) and 2-log(10) CFU/mL reductions, respectively, in the HFIM. Against a non-susceptible strain, durlobactam restored the activity of sulbactam with an AUC(0-24)/MICs of 34.0 and 46.8 using a polysulfone cartridge to achieve a 1-log(10) and 2-log(10) CFU/mL reduction. These magnitudes were reduced to 13.8 and 24.2, respectively, using a polyvinylidene fluoride cartridge with a membrane pore size of 0.1 mu m. In the one-compartment model, durlobactam AUC(0-24)/MIC to achieve 1-log(10) and 2-log(10) CFU/mL reduction were 7.6 and 33.4, respectively. Simulations of clinical ELF exposures in the HFIM showed cidal activity at MICs <= 4 mu g/mL. Penicillin binding protein 3 mutant strains with MICs of 8 mu g/mL may benefit from the addition of a carbapenem at clinical exposures.