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

Abstract

Infections caused by Acinetobacter baumannii are increasingly multidrug resistant and associated with high rates of morbidity and mortality. Sulbactam is a β-lactamase inhibitor with intrinsic antibacterial activity against A. baumannii. Durlobactam is a non-β-lactam β-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-log₁₀ and 2-log₁₀ 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-log₁₀ and 2-log₁₀ 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-log₁₀ and 2-log₁₀ 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 μm. In the one-compartment model, durlobactam AUC_0-24/MIC to achieve 1-log₁₀ and 2-log₁₀ CFU/mL reduction were 7.6 and 33.4, respectively. Simulations of clinical ELF exposures in the HFIM showed cidal activity at MICs ≤4 µg/mL. Penicillin binding protein 3 mutant strains with MICs of 8 μg/mL may benefit from the addition of a carbapenem at clinical exposures.

Keywords: Acinetobacter calcoaceticus; durlobactam; pharmacodynamics; pharmacokinetics; sulbactam.

Fig 1

Observed vs predictive concentration plot of sulbactam in the hollow fiber infection model vs A. baumannii ARC2058 (polysulfone cartridge).

Fig 2

Observed vs predictive concentration plot of sulbactam (A) and durlobactam (B) in the hollow fiber infection model vs A. baumannii ARC5081 (polysulfone cartridge).

Fig 3

PK sampling of sulbactam (q6h) with and without durlobactam regimens vs A. baumannii ARC5081 (1-h infusion).

Fig 4

Relationship between sulbactam (A) time above MIC, (B) C_max/MIC, and (C) AUC_0–24/MIC vs A. baumannii ARC2058 response in the HFIM (polysulfone cartridges).

Fig 5

Relationship between durlobactam AUC/MIC (A), C_max/MIC (B), and %Time > critical threshold value of 0.75 µg/mL (C) vs A. baumannii ARC5081 response in the HFIM (polysulfone cartridges).

Fig 6

Relationship between durlobactam AUC/MIC (A), C_max/MIC (B), and %Time > critical threshold value of 0.75 µg/mL (C) vs A. baumannii ARC5081 response in the HFIM (PVDF cartridges).

Fig 7

Relationship between durlobactam AUC_0–24, C_max, and %T > durlobactam threshold value of 0.75 µg/mL against A. baumannii ARC5081 response in the one-compartment model (color coded by regimen). %T > 0.75 µg/mL, time as a percentage of the dosing interval that the drug concentration remains above 0.75 µg/mL; AUC_0–24, area under the plasma concentration-time curve from time 0 to 24 h; CFU, colony-forming units; C_max, maximum (peak) plasma concentration; r ², correlation coefficient.

Fig 8

Relationship between the change in log₁₀ CFU/mL from baseline and durlobactam AUC_0-24 for A. baumannii ARC5081 examined in dose fractionation studies (q6h and q12h data only) AUC_0–24, area under the plasma concentration-time curve from time 0 to 24 h; CFU, colony-forming units; C_max, maximum (peak) plasma concentration; r ², correlation coefficient.

Fig 9

Time course CFU burden vs time for sulbactam 1 g q6h alone and in combination with 1-g q6h durlobactam compared to vehicle control and co-administration of either 1-g q6h of imipenem or 1-g q6h of meropenem against ARC3486, ARC5950, and ARC5955.