Humanized Exposures of a β-Lactam-β-Lactamase Inhibitor, Tazobactam, versus Non-β-Lactam-β-Lactamase Inhibitor, Avibactam, with or without Colistin, against Acinetobacter baumannii in Murine Thigh and Lung Infection Models.

β-lactam-β-lactamase inhibitors (BLIs) have previously demonstrated antimicrobial activity against Acinetobacter baumannii (AB). Colistin retains the highest susceptibility rate against A. baumannii, and has demonstrated synergy with other antimicrobials, including β-lactam-BLIs. Therefore, we assessed the potential individual activity and synergistic combinations in vivo against carbapenem-susceptible (CS) and multidrug-resistant (MDR) A. baumannii isolates in neutropenic thigh and lung infection models. In vitro, colistin and tazobactam MICs were 1 and 16 µg/mL against AB 25-49 (CS) and 1 and 128 µg/mL against AB 5075 (MDR) respectively. In the lung model, tazobactam alone and in combination with colistin achieved a 1-log reduction in CFU, while colistin alone was not active against AB 25-49. No activity was observed against AB 5075. In the thigh model, tazobactam with and without colistin was bacteriostatic against AB 25-49 but did not demonstrate any activity against AB 5075. Avibactam and colistin alone and in combination were not active against either isolate. No synergy was observed; however, we found tazobactam activity against A. baumannii. This activity was not observed for the non-β-lactam-BLI, avibactam. This suggests that binding to penicillin-binding proteins of the β-lactam molecule is required for tazobactam activity against A. baumannii. These data point to an added role of β-lactam-BLIs beyond their primary purpose of β-lactamase inhibition in the treatment of MDR A. baumannii infections by enhancing the activity of peptide antibiotics, a property that is not shared by the novel non-β-lactam-BLIs. Future studies are needed to define tazobactam and colistin activity in an A. baumannii infection model.