Humanized Exposures of a β-lactam - β-lactamase Inhibitor (BL-BLI), Tazobactam (TZB), versus a Non-β-lactam - β-lactamase Inhibitor, Avibactam (AVI), with or without Colistin (CST), against Acinetobacter baumannii (AB) in Murine Thigh and Lung Infection Models

Background: BL-BLIs were initially developed as a protection mechanism for β-lactam (BL) antibiotics from the inactivating effects of bacterial enzymes; however, these agents have previously demonstrated antimicrobial activity against AB. Herein, we assess potential individual activity and synergistic combinations in vivo against carbapenem-susceptible (CS) and multidrug-resistant (MDR) AB isolates in a neutropenic thigh and lung infection models.

Methods: CST and TZB MICs were determined in triplicate via broth microdilution and the modal MICs were reported. For the lung model, groups of 6 mice were inoculated with AB AZ25-49 (CS) or AB 5075 (MDR) and injected with a humanized regimen of TZB 0.5g q6h and a CST dose previously shown to result in bacterial stasis in a murine thigh infection model. For the thigh model, groups of 3 mice were inoculated with AB isolates as above. CST and humanized exposures of TZB (0.5g q6h) and AVI (0.5g q8h) were administered independently and in combination. After 24h, animals were euthanized, thighs or lungs excised, and antibacterial activity was measured as the change in thigh or lung bacterial density (Log₁₀ CFU) relative to the starting inoculum (0h).

Results: In vitro, CST and TZB MICs were 1 and 16 µg/mL against AB AZ25-49 and 1 and 128 µg/mL against AB 5075, respectively. In the lung model, TZB alone and in combination with CST achieved a 1-log reduction in CFU, while colistin alone was not active against AB AZ25-49. No activity was observed against AB 5075. In the thigh model, TZB with and without CST was bacterial static against AB AZ25-49, but did not demonstrate any activity against AB 5075. AVI and CST alone and in combination were not active against either isolate.

Conclusion: No synergy was observed; however, we found TZB activity against AB. This activity was not observed for the non-BL-BLI, AVI. This suggests that binding to penicillin-binding proteins of the BL molecule is required for TZB activity against AB. In vivo TZB activity was consistent with its MIC profile and showed enhanced activity in the lung model. These data point to the importance of BL-BLI beyond their primary purpose of β-lactamase inhibition in the treatment of MDR AB infections. Future studies are needed to define TZB activity in an AB infection model.