Enhanced bacterial killing with colistin/sulbactam combination against carbapenem-resistant Acinetobacter baumannii

Aims: Polymyxin-based combination therapy is often used to treat carbapenem-resistant Acinetobacter baumannii (A. baumannii) infections. Although sulbactam is intrinsically active against A. baumannii, few studies have investigated colistin/sulbactam combinations against carbapenem-resistant A. baumannii. Methods: Whole genome sequencing was undertaken on eight carbapenem-resistant (colistinsusceptible) isolates of A. baumannii from Chinese patients. Bacterial killing of colistin and sulbactam, alone and in combination, was examined with checkerboard (all isolates) and static and dynamic time kill studies (three isolates). In the dynamic studies, antibiotics were administered in various clinically relevant dosing regimens that mimicked patient pharmacokinetics. Results: The eight isolates consisted of ST195, ST191 and ST208 belonging to clonal complex 208, which is the most epidemic clonal type of A. baumannii globally. All isolates possessed Acinetobacterderived cephalosporinase (ADC-61 or ADC-78) and seven of eight isolates contained the carbapenemresistance gene bla(OXA-23). The colistin/sulbactam combination was synergistic against two of eight isolates in checkerboard studies. In time-kill studies, rapid bacterial killing of ca. 3-6 log(10) CFU/mL was observed with colistin monotherapy, followed by steady regrowth. Sulbactam monotherapy was generally ineffective. Substantially enhanced bacterial killing was observed with colistin/sulbactam combinations in both static and dynamic models, especially with the higher sulbactam concentration (2 g) and/or longer sulbactam infusion time (2 hours) in the dynamic model. Conclusions: This study was the first to use a pharmacokinetics/pharmacodynamics model to investigate synergistic activity of colistin/sulbactam combinations against A. baumannii. It showed that clinically relevant dosing regimens of colistin combined with sulbactam may substantially improve bacterial killing of multidrug-resistant and carbapenem-resistant A. baumannii. (C) 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

Automated summary

This study conducted whole genome sequencing on carbapenem-resistant Acinetobacter baumannii isolates and investigated the bacterial killing effects of colistin and sulbactam combination therapy. The results showed that higher sulbactam concentration and longer infusion time substantially enhanced bacterial killing in a dynamic model.