Non-polymyxin-based combinations as potential alternatives in treatment against carbapenem-resistant Acinetobacter baumannii infections

Mohd Sazlly Lim S 1 , Naicker S 2 , Ayfan AK 3 , Zowawi H 4 , Roberts JA 5 , Sime FB 6

Affiliations 

  • 1 Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, University of Queensland, Brisbane, Australia; Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia
  • 2 Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, University of Queensland, Brisbane, Australia; UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, Australia
  • 3 UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, Australia; Biochemistry Department, Faculty of Science, King Abdul-Aziz University, Jeddah, Saudi Arabia
  • 4 UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, Australia; College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Centre, Riyadh, Saudi Arabia
  • 5 Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, University of Queensland, Brisbane, Australia; UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, Australia; Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia; Division of Anaesthesiology, Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France
  • 6 Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, University of Queensland, Brisbane, Australia; UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, Australia. Electronic address: f.sime@uq.edu.au
Int J Antimicrob Agents, 2020 Oct;56(4):106115.
PMID: 32721600 DOI: 10.1016/j.ijantimicag.2020.106115

Abstract

Due to limited therapeutic options, combination therapy has been used empirically to treat carbapenem-resistant Acinetobacter baumannii (CRAB). Polymyxin-based combinations have been widely studied and used in the clinical setting. However, the use of polymyxins is often limited due to nephrotoxicity and neurotoxicity. This study aimed to evaluate the activity of non-polymyxin-based combinations relative to polymyxin-based combinations and to identify potential synergistic and bactericidal two-drug non-polymyxin-based combinations against CRAB. In vitro activity of 14 two-drug combinations against 50 A. baumannii isolates was evaluated using the checkerboard method. Subsequently, the two best-performing non-polymyxin-based combinations from the checkerboard assay were explored in static time-kill experiments. Concentrations of antibiotics corresponding to the fractional inhibitory concentrations (FIC) and the highest serum concentration achievable clinically were tested. The most synergistic combinations were fosfomycin/sulbactam (synergistic against 37/50 isolates; 74%), followed by meropenem/sulbactam (synergistic against 28/50 isolates; 56%). No antagonism was observed for any combination. Both fosfomycin/sulbactam and meropenem/sulbactam combinations exhibited bactericidal and synergistic activity against both isolates at the highest clinically achievable concentrations in the time-kill experiments. The meropenem/sulbactam combination displayed synergistic and bactericidal activity against one of two strains at concentrations equal to the FIC. Non-polymyxin-based combinations such as fosfomycin/sulbactam and meropenem/sulbactam may have a role in the treatment of CRAB. Further in vivo and clinical studies are required to scrutinise these activities further.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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