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

Abstract BACKGROUND & OBJECTIVE Due to limited therapeutic options, combination therapy has been used empirically to treat carbapenem-resistant Acinetobacter baumannii. Polymyxin-based combinations have been widely studied and used in the clinical setting. However, the use of polymyxins is often limited due to nephro- 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 carbapenem-resistant A. baumannii. METHODS In vitro activity of 14 two-drug combinations against 50 A. baumannii isolates were evaluated using the checkerboard method. Subsequently, 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. RESULTS 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 all combinations. 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 out of two strains at concentrations equal to the FIC. CONCLUSIONS Non-polymyxin based combinations such as fosfomycin-sulbactam and meropenem-sulbactam may have a role in the treatment of carbapenem-resistant A. baumannii. Further in vivo and clinical studies are required to scrutinize these activities further.