Activities of Vancomycin-Containing Regimens against Colistin-Resistant Acinetobacter baumannii Clinical Strains

Abstract

Treatment of infections due to extensively drug-resistant (XDR) Acinetobacter baumannii often involves the use of antimicrobial agents in combination. Various combinations of agents have been proposed, with colistin serving as the backbone in many of them. Recent data suggest that glycopeptides, in particular vancomycin, may have unique activity against laboratory-adapted and clinical strains of A. baumannii, alone and in combination with colistin. The aim of the present study was to test this approach against three unique colistin-resistant A. baumannii clinical strains using combinations of vancomycin (VAN), colistin (COL), and doripenem (DOR). All three strains possessed the signature phosphoethanolamine modification of the lipid A moiety associated with colistin resistance and unique amino acid changes in the PmrAB two-component signal transduction system not observed in colistin-susceptible strains. In checkerboard assays, synergy (defined as a fractional inhibitory concentration index [FICI] of ≤ 0.5) was observed between COL and VAN for all three strains tested and between COL and DOR in two strains. In time-kill assays, the combinations of COL-DOR, COL-VAN, and COL-DOR-VAN resulted in complete killing of colistin-resistant A. baumannii in 1, 2, and all 3 strains, respectively. In the Galleria mellonella moth model of infection, the combinations of DOR-VAN and COL-DOR-VAN led to significantly increased survival of the larvae, compared with other combinations and monotherapy. These findings suggest that regimens containing vancomycin may confer therapeutic benefit for infection due to colistin-resistant A. baumannii.