Carbapenem-associated multidrug-resistant Acinetobacter baumannii are sensitised by aztreonam in combination with polyamines

Abstract

Carbapenem-associated multidrug-resistant Acinetobacter baumannii (MDR-Ab) are common among clinical isolates worldwide and are a major therapeutic challenge. Previously it was shown that exogenous polyamines (spermine and spermidine) enhanced susceptibility to β-lactams but induced resistance to polymyxins in Pseudomonas aeruginosa. This study aimed to explore the possible availability of exogenous polyamines in treating carbapenem-associated MDR-Ab. The effects of polyamines on the growth rate of A. baumannii, minimum inhibitory concentrations (MICs) of antibiotics, and time–kill and chequerboard assays were determined. Roles of lipopolysaccharide (LPS) and β-lactamase activity of A. baumannii were also assessed for the polyamine effects. Growth of A. baumannii was unaffected at 4mM spermine and 16mM spermidine alone, but was significantly inhibited by a subinhibitory concentration of aztreonam (AZT) (8μg/mL) and those concentrations of the polyamines. MICs to AZT alone (≥128μg/mL) were reduced to the range 0.25–8μg/mL in combination with polyamines in all carbapenem-associated MDR-Ab. MICs to penicillins, but not to ceftazidime and meropenem, were also significantly reduced, whilst MICs to other antibiotics, including polymyxin B, were unaffected in combination with polyamines for all tested A. baumannii. Polyamine effects on AZT were strongly synergistic with bactericidal activity and were retained at concentrations of 5mM MgCl2 (or CaCl2) or 200mM NaCl. Roles of LPS and β-lactamase in the polyamine effects were excluded. Overall results suggest that AZT in combination with polyamines may be useful for the treatment of carbapenem-associated MDR-Ab.