Resumo

Introdution: The combination therapy has shown more effective results compared to monotherapies against KPC-producing bacteria due to the unfavorable profile of sensitivity of these organisms. Polymyxins are usually the cornerstone agents used in combination with tigecycline (TGC) for treatment of these infections. Some studies have suggesting that carbapenems might be the drug of choice for combination, notably if isolates presents low-level resistance to these agents. The aim of this study was to evaluate the in vitro activity of polymyxin B (PMB) in combination with imipenem (IPM), meropenem (MEM), and TGC against three distinct species of KPC-2-producing Enterobacteriaceae isolates by the time-kill assay (TKA). Methods: Isolates comprised six KPC-2-producing clinical strains, including two Klebsiella pneumoniae, two Enterobacter cloacae, and two Serratia marcescens. TKA was performed by inoculating 5×106 colony-forming units (CFU)/mL of the organisms into 10mL of fresh cation-adjusted Mueller–Hinton broth. Carbapenems and TGC were tested at fixed concentration of 4 and 1 mg/L, respectively, and PMB was tested at concentrations of 0.5, 1 and 2 mg/L. Results: When tested as single drug, PMB presented the higher activity against the isolates, with a significant reduction in CFU counting inthe first hours of incubation for most of strains. Conversely, IPM, MEM and TGC did not present bacteriostatic or bactericidal effect when tested alone. The combinations of PMB with carbapenems presented bactericidal effect against E. cloacae and K. pneumoniae, whereas for S. marcescens only a bacteriostatic effect was observed with MEM in all concentrations of PMB, and with IPM when the highest concentration of PMB was used. Although combinations with carbapenems were superior, PMB plus TGC also showed a bactericidal effect among E. cloacae and K. pneumoniae, but none bactericidal or bacteriostatic effect was demonstrated against the two isolates of S. marcescens.On the other hand, synergism was detected for all strains studied, at least, when the higher concentration of PMB was used in combination schemes. Conclusion: Our results showed promising results when PMB was combined to carbapenems against E. cloacae and K. pneumoniae isolates. It was also demonstrated a potential benefic effect in combining these antibiotics against highly resistant KPC-2-producing S. marcescens isolates.