In vitro activity of polymyxin B in combination with various antibiotics against extensively drug-resistant Enterobacter cloacae with decreased susceptibility to polymyxin B

Yiying Cai, Tze Peng Lim, Jocelyn Teo, Suranthran Sasikala, Winnie Lee, Yanjun HONG, Eric Chun Yong Chan, Thean Yen Tan, Thuan Tong Tan, Tse Hsien Koh, Li Yang Hsu, Andrea L. Kwa*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Against extensively drug-resistant (XDR) Enterobacter cloacae, combination antibiotic therapy may be the only option. We investigated the activity of various antibiotics in combination with polymyxin B using time-kill studies (TKS). TKS were conducted with four nonclonal XDR E. cloacae isolates with 5 log10 CFU/ml bacteria against maximum, clinically achievable concentrations of polymyxin B alone and in two-drug combinations with 10 different antibiotics. A hollow-fiber infection model (HFIM) simulating clinically relevant polymyxin B and tigecycline dosing regimens was conducted for two isolates over 240 h. Emergence of resistance was quantified using antibiotic-containing (3× MIC) media. Biofitness and stability of resistant phenotypes were determined. All XDR E. cloacae isolates were resistant to all antibiotics except for polymyxin B (polymyxin B MIC, 1 to 4 mg/liter). All isolates harbored metallo-β-lactamases (two with NDM-1, two with IMP-1). In single TKS, all antibiotics alone demonstrated regrowth at 24 h, except amikacin against two strains and polymyxin B and meropenem against one strain each. In combination TKS, only polymyxin B plus tigecycline was bactericidal against all four XDR E. cloacae isolates at 24 h. In HFIM, tigecycline and polymyxin B alone did not exhibit any killing activity. Bactericidal kill was observed at 24 h for both isolates for polymyxin B plus tigecycline; killing was sustained for one isolate but regrowth was observed for the second. Phenotypically stable resistant mutants with reduced in vitro growth rates were observed. Polymyxin B plus tigecycline is a promising combination against XDR E. cloacae. However, prolonged and indiscriminate use can result in resistance emergence.

Original languageEnglish
Pages (from-to)5238-5246
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number9
DOIs
Publication statusPublished - 1 Sep 2016

Scopus Subject Areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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