title: Evaluating Polymyxin B-Based Combinations against Carbapenem-Resistant Escherichia coli in Time-Kill Studies and in a Hollow-Fiber Infection Model.
abstract: Polymyxin B-based combinations have emerged as a mainstay treatment against carbapenem-resistant Escherichia coli (CREC). We investigated the activity of polymyxin B-based two-antibiotic combinations against CREC using time-kill studies (TKS) and validated the findings in a hollow-fiber infection model (HFIM). TKS were conducted using 5 clinical CREC strains at 5 log10CFU/ml against 10 polymyxin B-based two-antibiotic combinations at maximum clinically achievable concentrations. HFIMs simulating dosing regimens with polymyxin B (30,000U/kg/day) and tigecycline (100 mg every 12 h) alone and in combination were conducted against two CREC strains at 5 log10CFU/ml over 120 h. Emergence of resistance was quantified using antibiotic-containing media. Phenotypic characterization (growth rate and stability of resistant phenotypes) of the resistant isolates was performed. All five CREC strains harbored carbapenemases. Polymyxin B and tigecycline MICs ranged from 0.5 mg/liter to 2 mg/liter and from 0.25 mg/liter to 8 mg/liter, respectively. All antibiotics alone did not have bactericidal activity at 24 h in the TKS, except for polymyxin B against two strains. In combination TKS, only polymyxin B plus tigecycline demonstrated both bactericidal activity and synergy in two out of five strains. In the HFIM, polymyxin B alone was bactericidal against both CREC strains before regrowth was observed at 8 h. Phenotypically stable polymyxin B-resistant mutants were observed for both strains, with a reduced growth rate observed in one strain. Tigecycline alone resulted in a slow reduction in bacterial counts. Polymyxin B plus tigecycline resulted in rapid and sustained bactericidal killing up to 120 h. Polymyxin B plus tigecycline is a promising combination against CREC. The clinical relevance of our results warrants further investigations.
authors: Department of Pharmacy, Singapore General Hospital, Singapore.|Department of Pharmacy, National University of Singapore, Singapore.
authors: Yiying
authors: Y
authors: Cai
authors: Department of Pharmacy, Singapore General Hospital, Singapore.|Duke-NUS Medical School, Office of Clinical Sciences, Singapore.
authors: Tze-Peng
authors: TP
authors: Lim
authors: Department of Pharmacy, Singapore General Hospital, Singapore.
authors: Jocelyn Qi-Min
authors: 0000-0003-2508-3941
authors: JQ
authors: Teo
authors: Department of Pharmacy, Singapore General Hospital, Singapore.
authors: Suranthran
authors: S
authors: Sasikala
authors: Department of Pharmacy, National University of Singapore, Singapore.
authors: Eric Chun Yong
authors: EC
authors: Chan
authors: Department of Pharmacy, National University of Singapore, Singapore.
authors: Yan Jun
authors: YJ
authors: Hong
authors: Department of Pharmacy, Singapore General Hospital, Singapore.
authors: Winnie
authors: W
authors: Lee
authors: Department of Laboratory Medicine, Changi General Hospital, Singapore.
authors: Thean Yen
authors: TY
authors: Tan
authors: Department of Infectious Diseases, Singapore General Hospital, Singapore.
authors: Thuan Tong
authors: TT
authors: Tan
authors: Department of Pathology, Singapore General Hospital, Singapore.
authors: Tse Hsien
authors: TH
authors: Koh
authors: Division of Infectious Diseases, National University Health System, Singapore.
authors: Li Yang
authors: LY
authors: Hsu
authors: Department of Pharmacy, Singapore General Hospital, Singapore andrea.kwa.l.h@sgh.com.sg.|Department of Pharmacy, National University of Singapore, Singapore.|Duke-NUS Medical School, Emerging Infectious Diseases, Singapore.
authors: Andrea L
authors: AL
authors: Kwa
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives / Q000494:pharmacology; D011112:Polymyxin B / Q000494:pharmacology*; D000078304:Tigecycline
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000078304:Tigecycline; D008911:Minocycline; D011112:Polymyxin B
keywords: antibiotic combination testing; carbapenem-resistant Enterobacteriaceae; hollow-fiber infection model; polymyxin B