In Vitro Activity of Polymyxin B in Combination with Various Antibiotics against Extensively Drug-Resistant Enterobacter cloacae with Decreased Susceptibility to Polymyxin B.
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.
Singapore General Hospital, Department of Pharmacy, Singapore National University of Singapore, Department of Pharmacy, Singapore.
Yiying
Y
Cai
Singapore General Hospital, Department of Pharmacy, Singapore Duke-NUS Medical School, Office of Clinical Sciences, Singapore, Singapore.
Tze-Peng
TP
Lim
Singapore General Hospital, Department of Pharmacy, Singapore.
Jocelyn
0000-0003-2508-3941
J
Teo
Singapore General Hospital, Department of Pharmacy, Singapore.
Suranthran
S
Sasikala
Singapore General Hospital, Department of Pharmacy, Singapore.
Winnie
W
Lee
National University of Singapore, Department of Pharmacy, Singapore.
Yanjun
Y
Hong
National University of Singapore, Department of Pharmacy, Singapore.
Eric Chun Yong
EC
Chan
Changi General Hospital, Department of Laboratory Medicine, Singapore.
Thean Yen
TY
Tan
Singapore General Hospital, Department of Infectious Diseases, Singapore.
Thuan-Tong
TT
Tan
Singapore General Hospital, Department of Pathology, Singapore.
Tse Hsien
TH
Koh
National University of Singapore, Yong Loo Lin School of Medicine, Department of Medicine, Singapore.
Li Yang
LY
Hsu
Singapore General Hospital, Department of Pharmacy, Singapore National University of Singapore, Department of Pharmacy, Singapore Duke-NUS Medical School, Emerging Infectious Diseases, Singapore andrea.kwa.l.h@sgh.com.sg.
Andrea L
AL
Kwa
D000583:Amikacin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004338:Drug Combinations; D054796:Drug Dosage Calculations; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D004357:Drug Synergism; D016972:Enterobacter cloacae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification; D015870:Gene Expression; D006801:Humans; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000494:pharmacology; D015233:Models, Statistical; D011112:Polymyxin B / Q000494:pharmacology*; D013845:Thienamycins / Q000494:pharmacology; D000078304:Tigecycline; D001618:beta-Lactamases / Q000235:genetics*
D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D013845:Thienamycins; D000078304:Tigecycline; D000583:Amikacin; D001618:beta-Lactamases; D000077731:Meropenem; D008911:Minocycline; D011112:Polymyxin B