Increased activity of colistin in combination with amikacin against Escherichia coli co-producing NDM-5 and MCR-1.
Colistin and carbapenem are two lines of last-resort antibiotics against lethal infections caused by MDR Gram-negative pathogens. The emergence of carbapenemase-positive Escherichia coli with colistin resistance poses a serious threat to public health worldwide. Here we report, for the first time (to the best of our knowledge), a novel combination therapy used for the treatment of E. coli co-producing MCR-1 and NDM-5.



The MICs of colistin were determined alone and with 1-4 mg/L amikacin. A 7-by-4 time-kill array of colistin (0, 0.5, 1, 2, 4, 8 and 16 mg/L) and amikacin (0, 1, 2 and 4 mg/L) over 48 h was designed to characterize the in vitro activity of these agents alone and in combination against each E. coli isolate at an inoculum of 10 6 and 10 8 cfu/mL. The sigmoid E max model was utilized for better delineation of the concentration-effect relationship of each combination. In vivo effectiveness was investigated using a mouse model (combination therapy with intraperitoneal colistin plus amikacin compared with monotherapy).



For colistin-resistant isolates, the addition of amikacin demonstrated augmented susceptibility, reducing colistin MICs below the current susceptibility breakpoint. A concentration-dependent decrease in the EC 50 values of colistin was observed for all study isolates in the presence of increasing amikacin concentrations. Further in vivo treatment experiments demonstrated that this combination could achieve 1.5-2.8 log 10 killing after 24 h of therapy, while monotherapy was unable to achieve such a killing effect.



The combination of colistin and amikacin may be a promising therapeutic option for the treatment of lethal infections caused by NDM-5-bearing MCR-1-positive superbugs.
National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou 510642, China.|Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
Yu-Feng
YF
Zhou
National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou 510642, China.|Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
Meng-Ting
MT
Tao
National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou 510642, China.|Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Youjun
Y
Feng
National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou 510642, China.|Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
Run-Shi
RS
Yang
National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou 510642, China.|Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
Xiao-Ping
XP
Liao
National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou 510642, China.|Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
Ya-Hong
YH
Liu
National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou 510642, China.|Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
Jian
J
Sun
D000583:Amikacin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D003091:Colistin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D029968:Escherichia coli Proteins / Q000096:biosynthesis*; D051379:Mice; D008826:Microbial Sensitivity Tests; D001618:beta-Lactamases / Q000096:biosynthesis*
D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; C000614037:MCR-1 protein, E coli; D000583:Amikacin; C000615639:beta lactamase NDM-5, E coli; D001618:beta-Lactamases; D003091:Colistin