Yu-Feng Zhou1,2, Meng-Ting Tao1,2, Youjun Feng1,3, Run-Shi Yang1,2, Xiao-Ping Liao1,2, Ya-Hong Liu1,2, Jian Sun1,2. 1. National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou 510642, China. 2. Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China. 3. Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Abstract
Objectives: 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. Methods: 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). Results: 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. Conclusions: 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.
Objectives: 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. Methods: 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). Results: 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. Conclusions: 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.
Authors: Lynette M Phee; Frank Kloprogge; Rebecca Morris; John Barrett; David W Wareham; Joseph F Standing Journal: J Antimicrob Chemother Date: 2019-04-01 Impact factor: 5.790
Authors: Craig R MacNair; Jonathan M Stokes; Lindsey A Carfrae; Aline A Fiebig-Comyn; Brian K Coombes; Michael R Mulvey; Eric D Brown Journal: Nat Commun Date: 2018-01-31 Impact factor: 14.919