title: Validation of the mutant selection window hypothesis with fosfomycin against Escherichia coli and Pseudomonas aeruginosa: an in vitro and in vivo comparative study.
abstract: The purpose of this study was to validate the mutant selection window (MSW) hypothesis in vitro and in vivo with Escherichia coli and Pseudomonas aeruginosa exposed to fosfomycin. Two standard strains of Gram-negative bacteria, those are E. coli ATCC 25922 and P. aeruginosa ATCC 27853, were exposed to fosfomycin at concentrations below MIC, between the MIC and the mutant prevention concentration (MPC), and above the MPC in Luria-Bertani broth and in a tissue-cage infection model, respectively. With the in vitro time-kill studies, there were bacterial re-growth and emergence of resistance thereafter for both strains at antibiotic concentrations of × 4, × 8 and × 16 MIC. In our animal model, the loss in susceptibility of P. aeruginosa at fosfomycin concentrations fluctuated between the lower and upper boundaries of the MSW. In contrast, the emergence of resistant mutants of E. coli was not observed in vivo, regardless of fosfomycin dosage. Interestingly, the in vitro-isolated resistant mutants of E. coli showed a decreased growth rate compared with the susceptible parental strains, whereas no fitness cost in P. aeruginosa was observed. The emergence of antibiotic resistance is shaped by several factors. MSW theory may not apply to all antimicrobial-pathogen combinations. Before it can be used as a framework for the design of antimicrobial therapy, the existence of the window must be demonstrated not only in vitro but also in vivo.
authors.affiliation: Department of Infectious Diseases, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.|Department of Critical Care Medicine, Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Ai-Jun
authors.initials: AJ
authors.lastname: Pan
authors.affiliation: Department of Critical Care Medicine, Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Mei
authors.affiliation: Department of Infectious Diseases, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.|Anhui Center for Surveillance of Bacterial Resistance, Hefei, Anhui, China.|Institute of Bacterium Resistance, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Class 2012, The Eight-year Program on Clinical Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
authors.forename: Hong-Ru
authors.initials: HR
authors.lastname: Li
authors.affiliation: Department of Critical Care Medicine, Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Bao
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Infectious Diseases, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.|Anhui Center for Surveillance of Bacterial Resistance, Hefei, Anhui, China.|Institute of Bacterium Resistance, Anhui Medical University, Hefei, Anhui, China.|Department of Infectious Diseases, Chaohu Hospital affiliated to Anhui Medical University, Chaohu, Anhui, China.
authors.forename: Jia-Bin
authors.initials: JB
authors.lastname: Li
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015194:Diffusion Chambers, Culture; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D004926:Escherichia coli / Q000235:genetics*; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D005260:Female; D005578:Fosfomycin / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010100:Oxygen; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000235:genetics*; D012641:Selection, Genetic; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D005578:Fosfomycin; D010100:Oxygen