title: Tigecycline Nonsusceptibility Occurs Exclusively in Fluoroquinolone-Resistant Escherichia coli Clinical Isolates, Including the Major Multidrug-Resistant Lineages O25b:H4-ST131-H30R and O1-ST648.
abstract: Tigecycline (TGC) is a last-line drug for multidrug-resistant Enterobacteriaceae We investigated the mechanism(s) underlying TGC nonsusceptibility (TGC resistant/intermediate) in Escherichia coli clinical isolates. The MIC of TGC was determined for 277 fluoroquinolone-susceptible isolates (ciprofloxacin [CIP] MIC, <0.125 mg/liter) and 194 fluoroquinolone-resistant isolates (CIP MIC, >2 mg/liter). The MIC50and MIC90for TGC in fluoroquinolone-resistant isolates were 2-fold higher than those in fluoroquinolone-susceptible isolates (MIC50, 0.5 mg/liter versus 0.25 mg/liter; MIC90, 1 mg/liter versus 0.5 mg/liter, respectively). Two fluoroquinolone-resistant isolates (O25b:H4-ST131-H30R and O125:H37-ST48) were TGC resistant (MICs of 4 and 16 mg/liter, respectively), and four other isolates of O25b:H4-ST131-H30R and an isolate of O1-ST648 showed an intermediate interpretation (MIC, 2 mg/liter). No TGC-resistant/intermediate strains were found among the fluoroquinolone-susceptible isolates. The TGC-resistant/intermediate isolates expressed higher levels of acrA and acrB and had lower intracellular TGC concentrations than susceptible isolates, and they possessed mutations in acrR and/or marR The MICs of acrAB-deficient mutants were markedly lower (0.25 mg/liter) than those of the parental strain. After continuous stepwise exposure to CIP in vitro, six of eight TGC-susceptible isolates had reduced TGC susceptibility. Two of them acquired TGC resistance (TGC MIC, 4 mg/liter) and exhibited expression of acrA and acrB and mutations in acrR and/or marR In conclusion, a population of fluoroquinolone-resistant E. coli isolates, including major extraintestinal pathogenic lineages O25b:H4-ST131-H30R and O1-ST648, showed reduced susceptibility to TGC due to overexpression of the efflux pump AcrAB-TolC, leading to decreased intracellular concentrations of the antibiotics that may be associated with the development of fluoroquinolone resistance.
authors.affiliation: Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan sato.t@sapmed.ac.jp.
authors.forename: Toyotaka
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Shiraishi
authors.affiliation: Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Honda
authors.affiliation: Division of Laboratory Medicine, Sapporo Medical University Hospital, Sapporo, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shinagawa
authors.affiliation: Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Soh
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ogasawara
authors.affiliation: Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Division of Laboratory Medicine, Sapporo Medical University Hospital, Sapporo, Japan.|Department of Infection Control and Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Laboratory of Food Microbiology and Food Safety, Department of Health and Environmental Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Yokota
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D029968:Escherichia coli Proteins / Q000235:genetics; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006801:Humans; D007564:Japan; D008074:Lipoproteins / Q000235:genetics; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008911:Minocycline / Q000031:analogs & derivatives* / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009154:Mutation; D000078304:Tigecycline
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D029968:Escherichia coli Proteins; D024841:Fluoroquinolones; D008074:Lipoproteins; D026901:Membrane Transport Proteins; D008911:Minocycline; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000078304:Tigecycline; C083497:AcrA protein, E coli; C083496:AcrB protein, E coli; C073126:tolC protein, E coli
keywords: antimicrobial resistance; bacterial infection; efflux pump