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      Tigecycline Nonsusceptibility Occurs Exclusively in Fluoroquinolone-Resistant Escherichia coli Clinical Isolates, Including the Major Multidrug-Resistant Lineages O25b:H4-ST131-H 30R and O1-ST648


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          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 MIC 50 and MIC 90 for TGC in fluoroquinolone-resistant isolates were 2-fold higher than those in fluoroquinolone-susceptible isolates (MIC 50, 0.5 mg/liter versus 0.25 mg/liter; MIC 90, 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.

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          Author and article information

          Antimicrob Agents Chemother
          Antimicrob. Agents Chemother
          Antimicrobial Agents and Chemotherapy
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          14 November 2016
          24 January 2017
          February 2017
          : 61
          : 2
          : e01654-16
          [a ]Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan
          [b ]Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
          [c ]Division of Laboratory Medicine, Sapporo Medical University Hospital, Sapporo, Japan
          [d ]Department of Infection Control and Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
          [e ]Laboratory of Food Microbiology and Food Safety, Department of Health and Environmental Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan
          Author notes
          Address correspondence to Toyotaka Sato, sato.t@ 123456sapmed.ac.jp .

          Citation Sato T, Suzuki Y, Shiraishi T, Honda H, Shinagawa M, Yamamoto S, Ogasawara N, Takahashi H, Takahashi S, Tamura Y, Yokota S. 2017. Tigecycline nonsusceptibility occurs exclusively in fluoroquinolone-resistant Escherichia coli clinical isolates, including the major multidrug-resistant lineages O25b:H4-ST131-H 30R and O1-ST648. Antimicrob Agents Chemother 61:e01654-16. https://doi.org/10.1128/AAC.01654-16.

          PMC5278711 PMC5278711 5278711 01654-16
          Copyright © 2017 American Society for Microbiology.

          All Rights Reserved.

          : 29 July 2016
          : 21 September 2016
          : 8 November 2016
          Page count
          Figures: 3, Tables: 5, Equations: 0, References: 53, Pages: 14, Words: 8290
          Funded by: JSPS KAKENHI
          Award ID: 15H06521
          Award Recipient : Toyotaka Sato
          Funded by: JSPS KAKENHI
          Award ID: 25861574
          Award Recipient : Noriko Ogasawara
          Funded by: Yuasa Memorial Foundation
          Award Recipient : Toyotaka Sato
          Mechanisms of Resistance
          Custom metadata
          February 2017

          bacterial infection,antimicrobial resistance,efflux pump


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