Tigecycline Nonsusceptibility Occurs Exclusively in Fluoroquinolone-Resistant Escherichia coli Clinical Isolates, Including the Major Multidrug-Resistant Lineages O25b:H4-ST131-H30R and O1-ST648
Tigecycline Nonsusceptibility Occurs Exclusively in Fluoroquinolone-Resistant Escherichia coli Clinical Isolates, Including the Major Multidrug-Resistant Lineages O25b:H4-ST131-H30R and O1-ST648
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DOI：
10.1128/aac.01654-16
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发表时间：
2016-11
影响因子：
4.9
通讯作者：
Toyotaka Sato;Yuuki Suzuki;T. Shiraishi;H. Honda;M. Shinagawa;Soh Yamamoto;Noriko Ogasawara;Hiroki Takahashi;S. Takahashi;Y. Tamura;S. Yokota
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文献类型：
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作者：
Toyotaka Sato;Yuuki Suzuki;T. Shiraishi;H. Honda;M. Shinagawa;Soh Yamamoto;Noriko Ogasawara;Hiroki Takahashi;S. Takahashi;Y. Tamura;S. Yokota
替加环素（TGC）是治疗多重耐药肠杆菌科细菌的一线药物。我们研究了大肠埃希菌临床分离株中TGC不敏感（TGC耐药/中间）的机制。测定了277株氟喹诺酮类药物敏感分离株的TGC MIC（环丙沙星[CIP] MIC，2 mg/L）。氟喹诺酮类耐药分离株对TGC的MIC 50和MIC 90是氟喹诺酮类敏感分离株的2倍（MIC 50，0.5 mg/L vs 0.25 mg/L; MIC 90，1 mg/L vs 0.5 mg/L）。两个氟喹诺酮耐药分离株（O25 b：H4-ST 131-H30 R和O 125：H37-ST 48）对TGC耐药（MIC分别为4和16 mg/L），另外四个O25 b：H4-ST 131-H30 R分离株和一个O 1-ST 648分离株显示出中等解释（MIC，2 mg/L）。氟喹诺酮类药物敏感株中未发现耐药/中间型菌株。与敏感分离株相比，TG耐药/中间分离株表达更高水平的acrA和acrB，细胞内TGC浓度更低，并且它们具有acrR和/或马尔R突变。acrAB缺陷型突变体的MIC显著低于亲本菌株的MIC（0.25 mg/L）。在体外连续逐步暴露于CIP后，8株TGC敏感菌株中有6株TGC敏感性降低。其中2例获得TGC抗性（TGC MIC，4 mg/L），并表现出acrA和acrB的表达以及acrR和/或马尔R的突变。总之，氟喹诺酮类耐药大肠埃希菌群体。大肠杆菌分离株，包括主要的肠外致病谱系O25 b：H4-ST 131-H30 R和O 1-ST 648，由于外排泵AcrAB-TolC的过表达，显示出对TGC的敏感性降低，导致细胞内抗生素浓度降低，这可能与氟喹诺酮耐药性的发展有关。
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, 2 mg/liter). The MIC50 and MIC90 for 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.