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首页> 外文期刊>MBio >Amplification of Aminoglycoside Resistance Gene aphA1 in Acinetobacter baumannii Results in Tobramycin Therapy Failure
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Amplification of Aminoglycoside Resistance Gene aphA1 in Acinetobacter baumannii Results in Tobramycin Therapy Failure

机译：鲍曼不动杆菌中氨基糖苷抗性基因aphA1的扩增导致妥布霉素治疗失败

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Gene amplification is believed to play an important role in antibiotic resistance but has been rarely documented in clinical settings because of its unstable nature. We report a rise in MICs from 0.5 to 16?μg/ml in successive Acinetobacter baumannii isolated over 4?days from a patient being treated with tobramycin for an infection by multidrug-resistant A. baumannii, resulting in therapeutic failure. Isolates were characterized by whole-genome sequencing, real-time and reverse transcriptase PCR, and growth assays to determine the mechanism of tobramycin resistance and its fitness cost. Tobramycin resistance was associated with two amplification events of different chromosomal fragments containing the aphA1 aminoglycoside resistance gene part of transposon Tn6020. The first amplification event involved low amplification (6 to 10 copies) of a large DNA fragment that was unstable and conferred tobramycin MICs of ≤8?μg/ml. The second event involved moderate (10 to 30 copies) or high (40 to 110 copies) amplification of Tn6020. High copy numbers were associated with tobramycin MICs of 16?μg/ml, impaired fitness, and genetic instability, whereas lower copy numbers resulted in tobramycin MICs of ≤8?μg/ml and no fitness cost and were stably maintained in vitro. Exposure in vitro to tobramycin of the initial susceptible isolate and of the A.?baumannii AB0057 reference strain led to similar aphA1 amplifications and elevated tobramycin MICs. To the best of our knowledge, this is the first report of in vivo development of antibiotic resistance secondary to gene amplifications resulting in therapy failure. >IMPORTANCE A combination of whole-genome sequencing and mapping were used to detect an antibiotic resistance mechanism, gene amplification, which has been presumed for a long time to be of major importance but has rarely been reported in clinical settings because of its unstable nature. Two gene amplification events in a patient with an Acinetobacter baumannii infection treated with tobramycin were identified. One gene amplification event led to high levels of resistance and was rapidly reversible, while the second event led to low and more stable resistance since it incurred low fitness cost on the host. Gene amplification, with an associated rise in tobramycin MICs, could be readily reproduced in vitro from initially susceptible strains exposed to increasing concentrations of tobramycin, suggesting that gene amplification in A.?baumannii may be a more common mechanism than currently believed. This report underscores the importance of rapid molecular techniques for surveillance of drug resistance.
机译：人们认为基因扩增在抗生素耐药性中起着重要作用，但由于其不稳定的性质，在临床上很少有记载。我们报告了在连续4天内从接受妥布霉素治疗的多耐药性 A感染患者中分离出的鲍曼不动杆菌的MICs从0.5上升至16μg/ ml。鲍曼氏菌，导致治疗失败。通过全基因组测序，实时和逆转录酶PCR以及生长测定来确定妥布霉素抗性的机制及其适应性成本，对分离株进行表征。妥布霉素抗性与转座子Tn 6020 中包含 aphA1 氨基糖苷抗性基因部分的不同染色体片段的两个扩增事件有关。第一个扩增事件涉及不稳定的大DNA片段的低扩增（6至10个拷贝），并赋予妥布霉素MIC≤8？μg/ ml。第二事件涉及Tn 6020 的中等（10至30拷贝）或高（40至110拷贝）扩增。高拷贝数与妥布霉素MICs为16？μg/ ml，适应性受损和遗传不稳定性有关，而较低拷贝数导致妥布霉素MICs≤8？μg/ ml，无适应性费用，并且在体外可稳定维持。初始易感分离株和鲍曼不动杆菌AB0057参考菌株的妥布霉素的体外暴露导致相似的 aphA1 扩增和妥布霉素MIC升高。据我们所知，这是继基因扩增后导致治疗失败的抗生素体内发展的首次报道。 >重要性：全基因组测序和作图相结合用于检测抗生素抗药性机制，基因扩增，这种作用长期以来一直被认为具有重要意义，但在临床环境中鲜有报道由于其不稳定的性质。在妥布霉素治疗的鲍曼不动杆菌感染患者中鉴定出两个基因扩增事件。一个基因扩增事件导致高水平的抗药性并且可以迅速逆转，而第二个基因扩增事件导致低而更稳定的抗药性，因为它导致宿主的适应性成本较低。基因扩增与妥布霉素MIC的相关升高可以很容易地从暴露于不断增加的妥布霉素浓度的最初易感菌株中体外复制，这表明 A.?baumannii 可能是比目前认为更普遍的机制。该报告强调了快速分子技术对耐药性监测的重要性。

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