Zhang Yawei, Wang Xiaojuan, Wang Shifu, Sun Shijun, Li Henan, Chen Hongbin, Wang Qi, Wang Hui
Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China.
Department of Clinical Microbiology, Qilu Children's Hospital of Shandong University, Jinan, China.
Front Microbiol. 2021 Dec 1;12:756580. doi: 10.3389/fmicb.2021.756580. eCollection 2021.
Colistin and tigecycline are the last options against carbapenem-resistant hypervirulent (CR-hvKP). Intersecting resistance determinants have been detected between these antibiotics; however, there is only limited evidence of such association. Here, we describe a colistin-resistant CR-hvKP isolated from a patient with severe neonatal bacteremia treated with tigecycline as opposed to colistin before isolation of this strain, providing a clinical clue to colistin resistance under tigecycline pressure. Furthermore, an ST11-K64 KPC-2-producing, colistin-susceptible CR-hvKP strain was subjected to experimental evolution toward colistin resistance under tigecycline and colistin pressure to verify this phenomenon . The biological impact of acquiring colistin resistance on fitness and virulence was also studied. As expected, the parental strain rapidly developed colistin resistance under both tigecycline and colistin selection. However, different from the colistin resistance mechanism in the clinical strain that was due to an IS insertion in the gene, the mutants in this study developed colistin resistance through a ∼4.4 or ∼4.6 kb deletion including the locus as well as the , , , , , , and genes. Although the virulence of the colistin-resistant mutants, as determined in the model, decreased compared with that of the parent strain, it was still higher than that of NTUH-K2044. This suggests a slight virulence cost when CR-hvKP develops colistin resistance under tigecycline or colistin pressure. Together, our results provide clinical and experimental evidence for the association between colistin resistance and tigecycline pressure in CR-hvKP, highlighting a critical issue in the clinical setting.
黏菌素和替加环素是对抗碳青霉烯耐药高毒力肺炎克雷伯菌（CR-hvKP）的最后手段。已在这些抗生素之间检测到交叉耐药决定因素；然而，此类关联的证据有限。在此，我们描述了一株从患有严重新生儿菌血症的患者中分离出的耐黏菌素CR-hvKP，该患者在分离出此菌株之前接受了替加环素而非黏菌素治疗，这为替加环素压力下的黏菌素耐药提供了临床线索。此外，一株产生ST11-K64 KPC-2且对黏菌素敏感的CR-hvKP菌株在替加环素和黏菌素压力下进行实验性进化以验证这一现象。还研究了获得黏菌素耐药性对适应性和毒力的生物学影响。正如预期的那样，亲代菌株在替加环素和黏菌素选择下迅速产生了黏菌素耐药性。然而，与临床菌株中由于插入基因导致的黏菌素耐药机制不同，本研究中的突变体通过约4.4或约4.6 kb的缺失产生黏菌素耐药性，该缺失包括基因座以及、、、、、和基因。尽管在模型中测定的耐黏菌素突变体的毒力与亲代菌株相比有所降低，但仍高于NTUH-K2044。这表明当CR-hvKP在替加环素或黏菌素压力下产生黏菌素耐药性时，毒力会有轻微代价。总之，我们的结果为CR-hvKP中黏菌素耐药性与替加环素压力之间的关联提供了临床和实验证据，突出了临床环境中的一个关键问题。
