多黏菌素 B 异质性耐药碳青霉烯类耐药肺炎克雷伯菌的临床相关性、机制和进化：一项基于基因组的回顾性队列研究。
Clinical relevance, mechanisms, and evolution of polymyxin B heteroresistance carbapenem-resistant Klebsiella pneumoniae: A genomic, retrospective cohort study.
机构信息
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Central Laboratory, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
出版信息
Clin Microbiol Infect. 2024 Apr;30(4):507-514. doi: 10.1016/j.cmi.2024.01.014. Epub 2024 Feb 1.
OBJECTIVES
To study the clinical relevance, mechanisms, and evolution of polymyxin B (POLB) heteroresistance (PHR) in carbapenem-resistant Klebsiella pneumoniae (CRKP), potentially leading to a significant rise in POLB full resistant (FR) CRKP.
METHODS
Total of 544 CRKP isolates from 154 patients treated with POLB were categorized into PHR and POLB non-heteroresistance (NHR) groups. We performed statistical analysis to compare clinical implications and treatment responses. We employed whole-genome sequencing, bioinformatics, and PCR to study the molecular epidemiology, mechanisms behind PHR, and its evolution into FR.
RESULTS
We observed a considerable proportion (118 of 154, 76.62%) of clinically undetected PHR strains before POLB exposure, with a significant subset of them (33 of 118, 27.97%) evolving into FR after POLB treatment. We investigated the clinical implications, epidemiological characteristics, mechanisms, and evolutionary patterns of PHR strains in the context of POLB treatment. About 92.86% (39 of 42) of patients had PHR isolates before FR, highlighting the clinical importance of PHR. the ST15 exhibited a notably lower PHR rate (1 of 8, 12.5% vs. 117 of 144, 81.25%; p < 0.01). The ST11 PHR strains showing significantly higher rate of mgrB mutations by endogenous insertion sequences in their resistant subpopulation (RS) compared with other STs (78 of 106, 73.58% vs. 4 of 12, 33.33%; p < 0.01). The mgrB insertional inactivation rate was lower in FR isolates than in the RS of PHR isolates (15 of 42, 35.71% vs. 84 of 112, 75%; p < 0.01), whereas the pmrAB mutation rate was higher in FR isolates than in the RS of PHR isolates (8 of 42, 19.05% vs. 2 of 112, 1.79%; p < 0.01). The evolution from PHR to FR was influenced by subpopulation dynamics and genetic adaptability because of hypermutability.
DISCUSSION
We highlight significant genetic changes as the primary driver of PHR to FR in CRKP, underscoring polymyxin complexity.
目的
研究多黏菌素 B（POLB）异质性耐药（PHR）在耐碳青霉烯类肺炎克雷伯菌（CRKP）中的临床相关性、机制和演变，这可能导致 POLB 完全耐药（FR）CRKP 的显著增加。
方法
将 154 名接受 POLB 治疗的患者的 544 株 CRKP 分离株分为 PHR 和 POLB 非异质性耐药（NHR）组。我们进行了统计分析，以比较临床意义和治疗反应。我们采用全基因组测序、生物信息学和 PCR 研究了分子流行病学、PHR 背后的机制及其向 FR 的演变。
结果
我们发现，在 POLB 暴露前，有相当一部分（154 例中的 118 例，76.62%）临床未检测到 PHR 菌株，其中一个显著子集（118 例中的 33 例，27.97%）在 POLB 治疗后演变为 FR。我们研究了 PHR 菌株在 POLB 治疗背景下的临床意义、流行病学特征、机制和进化模式。大约 92.86%（42 例中的 39 例）的患者在 FR 之前有 PHR 分离株，这突出了 PHR 的临床重要性。ST15 表现出明显较低的 PHR 率（8 例中的 1 例，12.5%，而 144 例中的 117 例，81.25%；p<0.01）。与其他 ST 相比，ST11 的 PHR 菌株在其耐药亚群（RS）中 mgrB 突变的内源性插入序列显著更高（78/106，73.58%，而 4/12，33.33%；p<0.01）。FR 分离株中 mgrB 插入失活率低于 PHR 分离株的 RS（42 例中的 15 例，35.71%，而 112 例中的 84 例，75%；p<0.01），而 FR 分离株中 pmrAB 突变率高于 PHR 分离株的 RS（42 例中的 8 例，19.05%，而 112 例中的 2 例，1.79%；p<0.01）。从 PHR 到 FR 的进化受到亚群动力学和遗传适应性的影响，因为它们具有高突变性。
讨论
我们强调了遗传变化是 CRKP 中 PHR 向 FR 的主要驱动因素，突出了多黏菌素的复杂性。
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