{"title":"铜绿假单胞菌在头孢唑肟/阿维巴坦治疗后对新型β-内酰胺/β-内酰胺酶抑制剂组合产生交叉耐药性的体内分化进化。","authors":"Heng Cai, Minhua Chen, Yue Li, Nanfei Wang, Hanming Ni, Piaopiao Zhang, Xiaoting Hua, Yunsong Yu","doi":"10.1007/s15010-024-02432-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>To describe and characterize the evolutionary process of cross-resistance to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam of a carbapenem-resistant Pseudomonas aeruginosa (CRPA) lineage isolated from a patient receiving two courses of ceftazidime/avibactam treatment.</p><p><strong>Methods: </strong>The minimum inhibitory concentrations (MICs) of strains were determined by broth microdilution methods. The mutant genes were identified by the whole genome sequencing results. Cloning, knockout and complementation experiments were used to evaluate the impact of the resistance relative genes on the MICs. Reverse transcription-quantitative PCR was used to evaluate the relative expression of ampC and mexA. The fitness cost was measured by growth curve tests.</p><p><strong>Results: </strong>A total of 24 CRPA strains were isolated encompassing the whole ceftazidime/avibactam treatment. The CRPA strains developed high-level resistance to ceftazidime/avibactam and cross-resistance to ceftolozane/tazobactam or imipenem/relebactam, clustering into clade A and clade B, respectively. In both clades, the overexpression of AmpC was crucial to ceftazidime/avibactam resistance, which was driven by AmpD deficiency in clade A and dacB mutation in clade B, respectively. In clade A, mraY mutation and a new allele of AmpC (bla<sub>PDC-575</sub>) elevated resistance to ceftazidime/avibactam, with bla<sub>PDC-575</sub> also conferring resistance to ceftolozane/tazobactam. In clade B, mexB mutation was associated with the resistance to both ceftazidime/avibactam and imipenem/relebactam. Moreover, the fitness costs of P. aeruginosa strains typically increased with the higher MICs of ceftazidime/avibactam.</p><p><strong>Conclusion: </strong>Divergent resistance evolution resulted in a complex phenotype in the CRPA lineage, posing significant challenge to clinical treatment. The resistance surveillance needs to be prioritized, and new therapeutic strategies are urgently required.</p>","PeriodicalId":13600,"journal":{"name":"Infection","volume":null,"pages":null},"PeriodicalIF":5.4000,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"In vivo divergent evolution of cross-resistance to new β-lactam/β-lactamase inhibitor combinations in Pseudomonas aeruginosa following ceftazidime/avibactam treatment.\",\"authors\":\"Heng Cai, Minhua Chen, Yue Li, Nanfei Wang, Hanming Ni, Piaopiao Zhang, Xiaoting Hua, Yunsong Yu\",\"doi\":\"10.1007/s15010-024-02432-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>To describe and characterize the evolutionary process of cross-resistance to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam of a carbapenem-resistant Pseudomonas aeruginosa (CRPA) lineage isolated from a patient receiving two courses of ceftazidime/avibactam treatment.</p><p><strong>Methods: </strong>The minimum inhibitory concentrations (MICs) of strains were determined by broth microdilution methods. The mutant genes were identified by the whole genome sequencing results. Cloning, knockout and complementation experiments were used to evaluate the impact of the resistance relative genes on the MICs. Reverse transcription-quantitative PCR was used to evaluate the relative expression of ampC and mexA. The fitness cost was measured by growth curve tests.</p><p><strong>Results: </strong>A total of 24 CRPA strains were isolated encompassing the whole ceftazidime/avibactam treatment. The CRPA strains developed high-level resistance to ceftazidime/avibactam and cross-resistance to ceftolozane/tazobactam or imipenem/relebactam, clustering into clade A and clade B, respectively. In both clades, the overexpression of AmpC was crucial to ceftazidime/avibactam resistance, which was driven by AmpD deficiency in clade A and dacB mutation in clade B, respectively. In clade A, mraY mutation and a new allele of AmpC (bla<sub>PDC-575</sub>) elevated resistance to ceftazidime/avibactam, with bla<sub>PDC-575</sub> also conferring resistance to ceftolozane/tazobactam. In clade B, mexB mutation was associated with the resistance to both ceftazidime/avibactam and imipenem/relebactam. Moreover, the fitness costs of P. aeruginosa strains typically increased with the higher MICs of ceftazidime/avibactam.</p><p><strong>Conclusion: </strong>Divergent resistance evolution resulted in a complex phenotype in the CRPA lineage, posing significant challenge to clinical treatment. The resistance surveillance needs to be prioritized, and new therapeutic strategies are urgently required.</p>\",\"PeriodicalId\":13600,\"journal\":{\"name\":\"Infection\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2024-11-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Infection\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s15010-024-02432-5\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"INFECTIOUS DISEASES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Infection","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s15010-024-02432-5","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}
引用次数: 0
摘要
目的：描述并描述从一名接受两个疗程头孢他啶/阿维巴坦治疗的患者体内分离出的耐碳青霉烯类铜绿假单胞菌（CRPA）菌株对头孢他啶/阿维巴坦、头孢羟氨苄/他唑巴坦和亚胺培南/雷巴坦交叉耐药性的演变过程：方法：采用肉汤微稀释法测定菌株的最低抑菌浓度（MIC）。根据全基因组测序结果确定突变基因。利用克隆、基因敲除和互补实验来评估抗性相对基因对 MICs 的影响。反转录定量 PCR 被用来评估 ampC 和 mexA 的相对表达。通过生长曲线测试测量了适应性成本：结果：在整个头孢他啶/阿维巴坦治疗过程中，共分离出 24 株 CRPA 菌株。CRPA菌株对头孢他啶/阿维菌素产生了高度耐药性，并对头孢妥赞/他唑巴坦或亚胺培南/雷巴坦产生了交叉耐药性，分别聚类为A支系和B支系。在这两个支系中，AmpC 的过表达对头孢他啶/阿维巴坦的耐药性至关重要，这分别是由支系 A 中的 AmpD 缺乏和支系 B 中的 dacB 突变所驱动的。在支系 A 中，mraY 突变和新的 AmpC 等位基因（blaPDC-575）增强了对头孢他啶/阿维巴坦的耐药性，blaPDC-575 还赋予了对头孢洛赞/他唑巴坦的耐药性。在支系 B 中，mexB 突变与对头孢他啶/阿维巴坦和亚胺培南/雷巴坦的耐药性有关。此外，随着头孢唑肟/阿维巴坦的 MICs 越高，铜绿假单胞菌菌株的健康成本通常也会增加：结论：不同的耐药性进化导致了 CRPA 菌株复杂的表型，给临床治疗带来了巨大挑战。耐药性监测需要优先进行，并迫切需要新的治疗策略。
In vivo divergent evolution of cross-resistance to new β-lactam/β-lactamase inhibitor combinations in Pseudomonas aeruginosa following ceftazidime/avibactam treatment.
Purpose: To describe and characterize the evolutionary process of cross-resistance to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam of a carbapenem-resistant Pseudomonas aeruginosa (CRPA) lineage isolated from a patient receiving two courses of ceftazidime/avibactam treatment.
Methods: The minimum inhibitory concentrations (MICs) of strains were determined by broth microdilution methods. The mutant genes were identified by the whole genome sequencing results. Cloning, knockout and complementation experiments were used to evaluate the impact of the resistance relative genes on the MICs. Reverse transcription-quantitative PCR was used to evaluate the relative expression of ampC and mexA. The fitness cost was measured by growth curve tests.
Results: A total of 24 CRPA strains were isolated encompassing the whole ceftazidime/avibactam treatment. The CRPA strains developed high-level resistance to ceftazidime/avibactam and cross-resistance to ceftolozane/tazobactam or imipenem/relebactam, clustering into clade A and clade B, respectively. In both clades, the overexpression of AmpC was crucial to ceftazidime/avibactam resistance, which was driven by AmpD deficiency in clade A and dacB mutation in clade B, respectively. In clade A, mraY mutation and a new allele of AmpC (blaPDC-575) elevated resistance to ceftazidime/avibactam, with blaPDC-575 also conferring resistance to ceftolozane/tazobactam. In clade B, mexB mutation was associated with the resistance to both ceftazidime/avibactam and imipenem/relebactam. Moreover, the fitness costs of P. aeruginosa strains typically increased with the higher MICs of ceftazidime/avibactam.
Conclusion: Divergent resistance evolution resulted in a complex phenotype in the CRPA lineage, posing significant challenge to clinical treatment. The resistance surveillance needs to be prioritized, and new therapeutic strategies are urgently required.
期刊介绍：
Infection is a journal dedicated to serving as a global forum for the presentation and discussion of clinically relevant information on infectious diseases. Its primary goal is to engage readers and contributors from various regions around the world in the exchange of knowledge about the etiology, pathogenesis, diagnosis, and treatment of infectious diseases, both in outpatient and inpatient settings.
The journal covers a wide range of topics, including:
Etiology: The study of the causes of infectious diseases.
Pathogenesis: The process by which an infectious agent causes disease.
Diagnosis: The methods and techniques used to identify infectious diseases.
Treatment: The medical interventions and strategies employed to treat infectious diseases.
Public Health: Issues of local, regional, or international significance related to infectious diseases, including prevention, control, and management strategies.
Hospital Epidemiology: The study of the spread of infectious diseases within healthcare settings and the measures to prevent nosocomial infections.
In addition to these, Infection also includes a specialized "Images" section, which focuses on high-quality visual content, such as images, photographs, and microscopic slides, accompanied by brief abstracts. This section is designed to highlight the clinical and diagnostic value of visual aids in the field of infectious diseases, as many conditions present with characteristic clinical signs that can be diagnosed through inspection, and imaging and microscopy are crucial for accurate diagnosis. The journal's comprehensive approach ensures that it remains a valuable resource for healthcare professionals and researchers in the field of infectious diseases.
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