In vivo divergent evolution of cross-resistance to new β-lactam/β-lactamase inhibitor combinations in Pseudomonas aeruginosa following ceftazidime/avibactam treatment.
{"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":" ","pages":""},"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}
引用次数: 0
Abstract
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.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
