Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.
School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen, UK.
Int J Antimicrob Agents. 2019 Jun;53(6):774-780. doi: 10.1016/j.ijantimicag.2019.02.022. Epub 2019 Mar 2.
Pseudomonas aeruginosa is one of the most important pathogens in cystic fibrosis. This study was conducted to analyse the genetic basis and phylogenetic profile of resistance to ceftazidime/avibactam, ceftolozane/tazobactam and carbapenems in cystic fibrosis P. aeruginosa isolates. Whole genome sequence analysis was conducted of isolates resistant to piperacillin/tazobactam collected from seven hospitals in Scotland since the introduction of these two cephalosporin/β-lactamase inhibitor combinations. Ceftazidime resistance was primarily related to AmpC induction, as tested by cloxacillin inhibition assays, while high-level ceftazidime resistance not reversed by cloxacillin was associated with amino acid variations in AmpC. Only isolates resistant to both ceftazidime/avibactam and ceftolozane/tazobactam carried AmpD mutations, likely resulting in ampC overexpression. All isolates resistant to ceftazidime/avibactam and/or ceftolozane/tazobactam were resistant to carbapenems and showed inactivating mutations in the chromosomal oprD gene. None of the isolates bore class A, B, D plasmid-encoded carbapenemases. This study showed that mutational resistance emerged in phylogenetically distant lineages, which indicates the mutations occur independently without conferring a selective advantage to any phylogenetic lineage. These findings confirm the strong contribution of mutation-driven evolution to the population structure of P. aeruginosa.
铜绿假单胞菌是囊性纤维化的最重要病原体之一。本研究旨在分析囊性纤维化铜绿假单胞菌分离株对头孢他啶/阿维巴坦、头孢洛扎/他唑巴坦和碳青霉烯类药物耐药的遗传基础和系统发育特征。对苏格兰 7 家医院自这两种头孢菌素/β-内酰胺酶抑制剂组合引入以来分离出的对哌拉西林/他唑巴坦耐药的菌株进行了全基因组序列分析。头孢他啶耐药主要与 AmpC 诱导有关，通过氯唑西林抑制试验进行检测，而不能被氯唑西林逆转的高水平头孢他啶耐药与 AmpC 中的氨基酸变异有关。只有对头孢他啶/阿维巴坦和头孢洛扎/他唑巴坦均耐药的分离株携带 AmpD 突变，可能导致 ampC 过表达。所有对头孢他啶/阿维巴坦和/或头孢洛扎/他唑巴坦耐药的分离株均对碳青霉烯类药物耐药，并在染色体 oprD 基因中显示出失活突变。没有分离株携带 A、B、D 类质粒编码的碳青霉烯酶。本研究表明，突变耐药出现在系统发育上较远的谱系中，这表明突变是独立发生的，不会赋予任何系统发育谱系选择性优势。这些发现证实了突变驱动的进化对铜绿假单胞菌种群结构的强烈贡献。
