Selection and characterization of mutational resistance to aztreonam/avibactam in β-lactamase-producing Enterobacterales

阿兹屈南 阿维巴坦 头孢他啶/阿维巴坦 突变体 微生物学 生物 碳青霉烯 抗药性 他唑巴坦 头孢他啶 肠杆菌科 哌拉西林 β-内酰胺酶抑制剂 抗生素耐药性 头孢吡肟 遗传学 抗生素 细菌 铜绿假单胞菌 亚胺培南 基因
作者
Shazad Mushtaq,Anna Vickers,Nicholas Ellaby,Neil Woodford,David M. Livermore
出处
期刊:Journal of Antimicrobial Chemotherapy [Oxford University Press]
卷期号:77 (1): 98-111 被引量:11
标识
DOI:10.1093/jac/dkab346
摘要

Aztreonam/avibactam is being developed for its broad activity against carbapenemase-producing Enterobacterales, including those with metallo-β-lactamases (MBLs). Its potential to select resistance in target pathogens was explored. Findings are compared with previous data for ceftazidime/avibactam and ceftaroline/avibactam.Single-step mutants were sought from 52 Enterobacterales with AmpC, ESBL, KPC, MBL and OXA-48-like enzymes. Mutation frequencies were calculated. MICs were determined by CLSI agar dilution. Genomes were sequenced using Illumina methodology.Irrespective of β-lactamase type and of whether avibactam was used at 1 or 4 mg/L, mutants could rarely be obtained at >4× the starting MIC, and most MIC rises were correspondingly small. Putative resistance (MIC >8 + 4 mg/L) associated with changes to β-lactamases was seen only for mutants of AmpC, where it was associated with Asn346Tyr and Tyr150Cys substitutions. Asn346Tyr led to broad resistance to avibactam combinations; Tyr150Cys significantly affected only aztreonam/avibactam. MIC rises up to 4 + 4 mg/L were seen for producers of mutant KPC-2 or -3 enzymes, and were associated with Trp105Arg, Ser106Pro and Ser109Pro substitutions, which all reduced the MICs of other β-lactams. For producers of other β-lactamase types, we largely found mutants with lesions in baeRS or envZ, putatively affecting drug accumulation. Single mutants had lesions in ampD, affecting AmpC expression or ftsI, encoding PBP3.The risk of mutational resistance to aztreonam/avibactam appears smaller than for ceftazidime/avibactam, where Asp179Tyr arises readily in KPC enzymes, conferring frank resistance. Asn346 substitutions in AmpC enzymes may remain a risk, having been repeatedly selected with multiple avibactam combinations in vitro.
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