Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.
Center for Pathogen Research, West China Hospital, Sichuan University, Chengdu, China.
Int J Antimicrob Agents. 2022 Sep;60(3):106642. doi: 10.1016/j.ijantimicag.2022.106642. Epub 2022 Jul 22.
Aztreonam/avibactam is a promising antimicrobial combination with additional coverage for metallo-β-lactamases compared with ceftazidime/avibactam. A carbapenem-resistant bla-carrying Escherichia coli clinical isolate had four extra amino acids in penicillin-binding protein 3 (PBP3), which has been known to mediate reduced susceptibility to aztreonam/avibactam. This prompted us to investigate whether the strain could develop resistance to aztreonam/avibactam after exposure to the combination. A mutant with high-level resistance to aztreonam/avibactam [minimum inhibitory concentration (MIC), 512/4 mg/L] was obtained after 5-day exposure to 0.5 × MIC but it remained susceptible to ceftazidime/avibactam (MIC, 4/4 mg/L). The mutant had a single nucleotide polymorphism (SNP) in bla to encode KPC-21 with a Trp105Arg amino acid substitution. By cloning into E. coli BL21, bla could mediate reduced susceptibility to aztreonam/avibactam (MIC, from ≤0.03/4 to 1/4 mg/L), which was still below the breakpoint to define resistance. In contrast, when bla was cloned in E. coli 035125ΔpCMY42 with four extra amino acids in PBP3, which was generated in our previous work, the strain exhibited high-level resistance to aztreonam/avibactam (MIC, 256/4 mg/L). The above findings highlight that although aztreonam/avibactam has a broader spectrum than ceftazidime/avibactam, strains may develop resistance to the former combination but remain susceptible to the latter. The discrepancy is due to mutation of KPC-2 to KPC-21 in combination with the insertion of four extra amino acids in PBP3.
阿兹培能/阿维巴坦是一种很有前途的抗菌药物组合，与头孢他啶/阿维巴坦相比，对金属β-内酰胺酶的覆盖范围更广。一株携带 bla 的耐碳青霉烯大肠埃希菌临床分离株的青霉素结合蛋白 3（PBP3）中有四个额外的氨基酸，已知这会导致对阿兹培能/阿维巴坦的敏感性降低。这促使我们研究该菌株在接触该组合后是否会对阿兹培能/阿维巴坦产生耐药性。经过 5 天 0.5×MIC 浓度的暴露，获得了对阿兹培能/阿维巴坦具有高水平耐药性的突变株（MIC，512/4 mg/L），但对头孢他啶/阿维巴坦仍敏感（MIC，4/4 mg/L）。突变株 bla 中有一个单核苷酸多态性（SNP），可编码具有色氨酸 105 精氨酸取代的 KPC-21。通过克隆到 E. coli BL21 中，bla 可介导对阿兹培能/阿维巴坦的敏感性降低（MIC，从≤0.03/4 至 1/4 mg/L），仍低于定义耐药性的折点。相比之下，当 bla 克隆到我们之前的工作中在 PBP3 中产生的带有四个额外氨基酸的 035125ΔpCMY42 中的 E. coli 时，该菌株对阿兹培能/阿维巴坦表现出高水平耐药性（MIC，256/4 mg/L）。上述发现强调，尽管阿兹培能/阿维巴坦的光谱比头孢他啶/阿维巴坦更广，但菌株可能对前者的组合产生耐药性，但对后者仍保持敏感性。这种差异是由于 KPC-2 突变为 KPC-21 并与 PBP3 中的四个额外氨基酸插入相结合。
