Vázquez-Ucha Juan Carlos, Alonso-Garcia Isaac, Guijarro-Sánchez Paula, Lasarte-Monterrubio Cristina, Álvarez-Fraga Laura, Cendón-Esteve Arnau, Outeda Michelle, Maceiras Romina, Peña-Escolano Andrea, Martínez-Guitián Marta, Arca-Suárez Jorge, Bou Germán, Beceiro Alejandro
Microbiology Department, University Hospital A Coruña, Institute of Biomedical Research of A Coruña, A Coruña, Spain; CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.
Microbiology Department, University Hospital A Coruña, Institute of Biomedical Research of A Coruña, A Coruña, Spain.
Int J Antimicrob Agents. 2023 Apr;61(4):106738. doi: 10.1016/j.ijantimicag.2023.106738. Epub 2023 Feb 3.
Metallo-β-lactamase (MBL)-producing Enterobacterales are of particular concern because they are widely disseminated and difficult to treat, being resistant to almost all β-lactam antibiotics. Aztreonam is not hydrolysed by MBLs but is labile to serine β-lactamases (SBLs), which are usually co-produced by MBL-producing Enterobacterales. This study investigated the activity of aztreonam in combination with novel β-lactamase inhibitors (BLIs) against a national multi-centre study collection of strains co-producing MBLs and SBLs. Fifty-five clinical isolates co-producing MBLs (41 VIM producers, 10 NDM producers and 4 IMP producers) and SBLs were selected, and whole-genome sequencing (WGS) was performed. The minimum inhibitory concentration (MIC) values of aztreonam, aztreonam/avibactam, aztreonam/relebactam, aztreonam/zidebactam, aztreonam/taniborbactam, aztreonam/vaborbactam and aztreonam/enmetazobactam were determined. β-lactam/BLI resistance mechanisms were analysed by WGS. All BLIs decreased the MIC values of aztreonam for strains that were not susceptible to aztreonam. Aztreonam/zidebactam (MIC ≤1 mg/L for 96.4% of isolates), aztreonam/avibactam (MIC ≤1 mg/L for 92.7% of isolates) and aztreonam/taniborbactam (MIC ≤1 mg/L for 87.3 % of isolates) were the most active combinations. For other aztreonam/BLI combinations, 50-70% of the isolates yielded MIC values ≤1 mg/L. WGS data revealed that mutations in PBP3, defective OmpE35/OmpK35 porins, and the presence of extended-spectrum β-lactamases and class C β-lactamases were some of the resistance mechanisms involved in reduced susceptibility to aztreonam/BLIs. Combinations of aztreonam with new BLIs show promising activity against Enterobacterales co-producing MBLs and SBLs, particularly aztreonam/zidebactam, aztreonam/avibactam and aztreonam/taniborbactam. The present results show that these novel drugs may represent innovative therapeutic strategies by their use in yet-unexplored combinations as solutions for difficult-to-treat infections.
产金属β-内酰胺酶（MBL）的肠杆菌目细菌备受关注，因为它们广泛传播且难以治疗，对几乎所有β-内酰胺类抗生素均耐药。氨曲南不被MBL水解，但对丝氨酸β-内酰胺酶（SBL）不稳定，而产MBL的肠杆菌目细菌通常会同时产生SBL。本研究针对一个全国多中心研究收集的同时产MBL和SBL的菌株，调查了氨曲南与新型β-内酰胺酶抑制剂（BLI）联合使用的活性。选取了55株同时产MBL（41株产VIM、10株产NDM和4株产IMP）和SBL的临床分离株，并进行了全基因组测序（WGS）。测定了氨曲南、氨曲南/阿维巴坦、氨曲南/瑞来巴坦、氨曲南/齐他巴坦、氨曲南/他尼硼巴坦、氨曲南/瓦博巴坦和氨曲南/恩美他唑巴坦的最低抑菌浓度（MIC）值。通过WGS分析β-内酰胺/BLI耐药机制。对于对氨曲南不敏感的菌株，所有BLI均降低了氨曲南的MIC值。氨曲南/齐他巴坦（96.4%的分离株MIC≤1 mg/L）、氨曲南/阿维巴坦（92.7%的分离株MIC≤1 mg/L）和氨曲南/他尼硼巴坦（87.3%的分离株MIC≤1 mg/L）是活性最强的组合。对于其他氨曲南/BLI组合，50 - 70%的分离株MIC值≤1 mg/L。WGS数据显示，青霉素结合蛋白3（PBP3）突变、外膜孔蛋白OmpE35/OmpK35缺陷以及超广谱β-内酰胺酶和C类β-内酰胺酶的存在是导致对氨曲南/BLI敏感性降低的部分耐药机制。氨曲南与新型BLI的联合使用对同时产MBL和SBL的肠杆菌目细菌显示出有前景的活性，尤其是氨曲南/齐他巴坦、氨曲南/阿维巴坦和氨曲南/他尼硼巴坦。目前的结果表明，这些新药通过以尚未探索的联合方式用于治疗难治性感染，可能代表着创新的治疗策略。
