Servicio de Microbiología do Complejo Hospitalario Universitario da Coruña (CHUAC), Instituto de Investigación Biomédica da Coruña (INIBIC), Coruña, CIBER de Enfermedades Infecciosas, Spain.
Servicio de Microbiología, Hospital Provincial Pontevedra, Pontevedra, Spain.
Antimicrob Agents Chemother. 2022 Feb 15;66(2):e0167621. doi: 10.1128/AAC.01676-21. Epub 2021 Nov 22.
The global distribution of carbapenemases such as KPC, OXA-48, and metallo-β-lactamases (MBLs) gives cause for concern, as these enzymes are not inhibited by classical β-lactamase inhibitors (BLIs). The current development of new inhibitors is one of the most promising highlights for the treatment of multidrug-resistant bacteria. The activity of cefepime in combination with the novel BLIs zidebactam, taniborbactam, and enmetazobactam was studied in a collection of 400 carbapenemase-producing (CPE). The genomes were fully sequenced and potential mechanisms of resistance to cefepime/BLI combinations were characterized. Cefepime resistance in the whole set of isolates was 79.5% (MIC50/90 64/≥128mg/L). The cefepime/zidebactam and cefepime/taniborbactam combinations showed the highest activity (MIC ≤0.5/1 and ≤0.5/2 mg/L, respectively). Cefepime/zidebactam displayed high activity, regardless of the carbapenemase or extended-spectrum β-lactamase (ESBL) considered (99% of isolates displayed MIC ≤2 mg/L). Cefepime/taniborbactam displayed excellent activity against OXA-48- and KPC-producing and lower activity against MBL-producing isolates (four strains yielded MICs ≥16 mg/L: 2 NDM producers with an insertion in PBP3, one VIM-1 producer with nonfunctional OmpK35, and one IMP-8 producer). Cefepime/enmetazobactam displayed the lowest activity (MIC 1/≥128 mg/L), with MICs ≥16 mg/L for 49 MBL producers, 40 OXA-48 producers (13 with amino acid changes in OmpK35/36, 4 in PBPs and 11 in RamR) and 25 KPC producers (most with an insertion in OmpK36). These results confirm the therapeutic potential of the new β-lactamase inhibitors, shedding light on the activity of cefepime and BLIs against CPE and resistance mechanisms. The cefepime/zidebactam and cefepime/taniborbactam combinations are particularly highlighted as promising alternatives to penicillin-based inhibitors for the treatment of CPE.
碳青霉烯酶（如 KPC、OXA-48 和金属β-内酰胺酶（MBLs））在全球的分布令人担忧，因为这些酶不受经典β-内酰胺酶抑制剂（BLIs）的抑制。目前新抑制剂的开发是治疗多药耐药菌最有希望的亮点之一。本研究评估了头孢吡肟与新型 BLIs 齐他培南、他唑巴坦和恩美曲妥珠单抗联合应用的活性，对 400 株产碳青霉烯酶（CPE）的分离株进行了研究。对这些基因组进行了全序列测序，并对头孢吡肟/BLIs 联合用药的潜在耐药机制进行了研究。在整个分离株中，头孢吡肟的耐药率为 79.5%（MIC50/90 为 64/≥128mg/L）。头孢吡肟/齐他培南和头孢吡肟/他唑巴坦联合用药显示出最高的活性（MIC≤0.5/1 和≤0.5/2mg/L）。无论考虑何种碳青霉烯酶或超广谱β-内酰胺酶（ESBL），头孢吡肟/齐他培南均显示出高活性（99%的分离株 MIC≤2mg/L）。头孢吡肟/他唑巴坦对产 OXA-48 和 KPC 的分离株具有极好的活性，对产 MBL 的分离株活性较低（4 株分离株 MIC≥16mg/L：2 株产 NDM 者的 PBP3 中插入，1 株产 VIM-1 者的 OmpK35 无功能，1 株产 IMP-8 者的 OmpK35/36）。头孢吡肟/恩美曲妥珠单抗显示出最低的活性（MIC1/≥128mg/L），49 株产 MBL 的分离株、40 株产 OXA-48 的分离株（13 株在 OmpK35/36 中有氨基酸改变，4 株在 PBPs 中，11 株在 RamR 中有氨基酸改变）和 25 株产 KPC 的分离株的 MIC≥16mg/L。这些结果证实了新型β-内酰胺酶抑制剂的治疗潜力，阐明了头孢吡肟和 BLIs 对 CPE 的活性及耐药机制。头孢吡肟/齐他培南和头孢吡肟/他唑巴坦联合用药特别被认为是治疗 CPE 的青霉素类抑制剂的有前途的替代药物。
