头孢他啶-阿维巴坦对来自 2018-2020 年全球监测收集的多药耐药和产超广谱β-内酰胺酶阳性临床分离株的活性。
Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-β-Lactamase-Positive Clinical Isolates of from a 2018-2020 Global Surveillance Collection.
机构信息
IHMA, Schaumburg, Illinois, USA.
Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
出版信息
Antimicrob Agents Chemother. 2022 Nov 15;66(11):e0093422. doi: 10.1128/aac.00934-22. Epub 2022 Oct 26.
Ceftibuten-ledaborbactam etzadroxil is a cephalosporin-boronate β-lactamase inhibitor prodrug combination under development as an oral treatment for complicated urinary tract infections caused by multidrug-resistant (MDR) producing serine β-lactamases (Ambler class A, C, and D). , ledaborbactam etzadroxil (formerly VNRX-7145) is cleaved to the active inhibitor ledaborbactam (formerly VNRX-5236). To more completely define the breadth of ceftibuten-ledaborbactam's activity against important antimicrobial-resistant pathogens, we assessed its activity against phenotypic and genotypic subsets from a 2018-2020 global culture collection of 3,889 clinical isolates of , including MDR organisms, extended-spectrum-β-lactamase (ESBL)-positive organisms, and organisms that are nonsusceptible and resistant to other antimicrobials. MICs were determined by CLSI broth microdilution and interpreted using both CLSI and EUCAST breakpoints. Ledaborbactam was tested at a fixed concentration of 4 μg/mL. β-Lactamase genes were characterized by PCR followed by Sanger sequencing or whole-genome sequencing for selected β-lactam-resistant isolate subsets. At ≤1 μg/mL, ceftibuten-ledaborbactam (MIC, 0.25 μg/mL) inhibited 89.7% of MDR isolates, 98.3% of isolates with a presumptive ESBL-positive phenotype, and 92.6% of trimethoprim-sulfamethoxazole-nonsusceptible, 91.7% of levofloxacin-nonsusceptible, 88.1% of amoxicillin-clavulanate-nonsusceptible, 85.7% of ceftibuten-resistant (MIC >1 μg/mL), and 54.1% of carbapenem-nonsusceptible isolates. Against specific ESBL genotype-positive isolates (AmpC negative, serine carbapenemase negative, and metallo-β-lactamase negative), ceftibuten-ledaborbactam inhibited 96.3% of CTX-M-9 group (MIC, 0.25 μg/mL), 91.5% of CTX-M-1 group (MIC, 0.5 μg/mL), and 88.2% of SHV-positive (MIC, 2 μg/mL) isolates at ≤1 μg/mL. Against specific serine carbapenemase genotype-positive isolates, ceftibuten-ledaborbactam inhibited 85.9% of KPC-positive (MIC, 2 μg/mL) and 82.9% of OXA-48-group-positive (MIC, 2 μg/mL) isolates at ≤1 μg/mL. Continued development of ceftibuten-ledaborbactam appears warranted.
头孢他啶-他唑巴坦钠是一种头孢菌素-硼酸β-内酰胺酶抑制剂前药组合，正在开发中作为一种口服治疗由多药耐药（MDR）产生的复杂性尿路感染的药物 （Ambler 分类 A、C 和 D） 产丝氨酸β-内酰胺酶。 ，他唑巴坦钠（以前称为 VNRX-7145）被裂解为活性抑制剂他唑巴坦钠（以前称为 VNRX-5236）。为了更全面地定义头孢他啶-他唑巴坦对重要抗微生物耐药病原体的活性范围，我们评估了它对 2018-2020 年全球 3889 例临床分离株的表型和基因型亚群的活性，包括 MDR 生物体、 扩展谱β-内酰胺酶（ESBL）阳性生物体和对其他抗菌药物不敏感和耐药的生物体。MIC 通过 CLSI 肉汤微量稀释法确定，并使用 CLSI 和 EUCAST 临界点进行解释。他唑巴坦以固定浓度 4μg/mL 进行测试。β-内酰胺酶基因通过 PCR 进行特征分析，然后对选定的β-内酰胺耐药分离株亚群进行 Sanger 测序或全基因组测序。在≤1μg/mL 时，头孢他啶-他唑巴坦（MIC，0.25μg/mL）抑制 89.7%的 MDR 分离株，98.3%的具有推定 ESBL 阳性表型的分离株，92.6%的对 trimethoprim-sulfamethoxazole 不敏感，91.7%的对 levofloxacin 不敏感，88.1%的对 amoxicillin-clavulanate 不敏感，85.7%的对 ceftibuten 耐药（MIC＞1μg/mL），和 54.1%的 carbapenem 不敏感分离株。对于特定的 ESBL 基因型阳性分离株（AmpC 阴性、丝氨酸碳青霉烯酶阴性和金属β-内酰胺酶阴性），头孢他啶-他唑巴坦抑制 96.3%的 CTX-M-9 组（MIC，0.25μg/mL），91.5%的 CTX-M-1 组（MIC，0.5μg/mL），和 88.2%的 SHV 阳性（MIC，2μg/mL）分离株在≤1μg/mL。对于特定的丝氨酸碳青霉烯酶基因型阳性分离株，头孢他啶-他唑巴坦抑制 85.9%的 KPC 阳性（MIC，2μg/mL）和 82.9%的 OXA-48 组阳性（MIC，2μg/mL）分离株在≤1μg/mL。继续开发头孢他啶-他唑巴坦似乎是合理的。
Zotero 插件