Sader Helio S, Castanheira Mariana, Kimbrough John H, Kantro Valerie, Mendes Rodrigo E
JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty 52317, IA, USA.
JAC Antimicrob Resist. 2023 Mar 22;5(2):dlad032. doi: 10.1093/jacamr/dlad032. eCollection 2023 Apr.
Aztreonam/avibactam is under development to treat infections caused by Gram-negative bacteria. We evaluated the activities of aztreonam/avibactam and comparators against a global collection of carbapenem-resistant Enterobacterales (CRE), including ceftazidime/avibactam-resistant isolates.
Isolates were consecutively collected (24 924; 1/patient) from 69 medical centres in 36 countries during 2019-21. Isolates were susceptibility tested by CLSI broth microdilution. All CRE isolates (= 1098; 4.4%) were screened for carbapenemase (CPE) genes after genome sequencing. CRE susceptibility results were stratified by CPE, geography and resistance phenotype.
Aztreonam/avibactam inhibited 99.6% of CREs at ≤8 mg/L (MIC, 0.25/0.5 mg/L), including 98.9% (345/349) of ceftazidime/avibactam-resistant isolates. Aztreonam/avibactam activity was consistent across geographical regions (98.9%-100.0% inhibited at ≤8 mg/L), but susceptibility to comparators varied markedly. Susceptibility (CLSI criteria) for ceftazidime/avibactam and meropenem/vaborbactam ranged from 80.2% and 77.5% in Western Europe to 39.5% and 40.3% in the Asia-Pacific region, respectively. Aztreonam/avibactam retained activity against isolates non-susceptible to colistin (99.7% inhibited at ≤8 mg/L) or tigecycline (98.6% inhibited at ≤8 mg/L). A CPE gene was identified in 972 CRE isolates (88.5%). The most common CPEs were KPC (43.1% of CREs), NDM (26.6%) and OXA-48-like (18.7%); 57 isolates (5.2%) had >1 CPE gene. Aztreonam/avibactam inhibited 99.9% of CPE producers at ≤8 mg/L, whereas ceftazidime/avibactam and meropenem/vaborbactam exhibited limited activity against isolates producing MBL and/or OXA-48-like enzymes.
Aztreonam/avibactam activity was not adversely affected by clinically relevant CPEs. Our results support aztreonam/avibactam development to treat infections caused by CRE, including MBL producers.
氨曲南/阿维巴坦正在研发用于治疗革兰氏阴性菌引起的感染。我们评估了氨曲南/阿维巴坦及对照药物对全球收集的耐碳青霉烯类肠杆菌科细菌（CRE）的活性，包括对头孢他啶/阿维巴坦耐药的分离株。
在2019年至2021年期间，从36个国家的69个医疗中心连续收集分离株（24924株；每位患者1株）。采用美国临床和实验室标准协会（CLSI）肉汤微量稀释法进行药敏试验。对所有CRE分离株（共1098株，占4.4%）进行基因组测序后筛查碳青霉烯酶（CPE）基因。CRE药敏结果按CPE、地理区域和耐药表型进行分层。
氨曲南/阿维巴坦在≤8mg/L（最低抑菌浓度，0.25/0.5mg/L）时可抑制99.6%的CRE，包括98.9%（345/349）对头孢他啶/阿维巴坦耐药的分离株。氨曲南/阿维巴坦的活性在各地理区域一致（≤8mg/L时98.9%-100.0%被抑制），但对对照药物的敏感性差异显著。头孢他啶/阿维巴坦和美罗培南/瓦博巴坦的敏感性（根据CLSI标准）在西欧分别为80.2%和77.5%，在亚太地区分别为39.5%和40.3%。氨曲南/阿维巴坦对黏菌素不敏感（≤8mg/L时99.7%被抑制）或替加环素不敏感（≤8mg/L时98.6%被抑制）的分离株仍有活性。在972株CRE分离株（88.5%）中鉴定出CPE基因。最常见的CPE是KPC（占CRE的43.1%）、NDM（26.6%）和OXA-48样酶（18.7%）；57株（5.2%）有>1个CPE基因。氨曲南/阿维巴坦在≤8mg/L时可抑制99.9%的CPE产生菌，而头孢他啶/阿维巴坦和美罗培南/瓦博巴坦对产生金属β-内酰胺酶（MBL）和/或OXA-48样酶的分离株活性有限。
氨曲南/阿维巴坦的活性不受临床相关CPE的不利影响。我们的结果支持氨曲南/阿维巴坦用于治疗由CRE引起的感染，包括MBL产生菌的研发。
