Palwe Snehal, Bakthavatchalam Yamuna Devi, Khobragadea Kshama, Kharat Arun S, Walia Kamini, Veeraraghavan Balaji
Department of Environmental Science, S. B. College of Science, Aurangabad 431001, India.
Department of Clinical Microbiology, Christian Medical College, Vellore 632004, India.
Antibiotics (Basel). 2021 Oct 29;10(11):1318. doi: 10.3390/antibiotics10111318.
Ceftazidime/avibactam uniquely demonstrates activity against both KPC and OXA-48-like carbapenemase-expressing Enterobacterales. Clinical resistance to ceftazidime/avibactam in KPC-producers was foreseen in in-vitro resistance studies. Herein, we assessed the resistance selection propensity of ceftazidime/avibactam in expressing OXA-48-like β-lactamases ( = 10), employing serial transfer approach. Ceftazidime/avibactam MICs (0.25-4 mg/L) increased to 16-256 mg/L after 15 daily-sequential transfers. The whole genome sequence analysis of terminal mutants showed modifications in proteins linked to efflux (AcrB/AcrD/EmrA/Mdt), outer membrane permeability (OmpK36) and/or stress response pathways (CpxA/EnvZ/RpoE). In-vitro growth properties of all the ceftazidime/avibactam-selected mutants were comparable to their respective parents and they retained the ability to cause pulmonary infection in neutropenic mice. Against these mutants, we explored the activities of various combinations of β-lactams (ceftazidime or cefepime) with structurally diverse β-lactamase inhibitors or a β-lactam enhancer, zidebactam. Zidebactam, in combination with either cefepime or ceftazidime, overcame ceftazidime/avibactam resistance (MIC range 0.5-8 mg/L), while cefepime/avibactam was the second best (MIC: 0.5-16 mg/L) in yielding lower MICs. The present work revealed the possibility of ceftazidime/avibactam resistance in OXA-48-like through mutations in proteins involved in efflux and/or porins without concomitant fitness cost mandating astute monitoring of ceftazidime/avibactam resistance among OXA-48 genotypes.
头孢他啶/阿维巴坦对产KPC和产OXA - 48样碳青霉烯酶的肠杆菌科细菌均具有独特的抗菌活性。在体外耐药性研究中就已预见到产KPC菌株对头孢他啶/阿维巴坦的临床耐药情况。在此，我们采用连续传代方法评估了头孢他啶/阿维巴坦对10株产OXA - 48样β - 内酰胺酶菌株的耐药性选择倾向。经过15次每日连续传代后，头孢他啶/阿维巴坦的最低抑菌浓度（MIC）从0.25 - 4mg/L升高至16 - 256mg/L。对最终突变体的全基因组序列分析显示，与外排（AcrB/AcrD/EmrA/Mdt）、外膜通透性（OmpK36）和/或应激反应途径（CpxA/EnvZ/RpoE）相关的蛋白质发生了修饰。所有头孢他啶/阿维巴坦选择的突变体的体外生长特性与其各自亲本相当，并且它们保留了在中性粒细胞减少小鼠中引起肺部感染的能力。针对这些突变体，我们探究了β - 内酰胺类药物（头孢他啶或头孢吡肟）与结构多样的β - 内酰胺酶抑制剂或β - 内酰胺增强剂齐德巴坦的各种组合的活性。齐德巴坦与头孢吡肟或头孢他啶联合使用可克服头孢他啶/阿维巴坦耐药性（MIC范围为0.5 - 8mg/L），而头孢吡肟/阿维巴坦在产生较低MIC方面是第二有效的（MIC：0.5 - 16mg/L）。目前的研究揭示了产OXA - 48样菌株通过外排蛋白和/或孔蛋白的突变产生对头孢他啶/阿维巴坦耐药的可能性，且不会伴随适应性代价，这就要求对OXA - 48基因型中的头孢他啶/阿维巴坦耐药情况进行敏锐监测。
