Norwich Medical School, University of East Anglia, Norwich, UK.
Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England National Infection Service, London, UK.
J Antimicrob Chemother. 2018 Jan 1;73(1):126-133. doi: 10.1093/jac/dkx360.
Early β-lactamase inhibitors were combined with established penicillins, but different combinations may be more appropriate to counter current β-lactamase threats, with development facilitated by the US Generating Antibiotic Incentives Now (GAIN) Act. Cefepime/tazobactam is especially attractive, combining an AmpC-stable cephalosporin with a clinically established inhibitor, active against ESBLs and suitable for high-dose administration.
Organisms (n = 563) were clinical isolates submitted to the UK national reference laboratory. MICs were determined by CLSI agar dilution with tazobactam at 4 mg/L and, for a subset, at 8 mg/L.
Cefepime/tazobactam 8 + 4 mg/L achieved coverage of 96%-100% of Enterobacteriaceae with penicillinases, AmpC, ESBL, K1 or OXA-48 β-lactamases. Even at 1 + 4 mg/L, the combination inhibited >94% of isolates with penicillinases, AmpC enzymes or ESBLs. Most Enterobacteriaceae with KPC and NDM carbapenemase were resistant at current cefepime breakpoints but 80% of those with VIM types were susceptible at 8 + 4 mg/L. Tazobactam did little to potentiate cefepime against non-fermenter groups, though gains were seen against AmpC-producing Acinetobacter spp. and Stenotrophomonas maltophilia. Increasing the tazobactam concentration to 8 mg/L gave further small increases in activity against Enterobacteriaceae groups.
High-dose cefepime/tazobactam, justifying an 8 + 4 or 8 + 8 mg/L breakpoint, can achieve a carbapenem-like spectrum, with some additional coverage of OXA-48 (and maybe VIM) Enterobacteriaceae. Clinical evaluation is warranted.
早期的β-内酰胺酶抑制剂与已有的青霉素联合使用，但不同的组合可能更适合应对当前的β-内酰胺酶威胁，这得益于美国现在的抗生素激励生成法案（GAIN）。头孢吡肟/他唑巴坦特别有吸引力，它将一种 AmpC 稳定的头孢菌素与一种临床已建立的抑制剂结合在一起，对 ESBLs 有效，适用于高剂量给药。
该研究共纳入 563 株临床分离株，这些菌株均来自英国国家参考实验室。采用 CLSI 琼脂稀释法测定头孢吡肟的 MIC 值，其中包括在 4mg/L 他唑巴坦浓度下，以及一部分在 8mg/L 他唑巴坦浓度下的 MIC 值。
头孢吡肟/他唑巴坦 8 + 4mg/L 对产青霉素酶、AmpC、ESBL、K1 或 OXA-48 型β-内酰胺酶的肠杆菌科细菌的覆盖率达到 96%-100%。即使在 1 + 4mg/L 时，该组合也能抑制超过 94%的产青霉素酶、AmpC 酶或 ESBLs 的分离株。大多数携带 KPC 和 NDM 碳青霉烯酶的肠杆菌科细菌对当前头孢吡肟的折点耐药，但 80%的携带 VIM 型酶的分离株对 8 + 4mg/L 的头孢吡肟敏感。他唑巴坦对非发酵菌的增效作用不大，但对产 AmpC 的不动杆菌属和嗜麦芽窄食单胞菌的活性有所增强。将他唑巴坦的浓度增加到 8mg/L 可进一步提高对肠杆菌科细菌的活性。
高剂量头孢吡肟/他唑巴坦（ justifies an 8 + 4 or 8 + 8mg/L breakpoint）可实现类似碳青霉烯类的广谱抗菌活性，对 OXA-48（和可能的 VIM）型肠杆菌科细菌有一定的额外覆盖。需要进行临床评估。
