Mushtaq Shazad, Garello Paolo, Vickers Anna, Woodford Neil, Livermore David M
Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, National Infection Service, Public Health England, London, UK.
Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, National Infection Service, Public Health England, London, UK; Norwich Medical School, University of East Anglia, Norwich, UK.
Int J Antimicrob Agents. 2021 May;57(5):106318. doi: 10.1016/j.ijantimicag.2021.106318. Epub 2021 Mar 11.
Piperacillin/tazobactam has long been a broad-spectrum 'workhorse' antibiotic; however, it is compromised by resistance. One response is to re-partner tazobactam with cefepime, which is easier to protect, being less β-lactamase labile, and to use a high-dose and prolonged infusion. On this basis, Wockhardt are developing cefepime/tazobactam (WCK 4282) as a 2+2 g q8h combination with a 90-min infusion.
The activity of cc cefepime/tazobactam was assessed, with other tazobactam combinations as comparators, against 1632 Enterobacterales, 745 Pseudomonas aeruginosa and 450 other non-fermenters, as submitted to the UK National Reference Laboratory. These were categorised by carbapenemase-gene detection and interpretive reading of phenotypes, with MICs determined by British Society for Antimicrobial Chemotherapy agar dilution.
Although higher breakpoints may be justifiable, based on the pharmacodynamics, the results were reviewed against current cefepime criteria. On this basis, cefepime/tazobactam was broadly active against Enterobacterales with AmpC enzymes and extended-spectrum β-lactamases (ESBLs), even when they had ertapenem resistance, suggesting porin loss. At 8+8 mg/L, activity extended to > 90% of Enterobacterales with OXA-48 and KPC carbapenemases, although the MICs for KPC producers belonging to the international Klebsiella pneumoniae ST258 lineage were higher; metallo-β-lactamase producers remained resistant. Cefepime/tazobactam was less active than ceftolozane/tazobactam against Pseudomonas aeruginosa with AmpC de-repression or high-level efflux but achieved wider antipseudomonal coverage than piperacillin/tazobactam. Activity against other non-fermenters was species-specific.
Overall, cefepime/tazobactam had a spectrum exceeding those of piperacillin/tazobactam and ceftolozane/tazobactam and resembling or exceeding that of carbapenems. Used as a 'new-combination of old-agents' it has genuine potential to be 'carbapenem-sparing'.
哌拉西林/他唑巴坦长期以来一直是一种广谱“主力”抗生素；然而，它受到耐药性的影响。一种应对方法是将他唑巴坦与头孢吡肟重新组合，头孢吡肟更易于保护，因为其对β-内酰胺酶的稳定性较差，并且采用高剂量和延长输注时间的方式。在此基础上，沃克哈特公司正在研发头孢吡肟/他唑巴坦（WCK 4282），其组合为每8小时2克加2克，输注时间为90分钟。
以其他他唑巴坦组合为对照，对提交至英国国家参考实验室的1632株肠杆菌科细菌、745株铜绿假单胞菌和450株其他非发酵菌评估头孢吡肟/他唑巴坦的活性。通过碳青霉烯酶基因检测和表型解释性读数对这些细菌进行分类，最低抑菌浓度（MIC）由英国抗菌化疗协会琼脂稀释法测定。
尽管基于药效学，更高的断点可能是合理的，但根据当前头孢吡肟标准对结果进行了审查。在此基础上，头孢吡肟/他唑巴坦对具有AmpC酶和超广谱β-内酰胺酶（ESBLs）的肠杆菌科细菌具有广泛活性，即使它们对厄他培南耐药，这表明孔蛋白丢失。在8 + 8毫克/升时，活性扩展至超过90%具有OXA - 48和KPC碳青霉烯酶的肠杆菌科细菌，尽管属于国际肺炎克雷伯菌ST258谱系的KPC产生菌的MIC较高；金属β-内酰胺酶产生菌仍然耐药。对于具有AmpC去阻遏或高水平外排的铜绿假单胞菌，头孢吡肟/他唑巴坦的活性低于头孢洛扎/他唑巴坦，但比哌拉西林/他唑巴坦具有更广泛的抗假单胞菌覆盖范围。对其他非发酵菌的活性具有菌种特异性。
总体而言，头孢吡肟/他唑巴坦的抗菌谱超过了哌拉西林/他唑巴坦和头孢洛扎/他唑巴坦，与碳青霉烯类药物的抗菌谱相似或超过碳青霉烯类药物。作为“旧药新组合”使用，它具有真正的“碳青霉烯类药物节省”潜力。
