Int J Antimicrob Agents. 2021 Mar 11:106318. doi: 10.1016/j.ijantimicag.2021.106318. Online ahead of print.
Piperacillin/tazobactam has long been a broad-spectrum 'workhorse' antibiotic but 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+2g q8h combination with 90 min infusion. We assessed the activity of this combination, 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 BSAC agar dilution. Although higher values may be justifiable, based on the pharmacodynamics, we reviewed results against current cefepime breakpoints. On this basis, cefepime/tazobactam was broadly active against Enterobacterales with AmpC enzymes and ESBLs, even when these had ertapenem resistance suggesting porin loss. At 8+8 mg/L, activity extended to >90% of Enterobacterales with OXA-48 and KPC carbapenemases, although MICs for KPC producers belonging to the international Klebsiella pneumoniae ST258 lineage were higher; MBL producers remained resistant. Cefepime/tazobactam was less active than ceftolozane/tazobactam against Pseudomonas aeruginosa with AmpC derepression or high-level efflux but achieved wider antipseudomonal coverage than piperacillin/tazobactam. Activity against other non-fermenters was species-specific. Overall, cefepime/tazobactam has 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'.