Emergence of Resistance to Novel Cephalosporin-ß-Lactamase Inhibitor Combinations through the Modification of the Pseudomonas aeruginosa MexCD-OprJ Efflux Pump.

A ceftolozane-tazobactam- and ceftazime-avibactam-resistant Pseudomonas aeruginosa isolate was recovered after treatment (including azithromycin, meropenem, and ceftolozane-tazobactam) from a patient that had developed ventilator-associated pneumonia after COVID-19 infection. Whole-genome sequencing revealed that the strain, belonging to ST274, had acquired a nonsense mutation leading to truncated carbapenem porin OprD (W277X), a 7-bp deletion (nt213Δ7) in NfxB (negative regulator of the efflux pump MexCD-OprJ), and two missense mutations (Q178R and S133G) located within the first large periplasmic loop of MexD. Through the construction of mexD mutants and complementation assays with wild-type nfxB, it was evidenced that resistance to the novel cephalosporin-ß-lactamase inhibitor combinations was caused by the modification of MexD substrate specificity.

Cefepime/tazobactam compared with other tazobactam combinations against problem Gram-negative bacteria.

OBJECTIVES: 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 ß-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. METHODS: 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. RESULTS: 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 ß-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-ß-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. CONCLUSION: 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'.