In Vivo Activity of WCK 4282 (High-Dose Cefepime/Tazobactam) against Serine-β-lactamase-Producing Enterobacterales and Pseudomonas aeruginosa in the Neutropenic Murine Lung Infection Model
Abstract (248/250) Introduction: WCK 4282 (cefepime 2g/tazobactam 2g) maximizes systemic exposure of tazobactam and restores cefepime activity against various extended-spectrum β-lactamase (ESBL)- and cephalosporinase-producing strains in vitro. We describe clinical WCK 4282 exposure efficacy against various serine β-lactamase-producing Enterobacterales and Pseudomonas aeruginosa in a murine pneumonia model. Clinical cefepime-resistant isolates (17 Enterobacterales and 2 P. aeruginosa) were utilized. Isolates expressed ESBLs, cephalosporinases, and/or serine carbapenemases (KPC, OXA-48-like). WCK 4282 MICs were 4-32 μg/mL. For in vivo experiments, lungs of neutropenic mice were inoculated using standard inoculum (107 log10 CFU/mL). Serine-carbapenemase-producing isolates were also assessed using a low inoculum (1:5 dilution). Treatment mice received HSR of cefepime, meropenem (control for serine carbapenemase expression with low inoculum experiments), or WCK 4282 human-simulated regimens. Efficacy was assessed as change in log10 CFU/lung at 24h compared with 0h controls. Results: At standard inoculum, mean 0h bacterial burden was 6.65±0.23 log10 CFU/lung and increased at 24h by 2.48 ± 0.60 log10 CFU/lung among untreated controls. Lower inoculums initial bacterial burdens ranged from 5.81±0.12-6.39±0.13 log10 CFU/lung. At standard and/or low inoculums, cefepime and meropenem provided minimal activity. WCK 4282 produced >1-log10 reduction against 9/9 ESBL/cephalosporinase-producing strains. WCK 4282 provided variable activity among mice infected with standard or lower inoculums of OXA-48-like-producers. WCK 4282 exposures provided 0.53±1.07 log10 CFU/lung growth against KPC-producers at standard versus bacteriostasis (-0.15±0.54 change in log10 CFU/lung) at low inoculum. Conclusion: WCK 4282 produced potent in vivo activity against ESBL- and cephalosporinase-producing Enterobacterales and P. aeruginosa, and potential activity against OXA-48-like-producing Enterobacterales in a neutropenic pneumonia model.