Successful Use of Cefepime-Zidebactam (WCK 5222) as a Salvage Therapy for the Treatment of Disseminated Extensively Drug-Resistant New Delhi Metallo-ß-Lactamase-Producing Pseudomonas aeruginosa Infection in an Adult Patient with Acute T-Cell Leukemia.

With limited and often toxic treatment options, carbapenem-resistant Gram-negative infections are associated with significant mortality. Cefepime-zidebactam is a promising antibiotic option undergoing a phase 3 trial that has activity against diverse antibiotic-resistant mechanisms in Gram-negative pathogens due to its ß-lactam enhancer mechanism, mediating multiple PBP binding. We report a case of disseminated infection caused by a New Delhi metallo-ß-lactamase-producing, extensively drug-resistant Pseudomonas aeruginosa isolate in a patient with acute T-cell leukemia, successfully managed with cefepime-zidebactam as a salvage therapy.

Evaluation of the in vitro activity of WCK 5222 (cefepime/zidebactam) and currently available combination therapies against single- and double-carbapenemase producing Enterobacteriaceae: Expanding the zone of hope.

Cefepime/zidebactam (WCK 5222) is a ß-lactam/ß-lactam enhancer antibiotic designed to retain in vitro activity against Enterobacteriaceae that simultaneously produce metallo-ß-lactamase (MBL) and serine-ß-lactamase (SBL). Aztreonam (ATM) plus ceftazidime/avibactam (CZA) or meropenem/vaborbactam (M/V) is an attractive option for coverage of such strains, but clinical laboratories are not equipped to distinguish which is the more potent regimen to inform treatment decisions. We evaluated Enterobacteriaceae that expressed MBL and ≥1 SBL (n=15) using gradient diffusion strip (GDS) methods to (1) determine the minimum inhibitory concentration (MIC) of WCK 5222 and (2) compare the in vitro potency of CZA+ATM vs. M/V+ATM. All isolates were non-susceptible to ATM, CZA, and M/V and were inhibited by WCK 5222 at cefepime concentrations ≥2 log2 dilutions below the susceptible-dose dependent breakpoint of 8 mg/L (MIC50/90, 1/2 mg/L). Activity of CZA+ATM vs. M/V+ATM was compared using the zone of hope (ZOH) product, quantitated by multiplying the length (in mm) of inhibited growth adjacent to each GDS from the point of intersection. The median (interquartile range) ZOH product for CZA+ATM and M/V+ATM was 75.4 (62.8-93.7) and 23.5 (14.1-60.4), respectively (P=0.002). In strains with one carbapenemase (the MBL), the median ZOH products were not statistically different, but in strains with an OXA-type carbapenemase (n=6), the median product for CZA+ATM and M/V+ATM was 78.1 and 20.7, respectively (P=0.004). Thus, CZA+ATM may offer enhanced coverage over M/V+ATM of Enterobacteriaceae co-expressing MBL and SBL. Further preclinical in vivo evaluations of WCK 5222 monotherapy are warranted.

Comparative Evaluation of the In Vitro Activities of WCK 5222 (Cefepime-Zidebactam) and Combination Antibiotic Therapies against Carbapenem-Resistant Pseudomonas aeruginosa.

The in vitro activity of WCK 5222 (cefepime-zidebactam) was compared to that of several available combination therapies among 30 clinical carbapenem-resistant Pseudomonas aeruginosa (CRP) strains using gradient diffusion strips. The combinations included nonsusceptible ß-lactams (cefepime, ceftolozane-tazobactam, and meropenem) with amikacin and fosfomycin. WCK 5222 MICs ranged from 2 to 32 mg/liter, and 97% were ≤16 mg/liter, while 105/146 (72%) combinations demonstrated inhibition below established susceptibility breakpoints. WCK 5222 monotherapy may be preferred over the combinations assessed for CRP infections.