WCK 5222 (Cefepime-Zidebactam) Antimicrobial Activity against Clinical Isolates of Gram-Negative Bacteria Collected Worldwide in 2015

WCK 5222 consists of cefepime combined with zidebactam, a bicyclo-acyl hydrazide β-lactam enhancer antibiotic with a dual action involving binding to Gram-negative bacterial PBP2 and β-lactamase inhibition. We evaluated thein vitro activity of cefepime-zidebactam against 7,876 contemporary (2015) clinical isolates ofEnterobacteriaceae (n = 5,946),Pseudomonas aeruginosa (n = 1,291), andAcinetobacter spp. (n = 639) from the United States (n = 2,919), Europe (n = 3,004), the Asia-Pacific (n = 1,370), and Latin America (n = 583). The isolates were tested by a reference broth microdilution method for susceptibility against cefepime-zidebactam (1:1 and 2:1 ratios) and comparator agents. Cefepime-zidebactam was the most active compound tested againstEnterobacteriaceae (MIC50/90 , ≤0.03/0.12 μg/ml [1:1] and 0.06/0.25 μg/ml [2:1]; 99.9% of isolates were inhibited at ≤4 [1:1] and ≤8 μg/ml [2:1]). Cefepime-zidebactam was active against individualEnterobacteriaceae species (MIC50/90 , ≤0.03 to 0.06/≤0.03 to 0.5 μg/ml [1:1]) and retained potent activity against carbapenem-resistant isolates (MIC50/90 , 1/4 μg/ml; 99.3% of isolates were inhibited at ≤8 μg/ml [1:1]). Cefepime-zidebactam activity was consistent among geographic regions, and only one isolate showed MIC values of >8 μg/ml (1:1). Cefepime-zidebactam was also very active againstP. aeruginosa with MIC50/90 values of 1/4 μg/ml, and 99.5% of isolates were inhibited at ≤8 μg/ml (1:1). The MIC values for cefepime-zidebactam at the 1:1 ratio were generally 2-fold lower than those for cefepime-zidebactam at the 2:1 ratio (MIC50/90 , 2/8 μg/ml) and zidebactam alone (MIC50/90 , 4/8 μg/ml). AgainstAcinetobacter spp., cefepime-zidebactam at 1:1 and 2:1 ratios (MIC50/90 , 16/32 μg/ml for both) was 4-fold more active than cefepime or ceftazidime. Zidebactam exhibited potentin vitro antimicrobial activity against some organisms. These results support the clinical development of WCK 5222 for the treatment of Gram-negative bacterial infections, including those caused by multidrug-resistant isolates.