title: WCK 5222 (Cefepime-Zidebactam) Antimicrobial Activity against Clinical Isolates of Gram-Negative Bacteria Collected Worldwide in 2015.
abstract: 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 vitroactivity of cefepime-zidebactam against 7,876 contemporary (2015) clinical isolates ofEnterobacteriaceae(n= 5,946),Pseudomonas aeruginosa(n= 1,291), andAcinetobacterspp. (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 individualEnterobacteriaceaespecies (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. aeruginosawith MIC50/90values 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). AgainstAcinetobacterspp., 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 vitroantimicrobial 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.
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA helio-sader@jmilabs.com.
authors.forename: Helio S
authors.initials: HS
authors.lastname: Sader
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Castanheira
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Huband
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Jones
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Flamm
mesh_terms: D000150:Acinetobacter / Q000187:drug effects* / Q000302:isolation & purification; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D000073182:Carbapenem-Resistant Enterobacteriaceae / Q000187:drug effects; D000077723:Cefepime; D002511:Cephalosporins / Q000494:pharmacology*; D034242:Cyclooctanes / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000302:isolation & purification; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy; D006801:Humans; D008826:Microbial Sensitivity Tests; D010880:Piperidines / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000302:isolation & purification; D001618:beta-Lactamases / Q000235:genetics; D004338:Drug Combinations
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D000077723:Cefepime; D002511:Cephalosporins; D034242:Cyclooctanes; D010880:Piperidines; D001618:beta-Lactamases; C000624485:cefepime-zidebactam; D004338:Drug Combinations; C000624484:zidebactam
keywords: CRE; KPC; MDR; XDR; carbapenem-resistant Enterobacteriaceae; metallo-β-lactamases