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 ␤-lactam enhancer antibiotic with a dual action involving binding to Gram-negative bacterial PBP2 and ␤-lactamase inhibition. We evaluated the in vitro activity of cefepime-zidebactam against 7,876 contemporary (2015) clinical isolates of Enterobacteriaceae (n ϭ 5,946), Pseudomonas aeruginosa (n ϭ 1,291), and Acinetobacter spp. (n ϭ 639) from the United States (n ϭ 2,919), Europe (n ϭ 3,004), the Asia-Pacific (n ϭ 1,370), and Latin America (n ϭ 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. Cefepimezidebactam was the most active compound tested against Enterobacteriaceae (MIC 50/ 90, Յ0.03/0.12 g/ml [1:1] and 0.06/0.25 g/ml [2:1]; 99.9% of isolates were inhibited at Յ4 [1:1] and Յ8 g/ml [2:1]). Cefepime-zidebactam was active against individual Enterobacteriaceae species (MIC 50/90 , Յ0.03 to 0.06/Յ0.03 to 0.5 g/ml [1:1]) and retained potent activity against carbapenem-resistant isolates (MIC 50/90 , 1/4 g/ml; 99.3% of isolates were inhibited at Յ8 g/ml [1:1]). Cefepime-zidebactam activity was consistent among geographic regions, and only one isolate showed MIC values of Ͼ8 g/ml (1:1). Cefepime-zidebactam was also very active against P. aeruginosa with MIC 50/90 values of 1/4 g/ml, and 99.5% of isolates were inhibited at Յ8 g/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 (MIC 50/90 , 2/8 g/ ml) and zidebactam alone (MIC 50/90 , 4/8 g/ml). Against Acinetobacter spp., cefepime-zidebactam at 1:1 and 2:1 ratios (MIC 50/90 , 16/32 g/ml for both) was 4-fold more active than cefepime or ceftazidime. Zidebactam exhibited potent in 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.KEYWORDS carbapenem-resistant Enterobacteriaceae, CRE, MDR, XDR, KPC, metallo-␤-lactamases T he trend of increasing antimicrobial resistance is most troublesome for Gramnegative bacteria because few antimicrobial agents targeting this group of organisms have been developed successfully (1). The occurrence of carbapenemaseproducing Enterobacteriaceae has increased rapidly in the last few years in some geographic regions (2-4). In particular, clonal Klebsiella pneumoniae strains with K. pneumoniae carbapenemases (KPC; class A carbapenemases) have disseminated widely in the United States, Israel, and some European countries (3-7). We are now facing infections caused by extensively drug-resistant (XDR) and pandrug-resistant (PDR) organisms that are resistant to all (PDR) or almost all (XDR) antimicrobial agents

In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) against Multidrug-Resistant Pseudomonas aeruginosa in the Neutropenic Murine Thigh Infection Model

“…Our findings support the clinical translatability of previous in vitro data demonstrating zidebactam's enhancement of the activity of ␤-lactams against P. aeruginosa exhibiting various resistance mechanisms, including isolates resistant to ceftolozane-tazobactam, an agent often reserved for infections caused by MDR P. aeruginosa (3). Furthermore, our data demonstrated potent WCK 5222 in vivo activity against P. aeruginosa isolates at the top 10% of the WCK 5222 MIC distribution (7,8). In summary, data derived in the present study display the in vitro and in vivo activities of WCK 5222 against MDR and metallo-␤-lactamaseproducing P. aeruginosa, as well as assist with the delineation of the MIC susceptibility breakpoints.…”

In Vivo Efficacy of Humanized WCK 5222 (Cefepime-Zidebactam) Exposures against Carbapenem-Resistant Acinetobacter baumannii in the Neutropenic Thigh Model

“…In the neutropenic lung model, the authors demonstrated a Ͼ2-log 10 reduction in bacterial burden upon the administration of WCK 5222 HSR against 12 meropenem-resistant A. baumannii isolates with WCK 5222 MICs of 16 to 64 mg/liter, despite achieving %fT ϾMICs of cefepime and zidebactam in plasma as low as ϳ20% and ϳ4%, respectively, as shown in Table 1 (9). Previously published in vitro data demonstrated that zidebactam has the capability to potentiate the activity of cefepime against carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa isolates, as evidenced by the marked decline in WCK 5222 MICs relative to those of cefepime alone (13,14). However, zidebactam has been shown to cause a modest potentiation of cefepime against A. baumannii in vitro, as the WCK 5222 MICs remained high (Ն16 mg/liter).…”

In Vitro and In Vivo Activities of β-Lactams in Combination with the Novel β-Lactam Enhancers Zidebactam and WCK 5153 against Multidrug-Resistant Metallo-β-Lactamase-Producing Klebsiella pneumoniae

“…In previous works, our group has shown that two novel bicyclo-acyl hydrazide (BCH) ␤-lactam enhancers (BLEs), zidebactam and WCK 5153, selectively bind penicillin binding protein 2 (PBP2) of Acinetobacter baumannii and Pseudomonas aeruginosa (14,15). In these organisms, both compounds, through their PBP2 binding-driven ␤-lactam enhancer action, have demonstrated the ability to overcome several carbapenem resistance mechanisms in combination with ␤-lactams (13,(15)(16)(17). In the present study, we show for the first time the PBP binding profiles of BCH compounds and comparators for another clinically significant pathogen, K. pneumoniae, and the synergistic bactericidal action of these BLEs in combination with ␤-lactams (cefepime and aztreonam).…”