fr-264205 and Enterobacteriaceae-Infections

This study evaluated the in vitro activity of ceftolozane-tazobactam and comparator agents tested against Enterobacteriaceae and Pseudomonas aeruginosa isolates from hospitalized patients in the United States. Ceftolozane-tazobactam is an antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor. A total of 18,960 organisms (15,223 Enterobacteriaceae and 3,737 P. aeruginosa) were consecutively collected from 32 medical centers located in all nine U.S. census divisions from 2013 to 2016. Organisms were tested for susceptibility by broth microdilution. CLSI and EUCAST interpretive criteria were used. Ceftolozane-tazobactam (94.4% susceptible), amikacin (99.0% susceptible), and meropenem (98.0% susceptible) were the most active compounds tested against Enterobacteriaceae. Among the Enterobacteriaceae isolates tested, 1.9% (n = 286) were carbapenem-resistant Enterobacteriaceae (CRE) and 9.5% (n = 1,450) exhibited an extended-spectrum β-lactamase (ESBL) non-CRE phenotype. Although ceftolozane-tazobactam showed good activity against ESBL non-CRE phenotype strains of Enterobacteriaceae (87.5% susceptible), it lacked useful activity against CRE. Ceftolozane-tazobactam was the most potent β-lactam agent tested against P. aeruginosa isolates, with 97.3% susceptible. Only colistin was more active, inhibiting 99.5% of isolates. Ceftolozane-tazobactam also maintained good activity against multidrug-resistant P. aeruginosa, with 88.6% susceptible. Ceftolozane-tazobactam was the most active β-lactam agent tested against P. aeruginosa and was more active than available cephalosporins and piperacillin-tazobactam against Enterobacteriaceae.

Topics: Amikacin; Anti-Bacterial Agents; Cephalosporins; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Hospitals; Humans; Meropenem; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam; Thienamycins

Ceftolozane, formally CXA-101, is a new antipseudomonal cephalosporin that is also active in vitro against Enterobacteriaceae but is vulnerable to extended-spectrum β-lactamases (ESBLs). The addition of tazobactam is intended to broaden coverage to most ESBL-producing Escherichia coli and Klebsiella pneumonia as well as other Enterobacteriaceae. The in vitro activities of ceftolozane-tazobactam combinations against 67 clinically and molecularly characterized ESBL-producing isolates were examined by checkerboard MIC testing to evaluate their potential clinical feasibility and to assess the optimal tazobactam concentrations to be used in MIC determinations of ceftolozane. Isolates included those from E. coli (n = 32), K. pneumoniae (n = 19), Enterobacter cloacae (n = 15), and Citrobacter freundii (n = 1). Checkerboard experiments were performed to study interactions over the range of 0.008 to 64 mg/liter ceftolozane and 0.063 to 32 mg/liter tazobactam using 2-fold-dilution series. The MIC50 and MIC90 of ceftolozane alone for all isolates were 16 and ≥64 mg/liter, respectively. Increasing concentrations of tazobactam resulted in decreasing MICs of ceftolozane. The 50th and 90th percentile concentrations of tazobactam required to reduce the MIC of ceftolozane to 8 mg/liter for all organisms in this ESBL collection were 0.5 and 4 mg/liter, respectively. For E. coli, K. pneumoniae, and E. cloacae, these values were 0.5 and 2, 1 and 16, and 0.5 and 4 mg/liter, respectively. When combined with a fixed amount of 4 mg/liter tazobactam (current CLSI concentration used for susceptibility testing), 90% of the isolates would have an MIC of ≤4 mg/liter. The combination ceftolozane-tazobactam is a promising alternative option for treating infections due to ESBL-harboring isolates.

Topics: Anti-Bacterial Agents; beta-Lactamases; Cephalosporins; Drug Therapy, Combination; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Tazobactam

To evaluate the in vitro activity of ceftolozane/tazobactam and comparator agents tested against contemporary Gram-negative bacteria. Ceftolozane/tazobactam is an antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor.. A total of 10 532 Gram-negative organisms (2191 Pseudomonas aeruginosa and 8341 Enterobacteriaceae) were consecutively collected from 31 medical centres located in 13 European countries plus Turkey and Israel. The organisms were tested for susceptibility by broth microdilution methods as described by the CLSI M07-A9 document and the results interpreted according to EUCAST as well as CLSI breakpoint criteria. Selected ceftazidime- and/or meropenem-resistant P. aeruginosa isolates were screened for the presence of β-lactamase genes by PCR.. P. aeruginosa exhibited high rates of multidrug-resistant (31.9%) and extensively drug-resistant (24.6%) isolates and 11.6% of isolates were susceptible only to colistin. When tested against P. aeruginosa, ceftolozane/tazobactam (MIC(50), 1 mg/L) was generally 4-fold more active than ceftazidime (MIC(50), 4 mg/L) and inhibited >90% of isolates with an MIC of ≤8 mg/L in nine countries. In contrast, the highest susceptibility rates observed for ceftazidime and meropenem, respectively, were 86.0%/86.0% (UK) and 85.2%/86.1% (Ireland) (67.2%/67.1% overall). Ceftolozane/tazobactam (MIC(50/90), 0.25/2 mg/L; 93.7% and 95.2% inhibited at ≤4 and ≤8 mg/L, respectively), meropenem [MIC(50/90), ≤0.06/≤0.06 mg/L; 98.0% susceptible (EUCAST)] and tigecycline [MIC(50/90), 0.12/1 mg/L; 94.1% susceptible (EUCAST)] were the most active compounds tested against Enterobacteriaceae.. Ceftolozane/tazobactam was the most active β-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than currently available cephalosporins and piperacillin/tazobactam when tested against Enterobacteriaceae.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamase Inhibitors; Cephalosporins; Cross Infection; Enterobacteriaceae; Enterobacteriaceae Infections; Europe; Genotype; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam