fr-264205 and Disease-Models--Animal

The aim of this study was to compare ceftolozane with ceftazidime, piperacillin/tazobactam (TZP) and imipenem in an experimental rabbit model of Pseudomonas aeruginosa pneumonia. Efficacy was assessed following 2 days of treatment by total colony counts in different tissues (lung, spleen and blood culture). Mean ± standard deviation pulmonary bacterial loads were 4.9 ± 0.3, 3.6 ± 0.3, 4.8 ± 0.2, 5.5 ± 0.8 and 3.9 ± 0.3 log₁₀CFU/g of lung for ceftolozane (1g), ceftolozane (2g), ceftazidime, TZP and imipenem, respectively, compared with 6.3 ± 0.9 log₁₀CFU/g of lung for control animals. The higher ceftolozane dose [2g three times daily (t.i.d.)] showed significantly better efficacy than the lower dose (1g t.i.d.). In conclusion, in this rabbit model of P. aeruginosa pneumonia, ceftolozane had an efficacy equivalent to that of comparator agents at a dose of 1g t.i.d. and had better efficacy at a higher dose (2g t.i.d.).

Topics: Animal Structures; Animals; Anti-Bacterial Agents; Bacterial Load; Ceftazidime; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Female; Humans; Imipenem; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits; Treatment Outcome

CXA-101 is a novel antipseudomonal cephalosporin with enhanced activity against Gram-negative organisms displaying various resistance mechanisms. This study evaluates the efficacy of exposures approximating human percent free time above the MIC (%fT > MIC) of CXA-101 with or without tazobactam and piperacillin-tazobactam (TZP) against target Gram-negative organisms, including those expressing extended-spectrum β-lactamases (ESBLs). Sixteen clinical Gram-negative isolates (6 Pseudomonas aeruginosa isolates [piperacillin-tazobactam MIC range, 8 to 64 μg/ml], 4 Escherichia coli isolates (2 ESBL and 2 non-ESBL expressing), and 4 Klebsiella pneumoniae isolates (3 ESBL and 1 non-ESBL expressing) were used in an immunocompetent murine thigh infection model. After infection, groups of mice were administered doses of CXA-101 with or without tazobactam (2:1) designed to approximate the %fT > MIC observed in humans given 1 g of CXA-101 with or without tazobactam every 8 h as a 1-h infusion. As a comparison, groups of mice were administered piperacillin-tazobactam doses designed to approximate the %fT > MIC observed in humans given 4.5 g piperacillin-tazobactam every 6 h as a 30-min infusion. Predicted piperacillin-tazobactam %fT > MIC exposures of greater than 40% resulted in static to >1 log decreases in CFU in non-ESBL-expressing organisms with MICs of ≤32 μg/ml after 24 h of therapy. Predicted CXA-101 with or without tazobactam %fT > MIC exposures of ≥37.5% resulted in 1- to 3-log-unit decreases in CFU in non-ESBL-expressing organisms, with MICs of ≤16 μg/ml after 24 h of therapy. With regard to the ESBL-expressing organisms, the inhibitor combinations showed enhanced CFU decreases versus CXA-101 alone. Due to enhanced in vitro potency and resultant increased in vivo exposure, CXA-101 produced statistically significant reductions in CFU in 9 isolates compared with piperacillin-tazobactam. The addition of tazobactam to CXA-101 produced significant reductions in CFU for 7 isolates compared with piperacillin-tazobactam. Overall, human simulated exposures of CXA-101 with or without tazobactam demonstrated improved efficacy versus piperacillin-tazobactam.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Drug Combinations; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Penicillanic Acid; Phenotype; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam; Thigh