In Vivo Activities of Ceftolozane, a New Cephalosporin, with and without Tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae, Including Strains with Extended-Spectrum β-Lactamases, in the Thighs of Neutropenic Mice

Ceftolozane is a new cephalosporin with potent activity againstPseudomonas aeruginosa andEnterobacteriaceae . A neutropenic murine thigh infection model was used to determine which pharmacokinetic/pharmacodynamic index and magnitude drives the efficacy of ceftolozane with Gram-negative bacilli, to compare the rates ofin vivo killing ofP. aeruginosa by ceftolozane and ceftazidime, and to determine the impact of different ratios of ceftolozane plus tazobactam onEnterobacteriaceae containing extended-spectrum β-lactamases (ESBLs). Neutropenic mice had 106.2-7.1 CFU/thigh when treated with ceftolozane for 24 h with (i) various doses (3.12 to 1,600 mg/kg) and dosage intervals (3, 6, 12, and 24 h) against twoEnterobacteriaceae strains, (ii) 0.39 to 800 mg/kg every 6 h for fourEnterobacteriaceae and fourP. aeruginosa strains, and (iii) 400 or 800 mg/kg with 2:1. 4:1, and 8:1 ratios of tazobactam against fiveEnterobacteriaceae strains with ESBLs. The pharmacokinetics of ceftolozane at 25, 100, and 400 mg/kg were linear with peak/dose values of 1.0 to 1.4 and half-lives of 12 to 14 min. T>MIC was the primary index driving efficacy. For stasis (1 log kill), T>MIC was 26.3% ± 2.1% (31.6% ± 1.6%) for wild-typeEnterobacteriaceae , 31.1% ± 4.9% (34.8% ± 4.4%) forEnterobacteriaceae with ESBLs, and 24.0% ± 3.3% (31.5% ± 3.9%) forP. aeruginosa . At 200 mg/kg every 3 h, the rate ofin vivo killing ofP. aeruginosa was faster with ceftolozane than with ceftazidime (−0.34 to −0.41 log10 CFU/thigh/h versus −0.21 to −0.24 log10 CFU/thigh/h). The 2:1 ratio of ceftolozane with tazobactam was the most potent combination studied. The T>MIC required for ceftolozane is less than with other cephalosporins and may be due to more rapid killing.