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

Ceftolozane is a new cephalosporin with potent activity against Pseudomonas aeruginosa and Enterobacteriaceae. A neutropenic murine thigh infectionmodel was used to determine which pharmacokinetic/pharmacodynamic index andmagnitude drives the efficacy of ceftolozane with Gram-negative bacilli, to compare the rates of in vivo killing of P. aeruginosa by ceftolozane and cef-tazidime, and to determine the impact of different ratios of ceftolozane plus tazobactam on Enterobacteriaceae containing ex-tended-spectrum -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 two Enterobacteriaceae strains, (ii) 0.39 to 800 mg/kg every 6 h for four Enterobacteriaceae and four P. aeruginosa strains, and (iii) 400 or 800 mg/kg with 2:1. 4:1, and 8:1 ratios of tazobactam against five Enterobacteriaceae 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>MICwas the primary index driving effi-cacy. For stasis (1 log kill), T>MICwas 26.3% 2.1 % (31.6% 1.6%) for wild-type Enterobacteriaceae, 31.1% 4.9 % (34.8% 4.4%) for Enterobacteriaceaewith ESBLs, and 24.0% 3.3 % (31.5% 3.9%) for P. aeruginosa. At 200 mg/kg every 3 h, the rate of in vivo killing of P. aeruginosa was faster with ceftolozane than with ceftazidime (0.34 to0.41 log10 CFU/thigh/h versus 0.21 to0.24 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 andmay be due to more rapid killing. Enterobacteriaceae and Pseudomonas aeruginosa have been caus-ing increasing numbers of nosocomial infections, especially i