Pharmacodynamics of Ceftolozane Combined with Tazobactam against Enterobacteriaceae in a Neutropenic Mouse Thigh Model.

Ceftolozane is a new broad-spectrum cephalosporin and is combined with tazobactam to broaden the activity of ceftolozane against strains producing extended-spectrum beta-lactamases (ESBLs). We determined the pharmacodynamics (PD) of the combination in the neutropenic mouse thigh model to determine the optimal exposure of tazobactam. Treatment of CD-1 neutropenic mice was started 2 h after infection with ceftolozane every 2 h (q2h) alone or in combination with tazobactam at different dosing frequencies for 24 h, and the number of CFU in the thighs was determined before and after treatment. The maximum effect model was fit to the dose-response and the pharmacokinetic/PD index (PDI)-response to determine the PDI values for ceftolozane alone and ceftolozane in combination with tazobactam resulting in a static effect and a 1-log kill. The effect of tazobactam was dependent on the percentage of time that the free drug concentration remained above the concentration threshold (percent [Formula: see text]), whereby dosing q2h was more efficacious than dosing every 8 h (q8h), reducing the tazobactam daily dose by a factor 6.9 to 59.0 (n = 3 strains) to obtain a static effect. Using R2 as an indicator of the best fit of the percent [Formula: see text]-response relationships, the concentration threshold best correlating with the response varied from 0.5 to 2 mg/liter, depending on the strain. A similar result was obtained when the q2h and q8h regimens were analyzed. For all isolates tested, the mean [Formula: see text] for 0.5 mg/liter tazobactam was 28.2% (range, 17.5 to 45.8%) and 44.4% (range, 26.6 to 54.7%) for a static effect and a 1-log kill, respectively, at ceftolozane exposures that produced a ceftolozane concentration of 4 mg/liter (a concentration greater than the MIC) for 33.9 to 63.3% of a 24-h period under steady-state pharmacokinetic conditions. The main PDI that correlated with the effect of tazobactam was the [Formula: see text] achieved with a CT of 0.5 mg/liter tazobactam.

Plasma and epithelial lining fluid pharmacokinetics of ceftolozane and tazobactam alone and in combination in mice.

Ceftolozane is a new cephalosporin with activity against Gram-negative and Gram-positive microorganisms. However, the compound is susceptible to degradation by extended-spectrum beta-lactamases (ESBLs). Tazobactam is an ESBL inhibitor and is combined with ceftolozane to broaden its activity. Surprisingly, although tazobactam has been available for over 20 years, few if any reliable data exist on the tazobactam pharmacokinetic (PK) properties in mice. To evaluate the PK and pharmacodynamic (PD) relationships in mice, the PK properties of tazobactam and ceftolozane were extensively investigated. Thigh-infected neutropenic CD-1 mice were injected intraperitoneally with a single 0.1-ml dose containing ceftolozane, tazobactam, or both compounds. Ceftolozane was applied in 2-fold-increasing doses of 4 mg/kg of body weight to 64 mg/kg alone or in combination. Tazobactam was combined in reverse doses (thus, 64/4 mg/kg, 32/8 mg/kg, etc.) (n = 2 per time point). In separate validation experiments, ceftolozane-tazobactam was given alone or in combination at 32/8 mg/kg and 8/32 mg/kg (n = 4 per time point). Plasma samples (one per mouse) and bronchoalveolar lavage samples were collected at up to 12 time points until 6 h after administration. There were no significant differences in the ceftolozane and tazobactam PK alone versus combined, indicating no PK interaction. The PKs were linear and dose proportional for both compounds and showed a good penetration in the epithelial lining fluid. The estimated mean (standard deviation) half-life of ceftolozane was 0.287 h (0.031 h), and that of tazobactam was 0.176 h (0.026), and the V was 0.43 liter/kg and 1.14 liter/kg, respectively. The estimates of tazobactam parameters can also be used to (re)interpret PD data.