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

• Published in: Antimicrobial agents and chemotherapy Vol. 60; no. 12; pp. 7272 - 7279
• Main Authors: Melchers, M J, Mavridou, E, van Mil, A C, Lagarde, C, Mouton, J W
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.12.2016
• Subjects: Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; beta-Lactamases - genetics; Cephalosporins; Cephalosporins - pharmacokinetics; Cephalosporins - pharmacology; Drug Therapy, Combination; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - genetics; Escherichia coli - growth & development; Escherichia coli Proteins - genetics; Female; Klebsiella pneumoniae; Klebsiella pneumoniae - drug effects; Klebsiella pneumoniae - genetics; Klebsiella pneumoniae - growth & development; Mice; Microbial Sensitivity Tests; Penicillanic Acid; Penicillanic Acid - analogs & derivatives; Penicillanic Acid - pharmacokinetics; Penicillanic Acid - pharmacology; Pharmacology
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01580-16

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 R 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 C of 0.5 mg/liter tazobactam.