Impact of Renal Function on the Pharmacokinetics and Safety of Ceftolozane-Tazobactam
Open Access
- 1 April 2014
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 58 (4), 2249-2255
- https://doi.org/10.1128/aac.02151-13
Abstract
Ceftolozane-tazobactam is a novel antipseudomonal cephalosporin with a β-lactamase inhibitor. We investigated the pharmacokinetics (PK) and safety of ceftolozane-tazobactam in subjects with various degrees of renal function. In two phase I, open-label studies, a single dose of ceftolozane-tazobactam was administered as a 1-h intravenous infusion to 24 subjects with normal, mild, or moderate renal impairment (1,000/500 mg) and six subjects with severe renal impairment (500/250 mg). Six subjects with end-stage renal disease (ESRD) received two doses of ceftolozane-tazobactam (500/250 mg each), pre- and posthemodialysis (post-HD). PK parameters were determined by noncompartmental methods. Plasma exposure to ceftolozane-tazobactam increased as renal function declined with only slightly increased exposures in subjects with mild renal impairment; the median area under the concentration-time curve from time zero to infinity (AUC0-∞) for ceftolozane and tazobactam increased 1.4- and 1.2-fold, respectively. In subjects with moderate renal impairment, the AUC0-∞ increased 2.5- and 2.2-fold for ceftolozane and tazobactam, respectively. In subjects with severe renal impairment, the dose-normalized median AUC0-∞ for ceftolozane and tazobactam increased 4.4- and 3.8-fold, respectively. In ESRD subjects, ceftolozane and tazobactam concentrations declined rapidly following the start of HD, with approximately 66 and 56% reductions in overall exposure based on the AUC0-∞ before and after dialysis. Slight increases in exposure with mild renal impairment do not warrant a dose adjustment; however, subjects with moderate or severe renal impairment and those on HD require a decrease in the dose, a change in the frequency of administration, or both to achieve exposures within the established safety and efficacy margins of ceftolozane-tazobactam. Ceftolozane-tazobactam was well tolerated by all renal impairment groups.This publication has 11 references indexed in Scilit:
- Pharmacological Basis of β-Lactamase Inhibitor Therapeutics: Tazobactam in Combination with CeftolozaneAntimicrobial Agents and Chemotherapy, 2013
- 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 MiceAntimicrobial Agents and Chemotherapy, 2013
- Pharmacokinetics and Safety of Intravenous Ceftolozane-Tazobactam in Healthy Adult Subjects following Single and Multiple Ascending DosesAntimicrobial Agents and Chemotherapy, 2012
- Antimicrobial Activity of CXA-101, a Novel Cephalosporin Tested in Combination with Tazobactam against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides fragilis Strains Having Various Resistance PhenotypesAntimicrobial Agents and Chemotherapy, 2011
- In vitro activity of CXA-101 plus tazobactam (CXA-201) against CTX-M-14– and CTX-M-15–producing Escherichia coli and Klebsiella pneumoniaeDiagnostic Microbiology and Infectious Disease, 2011
- New AUC-Based Method to Estimate Drug Fraction Removed by HemodialysisKidney and Blood Pressure Research, 2004
- Basic pharmacodynamics of antibacterials with clinical applications to the use of β-lactams, glycopeptides, and linezolidInfectious Disease Clinics of North America, 2003
- State‐of‐the‐Art Clinical Article: Pharmacokinetic/Pharmacodynamic Parameters: Rationale for Antibacterial Dosing of Mice and MenClinical Infectious Diseases, 1998
- Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporinsDiagnostic Microbiology and Infectious Disease, 1995
- Single-dose pharmacokinetics of piperacillin and tazobactam in patients with renal diseaseClinical Pharmacology & Therapeutics, 1992