Ceftolozane/Tazobactam: A Novel Cephalosporin/β‐Lactamase Inhibitor Combination

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Abstract
Ceftolozane/tazobactam is a novel antipseudomonal β‐lactam/β‐lactamase inhibitor combination that is currently approved by the United States Food and Drug Administration for the treatment of complicated intraabdominal infections ( cIAI ) and complicated urinary tract infections ( cUTI ). It exhibits bactericidal properties through inhibition of bacterial cell wall biosynthesis, which is mediated through penicillin‐binding proteins ( PBP s). Ceftolozane is a potent PBP 3 inhibitor and has a higher affinity for PBP 1b compared with other β‐lactam agents. Ceftolozane/tazobactam differs from other cephalosporins due to its increased activity against some AmpC β‐lactamases and Pseudomonas aeruginosa . The addition of tazobactam provides enhanced activity against extended‐spectrum β‐lactamase ( ESBL )‐producing Enterobacteriaceae and certain anaerobic organisms. Population pharmacokinetic studies for ceftolozane and ceftolozane/tazobactam are best described by a two‐compartment model with zero‐order input and linear elimination. Similar to other cephalosporins, the best pharmacodynamic property to predict efficacy for ceftolozane/tazobactam is a concentration that remains above the minimum inhibitory concentration ( MIC ) for 40–50% of the dosing interval. For Enterobacteriaceae and P. aeruginosa strains, the time above the MIC (T > MIC ) needed to produce bactericidal activity was much less with ceftolozane than other cephalosporins, with T > MIC requirements of approximately 30%. For currently approved indications, the dose of ceftolozane/tazobactam is 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) intravenously every 8 hours given as a 1‐hour infusion. Ceftolozane has low plasma protein binding (20%) and is predominantly excreted unchanged in the urine (≥92%). Dosage adjustments are required for moderate‐to‐severe renal impairment and in patients receiving hemodialysis. Based on data from clinical trials, adverse effects due to ceftolozane/tazobactam do not differ considerably from other cephalosporins, with the most common being nausea, diarrhea, headache, and pyrexia. Ceftolozane/tazobactam is a promising new agent for the treatment of cIAI and cUTI , including those caused by multidrug‐resistant gram‐negative organisms.

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