Ceftolozane

Ceftolozane/tazobactam (TOL-TAZ), sold under the brand name Zerbaxa, is a combination antibiotic. It is used for the treatment of complicated urinary tract infections and complicated intra abdominal infections. Ceftolozane is a cephalosporin antibiotic, developed for the treatment of infections with gram-negative bacteria that have become resistant to conventional antibiotics. It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia. Ceftolozane/tazobactam (TOL-TAZ), sold under the brand name Zerbaxa, is a combination antibiotic. It is used for the treatment of complicated urinary tract infections and complicated intra abdominal infections. Ceftolozane is a cephalosporin antibiotic, developed for the treatment of infections with gram-negative bacteria that have become resistant to conventional antibiotics. It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia. Ceftolozane is combined with the β-lactamase inhibitor tazobactam, which protects ceftolozane from degradation. It was approved for medical use in the United States in 2014. Ceftolozane contains a 7-aminothiadiazole, affording increased activity against gram-negative organisms, as well as an alkoximino group, providing sta­bility against many β-lactamases. Ceftolozane has a dimethylacetic acid moiety that con­tributes to enhanced activity against P. aeruginosa. The addition of a bulky side chain (a pyrazole ring) at the 3-position prevents hydrolysis of the β-lactam ring via steric hindrance. Tazobactam is a penicillinate sul­fone β-lactamase inhibitor, which confers protection to the β-lactam ring. Ceftolozane exerts bactericidal activities against susceptible gram-negative and gram-positive infections by inhibiting essential penicillin-binding proteins (PBPs), which are required for peptidoglycan cross-linking for bacterial cell wall synthesis, resulting in inhibition of cell wall synthesis and subsequent cell death. Ceftolozane is an inhibitor of PBPs of P. aeruginosa (e.g. PBP1b, PBP1c, and PBP3) and E. coli (e.g., PBP3). Tazobactam is a potent β-lactamase inhibitor of most common class A and C β-lactamases. Tazobactam has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins; however, it is an irreversible inhibitor of some β-lactamase (certain penicillinases and cephalosporinases) and can covalently bind to some chromosomal and plasmid-mediated bacterial beta-lactamases. The addition of tazobactam strengthens the therapeutic response to ceftolozane, giving it the ability to treat a broader range of bacterial infections and resistant organisms. Ceftolozane–tazobactam is available as a 2:1 fixed combination (such that a 1.5-g dose of ceftolozane–tazobactam is composed of 1 g of ceftolozane and 500 mg of tazobactam). Ceftolozane-tazobactam is administered intravenously. For both ceftolozane and tazobactam, the peak plasma concentration occurs immediately after a 60-minute infusion, with a time to maximum concentration (tmax) of approximately one hour.The binding of ceftolozane to human plasma proteins is approximately 16% to 21%, while the binding of tazobactam is approximately 30%. The mean steady-state volume of distribution in healthy adult males after a single 1.5 g IV dose is 13.5 L for ceftolozane and 18.2 L for tazobactam, which is similar to extracellular fluid volume. Tissue distribution of ceftalozone-tazobactam is rapid and shows good penetration into the lung, rendering it an ideal treatment for bacterial pneumonia. The metabolism and excretion of ceftolo­zane are similar to those of most b-lactam antimicrobial agents. Certolozane is not metabolized to any significant extent and thus predominantly eliminated unchanged in the urine. Tazobac­tam is partially metabolized to an in­active metabolite, and both drug and metabolite are excreted in the urine (80% as unchanged drug).