General Information

Zerbaxa is a combination of ceftolozan, a novel cephalosporin, and tazobactam, a beta-lactamase inhibitor. 

Zerbaxa is specifically indicated for the treatment of patients 18 years or older with the following infections caused by designated susceptible microorganisms:

Complicated intra-abdominal infections

• caused by the following Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius.

Complicated Urinary Tract Infections, including Pyelonephritis

• caused by the following Gram-negative microorganisms: Escherichiacoli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa. 

Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP)

• caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Serratia marcescens.

Zerbaxa is supplied as a solution for intravenous infusion. The recommended dosage regimen of Zerbaxa (ceftolozane/tazobactam) for Injection is 1.5 g (1 g/0.5 g) administered every 8 hours by intravenous infusion over 1 hour in patients 18 years or older and with normal renal function or mild renal impairment. The duration of therapy should be guided by the severity and site of infection and the patient’s clinical and bacteriological progress.

Mechanism of Action

Zerbaxa is a combination of ceftolozane and tazobactam. Ceftolozane belongs to the cephalosporin class of antibacterial drugs. The bactericidal action of ceftolozane results from inhibition of cell wall biosynthesis, and is mediated through binding to penicillin-binding proteins (PBPs). Ceftolozane is an inhibitor of PBPs of P. aeruginosa (e.g. PBP1b, PBP1c, and PBP3) and E. coli (e.g., PBP3). Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is an irreversible inhibitor of some beta-lactamases (e.g., certain penicillinases and cephalosporinases), and can bind covalently to some chromosomal and plasmid-mediated bacterial beta-lactamases. 

Side Effects

Adverse effects associated with the use of Zerbaxa may include, but are not limited to, the following:

• nausea
• diarrhea
• headache
• pyrexia

Adverse reactions associated with the use of Zerbaxa for bacterial pneumonia may include, but are not limited to, the following: 

• hepatic transaminase increased
• renal impairment/renal failure
• diarrhea
• intracranial hemorrhage
• vomiting
• Clostridium difficile colitis

Clinical Trial Results

The FDA approval of Zerbaxa was based on the following studies:

Complicated Intra-Abdominal Infections:

A multinational, double-blind enrolled 979 adults hospitalized with cIAI who were randomized to Zerbaxa (ceftolozane/tazobactam 1 g/0.5 g intravenously every 8 hours) plus metronidazole (500 mg intravenously every 8 hours) or meropenem (1 g intravenously every 8 hours) for 4 to 14 days of therapy. The primary efficacy endpoint was clinical response, defined as complete resolution or significant improvement in signs and symptoms of the index infection at the test-of-cure (TOC) visit which occurred 24 to 32 days after the first dose of study drug. The primary efficacy analysis population was the microbiological intent-to-treat (MITT) population, which included all patients who had at least 1 baseline intra-abdominal pathogen regardless of the susceptibility to study drug. The MITT population consisted of 806 patients. Zerbaxa plus metronidazole was non-inferior to meropenem with regard to clinical cure rates at the TOC visit in the MITT population; 83% and 87.3%, respectively. 

Complicated Urinary Tract Infections

A multinational, double-blind study enrolled 1,068 adults hospitalized with cUTI (including pyelonephritis) who were randomized to Zerbaxa (ceftolozane/tazobactam 1 g/0.5 g intravenously every 8 hours) or levofloxacin (750 mg intravenously once daily) for 7 days of therapy. The primary efficacy endpoint was defined as complete resolution or marked improvement of the clinical symptoms and microbiological eradication. The primary efficacy analysis population was the microbiologically modified intent-to-treat (mMITT) population, which included all patients who received study medication and had at least 1 baseline uropathogen. The mMITT population consisted of 800 patients with cUTI, including 656 (82%) with pyelonephritis. Zerbaxa demonstrated efficacy with regard to the composite endpoint of microbiological and clinical cure at the TOC visit in both the mMITT and ME populations. In the mMITT population, the composite cure rate in Zerbaxa-treated patients with concurrent bacteremia at baseline was 23/29 (79.3%). Although a statistically significant difference was observed in the Zerbaxa arm compared to the levofloxacin arm with respect to the primary endpoint, it was likely attributable to the 212/800 (26.5%) patients with baseline organisms non-susceptible to levofloxacin. Among patients infected with a levofloxacin-susceptible organism at baseline, the response rates were similar.

Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP)

A total of 726 adult patients hospitalized with HABP/VABP were enrolled in a multinational, double-blind study comparing Zerbaxa 3g (ceftolozane 2g and tazobactam 1g) intravenously every 8 hours to meropenem (1g intravenously every 8 hours) for 8 to 14 days of therapy. All patients had to be intubated and on mechanical ventilation at randomization. Efficacy was assessed based on all-cause mortality at Day 28 and clinical cure, defined as complete resolution or significant improvement in signs and symptoms of the index infection at the test-of-cure (TOC) visit which occurred 7 to 14 days after the end of treatment. The analysis population was the intent-to-treat (ITT) population, which included all randomized patients. Zerbaxa (ceftolozane and tazobactam) was non-inferior to meropenem for 28-day all-cause mortality in the ITT population (all randomized patients), 24.0% (87/362) and 25.3% (92/364) respectively, for a weighted proportion difference of 1.1. In addition, Zerbaxa was non-inferior to meropenem for clinical response at Test-of-Cure (7-14 days after the end of therapy) in the ITT population, 54.4% (197/362) and 53.3% (194/364) respectively, for a weighted proportion difference of 1.1. In the ventilated HABP sub-group, a favorable response for Zerbaxa in 28-day all-cause mortality was observed, 24.2% (24/99) for Zerbaxa and 37.0% (40/108) for meropenem, respectively, for a weighted proportion difference of 12.8. In the VABP subgroup, 28-day all-cause mortality was 24.0% (63/263) for Zerbaxa and 20.3% (52/256) for meropenem, for a weighted proportion difference of -3.6.