11 September 2018 - - Apivotal Phase 3 clinical study evaluating US-based pharmaceutical company Merck and Co., Inc.'s (NYSE: MRK) antibiotic Zerbaxa (ceftolozane and tazobactam) at an investigational dose for the treatment of adult patients with either ventilated hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia met the pre-specified primary endpoints, demonstrating non-inferiority to meropenem, the active comparator, in Day 28 all-cause mortality and in clinical cure rate at the test-of-cure visit.

In the US, Zerbaxa is currently indicated in adult patients for the treatment of complicated urinary tract infections, including pyelonephritis, caused by certain Gram-negative microorganisms, and is indicated, in combination with metronidazole, in adult patients for the treatment of complicated intra-abdominal infections caused by certain Gram-negative and Gram-positive microorganisms.

Based on these results, Merck plans to submit supplemental new drug applications to the US Food and Drug Administration and European Medicines Agency seeking regulatory approval of Zerbaxa for this potential new indication.

The company plans to submit results from the study for presentation at a future scientific conference.

This prospective, randomised, double-blind, multicenter, non-inferiority, Phase 3 study assessed the safety and efficacy of Zerbaxa compared with meropenem in 726 adult patients diagnosed with either ventilated HABP or VABP requiring intravenous antibiotic therapy.

In the study, Zerbaxa was administered in an investigational 3g dose compared with meropenem 1g, each given intravenously every eight hours for eight to 14 days, or for 14 days for Pseudomonas aeruginosa infection. Meropenem is an approved broad-spectrum injectable antibiotic widely used to treat serious infections.

Zerbaxa is an antibacterial combination product for intravenous infusion consisting of the cephalosporin antibacterial drug ceftolozane sulfate and the beta-lactamase inhibitor tazobactam sodium.

Zerbaxa 1.5g (ceftolozane 1g and tazobactam 0.5g) is approved in the United States and is indicated in adult patients for the treatment of complicated urinary tract infections, including pyelonephritis, caused by the following Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.

Zerbaxa used in combination with metronidazole is indicated in adult patients for the treatment of 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.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zerbaxa and other antibacterial drugs, Zerbaxa should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Patients with renal impairment: Decreased efficacy of Zerbaxa has been observed in patients with baseline creatinine clearance of 30 to ≤50 mL/min. In a clinical trial, patients with cIAIs with CrCl >50 mL/min had a clinical cure rate of 85.2% when treated with Zerbaxa (ceftolozane and tazobactam) plus metronidazole vs. 87.9% when treated with meropenem.

In the same trial, patients with CrCl 30 to ≤50 mL/min had a clinical cure rate of 47.8% when treated with Zerbaxa plus metronidazole vs. 69.2% when treated with meropenem. A similar trend was also seen in the cUTI trial. Monitor CrCl at least daily in patients with changing renal function and adjust the dose of Zerbaxa accordingly.

Zerbaxa is contraindicated in patients with known serious hypersensitivity to ceftolozane/tazobactam, piperacillin/tazobactam, or other members of the beta-lactam class.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials.

Before initiating therapy with Zerbaxa, make careful inquiry about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactams. If an anaphylactic reaction to Zerbaxa occurs, discontinue use and institute appropriate therapy.

Clostridium difficile–associated diarrhea, ranging from mild diarrhea to fatal colitis, has been reported with nearly all systemic antibacterial agents, including Zerbaxa.

Careful medical history is necessary because CDAD has been reported to occur more than two months after the administration of antibacterial agents. If CDAD is confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible.

Development of drug-resistant bacteria: Prescribing Zerbaxa in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Adverse reactions: The most common adverse reactions occurring in ≥5% of patients were headache in the cUTI trial, and nausea, diarrhea and pyrexia in the cIAI trial.

For more than 100 years, Merck has contributed to the discovery and development of novel medicines and vaccines to combat infectious diseases.

In addition to a combined portfolio of antibiotic, antiviral and antifungal medicines, vaccines, and medicines for HIV and HCV, Merck has multiple programmes that span discovery through late-stage development. Merck currently has eight compounds in Phase 2/Phase 3 clinical trials for the potential treatment or prevention of infectious diseases.