The US Food and Drug Administration (FDA) has approved Actavis' Avycaz (ceftazidime-avibactam). Avycaz was approved for the treatment of adult patients with complicated intra-abdominal infections (cIAI) (in combination with metronidazole) and complicated urinary tract infections (cUTI) including pyelonephritis caused by designated susceptible bacteria, including certain Enterobacteriaceae and Pseudomonas aeruginosa.
Avycaz received a priority review based on phase II data from the company's clinical development programme and supporting in vitro data, and as such should be reserved for use in patients who have limited or no alternative treatment options.
Avycaz combines ceftazidime, a cephalosporin with in vitro activity against certain Gram-negative and Gram-positive bacteria, and avibactam, a non-beta-lactam beta-lactamase inhibitor that inactivates certain key beta-lactamases and protects ceftazidime from degradation by these beta-lactamases. The addition of avibactam to ceftazidime protects ceftazidime from breakdown by Extended Spectrum Beta-Lactamases (ESBL), Klebsiella pneumoniae carbapenemase (KPC) and AmpC producing pathogens. Avycaz is part of Actavis' leading portfolio of infectious disease products that address some of the most dangerous pathogens.
"The FDA approval of Avycaz is an important step forward in enhancing our ability to respond to serious infections caused by difficult to treat Gram-negative pathogens," says David Nicholson, executive vice president, Global Brands research and development, Actavis. "At Actavis, we are dedicated to helping bridge the gap in existing treatment options, and the development of new agents that may help address the urgent threat of these pathogens. We were very pleased to be working with the FDA to advance the approval of Avycaz as quickly as possible to make this important new treatment option available to physicians and patients at the earliest possible time."
Avycaz was granted priority review and approval as a Qualified Infectious Disease Product (QDIP) in accordance with the Generating Antibiotics Incentives Now (GAIN) Act, which made it eligible for the FDA's fast-track program and a five-year regulatory extension of exclusivity under the Hatch-Waxman Act.
"The recent increase in the incidence of multi-drug resistant Gram-negative pathogens poses a significant threat to patients and places a tremendous strain on the US healthcare system. The increasing prevalence of KPC-producing Enterobacteriaceae in particular, have become a major therapeutic challenge for physicians managing these infections. Unfortunately, there are currently a limited number of safe and effective antimicrobials to treat these serious infections," says Jose Vazquez, MD, FACP, FIDSA, Professor of Medicine, Chief, Infectious Diseases and Chair of the Antimicrobial Subcommittee at the Medical College of Georgia/Georgia Regents University.
The approval of Avycaz was supported in part by the FDA's previous findings of efficacy and safety for ceftazidime for the treatment of cIAI and cUTI. In addition, the contribution of avibactam to Avycaz was primarily established via in vitro data and animal models of infection. Avycaz was studied in two phase II, randomised, blinded, active-controlled, multicenter trials, one each in cIAI and cUTI, including pyelonephritis. These phase II studies were not designed with any formal hypotheses for inferential testing against the active comparators.
Avycaz (ceftazidime-avibactam) consists of ceftazidime, a cephalosporin, and avibactam, a non-beta-lactam beta-lactamase inhibitor, and is approved for the treatment of cIAI (in combination with metronidazole) and cUTI infections including pyelonephritis caused by designated susceptible microorganisms in patients 18 years of age and older. Avycaz should be reserved for use in patients who have limited or no alternative treatment options as limited clinical safety and efficacy data for Avycaz are currently available.
The addition of avibactam to ceftazidime protects ceftazidime from breakdown by certain beta-lactamases. Avycaz addresses important needs in the treatment of cUTI and cIAI due to designated susceptible Gram-negative pathogens.
Avycaz, in combination with metronidazole, is indicated for the treatment of cIAI caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Enterobacter cloacae, Klebsiella oxytoca and Pseudomonas aeruginosa.
Avycaz is indicated for the treatment of cUTI including pyelonephritis caused by the following susceptible microorganisms:Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Citrobacter freundii, Proteus spp. and Pseudomonas aeruginosa.
Avycaz demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC, and certain oxacillinases (OXA). Avycaz also demonstrated in vitro activity against P. aeruginosa in the presence of some AmpC beta-lactamases, and certain strains lacking outer membrane porin (OprD). Avycaz is not active against bacteria that produce metallo-beta lactamases and may not have activity against Gram-negative bacteria that overexpress efflux pumps or have porin mutations.
The recommended dosage of Avycaz for patients with normal renal function [creatinine clearance (CrCL) >50 mL/min] is 2.5 grams (2 grams ceftazidime and 0.5 grams avibactam) administered every 8 hours by intravenous (IV) infusion over two hours in patients 18 years of age and older. For patients with changing or impaired renal function (CrCL <50mL/min), CrCL should be monitored at least daily and the dosage of Avycaz should be adjusted accordingly. For treatment of cIAI, metronidazole should be given concurrently.