Ceftazidime/avibactam

Ceftazidime/avibactam
Combination of
Ceftazidime Cephalosporin antibiotic
Avibactam β-lactamase inhibitor
Clinical data
Trade names Avycaz, Zavicefta
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a615018
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration		 Intravenous infusion
ATC code J01DD52 (WHO)
Legal status
Legal status
Identifiers
PubChem (CID) 90643431
KEGG D10779
 NYesY (what is this?)

Ceftazidime/avibactam (CAZ-AVI)[1] is a fixed-dose combination drug containing an antibiotic—3rd generation cephalosporin ceftazidime and a novel non-β-lactam β-lactamase inhibitor avibactam. It was approved for use in the United States in February 2015,[2] and is sold under the brand name Avycaz, marketed by Allergan. In Europe, it was approved by the European Medicines Agency in 2016 and is sold as Zavicefta.

Medical use

Ceftazidime/avibactam was developed for the treatment of certain multidrug-resistant Gram-(−) infections.[3] Ceftazidime/avibactam is used for the treatment of complicated intra-abdominal infections (cIAI) In these cases it is used in the combination with metronidazole, which provides coverage for anaerobic pathogens. It is also used for the treatment of complicated urinary tract infections (cUTI), including acute pyelonephritis (AP), in adult patients. As with all other antibacterials, ceftazidime/avibactam should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria to avoid development of antimicrobial resistance.[4]

The antibacterial spectrum of ceftazidime/avibactam includes nearly all Enterobacteriaceae, including ceftazidime-resistant strains. The activity of ceftazidime/avibactam against the important hospital pathogen Pseudomonas aeruginosa is variable, due to the potential presence of other resistance mechanisms in addition to β-lactamase production. Synergy was observed for avibactam with ceftazidime in the Burkholderia cepacia complex.[5]

In the case of certain other bacterial pathogens, it offers little or no advantage over ceftazidime monotherapy, again due to the widespread expression of resistance mechanisms other than β-lactamase production. These include Haemophilus, Moraxella and Neisseria pathogens, and infections caused by Acinectobacter baumannii.[6]

Mechanism of action

Increasing resistance to cephalosporins among Gram-(−) bacterial pathogens, especially among hospital-acquired infections, results in part from the production of β-lactamase enzymes that deactivate these antibiotics. While the co-administration of a β-lactamase inhibitor can restore antibacterial activity to the cephalosporin, previously approved β-lactamase inhibitors such as tazobactam and clavulanic acid do not inhibit important classes of β-lactamases, including Klebsiella pneumoniae carbapenemases (KPCs), New Delhi metallo-β-lactamase 1 (NDM-1), and AmpC-type β-lactamases. Avibactam inhibits KPCs, AmpC, and some Class D β-lactamases, but is not active against NDM-1.[7]

Adverse reactions

The most common adverse reactions, occurring in 5% or more of patient receiving ceftazidime/avibactam during the Phase II clinical trials were gastrointestinal disorders (vomiting, nausea, constipation and abdominal pain), blood alkaline phosphatase increase, alanine aminotransferase increase, dizziness and anxiety.

Manufacturing

Within the recently passed Food and Drug Administration Safety and Innovation Act (FDASIA) is a provision known as the Generating Antibiotics Incentives Now (GAIN). This provision created the Qualified Infectious Disease Product (QIDP) designation for new drug candidates. Drugs given the QIDP designation must be indicated to treat serious and/or life-threatening diseases.The QIDP designation extends the patent life for 5 additional years for qualifying drugs and makes the drug eligible for fast tracking by the FDA. This effort was initiated to introduce new drugs on the market to treat serious infections for which effective therapy is currently absent or in short supply.[8] Avycaz is the fifth drug to receive this designation since the enacting of the program.[9]

Avycaz will be marketed in North America through Allergan Inc., while AstraZeneca will market it to the rest of the world. Having patents extending proprietary rights of the avibactam molecule/synthesis and the combination of avibactam with ceftazidime until 2026 and 2031, respectively, Allergan Inc. stands to benefit from this market for years to come.[10] Allergan Inc., when the drug was approved, projected the peak sales of Avycaz to reach between $250–500 million, and based on initial sales, $488,000 in April 2015 and $819,000 in May 2015, this projection seems to be on pace.[11] This market will never be as large as chronic medications, but given the early success of Avycaz, more manufacturers could enter the market to grab a share. This would greatly benefit the treatment of these newer drug-resistant bugs and infuse life into what has been a relatively stagnant market the past few decades.

Regulations

Avycaz is a prescription-only medication, which was fast-tracked by the FDA due to the shortage of drugs that effectively circumvent the resistance problem. One of the active pharmacological ingredients, ceftazidime, has long been proven to be safe, which allowed the FDA to expedite its approval. The FDA relegated its use to only those patients who are refractory to other treatments because of the limited clinical safety data and also to prevent prescribers from overusing this therapy if other effective treatment exists.[12] Additionally, the price gap between traditional therapy and Avycaz is quite large. The wholesale acquisition cost (WAC), which is the price the manufacturer will set for the wholesaler to purchase the drug, for Avycaz is $2,850 for ten 2 g vials.[13] While this is not the price the patient pays, the cost of a single day of treatment with Avycaz is more than a full 14-day regimen of currently used medications because of the availability of generic alternatives. This financial pressure should help with the FDA regulation in restricting its use.[14]

References

  1. ↑ "Briefing package: ceftazidime-avibactam. Anti-infective drugs advisory committee meeting" (PDF). fda.gov. U.S. Food and Drug Administration. Retrieved 27 June 2015.
  2. ↑ http://tools.wmflabs.org/citation-template-filling/cgi-bin/index.cgi?ddb=&type=url&id=http%3A%2F%2Fwww.accessdata.fda.gov%2Fscripts%2Fcder%2Fdrugsatfda%2Findex.cfm%3Ffuseaction%3DSearch.Label_ApprovalHistory%23labelinfo
  3. ↑ Lagacé-Wiens P, Walkty A, Karlowsky JA (2014). "Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections". Core Evid. 9: 13–25. doi:10.2147/CE.S40698. PMC 3908787Freely accessible. PMID 24493994.
  4. ↑ "AVYCAZ™ (ceftazidime-avibactam) for Injection, for Intravenous Use. Full Prescribing Information". avycaz.com. Actavis, Inc., 2015. Retrieved 27 June 2015.
  5. ↑ Mushtaq S, Warner M, Livermore DM (2010). "In vitro activity of ceftazidime+NXL104 against Pseudomonas aeruginosa and other non-fermenters". J Antimicrob Chemother. 65 (11): 2376–2381. doi:10.1093/jac/dkq306. PMID 20801783.
  6. ↑ Lagacé-Wiens P, Walkty A, Karlowsky JA (2014). "Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections". Core Evid. 9: 13–25. doi:10.2147/CE.S40698. PMC 3908787Freely accessible. PMID 24493994.
  7. ↑ "www.accessdata.fda.gov" (PDF).
  8. ↑ "Press Announcements - FDA approves new antibacterial drug Avycaz". www.fda.gov. Retrieved 2015-11-16.
  9. ↑ "FDA clears Actavis' combination antibacterial Avycaz". www.firstwordpharma.com. Retrieved 2015-11-16.
  10. ↑ "Generic Avycaz Availability - Drugs.com". www.drugs.com. Retrieved 2015-11-16.
  11. ↑ "Early Avycaz sales could signal bigger payoff for superbug-fighting antibiotics". FiercePharmaMarketing. Retrieved 2015-11-16.
  12. ↑ "Actavis Launches AVYCAZ™ (Ceftazidime-Avibactam) Anti-Infective In U.S.". www.prnewswire.com. Retrieved 2015-11-16.
  13. ↑ Micromedex® Healthcare Series [database online]. Greenwood Village, CO: Truven Health Analytics, Inc. Updated periodically. Accessed Nov 16, 2015.
  14. ↑ "Avycaz Approval and Labeling Restrictions". Allphase Pharma Consulting, LLC. 2015-08-26. Retrieved 2015-11-16.
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