Ceftazidime/avibactam

Ceftazidime/avibactam, sold under the brand name Avycaz among others, is a combination medication composed of ceftazidime, a cephalosporin antibiotic, and avibactam, a β-lactamase inhibitor.[2] It is used to treat complicated intra abdominal infections, urinary tract infections, and pneumonia.[2][3] It is only recommended when other options are not appropriate.[2] It is given by injection into a vein.[2]

Ceftazidime/avibactam
Combination of
CeftazidimeCephalosporin antibiotic
Avibactamβ-lactamase inhibitor
Clinical data
Trade namesAvycaz, Zavicefta, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa615018
License data
Pregnancy
category
  • US: B (No risk in non-human studies)
    Routes of
    administration    		Intravenous infusion
    ATC code
    Legal status
    Legal status
    Identifiers
    PubChem CID
    KEGG
     NY (what is this?)

    Common side effect include nausea, fever, liver problems, headache, trouble sleeping, and pain at the site of injection.[2] Severe side effects may include anaphylaxis, seizures, and Clostridium difficile-associated diarrhea.[2] While use appears to be safe in pregnancy the medication has not been well studied in this group.[4] Doses should be adjusted in those with kidney problems.[5] Ceftazidime works by interfering with the building of the bacterial cell wall while avibactam works by preventing ceftazidime's breakdown.[2]

    The combination was approved for medical use in the United States and Europe in 2015.[2][3] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[6] In the United States a course of treatment generally costs between US$7,500 to US$15,000 as of 2016.[5] In the United Kingdom this amount costs the NHS about £1,800 to £3,600 as of 2019.[7]

    Medical use

    Ceftazidime/avibactam is used to treat certain multidrug-resistant gram-negative infections.[8]

    Ceftazidime/avibactam is used for the treatment of:

    • complicated intra-abdominal infections. In these cases it is often used in combination with metronidazole, which provides coverage for anaerobic pathogens.[5]
    • complicated urinary tract infections, including acute pyelonephritis, in adults.
    • hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.[9]

    Bacterial activity

    For many bacterial infections, it offers little or no advantage over ceftazidime monotherapy, 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.[8]

    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.[10]

    Adverse events

    When used to treat life-threatening infections, ceftazidime/avibactam is more likely than carbapenem antibiotics to cause serious adverse events, including worsening kidney function and gastrointestinal adverse effects.[11]

    Mechanism of action

    Bacterial resistance to cephalosporins is often due to bacterial production of β-lactamase enzymes that deactivate these antibiotics. Avibactam inhibits some (but not all) bacterial ß-lactamases. Also, some bacteria are resistant to cephalosporins by other mechanisms, and therefore avibactam doesn't work. Avibactam is not active against New Delhi metallo-β-lactamase 1 (NDM-1).[12] Avibactam inhibits Klebsiella pneumoniae carbapenemases (KPCs), and AmpC-type β-lactamases, which are resistant to the other clinically-available β-lactamases, tazobactam and clavulanic acid.[13]

    Regulatory

    It was granted approval for marketing in the United States by the Food and Drug Administration (FDA) in February 2015.[14] It was granted approval for marketing in Europe by the European Medicines Agency in 2016. During its clinical development, ceftazidime/avibactam was designated as a Qualified Infectious Disease Product under the Generating Antibiotic Incentives Now provision of the Food and Drug Administration Safety and Innovation Act.[15][16] Development of ceftazidime/avibactam was fast-tracked by the FDA due to the shortage of drugs for treatment of infections due to antibiotic-resistant bacteria.

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    References
    1. "Briefing package: ceftazidime-avibactam. Anti-infective drugs advisory committee meeting" (PDF). U.S. Food and Drug Administration (FDA). Archived from the original (PDF) on 30 June 2015. Retrieved 27 June 2015.
    2. "Ceftazidime and Avibactam Sodium Monograph for Professionals". Drugs.com. Retrieved 25 October 2019.
    3. "Application for inclusion of ceftazidime-avibactam" (PDF). WHO. Retrieved 25 October 2019.
    4. "Avibactam / ceftazidime (Avycaz) Use During Pregnancy". Drugs.com. Retrieved 25 October 2019.
    5. Mosley JF, 2nd; Smith, LL; Parke, CK; Brown, JA; Wilson, AL; Gibbs, LV (August 2016). "Ceftazidime-Avibactam (Avycaz): For the Treatment of Complicated Intra-Abdominal and Urinary Tract Infections". Pharmacy and Therapeutics. 41 (8): 479–83. PMC 4959616. PMID 27504064.
    6. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
    7. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. X. ISBN 9780857113382.
    8. 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 3908787. PMID 24493994.
    9. https://www.allergan.com/assets/pdf/avycaz_pi
    10. 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.
    11. Sternbach N, Leibovici Weissman Y, Avni T, Yahav D (August 2018). "Efficacy and safety of ceftazidime/avibactam: a systematic review and meta-analysis". J. Antimicrob. Chemother. 73 (8): 2021–2029. doi:10.1093/jac/dky124. PMID 29659836.
    12. Lohans CT, Brem J, Schofield CJ (December 2017). "New Delhi Metallo-β-Lactamase 1 Catalyzes Avibactam and Aztreonam Hydrolysis". Antimicrob. Agents Chemother. 61 (12). doi:10.1128/AAC.01224-17. PMC 5700305. PMID 28971873.
    13. "Clinical Review, NDA 206494, Ceftazidime-avibactam" (PDF). Food and Drug Administration (FDA). 2015-02-18.
    14. "AVYCAZ (ceftazidime-avibactam) approval letter" (PDF). Food and Drug Administration (FDA). 2015-02-25. Retrieved September 10, 2019.
    15. "FDA approves new antibacterial drug Avycaz" (Press release). Food and Drug Administration (FDA). Archived from the original on 2015-11-17. Retrieved 2015-11-16.
    16. "FDA clears Actavis' combination antibacterial Avycaz". FirstWord Pharma. Retrieved 2015-11-16.
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