Aztreonam

Aztreonam

Clinical data
Trade names	Azactam, others
AHFS/Drugs.com	Monograph
MedlinePlus	a687010
Pregnancy category	AU: B1
Routes of administration	Intravenous, intramuscular, inhalation
ATC code	J01DF01 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only EU: Rx-only[1]
Pharmacokinetic data
Bioavailability	100% (IM) 0.1% (by mouth in rats) Unknown (by mouth in humans)
Protein binding	56%
Metabolism	Liver (minor %)
Elimination half-life	1.7 hours
Excretion	Kidney
Identifiers
IUPAC name 2-{[(1Z)-1-(2-Amino-1,3-thiazol-4-yl)-2-{[(2S,3S)-2-methyl-4-oxo-1-sulfoazetidin-3-yl]amino}-2-oxoethylidene]amino}oxy-2-methylpropanoic acid
CAS Number	78110-38-0^Y
PubChem CID	5742832
DrugBank	DB00355^Y
ChemSpider	4674940^Y
UNII	G2B4VE5GH8
KEGG	D00240^Y
ChEBI	CHEBI:161680^Y
ChEMBL	ChEMBL158^Y
CompTox Dashboard (EPA)	DTXSID0022640
ECHA InfoCard	100.071.652
Chemical and physical data
Formula	C13H17N5O8S2
Molar mass	435.43 g·mol^−1
3D model (JSmol)	Interactive image
Melting point	227 °C (441 °F) (dec.)
SMILES O=S(=O)(O)N2C(=O)[C@@H](NC(=O)C(=N\OC(C(=O)O)(C)C)/c1nc(sc1)N)[C@@H]2C
InChI InChI=1S/C13H17N5O8S2/c1-5-7(10(20)18(5)28(23,24)25)16-9(19)8(6-4-27-12(14)15-6)17-26-13(2,3)11(21)22/h4-5,7H,1-3H3,(H2,14,15)(H,16,19)(H,21,22)(H,23,24,25)/b17-8-/t5-,7-/m0/s1^Y Key:WZPBZJONDBGPKJ-VEHQQRBSSA-N^Y
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Aztreonam, sold under the brand name Azactam among others, is an antibiotic used primarily to treat infections caused by gram-negative bacteria such as Pseudomonas aeruginosa.^[2][3] This may include bone infections, endometritis, intra abdominal infections, pneumonia, urinary tract infections, and sepsis.^[2] It is given by intravenous or intramuscular injection or by inhalation.^[2]

Common side effects when given by injection include pain at the site of injection, vomiting, and rash.^[2] Common side effects when inhaled include wheezing, cough, and vomiting.^[2] Serious side effects include Clostridioides difficile infection and allergic reactions including anaphylaxis.^[2] Those who are allergic to other β-lactam have a low rate of allergy to aztreonam.^[2] Use in pregnancy appears to be safe.^[2] It is in the monobactam family of medications.^[2] Aztreonam inhibits cell wall synthesis by blocking peptidoglycan crosslinking to cause bacterial death.^[2]

Aztreonam was approved for medical use in the United States in 1986.^[2] It was removed from the World Health Organization's List of Essential Medicines in 2019.^[4][5] It is available as a generic medication.^[2] It is a manufactured version of a chemical from the bacterium Chromobacterium violaceum.^[6] Aztreonam is available in a combination with avibactam (aztreonam/avibactam).

Medical uses

Nebulized forms of aztreonam are used to treat infections that are complications of cystic fibrosis and are approved for such use in the EU and the US; they are also used off-label for non-CF bronchiectasis, ventilator-associated pneumonia, chronic obstructive pulmonary disease, mycobacterial disease, and to treat infections in people who have received lung transplants.^[7]

Aztreonam has strong activity against susceptible gram-negative bacteria, including Pseudomonas aeruginosa. It is resistant to some beta-lactamases, but is inactivated by extended-spectrum beta-lactamases.^{[citation needed]}

It has no useful activity against gram-positive bacteria or anaerobes. It is known to be effective against a wide range of bacteria including Citrobacter, Enterobacter, E. coli, Haemophilus, Klebsiella, Proteus, and Serratia species.^[8] The following represents minimum inhibitory concentration (MIC) susceptibility data for a few medically significant microorganisms.^[9]

• Staphylococcus aureus 8 - >128 μg/ml
• Staphylococcus epidermidis 8 - 32 μg/ml
• Streptococcus pyogenes 8 - ≥128 μg/ml

Spectrum of activity

Acinetobacter anitratus, Escherichia coli, Pseudomonas aeruginosa, and Proteus mirabilis are generally susceptible to aztreonam, while some staphylococci, Staphylococcus aureus, Staphylococcus haemolyticus and Xanthomonas maltophilia are resistant to it. Furthermore, Aeromonas hydrophila, Citrobacter koseri (Citrobacter diversus), Pantoea agglomerans (Enterobacter agglomerans), Haemophilus spp. and Streptococcus pyogenes have developed resistance to aztreonam to varying degrees.^[10]

Administration

Aztreonam is poorly absorbed when given orally, so it must be administered as an intravenous or intramuscular injection (brand name Azactam), or inhaled (brand name Cayston) using an ultrasonic nebulizer. In the United States, the Food and Drug Administration (FDA) approved the inhalation form in February 2010, for the suppression of P. aeruginosa infections in people with cystic fibrosis.^[11] It received conditional approval for administration in Canada and the European Union in September 2009,^[11] and has been fully approved in Australia.^[12]

Contraindications

Aztreonam can be safely used in people with a penicillin or cephalosporin allergy (except for people with a ceftazidime allergy as ceftazidime and aztreonam share a similar side chain).^[13] It is also frequently used as an alternative to aminoglycosides because is not ototoxic or nephrotoxic.^[14]

Side effects

Reported side effects include injection site reactions, rash, and rarely toxic epidermal necrolysis. Gastrointestinal side effects generally include diarrhea and nausea and vomiting. Although C. difficile infection is a possible complication of aztreonam therapy, this antibiotic is associated with a low risk of developing C. difficile infection.^[15] There may be drug-induced eosinophilia. Because of the unfused beta-lactam ring there is somewhat lower cross-reactivity between aztreonam and many other beta-lactam antibiotics, and it may be safe to administer aztreonam to many patients with hypersensitivity (allergies) to penicillins and nearly all cephalosporins.^[16] There is a much lower risk of cross-sensitivity between aztreonam and other beta-lactam antibiotics than within other beta-lactam antibiotics. However, there is a higher chance of cross-sensitivity if a person is specifically allergic to ceftazidime, a cephalosporin. Aztreonam exhibits cross-sensitivity with ceftazidime due to a similar side chain.^[17]

Mechanism of action

Aztreonam is similar in action to penicillin. It inhibits synthesis of the bacterial cell wall, by blocking peptidoglycan crosslinking. It has a very high affinity for penicillin-binding protein-3 and mild affinity for penicillin-binding protein-1a. Aztreonam binds the penicillin-binding proteins of Gram-positive and anaerobic bacteria very poorly and is largely ineffective against them.^[16] Aztreonam is bactericidal, but less so than some of the cephalosporins.^{[medical citation needed]}

Research

Aztreonam is under consideration for human infections sustained by metallo-beta-lactamase (MBL)-producing gram-negative bacteria. In these circumstances aztreonam is combined with ceftazidime/avibactam. The combination of aztreonam and avibactam are in phase III clinical trails.^[18][19] The combination of aztreonam and avibactam has demonstrated to be active against 80% of MBL isolates reaching a clinical infection resolution in 80% of MBL-infected patients.^[20]

Synergism between aztreonam and arbekacin or tobramycin against P. aeruginosa has been suggested.^[21]

References

1. "Cayston EPAR". European Medicines Agency. 21 June 2004. Retrieved 12 July 2024.
2. "Aztreonam". The American Society of Health-System Pharmacists. Retrieved 8 December 2017.
3. British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 381. ISBN 9780857111562.
4. World Health Organization (2019). Executive summary: the selection and use of essential medicines 2019: report of the 22nd WHO Expert Committee on the selection and use of essential medicines. Geneva: World Health Organization. hdl:10665/325773. WHO/MVP/EMP/IAU/2019.05. License: CC BY-NC-SA 3.0 IGO.
5. World Health Organization (2019). The selection and use of essential medicines: report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2019 (including the 21st WHO Model List of Essential Medicines and the 7th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization. hdl:10665/330668. ISBN 9789241210300. ISSN 0512-3054. WHO technical report series;1021.
6. Yaffe SJ, Aranda JV (2010). Neonatal and Pediatric Pharmacology: Therapeutic Principles in Practice. Lippincott Williams & Wilkins. p. 438. ISBN 9780781795388.
7. Quon BS, Goss CH, Ramsey BW (March 2014). "Inhaled antibiotics for lower airway infections". Annals of the American Thoracic Society. 11 (3): 425–34. doi:10.1513/annalsats.201311-395fr. PMC 4028738. PMID 24673698.
8. Mosby's Drug Consult 2006 (16th ed.). Mosby, Inc. 2006.
9. "Aztreonam Susceptibility and Minimum Inhibitory Concentration (MIC) Data" (PDF). toku-e.com. 3 February 2020.
10. "Aztreonam spectrum of bacterial susceptibility and Resistance" (PDF). Product Data Sheet. toku-e.com. Archived from the original (PDF) on 27 March 2014. Retrieved 15 May 2012.
11. Catherine L (22 February 2010). "Gilead's Inhaled Antibiotic for Lungs Wins Approval". BusinessWeek. Archived from the original on 2 March 2010. Retrieved 5 March 2010.
12. "FDA approves Gilead cystic fibrosis drug Cayston". BusinessWeek. 23 February 2010. Archived from the original on 1 March 2010. Retrieved 5 March 2010.
13. James CW, Gurk-Turner C (January 2001). "Cross-reactivity of beta-lactam antibiotics". Proceedings. 14 (1): 106–107. doi:10.1080/08998280.2001.11927741. PMC 1291320. PMID 16369597.
14. Johnson DH, Cunha BA (1995). "Aztreonam". Medical Clinics of North America. 79 (4): 733–743. doi:10.1016/S0025-7125(16)30036-0. PMID 7791420.
15. Di Bella S, Sanson G, Monticelli J, Zerbato V, Principe L, Giuffrè M, et al. (February 2024). Staley C, Abhyankar M (eds.). "Clostridioides difficile infection: history, epidemiology, risk factors, prevention, clinical manifestations, treatment, and future options". Clinical Microbiology Reviews. 37 (2): e0013523. doi:10.1128/cmr.00135-23. PMC 11324037. PMID 38421181.
16. AHFS Drug Information 2006 (2006 ed.). American Society of Health-System Pharmacists. 2006.
17. Terico AT, Gallagher JC (December 2014). "Beta-lactam hypersensitivity and cross-reactivity". Journal of Pharmacy Practice. 27 (6): 530–544. doi:10.1177/0897190014546109. PMID 25124380. S2CID 19275020.
18. Clinical trial number NCT03329092 for "A Study to Determine the Efficacy, Safety and Tolerability of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) Versus Meropenem (MER) ± Colistin (COL) for the Treatment of Serious Infections Due to Gram Negative Bacteria. (REVISIT)" at ClinicalTrials.gov
19. Clinical trial number NCT03580044 for "Efficacy, Safety, and Tolerability of ATM-AVI in the Treatment of Serious Infection Due to MBL-producing Gram-negative Bacteria" at ClinicalTrials.gov
20. Mauri C, Maraolo AE, Di Bella S, Luzzaro F, Principe L (August 2021). "The Revival of Aztreonam in Combination with Avibactam against Metallo-β-Lactamase-Producing Gram-Negatives: A Systematic Review of In Vitro Studies and Clinical Cases". Antibiotics. 10 (8): 1012. doi:10.3390/antibiotics10081012. PMC 8388901. PMID 34439062.
21. Kobayashi Y, Uchida H, Kawakami Y (December 1992). "Synergy with aztreonam and arbekacin or tobramycin against Pseudomonas aeruginosa isolated from blood". The Journal of Antimicrobial Chemotherapy. 30 (6): 871–2. doi:10.1093/jac/30.6.871. PMID 1289363.