Assessment of Safety Signals for Aztreonam in Different Age Groups: National and International Drug Safety Monitoring

Aztreonam is the only approved monocyclic β-lactam antibiotic for human use that is active against Gram-negative aerobes, primarily Pseudomonas аeruginosa. Aztreonam has been used for more than 35 years, and aztreonam lysine has been on the market for 15 years. Although the medicinal products show clinical and microbiological efficacy in severe infections and are significant for cystic fibrosis patients, little information is published on their safety. In the meantime, new data have accumulated.

The aim of the study was to analyse the data on adverse reactions in patients of different age groups receiving aztreonam, collected in the safety monitoring databases VigiBase and Pharmacovigilance.

Materials and methods: the data on adverse reactions associated with aztreonam, in any dosage form, from the individual case reports submitted to VigiBase (the database of the Uppsala Monitoring Centre) before 15.09.2021 and to Pharmacovigilance (the database for spontaneous reports in the Automated Information System of the Federal Service for Surveillance in Healthcare of the Russian Federation) before 05.10.2021.

Results: the analysis of adverse reactions during the use of aztreonam for approved indications showed differences in frequency, types and severity of the adverse reactions amongst the age groups. The most common adverse reaction with aztreonam was cystic fibrosis referred to in 1828 reports (12.0%). It was recorded more often in patients aged 18–44 years (39.2%).

Conclusions: the data obtained allowed the authors to identify a new safety signal for aztreonam, namely an increased risk of inefficacy or insufficient efficacy in cystic fibrosis considered an adverse reaction in the individual reports from the databases of spontaneous reports. Confirmation of the signal requires further monitoring.

1. Sykes RB, Bonner DP. Aztreonam: the first monobactam. Am J Med. 1985;78(2A):2–10. https://doi.org/10.1016/0002-9343(85)90196-2

2. Swabb EA. Review of the clinical pharmacology of the monobactam antibiotic aztreonam. Am J Med. 1985;78(2А):11–8. https://doi.org/10.1016/0002-9343(85)90197-4

3. Biedenbach DJ, Kazmierczak K, Bouchillon SK, Sahm DF, Bradford PA. In vitro activity of aztreonam–avibactam against a global collection of Gram-negative pathogens from 2012 and 2013. Antimicrob Agents Chemother. 2015;59(7):4239–48. https://doi.org/10.1128/aac.00206-15

4. Norrby SR. Clinical experience with aztreonam in Europe: a summary of studies in Belgium, England, Finland, Ireland, the Netherlands, Norway, Portugal, and Sweden. Rev Infect Dis. 1985;7(4):836–9. https://doi.org/10.1093/clinids/7.supplement_4.s836

5. Fuyii R, Meguro H, Arimasu O, Sunakawa K, Ishizuka Y, Nakazawa S, et al. Bacteriological, pharmacokinetic and clinical studies on aztreonam in the pediatric field. Pediatric Study Group of Aztreonam. Jpn J Antibiot. 1985;38(11):3195–216. PMID: 3912524

6. Tiddens HAWM, De Boeck K, Clancy JP, Fayon M, Arets HGM, Bresnik M, et al. Open label study of inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: The ALPINE study. J Cyst Fibros. 2015;14(1):111–9. https://doi.org/10.1016/j.jcf.2014.06.003

7. Castellani C, Duff AJA, Bell SC, Heijerman HGM, Munck A, Ratjen F, et al. ECFS best practice guidelines: the 2018 revision. J Cyst Fibros. 2018;17(2):153– 78. https://doi.org/10.1016/j.jcf.2018.02.006

8. Goetz D, Ren CL. Review of cystic fibrosis. Pediatr Ann. 2019;48(4):e154–61. https://doi.org/10.3928/19382359-20190327-01

9. Hatziagorou E, Orenti A, Drevinek P, Kashirskaya N, Mei-Zahav M, De Boeck K, et al. Changing epidemiology of the respiratory bacteriology of patients with cystic fibrosis-data from the European cystic fibrosis society patient registry. J Cyst Fibros. 2020;19(3):376– 83. https://doi.org/10.1016/j.jcf.2019.08.006

10. Varannai O, Gede N, Juhász MF, Szakács Z, Dembrovszky F, Németh D, et al. Therapeutic approach of chronic Pseudomonas infection in cystic fibrosis — a network meta-analysis. Antibiotics (Basel). 2021;10(8):936. https://doi.org/10.3390/antibiotics10080936

11. Elborn JS, Vataire AL, Fukushima A, Aballea S, Khemiri A, Moore C, et al. Comparison of inhaled antibiotics for the treatment of chronic Pseudomonas aeruginosa lung infection in patients with cystic fibrosis: systematic literature review and network meta-analysis. Clin Ther. 2016;38(10):2204–26. https://doi.org/10.1016/j.clinthera.2016.08.014

12. Scott CB, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med. 2020;8(1):65– 124. https://doi.org/10.1016/s2213-2600(19)30337-6

13. Davies JC, Martin I. New anti-pseudomonal agents for cystic fibrosis — still needed in the era of small molecule CFTR modulators? Expert Opin Pharmacother. 2018;19(12):1327–36. https://doi.org/10.1080/14656566.2018.1505864

14. Somayaji R, Nichols DP, Bell SC. Cystic fibrosis — ten promising therapeutic approaches in the current era of care. Expert Opin Investig Drugs. 2020;29(10):1107–24. https://doi.org/10.1080/13543784.2020.1805733

15. Kors van der Ent C, Elborn JS. Improving inhaled antibiotic treatment — practice defeats the proof. J Cyst Fibros. 2016;15(6):705–7. https://doi.org/10.1016/j.jcf.2016.10.003

16. Fiel SB. Aerosolized antibiotics in cystic fibrosis: current and future trends. Expert Rev Respir Med. 2008;2(4):479–87. https://doi.org/10.1586/17476348.2.4.479

17. Shi S, Klotz U. Age-related changes in pharmacokinetics. Curr Drug Metab. 2011;12(7):601–10. https://doi.org/10.2174/138920011796504527

18. Woo SD, Yoon J, Doo GE, Park Y, Lee Y, Lee SH, et al. Common causes and characteristics of adverse drug reactions in older adults: a retrospective study. BMC Pharmacol Toxicol. 2020;21:87. https://doi.org/10.1186/s40360-020-00464-9

19. Zalolochina KE, Ushkalova EA, Kazakov AS, Zyryanov SK, Polivanov VA. Analysis of adverse reactions in elderly patients based on quantitative methods of signal detection. Bezopasnost’ i risk farmakoterapii = Safety and Risk of Pharmacotherapy. 2021;9(3):144–53 (In Russ.) https://doi.org/10.30895/2312-7821-2021-9-3-144-153