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Antimicrobial resistance (AMR) is one of the most important challenges in modern clinical practice. The European regulatory network has a strategy to support prevention of AMR by applying specific referral procedures.


The aim of this study was to evaluate post-authorisation changes made in the product information of key antibiotics that underwent referral procedures between 2007 and 2020.


In a comprehensive analysis of the changes made for antibiotics, we extracted information on changes from the European Commission community register of medicinal products and the European Medicines Agency’s database for antibiotics that went through referrals. Changes made in the specific sections of the summary of product characteristics of each referral procedure were scrutinised.


We identified 15 antibiotics from seven classes of antibiotics during the study period. The outcome of all referrals included the restriction of antibiotic use. Therapeutic indications were revised for all antibiotics, with septicaemia and gonorrhoea most common diseases removed. Posology and/or method of administration was updated for all; the majority of referrals included adjustment of dosage for specific populations. Information on contraindication (most regarding hypersensitivity) and information on warnings was amended for all referrals.


Our findings highlight the importance of the regulatory actions. The changes made in the product information aim to ensure appropriate use. Ongoing harmonisation activities are likely to lead to further refinements and restrictions on individual antibiotics in support of rational use. However, further research is required to examine the impact of post-referral label changes on the clinical practice.


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  1. Mitsakakis K, Kaman WE, Elshout G, Specht M, Hays JP. Challenges in identifying antibiotic resistance targets for point-of-care diagnostics in general practice. Future Microbiol. 2018;13(10:1157-64.
  2. Shallcross LJ, Howard SJ, Fowler T, Davies SC. Tackling the threat of antimicrobial resistance: from policy to sustainable action. Philos Trans R Soc Lond B Biol Sci. 2015;370(1670):20140082.
  3. O’Neill J. Tackling drug-resistant infections globally: final report and recommendations. London: Wellcome Trust; May 2016. Available from: https://wellcomecollection.org/works/thvwsuba
  4. European Medicines Agency (EMA). Referral procedures. Amsterdam: EMA. [Accessed: October 2020 ]. Available from: https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures
  5. European Centre for Disease Prevention and Control (ECDC). Communication toolkit to promote prudent antibiotic use aimed at primary care prescribers. Stockholm: ECDC. [Accessed: October 2020]. Available from: https://antibiotic.ecdc.europa.eu/en/toolkit-primary-care-prescribers
  6. World Health Organization (WHO). Optimal use of antimicrobial medicines in human and animal health. Geneva: WHO. [Accessed: October 2020 ]. Available from: https://www.who.int/antimicrobial-resistance/global-action-plan/optimise-use/en/
  7. European Commission. Commission notice — EU Guidelines for the prudent use of antimicrobials in human health. Official Journal of the European Union (2017/C 212/01). Luxembourg: Publications Office of the European Union; 1 Jul 2017. Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A52017XC0701%2801%29
  8. European Commission. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Official Journal of the European Union L 311. Luxembourg: Publications Office of the European Union; 28 Nov 2001. Available from: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf
  9. Health and Consumers Directorate-General. Notice to applicants. Volume 2A: procedures for marketing authorisation. Chapter 3: Union referral procedures. Brussels: European Commission; May 2014. Available from: http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-2/2014-05_vol2a_chap_3.pdf
  10. Health and Consumers Directorate-General. Notice to applicants. A guideline on summary of product characteristics (SmPC). Brussels: European Commission; Sep 2009. Available from: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-2/c/smpc_guideline_rev2_en.pdf
  11. European Commission (EC). Public Health - Union Register of medicinal products. Brussels: EC. [Accessed: October 2020]. Available from: http://ec.europa.eu/health/documents/community-register/html/index_en.htm
  12. World Health Organization Collaborating Centre for Drug Statistics Methodology. Anatomical therapeutic chemical/defined daily dose index. Oslo: Norwegian Institute of Public Health; December 2019]. Available from: https://www.whocc.no/atc_ddd_index/?code=J01
  13. European Centre for Disease Prevention and Control (ECDC). Antimicrobial consumption – Annual Epidemiological Report for 2017. Stockholm: ECDC; Nov 2018. Available from: https://www.ecdc.europa.eu/en/publications-data/antimicrobial-consumption-annual-epidemiological-report-2017
  14. World Health Organisation (WHO). Critically important antimicrobials for human medicines. 6th revision. Geneva: WHO; 2018. Available from: https://www.who.int/foodsafety/areas_work/antimicrobial-resistance/cia/en/
  15. Falagas ME, Kasiakou SK, Saravolatz LD. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis. 2005;40(9):1333-41.  https://doi.org/10.1086/429323  PMID: 15825037 
  16. Büchler AC, Gehringer C, Widmer AF, Egli A, Tschudin-Sutter S. Risk factors for colistin-resistant Enterobacteriaceae in a low-endemicity setting for carbapenem resistance - a matched case-control study. Euro Surveill. 2018;23(30):1700777.  https://doi.org/10.2807/1560-7917.ES.2018.23.30.1700777  PMID: 30064544 
  17. Aghapour Z, Gholizadeh P, Ganbarov K, Bialvaei AZ, Mahmood SS, Tanomand A, et al. Molecular mechanisms related to colistin resistance in Enterobacteriaceae. Infect Drug Resist. 2019;12:965-75.  https://doi.org/10.2147/IDR.S199844  PMID: 31190901 
  18. Wertheim H, Van Nguyen K, Hara GL, Gelband H, Laxminarayan R, Mouton J, et al. Global survey of polymyxin use: A call for international guidelines. J Glob Antimicrob Resist. 2013;1(3):131-4.  https://doi.org/10.1016/j.jgar.2013.03.012  PMID: 24749079 
  19. Tsuji BT, Pogue JM, Zavascki AP, Paul M, Daikos GL, Forrest A, et al. International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy. 2019;39(1):10-39.  https://doi.org/10.1002/phar.2209  PMID: 30710469 
  20. The National Health Service (NHS). Ear nose and throat (ENT) infections antibiotic guidelines. London: NHS; 2018. Available from: http://www.srft.nhs.uk/EasysiteWeb/getresource.axd?AssetID=21768&type=full&servicetype=Inline
  21. Cals JW, Butler CC, Hopstaken RM, Hood K, Dinant GJ. Effect of point of care testing for C reactive protein and training in communication skills on antibiotic use in lower respiratory tract infections: cluster randomised trial. BMJ. 2009;338(may05 1):b1374.  https://doi.org/10.1136/bmj.b1374  PMID: 19416992 
  22. Singh A, Avula A, Zahn E. Acute bronchitis. In: StatPearls. Treasure Island: StatPearls Publishing; 2020.
  23. European Centre for Disease Prevention and Control (ECDC). Proper hand hygiene can prevent sepsis. Stockholm: ECDC; May 2018. Available from: https://ecdc.europa.eu/en/news-events/proper-hand-hygiene-can-prevent-sepsis
  24. Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. Lancet. 2018;392(10141):75-87.  https://doi.org/10.1016/S0140-6736(18)30696-2  PMID: 29937192 
  25. Downes KJ, Hahn A, Wiles J, Courter JD, Vinks AA. Dose optimisation of antibiotics in children: application of pharmacokinetics/pharmacodynamics in paediatrics. Int J Antimicrob Agents. 2014;43(3):223-30.  https://doi.org/10.1016/j.ijantimicag.2013.11.006  PMID: 24389079 
  26. The European Committee on Antimicrobial Susceptibility Testing (EUCAST). Clinical breakpoints - breakpoints and guidance; January 2020. Available from: https://eucast.org/clinical_breakpoints/
  27. Morales DR, Morant SV, MacDonald TM, Hallas J, Ernst MT, Pottegård A, et al. Impact of EU regulatory label changes for diclofenac in people with cardiovascular disease in four countries: Interrupted time series regression analysis. Br J Clin Pharmacol. 2020:bcp.14478.  https://doi.org/10.1111/bcp.14478  PMID: 32668021 

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