Seasonal variation in azithromycin prescription

In The Lancet Infectious Diseases, Ephraim Tsalik and colleagues1Tsalik EL Rouphael NG Sadikot RT et al.Efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections associated with low procalcitonin: a randomised, placebo-controlled, double-blind, non-inferiority trial.Lancet Infect Dis. 2022; (published online Dec 13.)https://doi.org/10.1016/S1473-3099(22)00735-6Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar published the results of a randomised, placebo-controlled, double-blind, non-inferiority trial on the efficacy and safety of azithromycin to treat non-pneumonia lower respiratory tract infections associated with low procalcitonin. Placebo was not non-inferior to azithromycin in terms of clinical improvement at day 5, which was the primary outcome. However, placebo was non-inferior at day 11 and day 28 in the per-protocol analysis. Most of the documented infections in this study were viral (54%), and only 1% were bacterial infections; the use of antibiotics in these patients is therefore questionable. In particular, the benefit of azithromycin in patients with non-pneumonia lower respiratory tract infections with low procalcitonin is unclear. This question remains of particular interest. First, prescription of azithromycin increases in cold months. We identified a clear increase in azithromycin prescriptions from September to April (2018–20) in the outpatient setting in the Alsace region, France (appendix). These data were collected through the French National Health Data System. This seasonal prescription pattern could have been due to the increased prevalence of respiratory tract infections, mostly as a result of winter viral epidemics, but also due to bacterial infections. Previous studies have shown seasonal variations in inappropriate prescribing for viral infection.2Durkin MJ Jafarzadeh SR Hsueh K et al.Outpatient antibiotic prescription trends in the United States: a national cohort study.Infect Control Hosp Epidemiol. 2018; 39: 584-589Crossref PubMed Scopus (85) Google Scholar, 3Dagan R Barkai G Givon-Lavi N et al.Seasonality of antibiotic-resistant Streptococcus pneumoniae that causes acute otitis media: a clue for an antibiotic-restriction policy?.J Infect Dis. 2008; 197: 1094-1102Crossref PubMed Scopus (80) Google Scholar This observation is reinforced by the predominance of viral infections in the study by Tsalik and colleagues.1Tsalik EL Rouphael NG Sadikot RT et al.Efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections associated with low procalcitonin: a randomised, placebo-controlled, double-blind, non-inferiority trial.Lancet Infect Dis. 2022; (published online Dec 13.)https://doi.org/10.1016/S1473-3099(22)00735-6Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar The key point is to distinguish between viral and bacterial infections. Interestingly, we also observed a clear peak in prescription of azithromycin during the first wave of the COVID-19 pandemic in 2020 in the Alsace region (appendix), which was severely affected by high rates of SARS-CoV-2 infection. This increase in prescription of azithromycin was also due to the fact that azithromycin in combination with hydroxychloroquine was thought to have antiviral or anti-inflammatory effects at the beginning of the COVID-19 pandemic, but this was later refuted.4Gautret P Lagier J-C Parola P et al.Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.Int J Antimicrob Agents. 2020; 56105949Crossref PubMed Scopus (3557) Google Scholar The inappropriate prescription of antibiotics, including azithromycin, has important consequences. First, the use of azithromycin has been associated with selection of both macrolide and non-macrolide resistance.5Doan T Worden L Hinterwirth A et al.Macrolide and nonmacrolide resistance with mass azithromycin distribution.N Engl J Med. 2020; 383: 1941-1950Crossref PubMed Scopus (60) Google Scholar Second, an increase in antibiotic resistance during the winter months due to increased prescriptions has been shown.3Dagan R Barkai G Givon-Lavi N et al.Seasonality of antibiotic-resistant Streptococcus pneumoniae that causes acute otitis media: a clue for an antibiotic-restriction policy?.J Infect Dis. 2008; 197: 1094-1102Crossref PubMed Scopus (80) Google Scholar Finally, azithromycin can contribute to the development of Clostridioides difficile infection. Even if the anti-inflammatory function of azithromycin could have a positive effect to alleviate or shorten the duration of clinical symptoms, azithromycin should not be used to treat viral infections. More tools are needed to distinguish between viral and bacterial respiratory tract infections and potentially identify other anti-inflammatory options with similar effects to azithromycin but without the associated negative consequences. FD declares personal fees from Gilead and Pfizer. YH declares personal fees from Pfizer. We thank the Direction Régionale du Service Médical Grand Est from the French Health Insurance. Download .pdf (.26 MB) Help with pdf files Supplementary appendix Efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections associated with low procalcitonin: a randomised, placebo-controlled, double-blind, non-inferiority trialPlacebo was not non-inferior to azithromycin in terms of clinical improvement at day 5 in adults with lower respiratory tract infection and a low procalcitonin concentration. After accounting for both the rates of clinical improvement and solicited adverse events at day 5, it is unclear whether antibiotics are indicated for patients with lower respiratory tract infection and a low procalcitonin concentration. Full-Text PDF