Azithromycin has been widely evaluated for its efficacy against COVID-19. The study by Timothy S C Hinks and colleagues1 adds value to the current literature, and we would like to share our comments.
As stated in the introduction of the Article,1 the antiviral and anti-inflammatory properties of azithromycin are suited to patients with early stage COVID-19. However, patients approaching 14 days since symptom onset might not represent the target study population (ie, those with mild-to-moderate disease), as some patients could be in the late stages of the disease or near resolution by this timepoint. Therefore, it is important to know how many patients were close to 14 days since symptom onset at enrolment, and the rationale behind choosing a 14-day window for inclusion.
It is not clear whether universal pre-determined criteria were used across all participating centres to categorise patients as having mild-to-moderate disease, and whether chest x-rays or CT scans, or both, were done before categorisation. According to the study schedule, participants were enrolled on day 0, received the first dose of azithromycin within 4 h of randomisation, and were followed up on days 14 and 28. To better understand this timeline, it is important to mention if enrolment and randomisation occurred on the same day. We would like to know if the azithromycin regimen (500 mg once daily for 14 days) was based on any pre-established guidelines or recommendations. We consider that it is unreasonable to expose someone with 14 days of symptoms, who might already be near resolution, to a further 14 days of treatment with azithromycin. The study protocol excluded patients with concomitant use of quinolones or macrolides during follow-up; however, additional antibiotics were permitted after randomisation. As concomitant medications can be confounders, their names and indications should be specified.
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We had recognised some numerical errors in the older version of the appendix and the Article regarding the total number of participants taking oral corticosteroids. However, we appreciate the authors' revision, and this error has now been corrected. Due to poor compliance with azithromycin (76 [52%] of 147), a separate subgroup analysis between compliers and non-compliers should be done to further evaluate the effectiveness of this drug. Participants who had received 80% or more doses of azithromycin by day 14 were compliant, but 80% of 28 tablets should be 22, not 24. According to the appendix of the Article,1 76 patients were considered as compliers, but only 73 patients took 28 tablets. We are curious to know how compliance was measured in these three remaining patients. To support the claim that antiviral activity needs to be assessed early in the disease, the authors inappropriately cited their own study protocol.2
Finally, nearly half of the study population included unconfirmed cases of COVID-19, which, in addition to poor compliance to azithromycin, might compromise the validity of the results.
We declare no competing interests.
References
- 1.Hinks TSC, Cureton L, Knight R, et al. Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial. Lancet Respir Med. 2021 doi: 10.1016/S2213-2600(21)00263-0. published online July 9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hinks TSC, Barber VS, Black J, et al. A multi-centre open-label two-arm randomised superiority clinical trial of azithromycin versus usual care in ambulatory COVID-19: study protocol for the ATOMIC2 trial. Trials. 2020;21:718. doi: 10.1186/s13063-020-04593-8. [DOI] [PMC free article] [PubMed] [Google Scholar]