Summary of COVID-19 azithromycin studies

1. Butler et al., Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial

1,323 patient azithromycin late treatment RCT: 16% lower need for oxygen therapy (p=0.69), 9% lower hospitalization (p=0.87), and 7% improved recovery (p=0.23).
RCT 1,388 outpatients in the UK showing no significant benefit with azithromycin. There was no significant difference in time to first reported recovery or risk of hospitalization or death by 28 days with azithromycin compared to usual care alone. Only 31% of participants had PCR-confirmed SARS-CoV-2 infection.
Mar 2021, The Lancet, https://www.sciencedirect.com/science/article/pii/S014067362100461X, https://c19p.org/butler4az

2. Sekhavati et al., Safety and effectiveness of azithromycin in patients with COVID-19: An open-label randomised trial

111 patient azithromycin late treatment RCT: 86% lower ventilation (p=0.12), 72% lower ICU admission (p=0.09), and 23% shorter hospitalization (p=0.02).
Randomized controlled trial of 111 hospitalized COVID-19 patients in Iran showing significantly shorter hospital stay, higher oxygen saturation, and lower respiratory rate at discharge with azithromycin plus hydroxychloroquine and lopinavir/ritonavir compared to hydroxychloroquine and lopinavir/ritonavir alone. There were no significant differences in ICU admission, intubation, or mortality, although there was a trend towards lower ICU admission with azithromycin (3.6% vs. 12.7%, p = 0.07). Patients with prior cardiac disease were excluded. The study is limited by the small sample size and open-label design.
Oct 2020, Int. J. Antimicrobial Agents, https://www.sciencedirect.com/science/article/pii/S0924857920303411, https://c19p.org/sekhavatiaz

3. Yilgwan et al., Clinical profile and Predictors of Outcomes of Hospitalized Patients with Laboratory-Confirmed Severe Acute Respiratory Syndrome Coronavirus 2 in Nigeria: A Retrospective Analysis of 13 High Burden States in Nigeria

3,462 patient azithromycin late treatment study: 67% lower mortality (p=0.0001).
Retrospective 3,462 hospitalized COVID-19 patients across 13 states in Nigiera, showing lower mortality with AZ. Authors note the worse results with a combination of CQ/HCQ and AZ, compared to either alone, may be related to the side effects becoming more significant for late stage patients.
May 2023, Nigerian Medical J., https://nigerianmedjournal.org/index.php/nmj/article/view/174, https://c19p.org/yilgwanazaz

4. Madamombe et al., Factors associated with COVID-19 fatality among patients admitted in Mashonaland West Province, Zimbabwe 2020-2022: a secondary data analysis

672 patient azithromycin early treatment study: 40% lower mortality (p=0.03).
Retrospective 672 COVID-19 patients in Zimbabwe, showing lower mortality with azithromycin treatment.
Mar 2023, Pan African Medical J., https://www.panafrican-med-journal.com/content/article/44/142/full, https://c19p.org/madamombeazaz

5. Piñana et al., Risk factors and outcome of COVID-19 in patients with hematological malignancies

azithromycin prophylaxis study: 58% lower mortality (p=0.02).
Retrospective study of 367 hematology patients with COVID-19 in Spain. Among 216 patients with very severe COVID-19, there was significantly lower mortality with azithromycin treatment. Mortality was also lower with HCQ, but without statistical significance.
Aug 2020, Experimental Hematology & Oncology, https://ehoonline.biomedcentral.com/articles/10.1186/s40164-020-00177-z, https://c19p.org/pinanaazaz

6. Lounnas et al., An Independent Analysis of a Retrospective Cohort of 30,423 Covid-19 Patients Treated at IHU-Mediterranean in Marseille, France: Part 1, Efficacy of early Treatment with Hydroxychloroquine and Azithromycin

azithromycin early treatment PSM study: 27% lower combined mortality/ICU admission (p=0.0005).
Independent analysis of the IHU-Mediterranean data [Brouqui] with 30,423 COVID-19 patients showing significantly lower risk of ICU admission or death with early treatment of hydroxychloroquine plus azithromycin (HCQ-AZ), and with azithromycin, both compared to no treatment.
Feb 2024, Archives of Microbiology & Immunology, https://www.fortunejournals.com/articles/an-independent-analysis-of-a-retrospective-cohort-of-30423-covid19-patients-treated-at-ihumediterranean-in-marseille-france-part-1.html, https://c19p.org/lounnas2azaz

7. Cavalcanti et al., Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

667 patient azithromycin late treatment RCT: 57% lower mortality (p=0.17), 54% higher ventilation (p=0.28), and 18% improved 7-point scale results (p=0.49).
Late stage RCT of 667 hospitalized patients with up to 14 days of symptoms at enrollment and receiving up to 4 liters per minute supplemental oxygen, not finding a significant effect after 15 days. Authors note: "the trial cannot definitively rule out either a substantial benefit of the trial drugs or a substantial harm", sample sizes are too small. The paper uses the terms mild and moderate, however all patients had serious enough disease to be hospitalized, and 14% were actually randomized in the ICU. The trial had significant protocol deviations and unusually low medication adherence. Authors note: "our aim was to exclude patients already receiving longer and potentially therapeutic doses of the study treatments" in explanation for why the study protocol was changed to exclude patients with previous use of the medications >24hrs. Analyzing these patients rather than excluding them may have revealed effectiveness with early use as shown in other studies. The..
Jul 2020, NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2019014, https://c19p.org/cavalcantiazaz

8. Dugot et al., The Association between Previous Antibiotic Consumption and SARS-CoV-2 Infection: A Population-Based Case-Control Study

156,299 patient azithromycin prophylaxis study: 12% fewer cases (p<0.0001).
Retrospective 31,260 COVID-19 cases and 125,039 matched controls, showing lower risk of COVID-19 with previous azithromycin use.
Mar 2023, Antibiotics, https://www.mdpi.com/2079-6382/12/3/587, https://c19p.org/dugotaz

9. Loucera et al., Real-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments

15,968 patient azithromycin prophylaxis study: 15% lower mortality (p=0.005).
Retrospective 15,968 COVID-19 hospitalized patients in Spain, showing lower mortality with existing use of several medications including metformin, HCQ, azithromycin, aspirin, vitamin D, vitamin C, and budesonide. Since only hospitalized patients are included, results do not reflect different probabilities of hospitalization across treatments.
Aug 2022, Virology J., https://virologyj.biomedcentral.com/articles/10.1186/s12985-023-02195-9, https://c19p.org/loucera3azaz

10. Abaleke et al., Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

7,763 patient azithromycin late treatment RCT: 3% lower mortality (p=0.5), 8% lower ventilation (p=0.29), and 9% higher hospital discharge.
RCT 7,763 hospitalized COVID-19 patients showing no significant differences with very late (75% on oxygen at baseline) azithromycin treatment. Only 91% of treatment patients received azithromycin and 17% of control patients received azithromycin or other macrolides.
Feb 2021, The Lancet, https://www.sciencedirect.com/science/article/pii/S0140673621001495, https://c19p.org/abalekeaz

11. Mehrizi et al., Drug prescription patterns and their association with mortality and hospitalization duration in COVID-19 patients: insights from big data

917,198 patient azithromycin late treatment study: 32% lower mortality (p<0.0001).
Retrospective study of 917,198 hospitalized COVID-19 cases covered by the Iran Health Insurance Organization over 26 months showing that antithrombotics, corticosteroids, and antivirals reduced mortality while diuretics, antibiotics, and antidiabetics increased it. Confounding makes some results very unreliable. For example, diuretics like furosemide are often used to treat fluid overload, which is more likely in ICU or advanced disease requiring aggressive fluid resuscitation. Hospitalization length has increased risk of significant confounding, for example longer hospitalization increases the chance of receiving a medication, and death may result in shorter hospitalization. Mortality results may be more reliable. Confounding by indication is likely to be significant for many medications. Authors adjustments have very limited severity information (admission type refers to ward vs. ER department on initial arrival). We can estimate the impact of confounding from typical usage..
Dec 2023, Frontiers in Public Health, https://www.frontiersin.org/articles/10.3389/fpubh.2023.1280434/full, https://c19p.org/mehriziazaz

12. Atefi et al., Evaluation of the efficacy and safety of oral N‐acetylcysteine in patients with COVID‐19 receiving the routine antiviral and hydroxychloroquine protocol: A randomized controlled clinical trial

60 patient azithromycin late treatment study: 85% lower mortality (p=0.31).
RCT 60 hospitalized COVID-19 patients evaluating the efficacy and safety of adding oral N-acetylcysteine (NAC) at 600mg three times daily to standard antiviral treatment regimens. There was lower mortality for patients that received azithromycin, without statistical significance.
Nov 2023, Immunity, Inflammation and Disease, https://onlinelibrary.wiley.com/doi/10.1002/iid3.1083, https://c19p.org/atefiazaz

13. Donida et al., First COVID-19 wave in the province of Bergamo, Italy: epidemiological and clinical characteristics, outcome and management of the first hospitalized patients

723 patient azithromycin late treatment study: 7% lower mortality (p=0.79).
Retrospective 723 hospitalized COVID-19 patients in Italy showing no significant difference with azithromycin treatment.
Jan 2024, BMC Infectious Diseases, https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-024-09034-4, https://c19p.org/donidaazaz

14. Yeramaneni et al., Famotidine Use Is Not Associated With 30-day Mortality: A Coarsened Exact Match Study in 7158 Hospitalized Patients With Coronavirus Disease 2019 From a Large Healthcare System

7,158 patient azithromycin late treatment study: 7% lower mortality (p=0.84).
Retrospective 7,158 hospitalized COVID-19 patients in the USA analyzing famotidine treatment, showing no significant difference in mortality with associated azithromycin treatment.
Feb 2021, Gastroenterology, https://www.gastrojournal.org/article/S0016-5085(20)35249-5/fulltext, https://c19p.org/yeramaneniazaz

15. Hinks et al., Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial

298 patient azithromycin late treatment RCT: 1% lower combined mortality/hospitalization (p=0.99) and 80% lower progression (p=0.24).
RCT 298 mild-to-moderate COVID-19 outpatients in the UK showing no significant difference in hospitalization or death with late azithromycin treatment. Treatment was delayed an average of 6 days from onset. 7 vs. 3 hospitalizations occurred by day 1 in the treatment vs. control groups in this open label trial (Figure 2).
Oct 2021, The Lancet Respiratory Medicine, https://www.sciencedirect.com/science/article/pii/S2213260021002630, https://c19p.org/hinksaz

16. Kuderer et al., Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study

928 patient azithromycin late treatment study: 27% higher mortality (p=0.46).
Retrospective 928 cancer patients, showing higher mortality with HCQ+AZ. The relative risks of different treatments suggest significant confounding by indication. Authors note that HCQ+AZ might not be the cause of increased mortality, but instead was given to patients with more severe COVID-19.
May 2020, Lancet, June 20, 2020, https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31187-9/fulltext, https://c19p.org/kudererazaz

17. Furtado et al., Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial

397 patient azithromycin late treatment RCT: 8% higher mortality (p=0.63) and 30% improvement (p=0.08).
Small RCT comparing the addition of AZ for very late stage patients on ventilation or oxygen. One notable result is that even within this extremely late stage population, results suggest increased efficacy with the addition of AZ for patients with earlier use of AZ/HCQ, OR 0.71 [0.25-2.03] (Figure S4). Patients received 8g of HCQ over 10 days, approaching the high levels used in the RECOVERY trial (9.2g over 10 days), showing significantly more adverse events than typical trials. 50% of patients were on mechanical ventilation at baseline. More than the increase in mortality at day 29 occurred on day 0, and more than 3x the increase occurred by day 2.
Sep 2020, The Lancet, https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31862-6/fulltext, https://c19p.org/furtadoazaz

18. AlQadheeb et al., Impact of common comorbidities on antimicrobial consumption and mortality amongst critically ill COVID-19 patients: A retrospective two center study in Saudi Arabia

848 patient azithromycin ICU study: 22% higher mortality (p=0.08).
Retrospective 848 ICU patients in Saudi Arabia, showing higher mortality with azithromycin in unadjusted results.
May 2023, Clinical Infection in Practice, https://www.sciencedirect.com/science/article/pii/S2590170223000122, https://c19p.org/alqadheebazaz

19. Huh et al., Association of prescribed medications with the risk of COVID-19 infection and severity among adults in South Korea

44,046 patient azithromycin prophylaxis study: 54% higher progression (p=0.33) and 42% fewer cases (p=0.1).
Retrospective database analysis showing no significant differences with azithromycin use.
Dec 2020, Int. J. Infectious Diseases, https://www.sciencedirect.com/science/article/pii/S1201971220325650, https://c19p.org/huh2azaz

20. Omrani et al., Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19

304 patient azithromycin early treatment RCT: 33% higher hospitalization (p=1), 67% lower progression (p=0.62), 100% worse recovery (p=0.5), and 4% worse viral clearance (p=0.63).
Low risk patient RCT for HCQ+AZ and HCQ vs. control, not showing any significant differences. Authors note that the results are not applicable to higher risk patients, that positive PCR may simply reflect detection of inactive (non-infectious) viral remnants, that an alternative dosage regimen may be more effective, and that medication adherence was unknown. HCQ dosing was 600mg/day for 1 week, therapeutic levels may not be reached for several days. There were no deaths or serious adverse events. Viral load was already very high at baseline.
Nov 2020, eClinicalMedicine, https://www.sciencedirect.com/science/article/pii/S2589537020303898, https://c19p.org/omraniazaz

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