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Three Part Question

[In adult patients admitted to hospital with confirmed or suspected COVID-19] does [Azithromycin] lead to [reduced mortality and/or reduced length of stay and/or reduced time to improvement and/or increased adverse events]

Clinical Scenario

A 65 year old man presented to the Emergency Department with hypoxia and confusion. Chest xray is consistent with severe COVID-19 pneumonia. COVID-19 was confirmed with PCR testing. A colleague mentions Azithromycin as a possible treatment. You wonder if Azithromycin would reduce mortality or length of stay. You also wonder if it is associated with increased adverse events.

Search Strategy

Medline using OVID interface
EMBASE using OVID interface
Medline using PubMed
Cochrane Library
Further Google Scholar search to ensure no missing relevant material

PubMed:
("Azithromycin"[All Fields]) AND ("Covid-19"[All Fields] OR "coronavirus"[All Fields] OR "Severe acute respiratory syndrome coronavirus 2"[All Fields] OR "SARS-CoV-2"[All Fields] OR "2019 novel coronavirus"[All Fields] OR "2019-nCoV"[All Fields] OR "coronavirus disease 2019"[All Fields]) AND (hasabstract[text] AND ("2019/12/01"[PDAT] : "3000/12/31"[PDAT]) AND English[lang])

OVID:
(exp *azithromycin/ or Azithromycin.mp.) and ((Covid-19 or coronavirus or Severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 or 2019 novel coronavirus or 2019-nCoV or coronavirus disease 2019).mp. LIMIT to (english language and yr="2019 -Current")


Cochrane:
Azithromycin AND COVID-19

Google Search:
(Azithromycin) AND (Covid-19 OR coronavirus OR Severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2 OR 2019 novel coronavirus OR 2019-nCoV OR coronavirus disease 2019) LIMIT to English AND Human

Search Outcome

Pubmed: 42 papers of which 12 relevant
Medline: 87 papers no new relevant research found
EMBASE: 98 papers no new relevant research found
Cochrane: 16 trials found but no new published research
Google Scholar: no new relevant papers found

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Rosenberg ES, Dufort EM, Udo T, et al May 11, 2020 USA	Admitted patients (>24 hours) with laboratory-confirmed COVID-19 from 25 hospitals (n=1438) 4 Groups: Receipt of both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither	Retrospective multicenter cohort study	Primary: in-hospital mortality	No significant differences in mortality between 4 groups.	Observational data with potential for bias. Groups significantly heterogenous with different age, sex, size and clinical conditions
			Secondary: Cardiac arrest and abnormal ECG findings (arrhythmia or QT prolongation).	Cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin but not hydroxychloroquine alone.
Alawan AA, Taher A, Alaradi AH. May 6, 2020 Bahrain	One, 33 year old patient	Case-Report	To describe clinical presentation, diagnostic and treatment process of severe case of COVID-19 in patient with ESRF.	Patient initially vitally stable, clinical deterioration requiring HDU level care. However after combination treatments responded gradually and discharged	Descriptive, single case report Observational link between medical therapy and clinical improvement Multiple therapies given simultaneously including antibiotic therapy, Lopinavir-Ritonavir, Ribavirin, Azithromycin, Hydroxychloroquine and Oseltamivir
Million M, Lagier JC, Gautret P, et al. May 5, 2020 France	Admitted patients with positive RT-PCR treated with hydroxychloroquine with azithromycin for at least 3 days (n=1061).	Retrospective case series	Mortality	8 participants died (0.75%)	Observational evidence only due to study design No control group, all received the same treatment. Multiple treatments assessed simultaneously
			Clinical worsening (transfer to ICU, and >10 day hospitalization)	Good clinical outcome for majority of participants (91.7%) but poor outcome for 46 participants (4.3%) which was associated with older age, severity of illness at admission and low HCQ serum concentration
			Viral shedding persistence (>10 days).	Prolonged viral carriage was observed in 47 patients (4.4%) and was associated to a higher viral load at diagnosis
Nair V, Jandovitz N, Hirsch JS et al April 29, 2020 USA	Ten kidney transplant recipients with positive RT-PCR, all given azithromycin with hydroxychloroquine (n=10)	Case-Series	Describe clinical presentation, management and outcomes of immunocompromised kidney transplant patients	Generally similar clinical presentation to non-immunosuppressed patients. 3 patients (30%) died, 5 patient (50%) developed AKI, 5 patients (50%) required ICU care 7 patients (70%) were eventually discharged with median stay of 11 days (4-17 days).	Descriptive case-series with only observational evidence No control group, no comparison group Multiple treatments given and confounders present
			Abnormal ECG findings (arrhythmia or QT prolongation).	No evidence of ECG changes or QT prolongation in any patients treated
Adreani J, Bideau M, Duflot I et al. April 25, 2020 France	Isolated virus combined with varying concentrations of both hydroxychloroquine and azithromycin	In-vitro study	Viral RNA replication	Viral replication was reduced when exposed to combination of hydroxychloroquine with azithromycin	In-vitro study with no clinical component Only combination treatment assessed therefore only synergistic in-vitro effect shown
Touret F, Gilles M, Barral K et al. April 3, 2020 (Pre-Print) France	Prestwick Chemical Library composed of 1,520 approved drugs in an infected cell-based assay	In-vitro study	Medications found to have in-vitro antiviral activity by inhibition index	Arbidol, Chloroquine and Hydroxychloroquine as well as Darunavir and Azythromycin shown to limit SARS-CoV-2 replication independently	In-vitro study with no clinical component
Gautret P, Lagier, JC, Parola P et al. March 20, 2020 France	Patients admitted to hospital with positive RT-PCR (n=36) 2 groups: Hydroxychloroquine (n=20) treated, 6 of which received combination with azithromycin, and control (n=16)	Non-randomized control trial (“open-label” trial).	Respiratory viral load (PCR).	Combination of azithromycin with hydroxychloroquine showed 100% clearance at day 6, whereas only 57.1% with hydroxychloroquine alone although this was better than control group	Excluded patients that met inclusion criteria without indication as to reason Small sample size with no randomisation No clear indication as to why azithromycin was started within treatment group for 6 patients Significant variation in demographics of groups
Gautret P, Lagier JC, Parola P et al. April 11, 2020 France	Patients admitted to an infectious diseases ward with positive RT-PCR, 6 participants from a previous study included as received this treatment (n=80)	Pilot observational study, Case-series	Clinical outcome	One patient died One patient admitted to ICU 65 patients discharged (81.2%)	Study asserts further investigation required as “potentially life-saving” Observational data, no comparison or control nor general population data included to compare Used data from participants from another study within the same centre
			Contagiousness as assessed by PCR and culture	PCR negative at Day 7 for 83%, and 93% at Day 8. Virus cultures from patient respiratory samples were negative in 97.5% of patients at Day 5.
			Length of stay in infectious disease unit (IDU).	Mean time from initiation to discharge was 4.1 days with a mean length of stay of 4.6 days.
Saleh M, Gabriels J, Chang D et al. April 29, 2020 USA	Hospitalised patients receiving treatment for suspected COVID -19 (n=201) Chloroquine (n=10), Hydroxychloroquine (n=191) + azithromycin combination therapy (n=119)	Prospective observational Study	Instances of TdP or arrhythmogenic death	No instances of TdP or arrhythmogenic death	No outcome for clinical outcome of infection in relation to treatment No control group or documentation of other medications/treatment given
			QT prolongation secondary to treatment	All medications led to prolongation of QTc, more significant in combination group of which 7 patients had to have treatment discontinued due to prolongation
Mercuro NJ, Yen CF, Shim DJ et al. May 1, 2020 USA	Patients admitted with positive RT-PCR and radiological findings consistent with COVID-19 who were given hydroxychloroquine (n=90) + azithromycin (n=53)	Prospective cohort study	Change in QT interval after receiving hydroxychloroquine +/- azithromycin	Prolongation of QTc was significant in both groups, with greater change in concomitant group	No outcome for clinical outcome of infection in relation to treatment No control group or documentation of other medications/treatment given
			Occurrence of other potential adverse drug events.	10 patients had hydroxychloroquine discontinued early because of potential adverse drug events, including intractable nausea, hypoglycemia, and 1 case of TdP
Sarayani A, Cicali B, Henriksen CH and Brown JD. April 19, 2020 USA	Analysis of FDA’s adverse event reporting system in relation to Hydroxychloroquine, hydroxychloroquine with azithromycin, azithromycin alone, amoxicillin with hydroxychloroquine and amoxicillin alone (>13m reports)	Comparative pharmacovigilance analysi	Events recorded included death and TdP/QT prolongation as well as accidents/injuries and depression as control events.	HCQ/CQ use was not associated with any adverse events ; Azithromycin used alone was associated with TdP/QT prolongation	Retrospective analysis of data that may have significant gaps, particularly when adverse events do not lead to clinical presentation Only assessing adverse events of medication and no applied clinically in COVID-19 context Unclear if confounding factors may change the results/other medications used

Comment(s)

In-vitro studies have shown some potential for azithromycin as a useful medication for the treatment of COVID-19, one of which has shown an independent in-vitro inhibition of the virus and another study only assessing and showing this effect in combination with hydroxychloroquine. There is a lack of high-level evidence and no current RCTs have been published to assess azithromycin as an effective treatment and much of the evidence presented assesses combination treatment with hydroxychloroquine simultaneously. There has been a number of clinical studies showing weak observational evidence that azithromycin may have some benefit shortening viral shedding which has been previously associated with better clinical outcomes. Rosenberg et al published a Retrospective multicenter cohort study which, despite flaws in study design, is the most comprehensive study to date which showed no significant difference in mortality or clinical outcome for groups receiving hydroxychloroquine, azithromycin , hydroxychloroquine + azithromycin combination, or best supportive care. This study also agrees with the other presented evidence that azithromycin may have a significant adverse effect on prolongation of QTc interval and increased risk of torsades de pointes or other arrhythmogenic complications, a finding not consistent with hydroxychloroquine treatment alone.

Clinical Bottom Line

There is no current evidence to support the use of Azithromycin in COVID-19. There is no evidence it improves clinical outcomes, reduces length of stay or improves mortality. There may be a significant risk of QTc prolongation and increased risk of arrhythmogenic complications in patients treated with azithromycin. In absence of evidence of benefit it is important to remember that we must: “first do no harm”.

References

1. Rosenberg ES, Dufort EM, Udo T, et al Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State The Journal of the American Medical Association 11 May 2020, E1-10
2. Alawan AA, Taher A, Alaradi AH. A Hemodialysis Patient With Severe COVID-19 Pneumonia The Cureus Journal of Medical Science May 6 2020; e7995
3. Million M, Lagier JC, Gautret P, et al. Early Treatment of COVID-19 Patients With Hydroxychloroquine and Azithromycin: A Retrospective Analysis of 1061 Cases in Marseille, France Travel Medicine and Infectious Disease 5 May 2020;
4. Nair V, Jandovitz N, Hirsch JS et al. COVID-19 in kidney transplant recipients American Journal of Transplantation 29 April 2020
5. Adreani J, Bideau M, Duflot I et al. In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect Microbial Pathogenesis 25 April 2020
6. Touret F, Gilles M, Barral K et al. In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication bioRxiv 3 April 2020
7. Gautret P, Lagier, JC, Parola P et al. Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-Randomized Clinical Trial international journal of antimicrobial agents 20 March 2020
8. Gautret P, Lagier JC, Parola P et al. Clinical and Microbiological Effect of a Combination of Hydroxychloroquine and Azithromycin in 80 COVID-19 Patients With at Least a Six-Day Follow Up: A Pilot Observational Study Travel Medicine and Infectious Disease 11 April 2020
9. Saleh M, Gabriels J, Chang D et al. The Effect of Chloroquine, Hydroxychloroquine and Azithromycin on the Corrected QT Interval in Patients with SARS-CoV-2 Infection Circulation: Arrhythmia and Electrophysiology 29 April 2020
10. Mercuro NJ, Yen CF, Shim DJ et al. Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19) JAMA Cardiology 1 May 2020
11. Sarayani A, Cicali B, Henriksen CH and Brown JD. Safety signals for QT prolongation or Torsades de Pointes associated with azithromycin with or without chloroquine or hydroxychloroquine Research in Social & Administrative Pharmacy 19 April 2020