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Hydroxychloroquine plus Azithromycin

Last Updated: May 12, 2020

Please also see the Hydroxychloroquine and Chloroquine sections, as some patients in those studies also received azithromycin as part of their treatment.

Recommendation:

  • The Panel recommends against the use of hydroxychloroquine plus azithromycin for the treatment of COVID-19, except in the context of a clinical trial (AIII).

Rationale for Recommendation:

Chloroquine and hydroxychloroquine for COVID-19 have been used in small randomized trials and in some case series with conflicting study reports (as described above). The combination of hydroxychloroquine and azithromycin is associated with QTc prolongation in patients with COVID-19. Given the long half-lives of both azithromycin (up to 72 hours) and hydroxychloroquine (up to 40 days), caution is warranted even when the two drugs are used sequentially instead of concomitantly.1

Clinical Data in COVID-19

Case Series of Hydroxychloroquine Plus Azithromycin

In a case series of 80 hospitalized patients with COVID-19 (including six patients from a previous study),2 patients were treated with hydroxychloroquine sulfate 200 mg three times daily for 10 days plus azithromycin 500 mg for 1 day followed by 250 mg once daily for 4 days. Mean time from symptom onset to treatment was about 5 days. Outcomes evaluated included the need for oxygen therapy or intensive care unit (ICU) transfer after ≥3 days of therapy, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) level by polymerase chain reaction (PCR), SARS-CoV-2 culture (in a subset of patients; a convenience sample), and length of stay in the infectious diseases ward.2

Clinical Results:

  • One (1.2%) patient died and three (3.8%) patients required ICU transfer, 12 (15%) patients required oxygen therapy.
  • 65 (81.2%) patients were discharged to home or transferred to other units for continuing treatment; 14 (17.4%) patients remained hospitalized at the time the study results were published.

Laboratory Results:

  • Nasopharyngeal (NP) SARS-CoV-2 PCR was negative in 83% of patients by Day 7 and 93% of patients by Day 8.
  • In the subset of patients who had respiratory sample viral cultures performed at Day 5, results were negative for 97.5% of the samples.

Limitations:

  • The trial's lack of a control group, which is particularly important because many people with mild disease improve in the absence of treatment.
  • The definition of "discharge" varied.
  • The lack of complete or longer-term follow-up.

Interpretation: The multiple issues with the trial design and the lack of a comparison group limit the usefulness of this study to inform recommendations.

Small Prospective Case Series of Hydroxychloroquine Plus Azithromycin

A prospective case series from France assessed eleven consecutive hospitalized patients with COVID-19.3

Results:

  • Eight of the 11 patients had significant co-morbid conditions: obesity (2), solid cancer (3), hematological cancer (2), and HIV-infection (1).
  • Ten of 11 patients were receiving supplemental oxygen upon treatment initiation.
  • All patients were treated with hydroxychloroquine 600 mg once daily for 10 days and azithromycin 500 mg once daily for 1 day followed by 250 mg once daily for 4 days.
  • Within 5 days, the condition of three patients worsened, including one patient who died and two patients who were transferred to the ICU.
  • Adverse events: Hydroxychloroquine was discontinued in one patient due to QTc prolongation.
  • Qualitative NP PCR remained positive at Days 5 and 6 after treatment initiation in 8 of 10 patients.

Limitations:

  • This is a case series that included only 11 patients.

Interpretation: In this small case series, most patients who received hydroxychloroquine plus azithromycin did not have rapid viral clearance.

Case Series of Changes in QTc Interval in Patients Who Received Hydroxychloroquine Plus Azithromycin

A case series in the United States reported changes in QTc interval in 84 patients with COVID-19 who received the combination of hydroxychloroquine 400 mg twice daily for 1 day, followed by 200 mg twice daily for 4 days, and azithromycin 500 mg once daily for 5 days.4

Results:

  • 84 patients, 74% male, mean age 63 ± 15 years, 65% had hypertension, baseline serum creatinine 1.4 mg/dL, 13% required vasopressors, 11% had coronary artery disease.
  • Among all the patients, 11% received neuropsychiatric drugs that may prolong QTc interval and 8% received other concomitant drugs (levofloxacin, lopinavir/ritonavir, or tacrolimus) that may prolong QTc.
  • Four patients died, without arrhythmia.
  • The mean baseline QTc was 435 ± 24 ms; the mean maximum QTc was 463 ± 32 ms.
  • The mean time to maximum QTc was 3.6 ± 1.6 days; ECG follow-up was done for a mean of 4.3 days.
  • 9 patients (11%) developed QTc >500 ms; the QTc increased by 40 to 60 ms and >60 ms in 18% and 12% of patients, respectively.

Limitations:

  • Case series, descriptive

Interpretation: This case series demonstrates that hydroxychloroquine and azithromycin in combination can prolong QTc, and that use of the combination warrants careful monitoring.

Clinical Trials

Clinical trials to test the safety and efficacy of chloroquine or hydroxychloroquine with or without azithromycin in people who have or are at risk for COVID-19 are underway in the United States and internationally. Please check ClinicalTrials.gov for the latest information.

References

  1. Institute for Safe Medication Practices. Medication Safety Alert! April 9, 2020. 2020. Available at: https://ismp.org/acute-care/special-edition-medication-safety-alert-april-9-2020/covid-19. Accessed: April 28, 2020.
  2. 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 Med Infect Dis. 2020:101663. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32289548.
  3. Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Médecine et Maladies Infectieuses. 2020;[In press]. Available at: https://www.sciencedirect.com/science/article/pii/S0399077X20300858?via%3Dihub#!
  4. Chorin E, Dai M, Shulman E, et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nature Medicine. 2020. Available at: https://doi.org/10.1038/s41591-020-0888-2.