We agree with colleagues that the hydroxychloroquine-azythromycin (HCQ-AZ) combination may potentially lead to drug-drug interactions [1]. Given that both drugs are known to have potential cardiotoxicity, we paid a rigorous attention to avoiding HCQ-AZ in patients with cardiac diseases, abnormal EKG, dyskalemia or the routine use of other interacting medications. The systematic pre-therapy workup included serum electrolyte analysis, and an electrocardiogram with corrected QT measurement (Bazett's formula). Close serum electrolyte analysis monitoring was performed in patients with low serum potassium levels at baseline. An electrocardiogram was routinely performed 48 hours after the start of treatment. Treatment with HCQ was discontinued when the corrected QT interval (QTc, Bazett's formula) was>500ms and the risk-benefit ratio of HCQ+AZ treatment was estimated by the infectious disease specialist and agreed with the cardiologist, to be between 460 and 500ms. The indications for this control ECG were restricted after an initial workup in 848 ECG from 424 patients (at day 0 and day 2 for each patient), showing that all contraindicative repolarization abnormalities had been detected on the first ECG [2]. Among 3,737 COVID-19 patients diagnosed at our institute in March-April 2020, 88 (2.4%) had cardiac contraindications to combination therapy, 45 (1.2%) patients were taking a drug with a potential risk of interactions with combination therapy and 10 (0.3%) had hypo or hyperkalaemia [3]. A total of 3,119 patients received HCQ-AZ for at least three days. QTc prolongation (>60 ms) was observed in 25 patients (0.67%), resulting in discontinuation of treatment in 12 cases, including three cases with QTc> 500 ms. No cases of torsade de pointe or sudden death were observed, including in the 9.5% of patients over 65 years of age.
Our current observations and practices illustrate the efficacy of this risk management procedures associated with the prescription of HCQ-AZ, which presents an excellent safety profile in COVID-19 patients, including elderly patients [4].
We agree that doxycycline has shown in vitro effect on SARS-CoV-2 [5]. However, synergistic between doxycycline and hydroxychloroquine in vitro effect has not been investigated so far, unlike azithromycin. Therefore, the combination of HCQ and doxycycline should only be proposed for patients with a contraindication to the HCQ-AZ regimen, independently of age.
Declaration of Competing Interest
The authors declare no competing interests.
Acknowledgments
Funding
No funding sources.
Ethical approval
Not applicable.
Footnotes
This article refers to 10.1016/j.ijantimicag.2020.105949 and 10.1016/j.ijantimicag.2020.106168.
References
- 1.Malek A.E., Granwehr B.P. Doxycycline as an alternative to azithromycin in elderly patients. Int J Antimicrob Agents. 2021 doi: 10.1016/j.ijantimicag.2020.106168. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Million M., Lagier J.C., Gautret P., Colson P., Fournier P.E., Amrane S. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France. Travel Med Infect Dis. May-Jun 2020;35 doi: 10.1016/j.tmaid.2020.101738. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Lagier J.C., Million M., Gautret P., Colson P., Cortaredona S., Giraud-Gatineau A. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis. Travel Med Infect Dis. Jul-Aug 2020;36 doi: 10.1016/j.tmaid.2020.101791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Hache G., Rolain J.M., Gautret P., Deharo J.C., Brouqui P., Raoult D. Combination of hydroxychloroquine plus azithromycin as potential treatment for COVID 19 patients: safety profile, drug interactions and management of toxicity. Microbial Drug Resistance. 2020 doi: 10.1089/mdr.2020.0232. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Gendrot M., Andreani J., Boxberger M., Jardot P., Fonta I., Le Bideau M. Antimalarial drugs inhibit the replication of SARS-CoV-2: An in vitro evaluation. Travel Med Infect Dis. Sep 8 2020;37 doi: 10.1016/j.tmaid.2020.101873. [DOI] [PMC free article] [PubMed] [Google Scholar]