Effect of Combination Therapy of Hydroxychloroquine and Azithromycin on Mortality in Patients With COVID‐19
Marinella Lauriola, Arianna Pani, Giovanbattista Ippoliti, Andrea Mortara, Stefano Milighetti, Marjieh Mazen, Gianluca Perseghin, Daniele Pastori, Paolo Grosso, Francesco Scaglione
Clinical and Translational Science, doi:10.1111/cts.12860
Conflicting evidence regarding the use of hydroxychloroquine (HCQ) and azithromycin for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection do exist. We performed a retrospective single-center cohort study including 377 consecutive patients admitted for pneumonia related to coronavirus disease 2019 (COVID-19). Of these, 297 were in combination treatment, 17 were on HCQ alone, and 63 did not receive either of these 2 drugs because of contraindications. The primary end point was in-hospital death. Mean age was 71.8 ± 13.4 years and 34.2% were women. We recorded 146 deaths: 35 in no treatment, 7 in HCQ treatment group, and 102 in HCQ + azithromycin treatment group (log rank test for Kaplan-Meier curve P < 0.001). At multivariable Cox proportional hazard regression analysis, age (hazard ratio (HR) 1.057, 95% confidence interval (CI) 1.035-1.079, P < 0.001), mechanical ventilation/continuous positive airway pressure (HR 2.726, 95% CI 1.823-4.074, P < 0.001), and C reactive protein above the median (HR 2.191, 95% CI 1.479-3.246, P < 0.001) were directly associated with death, whereas use of HCQ + azithromycin (vs. no treatment; HR 0.265, 95% CI 0.171-0.412, P < 0.001) was inversely associated. In this study, we found a reduced in-hospital mortality in patients treated with a combination of HCQ and azithromycin after adjustment for comorbidities. A large randomized trial is necessary to confirm these findings.
Conflict of Interest. All authors declared no competing interests for this work. Author Contributions. M.L., A.P., G.I., A.M., S.M., M.M., G.P., D.P., P.G., and F.S. wrote the manuscript. A.P., F.S., and M.L. designed the research. D.P. analyzed the data.
References
Al-Kofahi, Finding the dose for hydroxychloroquine prophylaxis for COVID-19: the desperate search for effectiveness, Clin. Pharmacol. Ther,
doi:10.1002/cpt.1874Arnold, Buckner, Hydroxychloroquine for treatment of SARS-CoV-2 infection? Improving our confidence in a model-based approach to dose selection, Clin. Transl. Sci
Bessiere, Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit, JAMA Cardiol,
doi:10.1001/jamacardio.2020.1787Cao, A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19
Chang, Inpatient use of ambulatory telemetry monitors for COVID-19 patients treated with hydroxychloroquine and/or azithromycin, J. Am. Coll. Cardiol
Cory, Impact of azithromycin treatment on macrophage gene expression in subjects with cystic fibrosis, J. Cyst. Fibros
Fantini, Chahinian, Yahi, Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: what molecular dynamics studies of virus-host interactions reveal, Int. J. Antimicrob. Agents,
doi:10.1016/j.ijantimicag.2020.106020Gao, Ray, Xiao, Ray, Suppression of inducible nitric oxide synthase expression and nitric oxide production by macrolide antibiotics in sulfur mustard-exposed airway epithelial cells, Basic Clin. Pharmacol. Toxicol
Gautret, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int. J. Antimicrob. Agents,
doi:10.1016/j.ijantimicag.2020.105949Geleris, Observational study of hydroxychloroquine in hospitalized patients with Covid-19, N. Engl. J. Med
Humeniuk, Safety, tolerability, and pharmacokinetics of remdesivir, an antiviral for treatment of COVID-19, in healthy subjects, Clin. Transl. Sci,
doi:10.1111/cts.12840Kawamura, Efficacy of azithromycin in sepsis-associated acute respiratory distress syndrome: a retrospective study and propensity score analysis, Springerplus
Kawamura, Ichikado, Takaki, Eguchi, Anan et al., Adjunctive therapy with azithromycin for moderate and severe acute respiratory distress syndrome: a retrospective, propensity score-matching analysis of prospectively collected data at a single center, Int. J. Antimicrob. Agents
Lauriola, Hydroxychloroquine and Azithromycin in COVID-19
Lippi, South, Henry, Electrolyte imbalances in patients with severe coronavirus disease 2019 (COVID-19), Ann. Clin. Biochem
Liu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov
Mercuro, Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease, JAMA Cardiol,
doi:10.1001/jamacardio.2020.1834Naksuk, Lazar, Peeraphatdit, Cardiac safety of off-label COVID-19 drug therapy: a review and proposed monitoring protocol, Eur. Heart J. Acute Cardiovasc. Care
Perinel, Towards optimization of hydroxychloroquine dosing in intensive care unit COVID-19 patients, Clin. Infect. Dis,
doi:10.1093/cid/ciaa394Rosenberg, Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state, JAMA
Tang, Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial, BMJ
Yao, In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), Clin. Infect. Dis,
doi:10.1093/cid/ciaa237Yeo, Impact of disease on plasma and lung exposure of chloroquine, hydroxy-chloroquine and azithromycin: application of PBPK modelling, Clin. Pharmacol. Ther,
doi:10.1002/cpt.1955Zimmermann, Ziesenitz, Curtis, Ritz, The immunomodulatory effects of macrolides-a systematic review of the underlying mechanisms, Front. Immunol
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