key: cord-0993297-l0tbak9l
authors: Kow, Chia Siang; Hasan, Syed Shahzad
title: Macrolides for patients with COVID-19 and concurrent pertussis infection
date: 2020-10-16
journal: Diagn Microbiol Infect Dis
DOI: 10.1016/j.diagmicrobio.2020.115245
sha: d333b6073099d128e845289a06ebe978763b962e
doc_id: 993297
cord_uid: l0tbak9l

nan

We read with interest the study by He et al. [1] which compared the type and frequency of bacterial co-infections between patients with coronavirus disease 2019 (COVID-19) and patients with other viral pneumonia. The authors [1] observed that the rate of pertussis co-infection was significantly higher in patients with COVID-19 pneumonia compared to patients with other viral pneumonia.

Therefore, pertussis co-infection should be one of the differential diagnoses in patients with COVID-19 demonstrating persistent coughing.

Macrolides are the preferred antibiotic therapy for pertussis infection [2] . In a Cochrane review which included 13 randomized controlled trials to evaluate the effectiveness of antimicrobial treatment for pertussis infection, it was observed that macrolide antibiotics (azithromycin, clarithromycin, and erythromycin) were effective for the eradication of Bordetella pertussis from the nasopharynx, either with the short-term or the long-term duration of antibiotic therapy [3] .

Nonetheless, we are concerned with the use of macrolides among patients with COVID-19 and concurrent pertussis infection. One of the macrolides, azithromycin, has been repurposed for the treatment of COVID-19, with or without combination with the antimalarials, chloroquine, and hydroxychloroquine. While the effectiveness of azithromycin has yet to be conclusively proven, there have been safety concerns with its use in COVID-19. A recent systematic review and metaanalysis reported an increased risk of death with the use of azithromycin in combination with hydroxychloroquine though this was not the case for the use of hydroxychloroquine alone, among patients with COVID-19 [4] .

Though some may believe that prolongation of the QTc interval with the use of azithromycin in combination with hydroxychloroquine may be the cause of increased death in this patient population, such prolongation does not increase the risk of arrhythmia since azithromycin prolongs the action potential instead of prolongs repolarization which tends to cause torsades de pointes [5] .

Instead, azithromycin (and possibly clarithromycin) could induce a novel proarrhythmic syndrome characterized by rapid, polymorphic ventricular tachycardia in the absence of QTc prolongation, due to intracellular loading of sodium ions with subsequent potentiation of sodium current in the cardiac cells and dysregulation of cardiac calcium homeostasis (similar to digoxin therapy) [6] .

In fact, an analysis of more than 1 million azithromycin exposures (before the COVID-19 pandemic)

reported that the use of azithromycin significantly increased the hazard of cardiovascular death [7] .

Likewise, a follow-up study of a randomized trial evaluating 4,373 patients with stable coronary heart disease who received either clarithromycin or placebo for the treatment of atherosclerosis reported an increased risk of cardiovascular mortality with the use of clarithromycin during the first three years of follow-up [8] .

These findings warrant further exploration, but in the meantime, macrolides should be administered with caution in patients with COVID-19 since COVID-19 has been associated with myocardial injury, and administration of macrolides may add to the cardiac insult. This may be the reason for the increased risk of death with the use of azithromycin in combination with hydroxychloroquine in this patient population. Trimethoprim-sulfamethoxazole is an acceptable alternative to macrolides; in the aforementioned Cochrane review, trimethoprim-sulfamethoxazole was also effective for the eradication of Bordetella pertussis [3] .

Funding: The writing of this manuscript did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Respiratory bacterial pathogen spectrum among COVID-19 infected and non-COVID-19 virus infected pneumonia patients

Pertussis: Microbiology, Disease, Treatment, and Prevention

Antibiotics for whooping cough (pertussis)

Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis

Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes

Azithromycin Causes a Novel Proarrhythmic Syndrome

Association of Azithromycin Use With Cardiovascular Mortality

Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10years in the CLARICOR randomised, blinded clinical trial