Azithromycin Causes a Novel Proarrhythmic Syndrome

Abstract

Background The widely-used macrolide antibiotic azithromycin increases risk of cardiovascular and sudden cardiac death, although the underlying mechanisms are unclear. Case reports, including the one we document here, demonstrate that azithromycin can cause rapid, polymorphic ventricular tachycardia in the absence of QT prolongation, indicating a novel proarrhythmic syndrome. We investigated the electrophysiologic effects of azithromycin in vivo and in vitro using mice, cardiomyocytes, and human ion channels heterologously expressed in human embryonic kidney (HEK 293) and Chinese hamster ovary (CHO) cells. Methods and Results In conscious telemetered mice, acute intraperitoneal and oral administration of azithromycin caused effects consistent with multi-ion channel block, with significant sinus slowing and increased PR, QRS, QT, and QTc intervals, as seen with azithromycin overdose. Similarly, in HL-1 cardiomyocytes, the drug slowed sinus automaticity, reduced phase 0 upstroke slope, and prolonged action potential duration. Acute exposure to azithromycin reduced peak SCN5A currents in HEK cells (IC50=110±3μM) and Na+ current in mouse ventricular myocytes. However, with chronic (24hour) exposure, azithromycin caused a ~2-fold increase in both peak and late SCN5A currents, with findings confirmed for INa in cardiomyocytes. Mild block occurred for K+ currents representing IKr (CHO cells expressing hERG; IC50=219±21μM) and IKs (CHO cells expressing KCNQ1+KCNE1; IC50=184±12μM), while azithromycin suppressed L-type Ca++ currents (rabbit ventricular myocytes; IC50=66.5±4μM) and IK1 (HEK cells expressing Kir2.1; IC50=44±3μM). Conclusions Chronic exposure to azithromycin increases cardiac Na+ current to promote intracellular Na+ loading, providing a potential mechanistic basis for the novel form of proarrhythmia seen with this macrolide antibiotic.

Considerations for Drug Interactions on QTc in Exploratory COVID-19 Treatment

“…Interestingly, azithromycin can also provoke non-pause-dependent polymorphic ventricular tachycardia. 11,12 The FDA Perspective supported the observations that azithromycin administration leaves the patient vulnerable to QTc interval prolongation and torsade de pointes. 13 Basic electrophysiologic studies suggest that both drugs can provoke proarrhythmia via mechanisms beyond block of IKr implicated in usual cases of torsade de pointes.…”

Considerations for Drug Interactions on QTc Interval in Exploratory COVID-19 Treatment

“…Interestingly, azithromycin can also provoke non-pause-dependent polymorphic ventricular tachycardia. 11,12 The FDA Perspective supported the observations that azithromycin administration leaves the patient vulnerable to QTc interval prolongation and torsade de pointes. 13 Basic electrophysiologic studies suggest that both drugs can provoke proarrhythmia via mechanisms beyond block of I Kr implicated in usual cases of torsade de pointes.…”

Dual effects of arsenic trioxide on tumor cells and the potential underlying mechanisms

“…To address whether hERG channels were involved in this process, 293 cells overexpressing hERG channels were used in the present study. hERG current and electrophysiological characteristics are relatively easy to detect in this cell model ( 28 – 30 ). hERG-293 cells were incubated with 0.1, 0.5 and 1 µM As 2 O 3 for 24 h. The results demonstrated that 0.1 µM As 2 O 3 was able to increase the expression of hERG channels compared with the control group.…”