What is the effect of Azithromycin on the QTc interval?

From the Guidelines

Azithromycin can prolong the QTc interval, increasing the risk of serious arrhythmias and sudden death.

Key Points

• The risk of QTc interval prolongation is rare, but more likely in patients with advanced age, female sex, heart disease, and those taking other QT-prolonging medications 1.
• Azithromycin can directly prolong the QT interval and also inhibit the metabolism of other proarrhythmogenic drugs by acting on cytochrome P450 in the liver 1.
• Factors increasing the risk of malignant arrhythmias with macrolides include age >80, female gender, heart disease, use of other QT prolonging medication, reduced drug elimination, bradycardia, prolonged QT interval before therapy, and genetic predisposition 1.
• Electrocardiographic monitoring may be considered for patients when concurrent medications that prolong the QTc interval are being used 1.
• The risk of cardiovascular death associated with azithromycin is estimated to be around 85 deaths per 1 million courses prescribed, which is relatively rare 1.

From the FDA Drug Label

QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with azithromycin (500 mg, 1000 mg, and 1500 mg once daily) Co-administration of azithromycin increased the QTc interval in a dose-and concentration-dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides, including azithromycin

Azithromycin increases the QTc interval in a dose-dependent manner. The maximum mean increases in QTcF were 5-9 ms with co-administration of 500-1500 mg azithromycin. This may impart a risk of developing cardiac arrhythmia and torsades de pointes, particularly in at-risk groups such as patients with known prolongation of the QT interval, congenital long QT syndrome, or those taking drugs known to prolong the QT interval 2 2.

From the Research

Effect of Azithromycin on QTc Interval

• The effect of azithromycin on the QTc interval has been studied in various patient populations, including those with community-acquired pneumonia and cystic fibrosis 3, 4, 5.
• A study published in 2024 found that azithromycin use was not associated with a statistically significant increase in QTc interval in ICU patients 3.
• Another study published in 2021 found that QTc interval prolongation was observed during inpatient azithromycin therapy for pneumonia, but was not associated with cardiac dysrhythmias during hospitalization 4.
• A review of case reports published in 2013 found that azithromycin-induced QTc interval prolongation and torsade de pointes were more likely to occur in patients with high baseline risk, including those with preexisting cardiovascular conditions and concomitant use of other QT-prolonging drugs 6.
• A study published in 2019 found that chronic azithromycin therapy was not associated with significant QTc prolongation in adult cystic fibrosis patients 5.
• A review of the literature published in 2014 found that the incidence of azithromycin-induced QTc prolongation and adverse cardiac events was fairly limited to patients with high baseline risk, including those with preexisting cardiovascular conditions and concomitant use of other QT-prolonging drugs 7.

Patient Populations at Risk

• Elderly women with heart disease may be at particularly high risk for azithromycin-induced QTc interval prolongation and torsade de pointes 6.
• Patients with preexisting cardiovascular conditions, concomitant use of other QT-prolonging drugs, and metabolic inhibitors may also be at higher risk 7, 6.
• Patients with cystic fibrosis receiving chronic azithromycin therapy do not appear to be at significant risk for QTc prolongation 5.

Clinical Implications

• Azithromycin should be used with caution in patients at high risk for QTc interval prolongation and torsade de pointes 7, 6.
• Electrocardiogram monitoring may be necessary for patients at high risk, especially during the initial treatment period 4.
• The benefits and risks of azithromycin therapy should be carefully weighed in patients with preexisting cardiovascular conditions and concomitant use of other QT-prolonging drugs 7, 6.