Can azithromycin (Zithromax) prolong the QT (quantum time) interval?

Azithromycin and QT Interval Prolongation

Yes, azithromycin definitely can prolong the QT interval and potentially lead to serious cardiac arrhythmias, including torsades de pointes, though this is a rare adverse effect. 1, 2

Mechanism and Evidence

Azithromycin prolongs the QT interval through several mechanisms:

• Blocks the rapidly activating delayed rectifier potassium current (IKr) in cardiac cells 1
• Can provoke proarrhythmia through mechanisms beyond IKr blockade 3
• FDA labeling specifically warns about QT prolongation risk 2

The American College of Cardiology, American Heart Association, and Heart Rhythm Society have listed azithromycin as a "definite cause of torsades de pointes" on crediblemeds.org 3, 1.

Risk Factors for Azithromycin-Induced QT Prolongation

Several patient-specific factors increase the risk:

• Female sex 1, 4
• Advanced age 1, 4
• Baseline QTc prolongation (≥500 ms) 1
• Congenital long QT syndrome 1, 2
• Electrolyte abnormalities (hypokalemia, hypomagnesemia) 1, 4
• Heart disease 4
• Bradycardia 4
• Concomitant use of other QT-prolonging medications 1, 2
• Fever and inflammatory states 1

Clinical Significance and Risk Assessment

The actual risk of serious arrhythmias varies significantly based on patient factors:

• The risk of fatal ventricular arrhythmia with macrolides compared to amoxicillin is estimated at 1:4,100 among high cardiovascular risk patients but <1:100,000 among low cardiovascular risk patients 1
• In a study of ICU patients receiving azithromycin for community-acquired pneumonia, no statistically significant increase in QTc interval was observed, suggesting that for many patients, QTc prolongation may not be a major concern 5
• However, another study found that QTc interval increases were observed during inpatient azithromycin therapy for pneumonia, with 10% of patients developing a QTc >500 ms after one dose 6

Recommendations for Clinical Practice

When considering azithromycin use:

1. Obtain a baseline ECG prior to administration, especially in high-risk patients 1
2. Review the patient's medication list for other QT-prolonging drugs 1
3. Check electrolyte levels, particularly potassium and magnesium 1
4. Consider withholding azithromycin in patients with:
   • Baseline QTc interval ≥500 ms
   • Known congenital long QT syndrome
   • Multiple risk factors for QT prolongation 1, 2
5. Monitor ECG during therapy in high-risk patients 1
6. Avoid concurrent use with other QT-prolonging medications when possible, particularly macrolides and quinolones 3

Important Caveats

• QT prolongation can occur even with standard dosing regimens
• The risk appears higher with intravenous administration compared to oral administration
• Elderly women with heart disease appear to be at particularly high risk 4
• Despite the FDA warning, some studies show conflicting results, with some showing no significant QTc prolongation in certain populations 5, 7

Remember that the presence of multiple risk factors compounds the risk of QT prolongation and subsequent arrhythmias. Most cases of azithromycin-induced torsades de pointes occur in patients with at least two additional risk factors 4.