Can Azithromycin (macrolide antibiotic) cause QT interval prolongation?

Azithromycin and QT Interval Prolongation

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

Mechanism and Evidence

Azithromycin has been recognized as a cause of QT interval prolongation through multiple mechanisms:

• It blocks the rapidly activating delayed rectifier potassium current (IKr) in cardiac cells 1
• It can also provoke proarrhythmia through mechanisms beyond IKr blockade 1
• The FDA has identified azithromycin as a medication that leaves patients at risk for QT prolongation and torsades de pointes 1

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 1.

Risk Factors for QT Prolongation with Azithromycin

Several factors increase the risk of azithromycin-induced QT prolongation:

• Patient-specific factors:

  • Female sex 1, 2
  • Advanced age 1, 2
  • Existing cardiovascular disease 2
  • Baseline QTc prolongation (≥500 ms) 1, 3
  • Congenital long QT syndrome 1, 3
  • Bradyarrhythmias or uncompensated heart failure 3

• Concurrent conditions:

  • Electrolyte abnormalities (hypokalemia, hypomagnesemia) 1, 3, 2
  • Fever 1
  • Inflammatory states 1
  • Bradycardia 2

• Medication-related factors:

  • Concomitant use of other QT-prolonging medications 1, 3, 4
  • Use of Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents 3

Clinical Significance and Incidence

The risk of serious arrhythmias with azithromycin appears to be dose and concentration-dependent 3. While QT prolongation is documented, the clinical significance varies:

• A 2021 study found QTc interval increases during inpatient azithromycin therapy for pneumonia (424 ms to 477 ms after one dose), with 10% of patients developing QTc >500 ms, though no documented dysrhythmias occurred during hospitalization 5

• A 2024 ICU study found no statistically significant increase in QTc interval with azithromycin use (average change of -4 ms) 6

• The risk of fatal ventricular arrhythmia with macrolides compared to amoxicillin is estimated at 1:4100 among high cardiovascular risk patients and <1:100,000 among low cardiovascular risk patients 1

Monitoring and Risk Mitigation

To minimize arrhythmia risk when prescribing azithromycin:

1. Assess baseline risk:

   • Obtain baseline ECG prior to administration, especially in high-risk patients 1, 4
   • Review patient's medication list for other QT-prolonging drugs 1, 4
   • Check electrolyte levels, particularly potassium and magnesium 1

2. Consider withholding azithromycin in patients with:

   • Baseline QTc interval ≥500 ms 1, 3
   • Known congenital long QT syndrome 1, 3
   • History of torsades de pointes 3
   • Uncontrolled electrolyte abnormalities 1, 3

3. Monitor during treatment:

   • Perform ECG monitoring during therapy in high-risk patients 1
   • Consider cardiac telemetry for highest-risk patients 4
   • Monitor QTc interval and withdraw azithromycin if QTc exceeds 500 ms 1
   • Maintain normal electrolyte levels 1

Clinical Pitfalls to Avoid

• Overlooking drug interactions: Many hospitalized patients receive multiple QTc-prolonging medications simultaneously, increasing risk 4
• Ignoring baseline ECGs: Studies show azithromycin is often prescribed despite abnormal baseline QTc 4
• Failure to recognize high-risk patients: Elderly women with heart disease appear particularly vulnerable to drug-related QTc prolongation and torsades de pointes 2
• Underestimating risk in critically ill patients: Comorbidities like electrolyte abnormalities, fever, and inflammatory states can further increase risk 1

In summary, while azithromycin can cause QT prolongation, the risk of serious arrhythmias is relatively low in patients without additional risk factors. However, careful assessment of patient risk factors and appropriate monitoring are essential, particularly in high-risk populations.