Do intravenous (IV) macrolide antibiotics increase the risk for ventricular arrhythmia compared to oral macrolide antibiotics?

From the Guidelines

Intravenous macrolide antibiotics do increase the risk for ventricular arrhythmia compared to oral formulations, particularly in patients with pre-existing risk factors such as age >80, female gender, heart disease, and use of other QT prolonging medication. This is due to the potential of macrolides to interfere with conduction in cardiac tissue, directly prolong the QT interval, and inhibit the metabolism of other proarrhythmogenic drugs by acting on cytochrome P450 in the liver 1. The risk of malignant arrhythmias with macrolides is well recognized and includes factors such as reduced drug elimination, bradycardia, prolonged QT interval before therapy, and genetic predisposition. Although the events are rare, with 85 deaths for each 1 million courses prescribed in the increased risk group, it is crucial to consider these risks when administering IV macrolides.

When considering the use of IV macrolides, it is essential to weigh the benefits against the potential risks, particularly in patients with underlying cardiac disease or other risk factors. Key considerations include:

• Baseline ECG monitoring to assess for pre-existing QT prolongation
• Correction of electrolyte abnormalities, such as hypokalemia or hypomagnesemia
• Avoidance of other QT-prolonging medications
• Using the lowest effective dose for the shortest duration possible
• Considering alternative antibiotic classes for patients at high risk of arrhythmias, when clinically appropriate. According to the British Thoracic Society guideline for the use of long-term macrolides in adults with respiratory disease, published in Thorax in 2020 1, these precautions can help minimize the risk of ventricular arrhythmia associated with IV macrolide use.

From the Research

Comparison of IV and Oral Macrolide Antibiotics

• The provided studies do not directly compare the risk of ventricular arrhythmia between IV and oral macrolide antibiotics.
• However, the studies suggest that macrolide antibiotics, in general, may increase the risk of ventricular arrhythmia, especially in patients with underlying risk factors such as old age, high dosage, rapid administration, and cardiac-related diseases 2.
• A study found that among older adults, macrolide antibiotics were not associated with a higher 30-day risk of ventricular arrhythmia than nonmacrolide antibiotics 3.
• Another study suggested that the risk of cardiac arrhythmias associated with macrolide antibiotics has been overestimated, and that chronic macrolides can be used safely in the majority of subjects for whom they are recommended 4.

Risk Factors for Ventricular Arrhythmia

• The studies identify several risk factors that increase the likelihood of ventricular arrhythmia in patients taking macrolide antibiotics, including:
  • Old age 2, 3
  • High dosage 2
  • Rapid administration 2
  • Cardiac-related diseases 2
  • Congenital or acquired impaired cardiac repolarization 5
  • Combination with class III antiarrhythmic drugs 5
  • Hypokalemia, hypomagnesemia, drug interactions, and bradycardia 5

Specific Macrolide Antibiotics and Risk of Ventricular Arrhythmia

• The studies suggest that different macrolide antibiotics may have varying levels of risk for ventricular arrhythmia:
  • Azithromycin was associated with a significant increase in the risk of ventricular arrhythmia and cardiovascular death in one study 6.
  • Clarithromycin was not associated with an increased risk of ventricular arrhythmia in another study 6.
  • Erythromycin was found to carry the greatest risk of QT prolongation and Tdp among macrolides in a systematic review 2.