A 28-year-old man with a history of long QT syndrome (corrected QT interval 480 ms at baseline) presents with acute exacerbation of chronic bronchitis. Sputum culture grows *Streptococcus pneumoniae*. The attending physician prescribes azithromycin 500 mg once daily for 5 days. The patient's current medications include metoprolol and atorvastatin. On day 2 of therapy, he develops palpitations and lightheadedness. ECG shows QTc interval of 560 ms with visible torsades de pointes. What is the primary mechanism by which azithromycin precipitated this arrhythmia in this patient?

Explanation

## Macrolide-Induced QT Prolongation and Torsades de Pointes ### Electrophysiological Mechanism **Key Point:** Macrolides block cardiac potassium channels (specifically the hERG/Kv11.1 channel), which is responsible for the rapid delayed rectifier potassium current (I~Kr~) during phase 3 of the cardiac action potential. This prolongs ventricular repolarization and the QT interval. ### Molecular Basis ```mermaid flowchart TD A[Macrolide enters cardiac myocyte]:::action --> B[Binds hERG potassium channel pore]:::action B --> C[Blocks K+ efflux during repolarization]:::action C --> D[Phase 3 prolonged]:::outcome D --> E[QT interval lengthens]:::outcome E --> F{Predisposing factors present?}:::decision F -->|Yes: baseline QT↑, female, hypokalaemia| G[Afterdepolarization & reentry]:::urgent G --> H[Torsades de pointes]:::urgent ``` ### Risk Factors for Macrolide-Induced Torsades | Risk Factor | Present in Case | Impact | |-------------|-----------------|--------| | Baseline QT prolongation (>460 ms) | Yes (480 ms) | Additive QT prolongation | | Macrolide choice | Azithromycin (high risk) | Potent hERG blocker | | Female sex | No | Increases risk (not applicable) | | Hypokalaemia | Unknown | Would increase risk | | Concurrent QT-prolonging drugs | Metoprolol (minimal) | Additive effect | | Bradycardia | Possible with metoprolol | Increases dispersion of repolarization | **High-Yield:** Among macrolides, **azithromycin** has the highest risk of QT prolongation and torsades de pointes, followed by erythromycin. Spiramycin has minimal cardiac effects. This is a dose-independent, predictable adverse effect in susceptible populations. **Clinical Pearl:** The QTc interval is corrected for heart rate using Bazett's formula: $QTc = \frac{QT}{\sqrt{RR}}$. A QTc >500 ms or an increase >60 ms from baseline is considered high-risk for arrhythmia. ### Why This Patient Is High-Risk 1. **Baseline QT prolongation** (480 ms): Already at upper limit of normal, indicating inherent or acquired channelopathy 2. **Azithromycin's potency**: Among the most cardiotoxic macrolides 3. **Rapid onset**: Symptoms on day 2 reflect the drug's accumulation in cardiac tissue (azithromycin has a long half-life of 40–68 hours) **Mnemonic:** **hERG** = **h**uman **E**ther-a-go-go-**R**elated **G**ene (encodes the potassium channel blocked by macrolides). ### Prevention and Management - **Baseline ECG** mandatory in patients with QT prolongation history - **Avoid macrolides** in long QT syndrome; use alternatives (amoxicillin-clavulanate, fluoroquinolone, or doxycycline for *S. pneumoniae*) - **If torsades develops**: Discontinue macrolide, correct hypokalaemia/hypomagnesaemia, consider IV magnesium, temporary pacing if bradycardic [cite:KD Tripathi 8e Ch 45; Harrison 21e Ch 276]