The antiarrhythmic agent amiodarone HCl (Cordarone, Pacerone) is used to treat complex ventricular arrhythmias and atrial fibrillation. It is unique among the antiarrhythmic arsenal, possessing the potential to block sodium, potassium, and calcium channels,¹ as well as beta- and alpha-adrenergic receptors. Although amiodarone prolongs the QT interval, it is rarely proarrhythmic.² Only a few case reports have been published that suggested that azithromycin (Zithromax), an azalide antibiotic, prolongs the QT interval.^3,4We describe the first documented case of torsades de pointes linked to an interaction between azithromycin and amiodarone.

Case Presentation
A 44-year-old white man presented to the emergency department with a 2-day history of progressive dyspnea and intermittent chest pain. He also had palpitations and a nonproductive cough. The patient had a history of paroxysmal atrial fibrillation and dilated cardiomyopathy and had been taking digoxin (Digitek, Lanoxin); warfarin sodium (Coumadin, Jantoven); quinapril HCl (Accupril); and maintenance amiodarone, which he had been taking for 1 year. He had no reported allergies.

Physical examination showed a well-nourished man with a blood pressure of 120/75 mm Hg, a pulse of 180 beats/min, and an irregularly irregular heart rhythm without murmurs, rubs, or gallops.

Results of laboratory testing were: serum digoxin, 0.2 ng/mL; magnesium, 1.5 mEq/L; potassium, 4.3 mEq/L; brain natriuretic peptide, 846 pg/mL; white blood cell count, 12.6 x 10³/µL, with an absolute neutrophil count of 8.7 x 10³/µL. Cardiac enzymes were within normal limits. Chest x-ray showed left-middle and right-lower lobe infiltrates. The electrocardiogram (ECG) demonstrated atrial fibrillation, with a rapid ventricular response and a corrected QT (QTc) interval of 460 ms (Figure 1).

In the emergency department, the patient received 12 mg of adenosine (Adenocard) and was started on a diltiazem (Cardizem) drip at 10 mg/hour. Intravenous (IV) azithromycin was administered for presumed community-acquired pneumonia. The patient was subsequently admitted to a telemetry-monitored unit.

Within 48 hours he developed torsades de pointes (Figure 2) and was successfully defibrillated to sinus rhythm, with no untoward effects (Figure 3). The ECG revealed a prolonged QTc of 675 ms (Figure 4), meaning that his QTc interval increased from 460 ms to 675 ms within 48 hours, resulting in torsades de pointes. The azithromycin and amiodarone were consequently discontinued. The QTc dropped to 412 ms after another 48 hours (Figure 5). Cardiac catheterization revealed normal coronary arteries with severely compromised left ventricular function. The patient received an implantable cardioverter-defibrillator.

Discussion
Torsades de pointes represents an unusual form of polymorphic ventricular tachycardia that is associated with a long QT interval. It occurs in congenital conditions, generally associated with a “channelopathy,” and in acquired conditions. The latter include electrolyte disturbances and the use of dietary supplements and drugs that prolong ventricular repolarization. Although the combination of azithromycin and amiodarone has been shown to prolong the QT interval,⁵this present case represents the first published presentation of torsades de pointes linked to amiodarone and azithromycin use.

Amiodarone is a unique antiarrhythmic compound with poorly understood electrophysiologic effects.⁶ It acts primarily by prolonging ventricular repolarization.⁶ For this reason it has been defined as a class III antiarrhythmic agent, but its electrophysiologic effects fit all 4 antiarrhythmic drug classes.⁶ Except for its remarkable antiarrhythmic and antifibrillatory efficacy, this compound rarely induces proarrhythmia, despite its significant class I properties.⁷ Amiodarone thus differs from other class III agents in reducing QT dispersion while prolonging the QT interval.⁸ Amiodarone prolongs the QT interval by several mechanisms involving action potential prolongation. Substantial QT prolongation, however, is expected with amiodarone, and this may be used as an indirect measure of the drug’s therapeutic effect.⁹

Agents that prolong the QT interval are particularly known for their potential to provoke the polymorphic ventricular tachycardia of torsades de pointes, but the reported incidence of torsades de pointes with amiodarone is less than 1%.¹⁰ The reason for this low incidence is unclear; some speculate that it may be due to homogeneous lengthening of the action potential duration and a lack of early afterdepolarizations. ^2,11

Macrolides are also associated with a variety of drug interactions (Table). The exact mechanism of QT prolongation and the resulting torsades de pointes associated with azithromycin is not well understood. Since azithromycin and erythromycin are both azalide antibiotics, they probably have similar properties and, therefore, similar mechanisms of action.

Erythromycin increases action potential durations and causes early afterdepolarizations and triggered activity in M cells, resulting in increased dispersions of refractoriness in ventricular tissue and torsades de pointes.¹² Azithromycin affects the metabolism of amiodarone by inhibiting the cytochrome (CY) P450 isoform CYP3A4, thus prolonging the QT interval and resulting in further increased dispersion of refractoriness and, ultimately, torsades de pointes.

Macrolide drug interactions may become clinically significant when erythromycin is administered concurrently with medications such as theophylline (Theolair), carbamazepine (Epitol, Tegretol), warfarin, digoxin, or ergotamine (Ergomar).¹³ Rhabdomyolysis has been linked to the concomitant administration of lovastatin and azithromycin or clarithromycin (1 case report each).¹⁴ The elevation of serum concentration has been shown to involve the inhibition of the metabolism of drugs metabolized by the CYP450 oxidase enzyme system.¹³ Macrolides, such as troleandomycin and erythromycin, may induce hepatic CYP450 isoenzymes, which alter the antibiotic structure capable of forming a stable, inactive complex with the heme iron(II) of CYP450.^13,15 These inactive complexes cause a reduction in the drug-metabolizing capacity of the enzyme system.¹⁵ These complexes, however, are not formed by all macrolides.¹³

Our patient had no other contributing factors, such as electrolyte disturbances or other inciting drug interactions, that could have caused the QT interval prolongation. The QT prolongation with amiodarone and azithromycin was profound (from 460 ms to 675 ms) and rapidly returned toward normal (412 ms) after both drugs were discontinued (Figure 5). We can only assume that the prolongation of the QT interval was a direct effect of azithromycin’s interaction with amiodarone, since the half-life of amiodarone is 18 to 60 days.

Conclusion
Azithromycin is becoming a common first-line antibiotic choice for the treatment of community-acquired pneumonia. Similarly, amiodarone is increasingly being used for the treatment of complex ventricular arrhythmias and atrial fibrillation. Our patient had community-acquired pneumonia and was started on IV azithromycin while taking amiodarone. Within 48 hours, his QTc interval increased dramatically and torsades de pointes ensued.

The administration of azithromycin to a patient taking an antiarrhythmic drug that prolongs the QT interval should be approached with great caution, since a life-threatening interaction culminating in torsades de pointes is possible. Further investigation into other potential and previously undocumented side effects of azithromycin may be indicated.

Acknowledgment
We thank Shirisha Bodana, DO, internal medicine resident at the University of Cincinnati, and Wally Sergent, PharmD, with the Jewish Hospital of Cincinnati, for their critical comments and suggestions.

Disclosure statement
Dr Brownstein receives grant/research support from Guidant and honoraria from AstraZeneca and KOS, is a consultant to St. Jude Medical and Medtronic, and is on the Speaker’s Bureau of AstraZeneca.

References
1. Kodama I, Kamiya K, Toyama J. Cellular electropharmacology of amiodarone. Cardiovasc Res. 1997;35:13-29.

2. Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia. Ann Intern Med. 1994;121: 529-535.

3. Matsunaga N, Oki Y, Prigollini A. A case of QT-interval prolongation precipitated by azithromycin. N Z Med J. 2003;116:U666.

4. Arellano-Rodrigo E, Garcia A, Mont L, et al. Torsade de pointes and cardiorespiratory arrest induced by azithromycin in a patient with congenital long QT syndrome [in Spanish]. Med Clin (Barc). 2001;117:118-119.

5. Samarendra P, Kumari S, Evans SJ, et al. QT prolongation associated with azithromycin/amiodarone combination. Pacing Clin Electrophysiol. 2001;24: 1572-1574.

6. Nattel S, Talajic M, Fermini B, et al. Amiodarone: pharmacology, clinical actions, and relationships between them. J Cardiovasc Electrophysiol. 1992;3:266-280.

7. Drouin E, Lande G, Charpentier F. Amiodarone reduces transmural heterogeneity of repolarization in the human heart. J Am Coll Cardiol. 1998;32:1063-1067.

8. Sager PT, Nademanee K, Antimisiaris M, et al. Antiarrhythmic effects of selective prolongation of refractoriness. Electrophysiologic actions of sematilide HCl in humans. Circulation. 1993;88: 1072-1082.

9. Nademanee K, Singh BN, Stevenson WG, et al. Amiodarone and post-MI patients. Circulation. 1993;88:764-774.

10. van Opstal JM, Schoenmakers M, Verduyn SC, et al. Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome. Circulation. 2001;104:2722-2727.

11. Antonelli D, Atar S, Freedberg NA, et al. Torsade de pointes in patients on chronic amiodarone treatment: contributing factors and drug interactions. Isr Med Assoc J. 2005;7:163-165.

12. Antzelevitch C, Sun ZQ, Zhang ZQ, et al. Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes. J Am Coll Cardiol. 1996;28: 1836-1848.

13. Bahal N, Nahata MC. The new macrolide antibiotics: azith­ro­mycin, clarithromycin, dirithromycin, and roxithromycin. Ann Pharmacother. 1992;26:46-55.

14. Grunden JW, Fisher KA. Lovastatin-induced rhabdomyolysis possibly associated with clarithromycin and azithromycin. Ann Pharmacother. 1997;31:859-863.

15. Tinel M, Descatoire V, Larrey D, et al. Effects of clarithromycin on cytochrome P-450. Comparison with other macrolides. J Pharmacol Exp Ther. 1989;250:746-751.

16. Bailey DG, Bend JR, Arnold JM, et al. Erythromycin-felodipine interaction: magnitude, mechanism, and comparison with grapefruit juice. Clin Pharmacol Ther. 1996;60:25-33.

17. Polis MA, Piscitelli SC, Vogel S, et al. Clarithromycin lowers plasma zidovudine levels in persons with human immunodeficiency virus infection. Antimicrob Agents Chemother. 1997;41: 1709-1714.