Torsades de pointes is a variant of polymorphic ventricular tachycardia, characterized by variable morphology of the QRS complexes and a ventricular rate of 150 to 250 beats/min. It is a potentially life-threatening ventricular dysrhythmia that may degenerate into ventricular fibrillation. Drugs are often implicated in torsades de pointes with QT interval prolongation. Recent reports have linked this condition with fluoroquinolones,^1-3 especially gatifloxacin (Tequin) and levofloxacin (Levaquin), which are widely prescribed for the treatment of community-acquired pneumonia and urinary tract infection (UTI).

Case Presentation
A 45-year-old white woman with hypothyroidism and systemic lupus erythematosus was admitted with several days’ history of dizziness, increasing hematuria, and bleeding around a left nephrostomy tube. On admission, she was taking fluconazole (Diflucan), levothyroxine sodium (eg, Synthroid, Levoxyl), conjugated estrogen, pantoprazole sodium (Protonix), bupropion HCl (Wellbutrin), and sertraline HCl (Zoloft).

Physical examination showed the patient had postural hypotension, with pulse rate of 104 beats/min; blood pressure, 86/51 mm Hg; and a low-grade fever at 99.2°F (37.3°C). Laboratory findings included: serum creatinine, 2.8 mg/dL (baseline creatinine, 1.7 mg/dL); blood urea nitrogen, 53 mg/dL; potassium, 3.6 mEq/L; leukocyte count, 21.0 x 10⁹/L; hemoglobin, 86 g/L; hematocrit, 24.5%. Magnesium level was unavailable. Urinalysis revealed yeast and more than 200 white blood cells per high-power field. Admission electrocardiogram (ECG) showed normal sinus rhythm, with QT interval of 288 ms and corrected QT (QTc) interval of 447 ms (Figure 1). She was resuscitated with intravenous (IV) fluid boluses and blood transfusions and was admitted to the intensive care unit. IV gentamicin, vancomycin (Vancoled), and fluconazole were administered, and her clinical status improved progressively.

The patient underwent right total nephrectomy to control the bleeding. Fluconazole was discontinued and IV levofloxacin, 250 mg/day, was initiated for UTI. Five days later, she developed torsades de pointes requiring defibrillation. After successful resuscitation, follow-up ECG showed normal sinus rhythm, with anterolateral T-wave inversion and prolonged QT and QTc intervals of 521 ms and 554 ms, respectively. Her electrolytes were normal. The patient was treated with

IV magnesium sulfate and potassium chloride. Review of her most recent ECGs before the event showed progressive prolongation of the QTc interval and an abnormal T wave. Lead II of the telemetry rhythm strips (Figure 2) demonstrated the classic short-long R-R interval sequence, leading to torsades de pointes (Figure 3). In the context of the fluconazole discontinuation, levofloxacin was presumed to be the offending drug and was therefore discontinued. Serial ECGs revealed that 2 days after the discontinuation of levofloxacin, the QTc interval had decreased to 475 ms (QT interval, 342 ms) and normalized after 5 days. The remainder of her hospital stay was uneventful.

Discussion
Levofloxacin, vancomycin, gentamicin, and fluconazole were initiated during the patient’s hospitalization. Of these drugs, only fluconazole has been reported to cause QTc interval prolongation or torsades de pointes.^4,5 Fluconazole, however, had been discontinued days before levofloxacin was initiated, and the patient had no known history of long QT syndrome. Her electrolytes had been normal before the event, which ruled out electrolyte imbalance as the sole cause. We therefore concluded that levofloxacin was the offending agent. We used Bazett’s formula (QTc = QT/√(R-R)) to calculate the QTc interval, where QTc is the rate-corrected QT interval in ms, QT is the measured QT interval in ms, and R-R is the R-R interval in seconds, corrected according to heart rate. QTc interval may not be accurate in extremes of heart rate, particularly tachycardia.

Long QT syndrome is more common in females, and the response to QT-interval–prolonging drugs is more exaggerated in females than in males, suggestive of a gender-related predisposition.^6,7 Two mechanisms have been proposed in the genesis of pause-dependant torsades de pointes in patients with acquired long QT syndrome.

Drugs that block the potassium channel delay repolarization, with development of an upstroke in late phase 2 or 3 of the monophasic action potential called “early after-depolarization.” This corresponds to the U wave seen on the surface lead ECG (Figure 4). If preceded by a pause, as seen frequently in atrial fibrillation or in complete heart block, the early after-depolarization may reach sufficient amplitude to trigger polymorphic ventricular tachycardia, which starts torsades de pointes. Reentry is the underlying mechanism for the perpetuation of this tachycardia.

An alternative explanation is that certain drugs produce heterogeneity in repolarization in the endocardium, midmyocardial cells or M cells, and epicardial cells. This causes regional differences in the refractory periods. A premature ventricular contraction may thus block in one direction and conduct around the area of physiologic block, establishing the process of reentry. This heterogeneity in repolarization is manifested on 12-lead ECGs as a difference in QT interval of 70 ms or more on chest leads. Amiodarone (Cordarone, Pacerone) acts by prolonging the repolarization, without causing significant increase in the heterogeneity of repolarization. Thus, the incidence of torsades de pointes is lower with amiodarone compared with sotalol (Betapace), which increases this heterogeneity, particularly in association with hypokalemia and bradycardia.⁸

Acquired long QT syndrome is usually associated with electrolyte abnormalities or exposure to certain medications, but other causes may also exist (Table). Various drugs and electrolyte disturbances that either reduce the outward repolarizing potassium current or interfere with the inward sodium and calcium fluxes trigger the initiation of early after-depolarizations. The development of early after-depolarizations leads to prolongation of the action potential duration and thus to QT interval prolongation. The latter has not been shown to be harmful by itself; however, under certain conditions, such as bradycardia and pauses, it can precipitate torsades de pointes or sudden death. The actual QT interval is a better indicator of after depolarization than the QTc interval.

Risk factors for QT interval prolongation include electrolyte derangements, drugs, comorbid conditions,  female gender, and genetic predisposition. Concurrent treatment with other drugs known to cause QT interval prolongation significantly amplifies the risk of developing torsades de pointes.

Recent in-vitro studies have indicated the ability of fluoroquinolones and ketoconazole to block the HERG gene, which in turn inhibits the delayed rectifier potassium channel and causes delayed repolarization.^9,10 This leads to early after-depolarizations, which can cause QT prolongation. These studies demonstrated that all fluoroquinolones, including levofloxacin, block the HERG gene and thus lead to QT interval prolongation.

Previous data and the present case report support the association between fluoroquinolones and the risk of QT interval prolongation, especially levofloxacin—one of the widely prescribed drugs in this class.^1,11,12 The rate of torsades de pointes with levofloxacin is 5.4 cases for every 10 million prescriptions.¹ The overall risk of torsades de pointes with fluoroquinolones is likely low, but the risk increases significantly in the presence of other conditions and drugs that prolong the QT interval. Therefore, the QT interval should be monitored with serial ECGs before administering a fluoroquinolone in a patient at high risk for QT interval prolongation and torsades de pointes.

Conclusion
Before initiating levofloxacin therapy, the physician needs to be aware of the patient’s electrolyte imbalances,  possible drug–drug interactions, and any history of unexplained syncope. Females are more predisposed to abnormal responses to QT-prolonging medications than males.  

References
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2. Amankwa K, Krishnan SC, Tisdale JE. Torsades de pointes associated with fluoroquinolones: importance of concomitant risk factors. Clin Pharmacol Ther. 2004; 75:242-247.

3. Gandhi PJ, Menezes PA, Vu HT, et al. Fluconazole- and levofloxacin-induced torsades de pointes in an intensive care unit patient [published correction appears in Am J Health Syst Pharm. 2004; 61: 141]. Am J Health Syst Pharm. 2003; 60:2479-2483.

4. Tholakanahalli VN, Potti A, Hanley JF, et al. Fluconazole-induced torsade de pointes. Ann Pharmacother. 2001; 35:432-434.

5. Wassmann S, Nickenig G, Bohm M. Long QT syndrome and torsade de pointes in a patient receiving fluconazole. Ann Intern Med. 1999; 131:797.

6. Makkar RR, Fromm BS, Steinman RT, et al. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA. 1993; 270: 2590-2597.

7. Bednar MM, Harrigan EP, Ruskin JN. Torsades de pointes associated with nonantiarrhythmic drugs and observations on gender and QTc. Am J Cardiol. 2002; 89: 1316-1319.

8. Wolbrette DL. Risk of proarrhythmia with class III antiarrhythmic agents: sex-based differences and other issues. Am J Cardiol. 2003; 91 (suppl): 39D-44D.

9. Kang J, Wang L, Chen XL, et al. Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG. Mol Pharmacol. 2001; 59: 122-126.

10. Bischoff U, Schmidt C, Netzer R, et al. Effects of fluoroquinolones on HERG currents. Eur J Pharmacol. 2000; 406:341-343.

11. Samaha FF. QTC interval prolongation and polymorphic ventricular tachycardia in association with levofloxacin. Am J Med. 1999; 107: 528-529.

12. Owens RC Jr, Ambrose PG. Torsades de pointes associated with fluoroquinolones [comment]. Pharmacotherapy. 2002; 22:663-672.