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Moxifloxacin-Induced QT Prolongation and Torsades: An Uncommon Effect of a Common Drug
CASE REPORT
Moxifloxacin-Induced QT Prolongation and Torsades: An Uncommon Effect of a Common Drug Aaref Badshah, MD, Mohammad Janjua, MD, Fahad Younas, MD, Abdul R. Halabi, MD, FACC and John F. Cotant, MD, FACC
Abstract: Torsade de pointes (TdP) or “twisting of the points” represents polymorphic ventricular tachycardia in the setting of prolonged QT interval and is characterized by QRS complexes that change in morphology and amplitude. We report a rare case of TdP, associated with QT interval prolongation, caused by intravenous moxifloxacin given for pneumonia in a 71-year-old African American man. Electrocardiogram initially revealed QT interval prolongation that led to torsades de pointes. These changes reverted to normal when moxifloxacin was held. Although the risk for quinolone-associated TdP seems to be low, caution is still warranted when given someone with high risk of QT prolongation. Key Indexing Terms: Moxifloxacin; Prolonged QT interval; ECG; Torsade de pointes. [Am J Med Sci 2009;338(2):164–166.]
T
he occurrence of torsade de pointes (TdP), a potentially life-threatening polymorphic ventricular tachyarrhythmia associated with QT interval prolongation, is increasingly being recognized as a complication of drug therapy. The proposed mechanism by which drugs cause QT prolongation and subsequent torsades is the inhibition of the rapidly activating component of the delayed rectifier potassium current (IKr). As a class, fluoroquinolones are generally well tolerated and safe with its most serious adverse affects being phototoxicity and QTc interval prolongation. Moxifloxacin, a third-generation fluoroquinolone, inhibits the rectifier current (IKr), leading to QT prolongation. Despite this undesired side effect, moxifloxacin-induced TdP is a rare occurrence, with only a handful of cases reported in recent literature.1–3 We report such an interesting case of TdP associated with moxifloxacin use.
CASE REPORT A 71-year-old African American man presented to the emergency department reporting of lethargy, nausea, and a dry cough that had progressively worsened over the course of a week. Medical history was significant for hypertension and left ventricular dysfunction with an estimated ejection fraction of 45%. His medications included enteric-coated aspirin (81 mg/d), lisinopril (5 mg/d), hydrochlorthiazide (12.5 mg/d), and over the counter vitamins. At admission, the patient was febrile with a core body temperature of 101.2 F, blood pressure of 110/79 mm Hg, pulse of 64, and respiratory rate of 22 with a room air oxygen saturation of From the Departments of Internal Medicine (AB, MJ, FY) and Cardiology (ARH, JFC), Saint-Joseph Mercy-Oakland, Pontiac, Michigan. Submitted February 1, 2009; accepted in revised form February 9, 2009. Correspondence: Aaref Badshah, MD, Department of Medical Education, Saint Joseph Mercy-Oakland, 44405 Woodward Avenue, Pontiac, MI 48341 (E-mail: [email protected]).
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92% that increased to 96% on 2 L of nasal oxygen. Physical examination revealed a flushed face and decreased breath sounds in the basilar region of the left posterior lung field. Initial laboratory data showed leukocytosis with a count of 16.5 ⫻ 103/mm. Serum potassium and magnesium level along with other electrolytes were within normal level. Serum thyroid-stimulating hormone and T4 levels were also within acceptable level. A 12-lead electrocardiogram revealed a normal sinus rhythm at 81 bpm with a QTc of 434 milliseconds. Chest x-ray revealed a patchy opacity in the left lower lobe, confirming the diagnosis of pneumonia. The patient was subsequently admitted to the medical floor and 400 mg of intravenous moxifloxacin was empirically started. That night the patient telemeter monitoring recorded frequent multifocal premature ventricular complexes and a short run of nonsustained monomorphic ventricular tachycardia. ECG at this time did not show any signs of ischemia, however, the QTc interval was prolonged at 565 milliseconds (Figure 1). After half an hour, the patient reported of “not feeling well.” He was noted to be pale, light headed, and shivering. Telemetry at this time revealed a short run of sustained polymorphic ventricular tachycardia with the undulation of the QRS complex (Figure 2). This tachycardia spontaneously reverted back to normal sinus without any intervention. Given the prolongation of his QTc interval along with the polymorphic ventricular tachycardia, a diagnosis of TdP was made. The patient was subsequently transferred to the coronary care unit for further observation and care. Serum electrolytes demonstrated normal potassium, magnesium, and calcium concentrations. Cardiac enzymes were also within normal limits. Moxifloxacin was discontinued at this time, replaced by a nonfluoroquinolone antibiotic. No further episodes of TdP were recorded, although daily ECG revealed QTc interval gradually shortening to normal values. The patient denied any further investigations. He is in good clinical condition following a 6-month reevaluation.
DISCUSSION TdP or twisting of the points is an arrhythmia first described by Francois Dessertenne in 1966. It represents polymorphic ventricular tachycardia in the setting of prolonged QT interval.4 TdP is characterized by a long–short initiation sequence along with undulation of the QRS axis around the isoelectric line, giving rise to a twisting appearance to the QRS complex, with tachycardia occurring irregularly at 160 to 250 beats/min.5 Although usually brief (⬍20 seconds) and self-terminating, TdP can become sustained and degenerate into ventricular fibrillation with fatal outcomes.5 Most acquired cases are associated with drug therapy and electrolyte abnormalities. About 3% of prescribed
The American Journal of the Medical Sciences • Volume 338, Number 2, August 2009
Moxifloxacin-Induced QT Prolongation and Torsades
FIGURE 1. A 12-lead ECG obtained within 6 hours of moxifloxacin administration. There is prolongation of the QT interval (QTc ⫽ 565 milliseconds), which was not present at the time of admission.
drugs can prolong the QTc interval.6 Antiarrhythmics have long been implicated in prolonging QT interval and triggering TdP, during chronic as well as acute toxicity.6 Other medications, including antipsychotic agents (haloperidol and phenothiazine) and antibiotics (macrolides and quinolone), have also been shown to prolong cardiac repolarization predisposing to TdP. Most of them are generally safe with a low risk of TdP in most cases; however, the risk increases in patients with underlying risk factors, such as female sex, bradycardia, ion-channel polymorphisms, electrolyte imbalance, hyperthermia, hypothyroidism, and subclinical or concealed long QT syndrome.7,8 In the past few years, new evidence has come to light suggesting genetic polymorphism in certain individuals predisposing to acquired QT interval prolongation.9 Such individuals develop overt QT interval prolongation only after exposure to a certain drug, such as IKr current blockers.10 This explains why some patients develop QT interval prolongation, under particular circumstances, whereas others do not. The fluoroquinolone group of antibiotics blocks the rapid component of the delayed rectifier potassium current (IKr). This current is responsible for potassium efflux and repolarizes the cell during the action potential. Any cause that blocks this IKr current (acquired or congenital) alters the flow of ions and prevents repolarization, resulting in decreased outflow of potassium ions from myocytes and prolongation of the QT interval. This mechanism explains the QT prolongation brought about by nearly all drugs causing this phenomenon.5 Although QT interval prolongation seems to be a class effect of all the quinolones, the magnitude of QT prolongation and the subsequent TdP vary between individual antibiotics. Some of these antibiotics, including sparfloxacin and grepafloxacin (fluoroquinolones), have been withdrawn from the market because of fatal TdP. On the other hand, moxifloxacin is one of the more prefer© 2009 Lippincott Williams & Wilkins
able antibiotics being used in recent years because of its longer half-life and excellent activity against anaerobic and atypical organisms.11 Although moxifloxacin prolongs the QTc interval more than some of the other fluoroquinolone,12 the occurrence of torsades is considered to be the lowest among all the fluoroquinolones.13 A review of our patient’s case did not reveal any family history of congenital long-QT syndrome or conduction abnormality of any sort and no immediate family was available for molecular genetic screening. The patient was not on any QT-prolonging drug prior to her hospitalization and no electrolyte imbalance was evident at the time of admission. Using the Naranjo probability scale, the occurrence of TdP in our patient can, therefore, be probably related to moxifloxacin administration,14 evidenced by a strong temporal relationship that seems to be present between QT prolongation and moxifloxacin administration. Furthermore, the QTc interval shortened to baseline following moxifloxacin discontinuation and did not recur when a nonfluoroquinolone antibiotic was started. It is also probable that our patient’s age and compromised cardiac status along with possible underlying genetic factors might have provided the appropriate baseline milieu for the dramatic increase in the QTc interval after receiving only a single dose of intravenous moxifloxacin.
CONCLUSION In conclusion, physicians should be aware of the risk of TdP while prescribing moxifloxacin, particularly, in patients with prolonged baseline QTc intervals and/or multiple risk factors for the development of TdP. Therefore, moxifloxacin administration in such patients should be monitored closely and, if possible, an alternative drug that does not interfere with the QTc interval should be chosen.
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FIGURE 2. Telemetry strip a few hours after intravenous moxifloxacin administration, demonstrating a run of polymorphic ventricular tachycardia (Torsade de pointes).
REFERENCES 1. Sherazi S, DiSalle M, Daubert JP, et al. Moxifloxacin-induced torsades de pointes. Cardiol J 2008;15:71–3. 2. Dale KM, Lertsburapa K, Kluger J, et al. Moxifloxacin and torsade de pointes. Ann Pharmacother 2007;41:336 – 40. 3. Altin T, Ozcan O, Turhan S, et al. Torsade de pointes associated with moxifloxacin: a rare but potentially fatal adverse event. Can J Cardiol 2007;23:907– 8. 4. Gowda RM, Khan IA, Wilbur SL, et al. Torsade de pointes: the clinical considerations. Int J Cardiol 2004;96:1– 6. 5. De Ponti F, Poluzzi E, Montanaro N. QT-interval prolongation by noncardiac drugs: lessons to be learned from recent experience. Eur J Clin Pharmacol 2000;56:1–18. 6. Roden M. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013–22. 7. Owens RC, Ambrose PG. Torsades de pointes associated with fluoroquinolones. Pharmacotherapy 2002;22:663– 8. 8. Demolis JL, Kubitza D, Tenneze L, et al. Effect of a single dose
166
of moxifloxacin (400 mg and 800 mg) on ventricular repolarization in healthy subjects. Clin Pharmacol Ther 2000;68:658 – 66. 9. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 2001;103:89 –95. 10. Napolitano C, Schwartz PJ, Brown AM, et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and lifethreatening arrhythmias. J Cardiovasc Electrophysiol 2000;11:691– 6. 11. Bertino J, Fish D. The safety profile of the fluoroquinolones. Clin Ther 2000;22:798 – 817. 12. Noel GJ, Natarajan J, Chien S, et al. Effects of three fluoroquinolones on QT interval in healthy adults after single doses. Clin Pharmacol Ther 2003;73:292–303. 13. Frothingham R. Rates of torsades de pointes associated with ciprofloxacin, oxafloxacin, gatifloxacin and moxifloxacin. Pharmacotherapy 2001;21:1468 –72. 14. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30: 239 – 45.
Volume 338, Number 2, August 2009
Moxifloxacin-Induced QT Prolongation and Torsades: An Uncommon Effect of a Common Drug Aaref Badshah, MD, Mohammad Janjua, MD, Fahad Younas, MD, Abdul R. Halabi, MD, FACC and John F. Cotant, MD, FACC
Abstract: Torsade de pointes (TdP) or “twisting of the points” represents polymorphic ventricular tachycardia in the setting of prolonged QT interval and is characterized by QRS complexes that change in morphology and amplitude. We report a rare case of TdP, associated with QT interval prolongation, caused by intravenous moxifloxacin given for pneumonia in a 71-year-old African American man. Electrocardiogram initially revealed QT interval prolongation that led to torsades de pointes. These changes reverted to normal when moxifloxacin was held. Although the risk for quinolone-associated TdP seems to be low, caution is still warranted when given someone with high risk of QT prolongation. Key Indexing Terms: Moxifloxacin; Prolonged QT interval; ECG; Torsade de pointes. [Am J Med Sci 2009;338(2):164–166.]
T
he occurrence of torsade de pointes (TdP), a potentially life-threatening polymorphic ventricular tachyarrhythmia associated with QT interval prolongation, is increasingly being recognized as a complication of drug therapy. The proposed mechanism by which drugs cause QT prolongation and subsequent torsades is the inhibition of the rapidly activating component of the delayed rectifier potassium current (IKr). As a class, fluoroquinolones are generally well tolerated and safe with its most serious adverse affects being phototoxicity and QTc interval prolongation. Moxifloxacin, a third-generation fluoroquinolone, inhibits the rectifier current (IKr), leading to QT prolongation. Despite this undesired side effect, moxifloxacin-induced TdP is a rare occurrence, with only a handful of cases reported in recent literature.1–3 We report such an interesting case of TdP associated with moxifloxacin use.
CASE REPORT A 71-year-old African American man presented to the emergency department reporting of lethargy, nausea, and a dry cough that had progressively worsened over the course of a week. Medical history was significant for hypertension and left ventricular dysfunction with an estimated ejection fraction of 45%. His medications included enteric-coated aspirin (81 mg/d), lisinopril (5 mg/d), hydrochlorthiazide (12.5 mg/d), and over the counter vitamins. At admission, the patient was febrile with a core body temperature of 101.2 F, blood pressure of 110/79 mm Hg, pulse of 64, and respiratory rate of 22 with a room air oxygen saturation of From the Departments of Internal Medicine (AB, MJ, FY) and Cardiology (ARH, JFC), Saint-Joseph Mercy-Oakland, Pontiac, Michigan. Submitted February 1, 2009; accepted in revised form February 9, 2009. Correspondence: Aaref Badshah, MD, Department of Medical Education, Saint Joseph Mercy-Oakland, 44405 Woodward Avenue, Pontiac, MI 48341 (E-mail: [email protected]).
164
92% that increased to 96% on 2 L of nasal oxygen. Physical examination revealed a flushed face and decreased breath sounds in the basilar region of the left posterior lung field. Initial laboratory data showed leukocytosis with a count of 16.5 ⫻ 103/mm. Serum potassium and magnesium level along with other electrolytes were within normal level. Serum thyroid-stimulating hormone and T4 levels were also within acceptable level. A 12-lead electrocardiogram revealed a normal sinus rhythm at 81 bpm with a QTc of 434 milliseconds. Chest x-ray revealed a patchy opacity in the left lower lobe, confirming the diagnosis of pneumonia. The patient was subsequently admitted to the medical floor and 400 mg of intravenous moxifloxacin was empirically started. That night the patient telemeter monitoring recorded frequent multifocal premature ventricular complexes and a short run of nonsustained monomorphic ventricular tachycardia. ECG at this time did not show any signs of ischemia, however, the QTc interval was prolonged at 565 milliseconds (Figure 1). After half an hour, the patient reported of “not feeling well.” He was noted to be pale, light headed, and shivering. Telemetry at this time revealed a short run of sustained polymorphic ventricular tachycardia with the undulation of the QRS complex (Figure 2). This tachycardia spontaneously reverted back to normal sinus without any intervention. Given the prolongation of his QTc interval along with the polymorphic ventricular tachycardia, a diagnosis of TdP was made. The patient was subsequently transferred to the coronary care unit for further observation and care. Serum electrolytes demonstrated normal potassium, magnesium, and calcium concentrations. Cardiac enzymes were also within normal limits. Moxifloxacin was discontinued at this time, replaced by a nonfluoroquinolone antibiotic. No further episodes of TdP were recorded, although daily ECG revealed QTc interval gradually shortening to normal values. The patient denied any further investigations. He is in good clinical condition following a 6-month reevaluation.
DISCUSSION TdP or twisting of the points is an arrhythmia first described by Francois Dessertenne in 1966. It represents polymorphic ventricular tachycardia in the setting of prolonged QT interval.4 TdP is characterized by a long–short initiation sequence along with undulation of the QRS axis around the isoelectric line, giving rise to a twisting appearance to the QRS complex, with tachycardia occurring irregularly at 160 to 250 beats/min.5 Although usually brief (⬍20 seconds) and self-terminating, TdP can become sustained and degenerate into ventricular fibrillation with fatal outcomes.5 Most acquired cases are associated with drug therapy and electrolyte abnormalities. About 3% of prescribed
The American Journal of the Medical Sciences • Volume 338, Number 2, August 2009
Moxifloxacin-Induced QT Prolongation and Torsades
FIGURE 1. A 12-lead ECG obtained within 6 hours of moxifloxacin administration. There is prolongation of the QT interval (QTc ⫽ 565 milliseconds), which was not present at the time of admission.
drugs can prolong the QTc interval.6 Antiarrhythmics have long been implicated in prolonging QT interval and triggering TdP, during chronic as well as acute toxicity.6 Other medications, including antipsychotic agents (haloperidol and phenothiazine) and antibiotics (macrolides and quinolone), have also been shown to prolong cardiac repolarization predisposing to TdP. Most of them are generally safe with a low risk of TdP in most cases; however, the risk increases in patients with underlying risk factors, such as female sex, bradycardia, ion-channel polymorphisms, electrolyte imbalance, hyperthermia, hypothyroidism, and subclinical or concealed long QT syndrome.7,8 In the past few years, new evidence has come to light suggesting genetic polymorphism in certain individuals predisposing to acquired QT interval prolongation.9 Such individuals develop overt QT interval prolongation only after exposure to a certain drug, such as IKr current blockers.10 This explains why some patients develop QT interval prolongation, under particular circumstances, whereas others do not. The fluoroquinolone group of antibiotics blocks the rapid component of the delayed rectifier potassium current (IKr). This current is responsible for potassium efflux and repolarizes the cell during the action potential. Any cause that blocks this IKr current (acquired or congenital) alters the flow of ions and prevents repolarization, resulting in decreased outflow of potassium ions from myocytes and prolongation of the QT interval. This mechanism explains the QT prolongation brought about by nearly all drugs causing this phenomenon.5 Although QT interval prolongation seems to be a class effect of all the quinolones, the magnitude of QT prolongation and the subsequent TdP vary between individual antibiotics. Some of these antibiotics, including sparfloxacin and grepafloxacin (fluoroquinolones), have been withdrawn from the market because of fatal TdP. On the other hand, moxifloxacin is one of the more prefer© 2009 Lippincott Williams & Wilkins
able antibiotics being used in recent years because of its longer half-life and excellent activity against anaerobic and atypical organisms.11 Although moxifloxacin prolongs the QTc interval more than some of the other fluoroquinolone,12 the occurrence of torsades is considered to be the lowest among all the fluoroquinolones.13 A review of our patient’s case did not reveal any family history of congenital long-QT syndrome or conduction abnormality of any sort and no immediate family was available for molecular genetic screening. The patient was not on any QT-prolonging drug prior to her hospitalization and no electrolyte imbalance was evident at the time of admission. Using the Naranjo probability scale, the occurrence of TdP in our patient can, therefore, be probably related to moxifloxacin administration,14 evidenced by a strong temporal relationship that seems to be present between QT prolongation and moxifloxacin administration. Furthermore, the QTc interval shortened to baseline following moxifloxacin discontinuation and did not recur when a nonfluoroquinolone antibiotic was started. It is also probable that our patient’s age and compromised cardiac status along with possible underlying genetic factors might have provided the appropriate baseline milieu for the dramatic increase in the QTc interval after receiving only a single dose of intravenous moxifloxacin.
CONCLUSION In conclusion, physicians should be aware of the risk of TdP while prescribing moxifloxacin, particularly, in patients with prolonged baseline QTc intervals and/or multiple risk factors for the development of TdP. Therefore, moxifloxacin administration in such patients should be monitored closely and, if possible, an alternative drug that does not interfere with the QTc interval should be chosen.
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Badshah et al
FIGURE 2. Telemetry strip a few hours after intravenous moxifloxacin administration, demonstrating a run of polymorphic ventricular tachycardia (Torsade de pointes).
REFERENCES 1. Sherazi S, DiSalle M, Daubert JP, et al. Moxifloxacin-induced torsades de pointes. Cardiol J 2008;15:71–3. 2. Dale KM, Lertsburapa K, Kluger J, et al. Moxifloxacin and torsade de pointes. Ann Pharmacother 2007;41:336 – 40. 3. Altin T, Ozcan O, Turhan S, et al. Torsade de pointes associated with moxifloxacin: a rare but potentially fatal adverse event. Can J Cardiol 2007;23:907– 8. 4. Gowda RM, Khan IA, Wilbur SL, et al. Torsade de pointes: the clinical considerations. Int J Cardiol 2004;96:1– 6. 5. De Ponti F, Poluzzi E, Montanaro N. QT-interval prolongation by noncardiac drugs: lessons to be learned from recent experience. Eur J Clin Pharmacol 2000;56:1–18. 6. Roden M. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013–22. 7. Owens RC, Ambrose PG. Torsades de pointes associated with fluoroquinolones. Pharmacotherapy 2002;22:663– 8. 8. Demolis JL, Kubitza D, Tenneze L, et al. Effect of a single dose
166
of moxifloxacin (400 mg and 800 mg) on ventricular repolarization in healthy subjects. Clin Pharmacol Ther 2000;68:658 – 66. 9. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 2001;103:89 –95. 10. Napolitano C, Schwartz PJ, Brown AM, et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and lifethreatening arrhythmias. J Cardiovasc Electrophysiol 2000;11:691– 6. 11. Bertino J, Fish D. The safety profile of the fluoroquinolones. Clin Ther 2000;22:798 – 817. 12. Noel GJ, Natarajan J, Chien S, et al. Effects of three fluoroquinolones on QT interval in healthy adults after single doses. Clin Pharmacol Ther 2003;73:292–303. 13. Frothingham R. Rates of torsades de pointes associated with ciprofloxacin, oxafloxacin, gatifloxacin and moxifloxacin. Pharmacotherapy 2001;21:1468 –72. 14. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30: 239 – 45.
Volume 338, Number 2, August 2009