BRIEF OBSERVATION

QT Prolongation andTorsades de PointesAssociated withClarithromycinKathy L. Lee, MBMan-Hong Jim, MBSydney C. Tang, MBYau-Ting Tai, MB

Clarithromycin is a macrolide antibiotic that pos-sesses an improved antimicrobial spectrum andside-effect profile compared with erythromycin.

Torsades de pointes is known to be related to erythromy-cin(1–5), but its association with clarithromycin has notbeen reported. In this article, we describe 2 patients whodeveloped QT prolongation and torsades de pointes afterreceiving clarithromycin.

CASE REPORTS

Case 1. A 40-year old male intravenous drug addict withbronchiectasis and cor pulmonale was admitted with ful-minant bronchopneumonia. Serum biochemistry re-vealed impaired liver function: alanine aminotransferase449 U/L (normal 6 to 53), apartate aminotransferase 770U/L (13 to 33), alkaline phosphatase 88 U/L (49 to 138),total bilirubin 43 (mmol/L (7 to 19), albumin 26 g/L (44to 56), globulin 31 g/L (24 to 36). Serologic markers forviral hepatitis were not present, and renal function wasnormal. Electrocardiogram on admission showed sinusrhythm at 80 beats per minute, right axis deviation, rightventricular strain, QT interval 380 msec and QTc 430msec. Echocardiogram showed a normal left ventricle,dilated main pulmonary artery and right ventricle withsevere tricuspid regurgitation, consistent with cor pul-monale. The patient was treated with intravenous peni-cillin and gentamicin without response, then switched tointravenous ceftazidime, vancomycin, and oral clarithro-mycin (500 mg BID). One week later, he developed recur-rent torsades de pointes with degeneration into ventric-ular fibrillation requiring defibrillation and cardiopul-monary resuscitation. The QT interval was prolonged to600 msec and QTc to 670 msec. The serum potassium andmagnesium levels were normal. The ventricular arrhyth-mia was controlled by overdrive ventricular pacing. Cla-rithromycin was withdrawn while all other antibioticswere continued. The QT interval normalized after 7 days.

The patient was stabilized and remained well at 12-month follow-up.

Case 2. A 25-year-old woman with Goodpasture syn-drome, end-stage renal failure on hemodialysis, and bi-opsy-proven chronic hepatitis C was admitted for bron-chopneumonia. Serum electrolytes and liver enzymeswere normal, urea 3.5 mmol/L, and creatinine 254mmol/L. ECG showed sinus rhythm at 114 beats perminute, normal axis, normal QRS, QT interval 300 msecand QTc 420 msec. Echocardiogram showed a mildly di-lated left ventricle with ejection fraction of 40%. She wastreated with intravenous ceftazidime, amikacin, and oralclarithromycin (500 mg BID). After 7 days, she developedrecurrent torsades de pointes (Figure) with hypotensionand convulsions. The QT interval was 600 msec and theQTc was 775 msec. Serum potassium and magnesiumwere normal. After stopping clarithromycin, the QT in-terval returned to normal in 6 days, and there was nofurther torsades de pointes. At 9-month follow-up, sheremained free of arrhythmias.

DISCUSSION

In both patients, a strong termporal relation existed be-tween clarithromycin administration and the develop-ment of QT prolongation and torsades de pointes. Noother cause such as electrolyte imbalance could be iden-tified. The QT interval normalized and the ventriculararrhythmia subsided with no recurrence after clarithro-mycin withdrawal.

Torsades de pointes is potentially life-threatening ar-rhythmia caused by early after-depolarizations (6). It hasbeen shown in vitro that erythromycin can prolong ac-tion potential duration and delay repolarization(4). Bothactions may predispose to the development of early after-depolarizations. Erythromycin also may block the selec-tive delayed rectifier potassium current IKr in isolated ca-nine Purkinje fibers (7). Blockade of IKr leads to prolon-gation of action potential duration and may promoteearly after-depolarizations. These findings provide strongevidence for the cellular mechanism of erythromycin-as-sociated torsades de pointes. Clarithromycin has a similarmacrolide structure as erythromycin, and may thus sharesimilar electrophysiological properties and arrhythmo-genic potential. Its active metabolite 14(R)-hydroxy-cla-rithromycin may also affect IKr and prolong QT intervalas it is structurally similar to the parent compound. Or-ganic heart disease was present in both patients and mighthave increased their propensity to develop torsades depointes.

Clarithromycin is predominantly metabolized by theliver. Renal excretion may constitute 20% to 30% of the

q1998 by Excerpta Medica, Inc. 0002-9343/98/$19.00 395All rights reserved. PII S0002-9343(98)00059-X

total body clearance (8). Its marked lipid solubility sug-gests that it is poorly dialyzable. In patients with liver orrenal impairment, accumulation of the parent drug andits active metabolite 14(R)-hydroxy clarithromycin mayoccur (9). Assays for levels of clarithromycin and its 14-hydroxy metabolite were not performed in our patients.However, the first patient had impaired liver functionowing to hepatic congestion and the second patient hadchronic hepatitis and end-stage renal failure.

Our observation suggests that QT prolongation andtorsades de pointes is a class-specific side effect of themacrolides and is not limited to erythromycin alone.With increasing use of clarithromycin for pulmonary in-fections and Helicobactor pylori eradication, cliniciansshould be aware of the possibility of clarithromycin-in-duced QT prolongation and torsades de pointes, espe-cially in patients with structural heart disease and hepaticor renal impairment.

AddendumSince submission of this manuscript, there has been areport of torsades de pointes in 2 chronic renal failurepatients treated with cisapride and clarithromycin (10).

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From the Department of Medicine, Queen Mary Hospital, Pokfulam,Hong Kong.

Correspondence should be addressed to Kathy L. Lee, MB, Departmentof Medicine, Queen Mary Hospital, 102, Pokfulam Road, Pokfulam, HongKong.

Manuscript submitted May 2, 1997 and accepted in revised formDecember 23, 1997.

Figure. Electrocardiographic rhythm strips (lead I and lead III) of patient 2 showing QT prolongation and initiation of torsades depointes after an atrial premature beat that led to a typical short-long-short RR interval sequence.

Torsades de Pointes and Clarithromycin/Lee et al

396 April 1998 THE AMERICAN JOURNAL OF MEDICINEt Volume 104