Prolongation of QT interval is probably a class effect of fluoroquinolones

EDITOR--Yap and Camm emphasise the risk of torsades de pointes associated with non-cardiac drugs that prolong the s interval.[1] They comment on the fluoroquinolone antimicrobial agents grepafloxacin and sparfloxacin causing QT prolongation but also the apparent lack of this effect with levofloxacin. We recently cared for a patient who developed torsades de pointes while taking levofloxacin, which prompted us to examine retrospectively paired electrocardiograms in other patients to compare QTc intervals before and after they started treatment with this drug.

Twenty three patients who received a standard dose of 500 mg levofloxacin daily had cardiograms that could be compared for QTc prolongation. Prolongation of [is greater than] 30 ms was found in four patients and of [is greater than] 60 ms in two patients. Absolute QT interval prolongation of [is greater than] 500 ms was present in four, one of whom developed torsades de pointes. This patient was also receiving amiodarone, which is known to prolong the QTc interval but not commonly associated with pro-arrhythmia when used alone.

The United States Food and Drug Administration's spontaneous reporting system documents 11 other cases of torsades de pointes in patients receiving levofloxacin, and Samaha reported on an additional patient who also was receiving amiodarone.[2] Studies in rabbit Purkinje fibres have shown a concentration-dependent prolongation of the maximal rate of depolarisation at concentrations of ofloxacin up to 100 [micro]mol/l, but the trend did not achieve significance.[3] Serum concentrations of 8 [micro]mol/l are achieved by levofloxacin, but the affinity for cardiac tissues is unknown. The Food and Drug Administration has recently requested studies of levofloxacin on cardiac electrophysiology.

Our data indicate that prolongation of the QT interval is probably a class effect of the fluoroquinolones including levofloxacin. Care should be taken when this agent is used with type IA and type III antiarrhythmic agents and in situations such as hypokalaemia and hypomagnesaemia that increase the risk of pro-arrhythmic events.

Paul B Iannini chairman, department of medicine paul.iannini@danhosp.org

Sanjay Doddamani resident in medicine

Eteri Byazrova resident in medicine

Iulia Curciumaru resident in medicine

Harvey Kramer senior attending cardiologist Danbury Hospital, Danbury, CT 06810, USA

Competing interests: PBI is a consultant for Bristol-Myers Squibb, Aventis, SmithKline Beecham, Bayer, Roche, Glaxo, TAP, and Abbott pharmaceutical companies. None declared for SD, EB, IC, and HK.

[1] Yap YG, Camm J. Risk of torsades de pointes with non-cardiac drugs. BMJ 2000;320:1158-9. (29 April.)

[2] Samaha FF. QTc interval prolongation and polymorphic ventricular tachycardia in association with levofloxacin. Am J Med 1999; 107:528-9.

[3] Adamantidis MM, Dumotier BM, Caron JF, Border R. Sparfloxacin but not levofloxacin or ofloxacin prolongs cardiac repolarization in rabbit Purkinje fibers. Fundam Clin Pharmacol 1998;12:70-6.

Grapefruit juice is source of potentially life threatening adverse drug reactions

EDITOR--Yap and Camm state that "In clinical practice, adverse effects of QT prolonging drugs can be prevented by not exceeding the recommended dose; by restricting the dose in patients with pre-existing heart disease or other risk factors; and by avoiding concomitant administration of drugs that inhibit drug metabolism or excretion, prolong the QT interval, or produce hypokalaemia."[1] This leaves out one important point.

Grapefruit juice inhibits the same cytochrome P450 as the imidazoles and macrolides.[2] As a result, QT prolongation from interactions between these drugs and cisapride or terfenadine (among others) is just as likely as QT prolongation from interactions between grapefruit juice and cisapride or terfenadine. It was my understanding that the regulatory changes that led to terfenadine being removed from the shelves and made a prescription only drug were partly a result of this effect.[3]

The effect was first noted in 1989 when grapefruit juice was used as a masking agent for the taste of felodipine in a small study on the interaction between alcohol and felodipine.[4] The effect has been widely studied and involves not only cisapride and felodipine (but not non-dihydropyridine calcium channel blockers) but also carbamazepine, caffeine (but not theophylline), ethinyloestradiol, cyclosporin, coumarin, some of the statins, saquinavir, and some benzodiazepines.[1 5]

The effect of grapefruit juice is perhaps not as well known or appreciated as it should be and is a source of potentially life threatening adverse drug reactions that are easily avoidable. Doctors and the general public need to be aware of this effect as even seemingly harmless drugs may lead to serious effects.

Phillip Marinucci career medical officer Coffs Harbour Base Hospital Emergency Department, Coifs Harbour, NSW, Australia drpm@ozemail.com.au

Competing interests: None declared.

[1] Yap YG, Camm J. Risk of torsades de pointes with non-cardiac drugs. BMJ 2000;320:1158-9. (29 April.)

[2] Grapefruit juice interactions. Pharmacy.net. (Provided by L Bryant 14 November 1997.) www.pharmacy.net.nz/ druginfo/article.cfm?ID = 109 (accessed 14 Dec 2000).

[3] Wise J. Hay fever drug to become prescription only. BMJ 1997;314:1297.

[4] Bailey DG, Spence JD, Edgar B, Bayliff CD, Arnold JMO. Ethanol enhances the hemodynamic effects of felodipine. Clin Invest Med 1989; 12:357-62.

[5] Fuhr U. Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance. Drug Safety 1998;18:251-72.