Infection Review Proarrhythmic Potential of Antimicrobial Agents J. Simkó, A. Csilek, J. Karászi, I. Lorincz} Abstract ization and repolarization. Describing the QT interval Several antiarrhythmic and non-cardiovascular drug therapies should always include the assessment of T wave mor- including antimicrobial agents have been implicated as the phology and appearance of abnormal TU patterns. The causes for QT interval prolongation, torsades de pointes (TdP) analysis of all 12 leads and multiple measurements in each ventricular tachycardia and sudden cardiac death. Most of the ECG is necessary. Since the duration of the QT interval is drugs that have been associated with the lengthening of the heart-rate dependent, correction to heart rate is needed. QT interval or development of TdP can also block the rapidly There are several methods for adjusting the QT interval to activating component of the delayed rectifier potassium heart rate, the most widely used is Bazett’s formula: current (IKr) in the ventricular cardiomyocytes. This article QTc = QT/ÖRR, where QTc is the corrected QT interval presents a review of the current literature on the QT interval and RR is the time in seconds between two R waves. The prolonging effect of antimicrobials based on the results of the adequacy of Bazett’s formula has been questioned; it in vitro, in vivo studies and case reports. Our observations were overcorrects QT interval at fast heart rates and under- derived from currently available Medline database. As we corrects it at low heart rates. A corrected QT interval found, the most frequently QT interval prolonging antimicro- (QTc)of‡ 440 ms is defined as abnormal [2]. During bials are erythromycin, clarithromycin, fluoroquinolones, phase I/II studies a drug-related increase in mean QTc as halofantrine, and pentamidine. Almost every antimicrobial- small as 6 ms between baseline and maximal drug effect associated QT interval prolongation occurs in patients with should be taken seriously. Moreover, a single outlier with multiple risk factors of the following: drug interactions, drug-induced QT prolongation > 500 ms or an increase by female gender, advanced age, structural heart disease, genetic 60 ms from baseline may be more important [3]. predisposition, and electrolyte abnormalities. In conclusion, QT dispersion, defined as the difference between the physicians should avoid prescribing antimicrobials having QT- longest and shortest QT intervals on a 12-lead ECG, prolonging potential for patients with multiple risk factors. seems to be an approximate and imprecise expression of Recognition and appropriate treatment of TdP are also repolarization abnormalities and should not be taken as a indispensable. gold standard for a non-invasive measure of repolariza- tion heterogeneity [3]. The prolongation of the ventricular myocyte repo- Infection 2008; 36: 194–206 larization is caused either by a reduction of outward DOI 10.1007/s15010-007-7211-8 current or an increase of inward current [3]. While con- genital LQTS can be caused by mutations that produce the loss of function of different K+ currents or gain of function of Na+ currents, virtually all drugs with QT Introduction interval prolonging potential block the rapidly activating The term torsades de pointes (TdP) refers to a ventricular component of cardiac delayed rectifier K+ current (IKr) tachycardia characterized by alternating QRS axis of 180° [4]. IKr is rapidly activated by depolarization during the during attacks and QT interval prolongation between at- action potential and thereafter participates in repolariza- tacks (Figure 1). The attacks may stop spontaneously, but tion. IKr is carried by HERG (human ether-a-go-go re- sometimes they persist long enough to provoke syncope, or even sudden cardiac death if ventricular fibrillation evolves [1]. The long QT syndrome (LQTS) is charac- terized by dragging ventricular repolarization (Figure 2) J. Simkó (corresponding author) First Department of Internal Medicine, Semmelweis Hospital, Csabai and high risk of TdP or ventricular fibrillation. LQTS can kapu 9-11, Miskolc 3529, Hungary; Phone: (+36/46) 555666; Fax: -562592 be either idiopathic (congenital) or acquired. The ac- e-mail: [email protected] quired form is a potentially fatal side effect of class I and A. Csilek, J. Karászi Dept. of Infectology, Semmelweis Hospital, Miskolc, Hungary class III antiarrhythmic agents and several other drugs I. Lorincz} (antihistamines, antipsychotics, antimicrobials, etc.). First Department of Internal Medicine, Medical and Health Science The QT interval is the time from the beginning of the Center, University of Debrecen, Debrecen, Hungary QRS complex to the end of the T wave in the surface Received: May 10, 2007 Æ Revision accepted: October 24, 2007 ECG. It represents the duration of ventricular depolar- Published online: May 3, 2008 194 Infection 36 Æ 2008 Æ No. 3 Ó URBAN &VOGEL J. Simkó et al. Proarrhythmic Potential of Antimicrobial Agents Figure 1. Initiation of torsades de pointes. Note the prolonged QT interval of the last preceding beat, the twisting polarity and the changing amplitude of the QRS complexes during the arrhythmia. Figure 2. Precordial ECG leads of a patient between epizodes of torsades de pointes. Note the third degree atrioventricular block, the prolonged QT interval, and the large negative T waves. lated gene) K+ channel proteins coded by KCNH2 gene. HIV proteases, and metronidazole have also been asso- Drugs blocking the HERG with high affinity interact ciated with TdP but the mechanism of the QT-prolonging primarily with the aromatic side groups of the channel, effect is less clear. The European Society of Cardiology Tyr (Y652) and Phe (F656) [5]. Prolongation of the considers erythromycine, clarithromycine, grepafloxacin, repolarization can facilitate the development of early af- sparfloxacin, cotrimoxazole, spiramycin (from antibiot- terdepolarizations mainly in M (midmyocardial) cells and ics), amantadine (from antiviral drugs), ketoconazole, Purkinje cells. Early depolarization-induced premature itraconazole (from antifungal drugs), pentamidine, chlo- ventricular beats can trigger reentry and TdP if increased roquine, halofantrine and quinine (from antiprotozoal and dispersion of repolarization is present. antimalarial drugs), as drugs that can generate TdP [3]. This paper presents a review on the QT interval However, in most of the publications there were only prolonging effect of antimicrobials. The authors wish to anecdotal reports on arrhythmia during antimicrobal call the health professionals’ attention to this potentially treatment, without demonstrating a clear-cut connection. lethal side effect of certain antibiotics, antifungal, anti- In the macrolide group, erythromycin and clarithromycin malarial, and antiviral agents, and discuss the facilities of have the greatest potential for causing QT interval pro- prevention and therapy. Our observations were derived longation and TdP [6]. Cardiotoxicity is a class effect of from Medline database until April 2007 using the key fluoroquinolones but there are great differences between words ‘‘QT interval’’, ‘‘torsades de pointes’’, ‘‘macro- the various members of this group in their proarrhythmic lides’’, ‘‘fluoroquinolones’’, ‘‘antifungals’’, ‘‘antimalari- potential [2]. The cardiotoxic risk of imidazole antifungals als’’, ‘‘antivirals’’, and ‘‘acquired long QT syndrome’’. We is in great part due to their ability to inhibit the metabo- then reviewed the references of the original articles for lization of several drugs with QT-prolonging effect [7]. In additional publications. the group of antimalarials, halofantrine, chloroquine, and Several antimicrobial agents have been associated quinine may cause QT interval prolongation and TdP [8, with QT prolongation and/or TdP in clinical reports. Most 9]. Intravenous pentamidine therapy has been reported to of them have a well-documented IKr-blocking effect provoke TdP in several case reports, whereas inhalatory (erythromycin, clarithromycin, grepafloxacin, gatifloxa- pentamidine is considered to be relatively safe [10]. cin, sparfloxacin, moxifloxacin, and halofantrine). Tri- The predisposing factors to be emphasized are female methoprim-sulfamethoxazole, amantadine, clindamycin, gender, organic heart disease, taking another QT interval Infection 36 Æ 2008 Æ No. 3 Ó URBAN &VOGEL 195 J. Simkó et al. Proarrhythmic Potential of Antimicrobial Agents prolonging medication at the same time, reduced drug isolated heart preparations from guinea pigs and dogs elimination (due to drug interaction, renal or hepatic [16, 17]. It also increased the QT interval in isolated dysfunction), hypokalaemia or hypomagnesaemia, brady- perfused rabbit hearts. The overall drug-effect relation- cardia, prolonged heart rate corrected QT interval (more ship was significantly different in males and females, than 450 ms) interval before therapy and genetic predis- former requiring more than ten times the concentration position. Congenital LQTS is assumed to occur sometimes of erythromycin to produce the same QT interval pro- in ‘‘forme fruste’’ with only drug-induced QT interval longation [18]. prolongation and only drug-induced development of TdP In the majority of the reported cases on the associa- in spite of the underlying cardiac ion channel mutation tion of erythromycin and arrhythmia intravenous use of [11]. Justo and Zeltser [4] studied 61 reports on 78 patients the drug is involved. Rapid injections of erythromycin and with antibiotics-induced TdP. Most