F T HERAPEUTICS. Risk Assessment for Antimicrobial Agent-Induced QTc Interval Prolongation and Torsades de Pointes. Robert C. Owens, Jr., Pharm.D.

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1 R EVIEWS _ F T HERAPEUTICS Risk Assessment for Antimicrobial Agent-Induced QTc Interval Prolongation and Torsades de Pointes Robert C. Owens, Jr., Pharm.D. Over the past several years a multitude of new pharmaceutical agents have been released to the market. Several of them were withdrawn altogether or their use severely restricted to certain indications due to unexpected adverse events, including fatalities. Progress in developing new compounds clearly has surpassed our technology, in some cases, to measure and predict certain toxicities. Prolongation of the QT interval, which may lead to potentially lifethreatening ventricular arrhythmias such as torsades de pointes, is one example. Regulatory agencies such as the Food and Drug Administration are increasing standards by which drugs are evaluated for cardiac toxicity related to QT interval prolongation. It is imperative that clinicians be knowledgeable of the risk factors for QT prolongation and avoid the use of culpable agents in patients at risk for QT prolongation. (Pharmacotherapy 2001;21(3): ) OUTLINE Mechanisms Underlying QT Interval Prolongation The Cardiac Action Potential Inherited Long QT Syndrome Acquired QT Prolongation Risk Assessment Preclinical Assays Clinical Measures of Risk Assessment of QTc Prolongation by Antimicrobial Class Macrolides Trimethoprim-Sulfamethoxazole Pentamidine Azoles Fluoroquinolones Pharmacokinetic Considerations Structure-Toxicity Relationships Summary From the Departments of Clinical Pharmacy and Infectious Diseases, Maine Medical Center, Portland, Maine, and the Department of Medicine, University of Vermont, College of Medicine, Burlington, Vermont. Address reprint requests to Robert C. Owens, Jr., Pharm.D., Department of Clinical Pharmacy Services and Infectious Diseases, Maine Medical Center, 22 Bramhall Street, Portland, ME Prolongation of the QT interval is associated with a risk of developing potentially lifethreatening ventricular tachyarrhythmias such as torsades de pointes and may arise due to inherited or acquired causes. 1 3 The most common acquired form is drug induced. Increased awareness of the potential for this condition was triggered by withdrawal from the marketplace of four drugs: the fluoroquinolone antibiotic grepafloxacin, the prokinetic agent cisapride, and the antihistamines terfenadine and astemizole. When contemplating drug therapy, careful assessment of risk versus benefit is necessary, and for certain agents, a narrow therapeutic index is unavoidable. This especially holds true for antimicrobials. Administration of aminoglycosides for synergy in patients with enterococcal endocarditis and of amphotericin B for resistant fungal infections are examples of therapies with associated risks that must be taken because safer alternatives are not available. Antiinfectives include several compounds that are known to affect the QT interval, such as certain fluoroquinolones and macrolides, pentamidine, trimethoprim-sulfamethoxazole (TMP-SMX), and

2 302 PHARMACOTHERAPY Volume 21, Number 3, 2001 azole antifungal agents. Stanley Falkow once used the quotation from cartoon character Pogo that seems fitting here, I have met the enemy and he is us. The concern is that clinicians are not adequately informed of a drug s warning and caution statements found in its product labeling. Clinicians must be cognizant of this information to avoid improper drug selection for populations at risk and to avoid potential drug interactions. It is imperative that we, as clinicians and researchers, appreciate the complexities of this form of iatrogenic toxicity so as to recognize and prevent harmful events in patients. Mechanisms Underlying QT Interval Prolongation The Cardiac Action Potential The cardiac action potential is the fundamental unit of electrical activity in the heart (Figure 1). Its voltage contour is shaped by the numbers and types of specific ion channels and ion transporters in the surface membrane of each myocyte. 4 Since the complement of channels and transporters varies in different regions of the heart, the shape of the action potential is different in atrial, ventricular, and nodal tissue. Dominant ion currents that contribute to the action potential in a myocyte from the ventricle are shown in Figure 1. Initial depolarization (phase 0) is generated by rapid influx of sodium Figure 1. Ionic and molecular basis of the cardiac action potential. (From reference 3 with permission.) ions (I Na ), whose positive charge depolarizes the membrane toward more positive potentials. Once depolarized, the membrane repolarizes transiently due primarily to potassium ion efflux (I to ) to form a notch in the contour of the action potential (phase 1). The membrane remains depolarized during the plateau phase (phase 2), where net current flux is small, resulting from a near balance of positive charges moving inward (carried predominantly by calcium ions, I Ca, with a smaller component contributed by a persistent sodium influx) and positive charges moving outward (carried predominantly by two components of the delayed rectifier potassium current, one that activates rapidly, I Kr, and the other that activates slowly, I Ks ). The inward calcium current mediates additional calcium release from stores within myocytes and activates the contractile machinery during mechanical systole. With time, outward potassium currents dominate residual inward calcium and sodium currents, and the efflux of positive charge allows the membrane to repolarize to its resting potential (phase 3), from which it is soon ready for the next heartbeat. In myocardial cells, such as sinoatrial nodal cells and atrioventricular nodal cells, a pacemaker current (I f ) mediates gradual membrane depolarization (phase 4) until a threshold potential is reached that triggers phase 1 and the ensuing heartbeat. Several interventions that induce very small changes in individual ion currents have the potential to upset the delicate balance that controls the duration of the action potential in ventricular myocytes. Those that allow the action potential to prolong contribute to a state of electrical instability during the repolarization phase in which the membrane potential may abruptly reverse its course and depolarize to produce an early after-depolarization that in turn may trigger a second action potential. If the second action potential excites the rest of the ventricle, a premature ventricular complex will appear on the electrocardiogram (ECG). This pathophysiologic process may be repetitive and self-sustaining, thereby giving rise to a series of after-depolarizations that result in a polymorphic ventricular arrhythmia, called torsades de pointes (twisting of the points) by the French cardiologist Dessertenne. 5 If sustained and rapid, this arrhythmia can be life threatening. Torsades de pointes is the descriptor generally applied to a polymorphic ventricular tachycardia that occurs in the setting of a prolonged QT interval. Often the most prolonged interval is the

3 ANTIMICROBIAL DRUG-INDUCED QTc INTERVAL PROLONGATION Owens 303 one just before the start of tachyarrhythmia. The standard surface ECG represents a temporal and spatial summation of individual action potentials across the entire heart. The QRS complex corresponds to the depolarization phase of the action potential. The width of the QRS complex roughly correlates with the time required for the wave of depolarization to spread from ventricular myocyte to ventricular myocyte and to activate both left and right ventricles. The QT interval encompasses both depolarization and repolarization phases of the action potential. Delays in depolarization, such as those that occur with bundle branch block or intraventricular conduction delay, also may modestly prolong the QT interval but are not inherently associated with an arrhythmia risk. In the absence of intermittent intraventricular conduction delays (intermittent or variable bundle branch block), changes in the QT interval reflect changes in cardiac repolarization. Factors that impede membrane repolarization and lengthen action potential duration in individual myocytes may cause the QT interval to be prolonged. The QT interval is also modulated by heart rate, autonomic tone, gender, and age. The length of the QT interval varies inversely with heart rate and therefore shortens as heart rate increases. To compare QT intervals over time for an individual or across a population, it is necessary to return the measured interval to normal for heart rate effects. Several correction schemes have been employed, such as Bazett s formula that generates a corrected QT interval (QTc) according to: QTc = QT/(RR) 0.5 where RR is the average interval in seconds between QRS complexes. 6 The QT and QTc often are presented in units of milliseconds (range of normal described below). The risk of developing torsades de pointes is proportional to degree of QTc prolongation. 7 Although Bazett s formula is the most widely used correction scheme, considerable controversy surrounds its adequacy, especially when there are significant variations in heart rate. 8 Unlike the QRS interval, which has a nearly fixed duration for a given individual, the QT interval is dynamic with variability that exists from beat to beat on a diurnal basis and from day to day Fluctuations in autonomic tone are predominant factors that modulate QTc variability. Other contributing factors are concomitant drugs 12 and myocardial ischemia. 13 Inherited Long QT Syndrome Inherited forms of long QT syndrome (LQTS) are caused by mutations in genes that modulate cardiac repolarization. Although not the focus of this review, these forms are thought to be important in predisposing to acquired long QT syndrome, specifically drug-induced QT prolongation. 14 In families, this disorder is an autosomal dominant form (Romano-Ward syndrome) or an autosomal recessive form that is accompanied by congenital deafness (Jervell- Lange-Nielsen syndrome). There are also sporadic forms of LQTS in which no other family members are obviously affected. The estimated gene prevalence of LQTS is 1/7000 individuals. 15 Principal clinical manifestations are recurrent syncope, QT interval prolongation, and T and U wave abnormalities on ECG, torsades de pointes, and sudden cardiac death. Frequencies of syncope and sudden cardiac death vary by family, by gene, and by mutation, reflecting a complex set of environmental factors and other modifier genes that contribute to the risk. Several LQTS genotypes have been identified, involving five genes and one additional chromosomal location. 3 Mutations in each identified gene alter the function of an ion channel protein that plays an important role in cardiac repolarization. The delay in cellular repolarization is produced by either an increase in positive inward sodium current or a decrease in positive outward potassium current, and usually results in prolongation of the QT interval. As some families cannot be linked with any known genes or loci, at least one, and perhaps several, other chromosomal loci underlie LQTS. Acquired QT Prolongation Numerous factors underlie acquired forms of LQTS (Table 1). 16 In most cases, reversal of the associated disorder leads to a return of the QT interval to normal. Members of many drug classes are known to prolong the QT interval 16, 17 (Table 2). Classes Ia and III antiarrhythmics, several antimicrobials (e.g., macrolides, pentamidine, fluoroquinolones), tricyclic antidepressants, certain nonsedating antihistamines, several typical and atypical antipsychotics, and the prokinetic agent cisapride are most frequently associated with acquired LQTS. Azole antifungal drugs may directly cause small increases in QTc interval, but most reports of cardiac toxicity stem from potentiation of the QT-prolonging effect of certain other agents by inhibiting their

4 304 PHARMACOTHERAPY Volume 21, Number 3, 2001 Table 1. Acquired Forms of Long QT Syndrome Category Subcategory Disorder Myocardial diseases Ischemia Acute ischemia, infarction Myopathy Idiopathic cardiomyopathy, HIV disease Inflammation Myocarditis Conduction delay Bundle branch block, intraventricular Miscellaneous Conduction delay, mitral valve prolapse Metabolic abnormalities Electrolyte abnormalities Hypokalemia, hypomagnesemia, Hypocalcemia Miscellaneous Hypothyroidism, hepatic failure, hemodialysis, hypothermia, hypoglycemia, anorexia, liquid protein diets, pheochromocytoma Bradycardia Marked sinus bradycardia, high-grade AV block CNS disorders Hemorrhage, trauma, tumor, stroke, infection, radical neck dissection AV = atrioventricular; CNS = central nervous system. Table 2. Drug-Induced QT Interval Prolongation Class Subclass Specific Drugs Anesthetic agents Enflurane, isoflurane, halothane Antiarrhythmic agents Ia Quinidine, disopyramide, procainamide III Dofetilide, sotalol, amiodarone, ibutilide Antimicrobials Azole Ketoconazole, itraconazole, fluconazole Fluoroquinolone Grepafloxacin, sparfloxacin, moxifloxacin, levofloxacin, gatifloxacin, gemifloxacin Macrolide Erythromycin, clarithromycin Ketolide Telithromycin Antiviral Pentamidine Other Trimethoprim-sulfamethoxazole Antidepressants Tricyclic Imipramine, amitriptyline, desipramine, nortriptyline Tetracyclic Doxepin Antihistamines Nonsedating Terfenadine, astemizole Antipsychotics Phenothiazine Thioridazine, mesoridazine Butyrophenone Haloperidol Diphenyl butylpyridine Pimozide Atypical Risperidone, quetiapine, ziprasidone Cholinergic agents Cisapride Diuretics Indapamide Other Ionic contrast media, organophosphate insecticides, arsenic metabolism by the cytochrome P450 (CYP) 3A4 18, 19 enzyme system (e.g., terfenadine; Table 3). Risk Assessment It is not possible to precisely gauge the risk that an individual compound will prolong the QT interval in an individual patient and thereby increase the risk for torsades de pointes. The most reliable negative risk predictor for any agent is a long history of safe administration across many patient subgroups. For the clinician in practice, available reference sources are product labeling for individual compounds, primary literature citations, and select review articles that describe preclinical and clinical electrophysiology and safety data, data available from the Food and Drug Administration (FDA) Web site that summarize advisory panel hearings, and case reports from the medical literature. 20 However, challenges arise in attempting to interpret these data, in part because methodologic details are 21, 22 often scant or inconsistent across studies. Several strategies have been applied in attempts to assess the risk of clinically significant druginduced QT interval prolongation. Preclinical Assays Specific genes encode major ion channels in the heart. 15 Recombinant DNA technology employing these genes facilitated development of

5 ANTIMICROBIAL DRUG-INDUCED QTc INTERVAL PROLONGATION Owens 305 Table 3. Drugs that Interact with the Cytochrome P450 3A4 Isoenzyme System 19 Inhibitors Inducers Amiodarone Carbamazepine Atorvastatin Phenobarbital Clarithromycin Phenytoin Erythromycin Primidone Cimetidine Rifabutin Cisapride Rifampin Cyclosporine Tobacco Diltiazem Dofetilide Fluconazole Fluoxetine Fluvastatin Fluvoxamine Grapefruit juice Indinavir Itraconazole Ketoconazole Lovastatin Metronidazole Mibefradil Nefazodone Nelfinavir Nicardipine Nifedipine Omeprazole Paclitaxel Pravastatin Quinine (tonic water) Quinupristin-dalfopristin Ritonavir Saquinavir Sertraline Simvastatin Telithromycin Troleanodmycin Verapamil Zafirlukast Zileuton in vitro assays that permit measurement of the degree of block of individual ion channels by a drug across a range of concentrations. The most common cause of drug-induced QT prolongation is block of the human ether a-go-go related gene (HERG)-encoded delayed rectifier potassium current, I Kr. As a result, literature reports document 50% inhibitory concentrations (IC 50 ) for block of the HERG potassium channel for many of the drugs listed in Table 2. The most potent HERG-blocking drugs (IC 50 < 1 µm), such as dofetilide, terfenadine, and cisapride, appear to have the greatest risk for QT prolongation and torsades de pointes. Other drugs with higher IC 50 levels also may pose a risk depending on their therapeutic free plasma levels and degree of accumulation in cardiac tissues. The FDA has requested that certain antiinfective agents (e.g., Table 4. CPMP Suggested Ranges for QTc Intervals (msec) 24 QTc a Men Women Normal < 430 < 450 Borderline Prolonged > 450 > 470 a QTc determined by Bazett s formula. gatifloxacin, levofloxacin, moxifloxacin) undergo in vitro testing to determine their effects on the I Kr channel. Although potentially useful as a screening tool for identifying drugs that may prolong the QT interval, the HERG assay may not adequately capture agents whose effect is not solely mediated by block of the HERG potassium channel. Other tests performed in multicellular preparations of cardiac tissue or in living animals provide a more physiologic assessment of drug effects. These tests include measurements of action potential duration in isolated Purkinje fibers from the rabbit or dog ventricle, action potential duration in isolated papillary muscle from the guinea pig ventricle, and QT intervals in intact rodent and nonrodent species (dog, monkey). Each test is sensitive to block of the I Kr current as well as to other mechanisms that prolong cardiac repolarization, such as block of the I Ks delayed rectifier potassium current. In vitro and in vivo experimental models of torsades de pointes are occasionally examined to explore proarrhythmia risk further; they are described elsewhere. 23 Individual pharmaceutical companies use one or more of these tests as part of preclinical safety testing. It is important to note that none of the above assays has been validated in a prospective manner for predicting whether a drug will produce clinically significant QT interval prolongation in humans. Clinical Measures of Risk The best clinical marker for risk of torsades de 15, 24 pointes is the QTc interval. However, disagreement exists in definitions of normal and prolonged intervals. This difficulty is highlighted by a study that compared QTc intervals in 83 carriers of a LQTS gene and 116 nonaffected family members. The range for gene carriers, msec (mean 490 msec), overlapped significantly with the range in noncarriers, msec (mean 420 msec). 25 The Committee for Proprietary Medicinal Products

6 306 PHARMACOTHERAPY Volume 21, Number 3, 2001 (CPMP), one of the two main scientific bodies of the European Agency for the Evaluation of Medicinal Products, convened an ad hoc group of experts to address issues related to drug-induced QT interval prolongation. The outcome was a points to consider document published in 1997 in which the CPMP suggested ranges for normal, borderline, and prolonged QTc intervals (Table 4) and identified several other ECG measures for estimating the potential risk of drug-induced arrhythmias. 24 For an individual patient taking a new drug, CPMP proposed that an increase in the QTc of msec may represent a drug effect and therefore raises concern about the potential risk ; and a QTc greater than 500 msec or an increase of greater than 60 msec raises clear concern about the potential risk. For example, in a high-risk group of patients with clinically significant cardiac arrhythmias treated with sotalol, those with a drug-induced QTc above 500 msec or an increase of more than 65 msec had a greater than 3% frequency of torsades de pointes. 26 Although the recommendations are likely to undergo significant revision, they provide a useful framework for considering ECG values that may be important in assessing proarrhythmia risk. Additional technical challenges in clinical trials for assessing the mean change in QTc interval between treatment and placebo arms are spontaneous 27 and diurnal variabilities 10 for an individual subject, intraobserver and interobserver variability in measuring the QT interval, and variability in algorithms employed to define the end of the interval on a standard 12-lead ECG. 28 Optimally, the ECG should be done at the time that the peak serum drug (and/or major metabolite) concentration is anticipated. For example, dofetilide produces dose-dependent QTc prolongation that peaks at the end of a 15- minute infusion, 29 and statistically significant QTc prolongation during intravenous infusion of erythromycin is absent 5 minutes after the infusion is complete. 30 Furthermore, when feasible, the ECG should be done when steadystate drug concentrations are achieved. Measurement of QT dispersion (QTd) is another assessment of repolarization abnormalities. The QTd is calculated from a standard 12-lead ECG as the difference between the longest and shortest QTs in any lead. It is thought to reflect regional heterogeneity of the duration of the cellular action potential throughout the heart, and this approach is touted as a means to assess the risk of proarrhythmia after drug administration. However, QTd is not validated, suffers from poor reproducibility and methodologic challenges, and is considered investigational by health 24, 31, 32 authorities. Early clinical studies of agents identified preclinically as having the potential to prolong the QTc interval should involve collection of extensive electrophysiologic data not only in healthy volunteers, but also in patients with pertinent organ dysfunction relative to drugs route(s) of elimination so that these additional risk factors can be evaluated. It is imperative that such studies incorporate a standard approach to ECG recording, establish careful dose-response relationships, examine pharmacodynamic values in special patient populations, and fully characterize drug interaction potential. 33 Ultimately, the overall risk assessment for a new drug is based on a composite of preclinical and clinical studies, with greatest weight applied to patient ECG data. For an individual patient, the risk of proarrhythmia after administration of a drug known to prolong the QTc interval is influenced most strongly by baseline QTc interval, QTc interval after the first dose or at steady state, serum potassium concentration, concomitant medical illnesses (structural heart disease), and concomitant therapy with agents that may prolong the QTc or alter the metabolism of the administered compound. Each individual s genetically determined set of ion channels (genetic variants in the I Kr potassium channel) is another important and probably underappreciated predisposing factor. At present, however, genetic prescreening is not possible due to the large and incompletely described number of genetic polymorphisms that modulate cardiac excitability. Assessment of QTc Prolongation by Antimicrobial Class Macrolides Macrolide antibiotics appear to be associated with the greatest degree of QTc interval prolongation and risk for torsades de pointes. This is due not only to the metabolic interaction potential (drug interactions as a result of inhibition of CYP enzymes) but also to an intrinsic arrhythmogenic capability. A comparative pharmacodynamic study in the rat model approximating human concentrations listed the rank order of arrhythmogenic potential to be erythromycin > clarithromycin >

7 ANTIMICROBIAL DRUG-INDUCED QTc INTERVAL PROLONGATION Owens 307 azithromycin. 34 These differences in the animal model were observed in the same rank order in humans as indicated by reports published from the MedWatch safety database. 35 Specifically discussed are various macrolides and chemically related compounds (e.g., azalide, ketolide agents) and their association with QTc interval prolongation and arrhythmic potential. Unfortunately, very little information exists regarding new longer-acting formulation of clarithromycin and telithromycin, a new ketolide, so discussion of these agents is somewhat limited. Erythromycin In vitro and in vivo studies revealed that erythromycin prolongs cardiac repolarization primarily through blockade of the I Kr channel Numerous factors often contribute to QTc prolongation by erythromycin, including dosage and route of administration. In the Purkinje fiber model, the drug caused no effect on action potential duration at a concentration of 10 mg/l, whereas moderate changes were described at 50 mg/l and considerable effects at 100 mg/l. 39 In humans, peak serum concentrations after a 1-g intravenous dose of erythromycin approximate 30 mg/l, and after orally administered, formulations range from only 2 4 mg/l. Thus it is 38, 40 not surprising that among dosages employed clinically, a high dosage (4 g/day) administered intravenously is associated with an increased risk for torsades de pointes relative to oral administration. Other conditions leading to increased 38, 41 erythromycin serum concentrations and risk of torsades de pointes are short intravenous infusion 30, 42 and the presence of severe hepatic disease. However, even slow intravenous infusions of standard dosages occasionally caused significant 30, 37 QTc prolongation. Adding to complexity, erythromycin has a significant potential for drug interactions that further increases the risk of QTc prolongation and torsades de pointes. They include concomitant administration with agents that prolong the QTc interval (class Ia or III antiarrhythmics), those whose metabolism by the CYP3A4 system is inhibited by erythromycin (e.g., terfenadine, cisapride), or those that may alter the delicate electrolyte balance (e.g., potassium-depleting diuretics that may produce 37, 38, hypokalemia). When astemizole and cisapride were available in the United States, concurrent administration with erythromycin, clarithromycin, or troleandomycin was contraindicated. Extreme caution should precede concurrent therapy with other agents such as classes Ia and III antiarrhythmics and potassium-depleting diuretics with these macrolides. As with other drugs that prolong the QT interval, administration of erythromycin to patients with underlying heart disease is associated with an increased risk of developing 16, 42, 45 torsades de pointes. In a series of patients who received intravenous erythromycin, those with structural heart disease (defined as ischemic, valvular, or hypertensive disease) had increased QTc intervals compared with those without heart disease (p<0.05). 42 Since patients with identifiable risk factors that may potentiate QTc interval prolongation are at the greatest risk for torsades de pointes, they should not be treated with macrolides or should be monitored carefully. Clarithromycin Clarithromycin has intrinsic ability to prolong the QTc interval and was associated with torsades de pointes when administered both alone and with interacting drugs such as cisapride Its specific molecular cause of QTc interval prolongation is not well described, although the mechanism is likely to be similar to other druginduced QTc interval effects mediated through blockade of the I Kr channel. 49 Clarithromycin inhibits the CYP3A4 enzyme system and therefore shares a list of potentially serious drug interactions similar to erythromycin. In two patients with torsades de pointes taking clarithromycin, no drug interactions were identified and no electrolyte abnormalities were present. 46 One patient had significantly elevated hepatic enzymes and the other had biopsyproved hepatitis C and was undergoing hemodialysis. Since clarithromycin and its active 14-hydroxy metabolite are eliminated by hepatic and renal routes, their accumulation to supratherapeutic levels may have been responsible for the QTc prolongation. Torsades de pointes developed in two patients taking clarithromycin 400 mg/day for treatment of respiratory tract infections. 50 As in the previous report, no underlying drug interactions could explain the development of arrhythmias. In healthy volunteers, both cisapride and clarithromycin were associated with mean increases (~6 msec) in QTc interval at steadystate concentrations. 51 Notably, combination of

8 308 PHARMACOTHERAPY Volume 21, Number 3, 2001 these agents led to a 3-fold increase in cisapride concentrations and a significant prolongation of QTc interval by 25 msec After a report of two sudden deaths in patients taking pimozide and clarithromycin, pimozide is now contraindicated in patients receiving macrolides and other agents that inhibit the CYP3A4 enzyme system. 52 Clarithromycin appears to have a less pronounced effect on the QTc interval than parenteral erythromycin in otherwise healthy patients without risk factors for torsades de 10, 30, 37 pointes. This may be due to lack of widespread availability of an intravenous formulation that would result in higher serum concentrations than would the oral formulation. Nonetheless, the drug should be avoided in patients already at risk for QTc interval prolongation. A once-daily formulation of clarithromycin was approved under the trade name Biaxin XL. Unfortunately, few data are available regarding its impact on the QTc interval. Azithromycin Azithromycin, an azalide that is chemically dissimilar to other macrolides, does not interact with the CYP3A4 system, and does not interact with terfenadine. 53 Despite lack of interaction potential that is partly responsible for QTc interval prolongation by other drugs, the FDA s Pink Sheet reported 10 cases of QTc-related cardiac events/10 million prescriptions of the agent. 35 Telithromycin Telithromycin is a member of a new class of macrolide-derivative compounds known as the ketolides. Although little is known about it with respect to specific effects on QTc interval prolongation and safety, the compound is an inhibitor of the CYP3A4 isoenzyme system. To this, a list of potential drug interactions with telithromycin similar to that reported for erythromycin can be expected, including increased risk for torsades de pointes if taken concurrently with other at-risk drugs such as cisapride and pimozide. Trimethoprim-Sulfamethoxazole Until recently, the effect of TMP-SMX on the QTc interval was not well characterized and there were few data regarding its effects on the I Kr channel as measured by HERG and animal Purkinje fiber studies. After decades of oral and intravenous administration in a variety of patient populations, only two reported cases were revealed by a MEDLINE search of TMP-SMXassociated QTc prolongation leading to 54, 55 ventricular arrhythmias. This relative dearth of data might lead one to expect a minimal impact in vitro, in in vivo animal models, and in humans, given the large denominator of patients that have taken this drug over the years. However, a study identified 98 patients with drug-induced arrhythmias, of whom a small number had genetic mutations in various ion channels. Specifically, a patient with a previously normal QT interval developed prolongation greater than 600 msec after receiving TMP-SMX. 14 This patient had a single-nucleotide polymorphism (SNP) in the MiRP1 gene that encodes a subunit of the I Kr potassium channel. When expressed in an in vitro system, I Kr channels with this SNP were inhibited by therapeutic concentrations of SMX that had no effect on normal I Kr channels. The patient s DNA and the mutant HERG were isolated and exposed to concentrations of each component individually. Although the effects of HERG blockade after exposure to TMP were observed, the concentrations far surpassed those that are clinically attainable in humans. However, SMX showed significant blockade of mutant I Kr channels at concentrations usually achieved in patients, but of interest, did not have an effect on nonmutant I Kr channels. It is estimated that 1 2% of the population has this SNP that potentially places them at risk for druginduced proarrhythmic events. 14 The authors suggested that this may explain why most therapeutic courses of TMP-SMX are tolerated without QT-related events, and why some patients are more susceptible to the effect of certain drugs than others. Pentamidine At least 15 reports described torsades de pointes associated with pentamidine Similar to QT interval prolongation occurring with other drugs, these cases were somewhat clouded by confounding variables (e.g., electrolyte abnormalities, concomitant administration of agents known to prolong the QTc interval). For pentamidine, and similar to other drugs associated with torsades de pointes, the exact mechanism for this toxicity is not well understood. Procainamide shares a similar

9 ANTIMICROBIAL DRUG-INDUCED QTc INTERVAL PROLONGATION Owens 309 chemical structure to pentamidine, which may explain its effect on the QTc interval. From a molecular perspective, it is unclear exactly how and why pentamidine exerts this effect. An open, nonrandomized, prospective study evaluated patients infected with the human immunodeficiency virus (HIV) who received pentamidine intravenously. 66 Eighteen patients were enrolled and four were excluded from the statistical analysis after receiving only one to two doses of pentamidine. Patients were excluded if they had a history of cardiac disease, arrhythmia, or electrolyte abnormality; were taking drugs associated with arrhythmias (e.g., class Ia or III antiarrhythmic drugs, tricyclic antidepressants, phenothiazines); had ischemia on baseline ECG or prolonged QTc interval above 480 msec; or had other factors such as congenital long QT interval syndrome, bradycardia, and pacemaker. Patients received pentamidine isethionate 4 mg/kg/day intravenously over 1 hour through a peripheral venous catheter. Five patients developed significant QTc prolongation (mean increase 120 ± 30 msec) during infusion. Three of the five developed torsades de pointes, with one fatality. Of interest, nine patients also received standard dosages of either ketoconazole or fluconazole, which are known to contribute to QT interval prolongation. Two patients who did not receive either fluconazole or ketoconazole had QTc interval prolongation and one developed torsades de pointes, as did two of the nine patients who received a combination of an azole and pentamidine. Because pentamidine is not an inhibitor of CYP3A4 isoenzymes, a pharmacokinetic drug interaction involving this particular system would not explain the arrhythmias. Pentamidine is a substrate for CYP2C19. Conceivably, the contribution of both agents prolonging the QTc interval independently may have resulted in the overall outcome, but that is merely speculation. Azoles Ketoconazole, itraconazole, and fluconazole are capable of prolonging the QTc interval In the absence of interacting drugs, azoles are associated with a low risk of torsades de pointes. At dosages of 200 mg every 12 hours for 4 days, ketoconazole resulted in a mean increase in QTc interval of 5.5 msec compared with placebo in volunteers (p<0.02). 67 As with other agents that prolong the QT interval, higher plasma levels of azoles are associated with an increased risk of proarrhythmia. For example, in a patient who received a 5-week course of parenteral fluconazole mg/day followed by 2 days of intraperitoneal administration, the peak plasma concentration reached 216 mg/l compared with normal peak concentrations of mg/l after 400 and 800 mg, respectively. 69, 70 During the time of excessive fluconazole plasma concentrations, the patient developed torsades de pointes. After fluconazole was discontinued, paroxysmal ventricular arrhythmias continued over 3 days until the plasma concentration dropped significantly. Because of its long half-life, fluconazole may accumulate over time in patients with impaired renal function, resulting in prolonged pharmacologic and toxicologic effects. However, this patient did not have impaired organ function or other reasons for QTc prolongation (no concomitant drugs with QTc-prolonging effects, electrolyte disturbances, neurologic disease, cardiac disorders) but did receive parenteral and intraperitoneal fluconazole. Patients receiving azoles should be followed carefully for dosage adjustments, potential drug interactions, and electrolyte imbalance to minimize the possibility of proarrhythmia. Azoles inhibit CYP3A4, and therefore more marked QTc prolongation may result from interactions with drugs metabolized by that system. Both ketoconazole and itraconazole are more potent inhibitors of CYP3A4 than fluconazole and thus are more likely to have significant drug interactions that precipitate torsades de pointes. 68 The product labeling of itraconazole includes a long list of contraindicated agents, primarily those metabolized by CYP3A4. 71 Torsades de pointes was reported as a result of interactions between itraconazole and terfenadine, astemizole, cisapride, and 18, quinidine. Unfortunately, data regarding the exact mechanism of azole-mediated QTc prolongation (HERG studies) are not published in a MEDLINE-retrievable source. Further data regarding the inherent capacity of azole antifungals to prolong the QTc interval seem in order, particularly in light of a host of new antiaspergillus azoles being developed. Fluoroquinolones Until recently, quinolone antibiotics had not received remarkable attention regarding cardiac toxicity or QTc prolongation. Selected reviews attempted to characterize the proarrhythmia risk

10 310 PHARMACOTHERAPY Volume 21, Number 3, 2001 Table 5. Summary of Fluoroquinolone QTc Interval Data Sparfloxacin 78, 80, 82, Grepafloxacin 20, 35, 80, 88 Levofloxacin 79, 85, , 92, 93 Trovafloxacin Animal data Dogs mg/kg, QT Rabbits mg/kg, No data No data prolongation occurred arrhythmia developed in 1/4 animals In vitro studies Significant effect on rabbit HERG 15.2% No significant effects No data (HERG, Purkinje fibers at inhibition at 10 µm on rabbit Purkinje Purkinje fiber) concentrations of fibers at concentrations µm; HERG ranging from µm; 16.9% inhibition at 10 µm HERG no data QTc interval Yes Yes Minimal No prolongation in humans Mean ± SD p.o ± 27.6 msec p.o. 8 msec 4.6 msec ± 23 msec No data QTc interval prolongation in humans QTc interval > 500 msec from baseline No data 1/37 pts Not observed in prolongation in 10/880 pts clinical trials outlier values (> 60 msec from baseline or > 500msec overall) Additive QTc Yes No data 4/37 pts No data prolongation effects with other QTcprolonging agents Patients at risk Yes No No No for QTc interval prolongation excluded from trials of drugs in this class, principally grepafloxacin 22, 78 and sparfloxacin. Although considered by some as a class effect, 79 the potential to prolong the QTc interval is not equal for all quinolones. Furthermore, as with other drugs that prolong the interval, the risk of prolongation associated with a quinolone is related not only to its intrinsic potential to block the I Kr current, but also to its potential interaction with other drugs capable of prolonging the interval (e.g., pharmacodynamic additive effects). In an in vitro assay that measured the degree of block of I Kr, there was more than an order of magnitude difference in the IC 50 for block of the HERG potassium channel among different fluoroquinolones. 80 Sparfloxacin and grepafloxacin are the most potent inhibitors of HERG, and both were associated with proarrhythmia including 35, fatal arrhythmias. In contrast, ciprofloxacin, the weakest HERG blocker of the class, is associated infrequently with QTc interval prolongation or torsades de pointes. Therefore, the risk of clinically significant QTc interval prolongation by a fluoroquinolone appears to correlate well with the magnitude of its I Kr channel block. The following is a compilation of available data regarding electrophysiologic effects from in vitro, animal, and human studies for newer-generation fluoroquinolones. Table 5 21, 35, 78 80, 82, 82, compares the agents. Sparfloxacin Sparfloxacin was the first fluoroquinolone to undergo close scrutiny for QTc prolongation because of related findings in preclinical development. 84 In dogs, it prolonged the interval after oral dosing. 82 In two studies, oral sparfloxacin 45 and 300 mg/kg prolonged the

11 ANTIMICROBIAL DRUG-INDUCED QTc INTERVAL PROLONGATION Owens 311 Table 5. (continued) Moxifloxacin 79, 80, Gatifloxacin 80, 97, 98 99, 100 Gemifloxacin Dogs 90 mg/kg resulted No data No data in a 25-msec QT interval prolongation (no arrhythmias) HERG: 10.3% HERG 3.3% HERG: no data inhibition at 10 µm inhibition at 10 µm p.o. minimal Minimal Minimal p.o. 6 ± 26 msec, p.o. and i.v.: p.o. 5 ± 25.6 msec i.v msec 2.9 ± 16.5 msec > 60 msec from None > 60 msec from baseline in 3/107 pts baseline in 4/137 > 500 msec overall in 2/137 Yes Yes Unknown Yes No No data interval around the time of peak concentration, leading to proactive monitoring in human phase I and certain phase III trials. 82 Cardiac pharmacodynamics were investigated in placebo-controlled studies of three sparfloxacin regimens (loading dose, daily dose) 200 mg, 100 mg; 400 mg, 200 mg; and 800 mg, 400 mg in 90 healthy male volunteers without underlying risk factors for QTc interval prolongation. 101 Placebo-adjusted increases in QTc on day 1 were 9, 16, and 28 msec after receipt of the three regimens, respectively. Approximately 10% of patients had QTc intervals exceeding the a priori normal cutoff of 460 msec. In light of this response in healthy men, consideration must be given to the magnitude of QT prolongation in healthy women as well as in patients at risk for QTc interval prolongation for whom this agent is prescribed. Because QTc prolongation was identified in preclinical development, patients considered for these trials were excluded if they had congenital long QT syndrome, a QTc interval greater than 440 msec at inclusion, concomitant drug(s) known to prolong the interval (e.g., quinidine, terfenadine, astemizole, probucol, class Ia antiarrhythmic agents, bepridil, sotalol, tricyclic antidepressants, phenothiazines), or a pulse rate above 40 beats/minute at rest (only in Europe, where bradycardia was included as a risk factor for torsades de pointes). 82 At the conclusion of phase III trials in Europe, a safety board concluded that the frequency and severity of adverse events associated with sparfloxacin did not differ significantly from those of comparator groups. 82 After the drug was introduced for clinical use in France in 1994, spontaneous reporting of adverse events over 8 months revealed seven cases of serious cardiacrelated adverse events. 82 Of these, three cases of reversible ventricular tachycardia and two fatalities attributed to sudden death occurred in patients with other risk factors for QTc prolongation. Although these adverse cardiac events appear to occur relatively infrequently, they may reflect the difference between clinical trials (e.g., restrictive enrollment criteria, careful follow-up) and actual practice. In a trial comparing sparfloxacin with clarithromycin for treatment of community-acquired pneumonia, sparfloxacin caused QTc interval prolongation in four patients (2.4%) versus no patients in the clarithromycin arm. 83 In vitro HERG studies reported sparfloxacin s inhibition of the I Kr channel at concentrations corresponding to supraphysiologic concentrations 80, 102 by about 5-fold (2.4 ± 0.61 mg/ml). The lowest concentration tested (10 µm) revealed 17% inhibition of the HERG channel that escalated to 35% and 61% at concentrations of 30 and 100 µm, respectively. Sparfloxacin has been associated with severe complications of cardiac toxicity, including death. In fact, 145 reports of QT-related cardiac events exist/49,000 patients from the FDA s postmarketing adverse event database. 35 Once more, one must carefully consider patients underlying medical problems and potential for additive drug interactions, and not exceed recommended dosages and duration of therapy. Grepafloxacin Grepafloxacin was removed voluntarily from the worldwide market in late 1999 due to reports

12 312 PHARMACOTHERAPY Volume 21, Number 3, 2001 of seven cardiac-related fatalities and three cases of torsades de pointes. 35 The withdrawal statement read, Glaxo Wellcome has recently concluded an extensive review of the safety of Raxar (grepafloxacin) and determined that due to an effect of Raxar on cardiac repolarization, manifested as QT interval prolongation on the ECG, some patients may be at risk of a very serious ventricular arrhythmia known as torsades de pointes when treated with the product. Published studies describing the agent s clinical effects on QT interval are not available. However, the product labeling included this statement in the contraindication section: because prolongation of the QTc interval has been observed in healthy volunteers receiving Raxar, Raxar tablets are contraindicated in patients with known QTc prolongation. Raxar tablets are also contraindicated in patients being treated concomitantly with medications known to prolong the QTc interval and/or torsades de pointes (e.g., terfenadine) unless appropriate cardiac monitoring can be assured (e.g., in hospitalized patients). In addition, the warning section of the product labeling, states, Raxar is not recommended for use in patients with ongoing pro-arrhythmic conditions (e.g., hypokalemia, significant bradycardia, congestive heart failure, myocardial ischemia, and atrial fibrillation). 88 The effects of intravenous grepafloxacin and ciprofloxacin on the cardiovascular system were assessed in an anesthetized rabbit model. 21 Grepafloxacin caused dose-related transient arrhythmias in all animals that received 30 mg/kg, and one developed ventricular tachycardia. At this dose, ciprofloxacin was not associated with arrhythmias; however, at 10 times the dose (300 mg/kg), ventricular tachycardia was noted. In vitro HERG assay studies revealed grepafloxacin s potent ability to inhibit the I Kr channel, which approximated 5- to 10-fold greater concentrations than usually observed in 80, 103 patients with normal organ function. The agent had 15% inhibition of the I Kr channel at the lowest concentration studied (10 µm), which increased to 87% at 300 µm. Of fluoroquinolones that prolong the QT interval, only grepafloxacin significantly interacts with the CYP enzyme system. Similar to ciprofloxacin, it inhibits the 1A2 system responsible for theophylline metabolism but does not disrupt the metabolism of agents that use the 3A4 system. 88 Fluoroquinolones as a group do not interfere with 3A4 metabolism and would not be expected to potentiate drug effects leading to torsades de pointes from this basis. 104 However, those that prolong the QT interval may cause an additive pharmacodynamic effect when combined with other agents that do so as well, independent of any relationship to CYP inhibition. Levofloxacin Levofloxacin has been available in the U.S. for 3 years. To date, two case reports described torsades de pointes in patients receiving the 89, 90 drug. The effects of levofloxacin on QTc prolongation were measured in 37 hospitalized patients. 90 Patients were evenly balanced with respect to gender, and mean age was 70 years (range yrs). Mean QTc prolongation attributed to levofloxacin compared with baseline was 4.6 msec (range -47 to +92 msec). Risk factors for QTc prolongation existed in eight patients with electrolyte disturbances and in six who were receiving TMP-SMX, amiodarone, cisapride, or fluoxetine. Of 37 patients, the frequency of outliers, defined as QTc above 60 msec from baseline and above 500 msec overall, was 3% (1/37) and 11% (4/37), respectively. Of four patients with prolongation above 500 msec overall, one developed torsades de pointes. As a potential concurrent risk factor, the patient was also receiving amiodarone. The FDA adverse event-reporting system reported 15 cases of QT-related ventricular arrhythmias or cardiac arrest/10 million prescriptions of levofloxacin, although details of causality were not available. 35 Of interest, another 18 cases of associated QT-related events were reported/10 million prescriptions with the racemic mixture of levofloxacin, ofloxacin. One group studied the effect of levofloxacin, ofloxacin, and sparfloxacin on cardiac repolarization of Purkinje fibers in rabbits. 85 Whereas concentrations of both ofloxacin and levofloxacin up to 100 µm did not appear to be associated with altered action potential duration, sparfloxacin lengthened the action potential in a concentration-dependent fashion at concentrations as low as 10 µm. The HERG assay data for the agent have not been published. The FDA revised the precaution section of the product labeling to indicate that rare cases of torsades de pointes occurred in patients taking levofloxacin, reflecting the numbers of reported cases. To evaluate the risk for cardiac adverse events further, Ortho-McNeil agreed to perform

13 ANTIMICROBIAL DRUG-INDUCED QTc INTERVAL PROLONGATION Owens 313 additional studies to assess levofloxacin s potential for QTc prolongation. These include in vitro studies to quantify the inhibitory effect of levofloxacin on the I Kr channel as well as human dose-response studies to measure QTc and absolute QT intervals in healthy volunteers over a broad age range, including those older than 65 years. Gatifloxacin Gatifloxacin was approved by the FDA in December 1999 for treatment of upper and lower respiratory tract and urinary tract infections including pyelonephritis. The label states that gatifloxacin may have the potential to prolong the QT interval in some patients. It also states that due to lack of clinical experience, the drug should be avoided in patients with known prolongation of the QT interval, those with uncorrected hypokalemia, and patients receiving class Ia or III antiarrhythmic agents. The label further acknowledges that no cardiovascular morbidity or mortality attributable to QTc prolongation occurred with gatifloxacin treatment in over 4000 patients including patients receiving drugs known to prolong the QT interval and patients with uncorrected hypokalemia. Both gatifloxacin and moxifloxacin have been subjected to most rigorous postmarketing cardiac safety evaluations conducted outside cardiac pharmaceutical therapy. To date, oral gatifloxacin has been prescribed to more than 1,298,196 patients in the U.S. alone, with two cases of torsades de pointes reported (data on file, Bristol-Myers Squibb). Both episodes occurred in patients with several risk factors for this cardiac event including concomitant drugs known to prolong the QT interval (sotalol or fluconazole), underlying conduction disorders (bradycardia, syncope of unknown cause), and/or electrolyte derangements (hypomagnesemia). Consequently, the causality of these arrhythmias is difficult to establish. Gatifloxacin was not associated with QTc prolongation in preclinical investigations including animal models of proarrhythmia. Volunteer studies revealed a mean ± SD QTc prolongation of 2.9 ± 16.5 msec, with no individual values greater than 450 msec and no drug-induced increases in QTc duration relative 97, 98 to baseline that were greater than 60 msec. As a result, no exclusion criteria related to QTc interval prolongation were incorporated into phases II and III clinical trials In fact, 139 patients with uncorrected hypokalemia and 118 receiving concurrent agents known to cause QTc prolongation (cisapride, amiodarone, amitriptyline, etc.) were enrolled. 98 None of these patients experienced cardiac-related morbidity or 97, 98 mortality associated with QTc prolongation. Gatifloxacin s impact on inhibition of the I Kr channel was studied with the HERG assay. 80 The percentage inhibition of the I Kr channel at in vitro concentrations that approximate those clinically achievable in humans (10 µm) was minimal (3.3%) and comparable with that with ciprofloxacin (5.1%) at the same concentration. At 30 µm, a concentration that is more than 3- fold greater than that normally achieved in humans, the percentage inhibition of I Kr by gatifloxacin was less than that seen with other fluoroquinolones tested at the 10-µM concentration with the exception of ciprofloxacin at 6.3%. Gatifloxacin s effect on the I Kr channel is similar to that of ciprofloxacin for in vitro concentrations that span the expected therapeutic range. Completed trials did not exclude patients at risk for QTc interval prolongation, and no untoward cardiovascular toxicity was reported. Postmarketing studies are being conducted in an effort to characterize further the drug s effect on QTc prolongation. A comparative, placebo-controlled, single-dose, dose-escalating study comparing quinolone and nonquinolone antibiotics in healthy subjects is under way. The timing of sample collection will occur at the anticipated peak serum concentration. A second study will assess cardiac effects at steady state in healthy subjects. As a part of collecting important safety information and in an attempt to characterize the postmarketing gatifloxacin experience, a surveillance study was designed. 112 More than 15,000 patients were enrolled in an open-label, multicenter, noncomparative phase IV trial to evaluate the drug s safety and efficacy in patients with respiratory tract infections. With respect to overall cardiac safety profiles, no arrhythmias were reported to have occurred. Safety data in patients with cardiovascular disease were presented recently. 113 Of 15,752 patients who received standard dosages in this outpatientbased study, 4906 had underlying cardiovascular disease or were receiving cardiovascular drugs. Cardiovascular adverse events included one case each of myocardial infarction, congestive heart failure, and chest pain, and none were determined to be related to gatifloxacin.