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Therapeutic Advances in Infectious Disease : the need to study case reports
W. Victor R. Vieweg, Jules C. Hancox, Mehrul Hasnain, Jayanthi N. Koneru, Michael Gysel and Adrian Baranchuk Therapeutic Advances in Infectious Disease The online version of this article can be found at: can be found at:
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Therapeutic Advances in Infectious Disease Clarithromycin, QTc interval prolongation and torsades de pointes: the need to study Reprints and permissions:http://www.sagepub.co.uk/journalsPermissions.nav W. Victor R. Vieweg, Jules C. Hancox, Mehrul Hasnain, Jayanthi N. Koneru, Michael Gyseland Adrian Baranchuk Abstract:Background: The manufacturers of clarithromycin sought a drug similar in efficacy toerythromycin but with a superior side-effect profile. They generally achieved this outcome, butpostmarketing findings identified a series of reports linking clarithromycin to QTc intervalprolongation and torsades de pointes (TdP) ultimately leading to a Black Box Warning. Wesought to clarify risk factors associated with TdP among case reports of patients receivingclarithromycin linked to QTc interval prolongation and TdP.
Methods and results: In a detailed literature search, we found 15 women, five men, and one boy meeting our search criteria. Among the 17 adults with reported clarithromycin dose and con-current QTc interval measurement, we found no statistically significant relationship betweenclarithromycin dose and QTc interval duration. This did not change for the adults who developedTdP. Among adults, major risk factors were female sex (15), old age (11) and heart disease (17).
A total of eight adult subjects had all three major risk factors and 14 of the 20 adults had at leasttwo major risk factors. All adult subjects had at least two risk factors besides clarithromycin. Atotal of four of the 20 adults received cisapride and three received disopyramide. Three adultswere considered to suffer from some aspect of the congenital long QT syndrome.
Conclusions: We believe that the risk factor description for this drug should be refined to emphasize the major risk factors of (1) female sex, (2) old age and (3) heart disease.
Keywords: Clarithromycin, drug-induced QTc interval prolongation, risk factors, torsades depointes Clarithromycin is the most widely used macro- linked in some fashion to QTc interval pro- W. Victor R. Vieweg, MDDepartments of Psychiatry lide antibiotic in the United Kingdom and is longation and torsades de pointes (TdP) [Bril strongly recommended for patients with severe Virginia CommonwealthUniversity, 17 Runswick et al. 2013]. The drug’s use among patients Bril and colleagues, in a study of antimicrobial with chronic obstructive pulmonary disease or agents linked to QTc interval prolongation, out- community-acquired pneumonia is associated lined risk factors using a flowchart [Bril et al.
with increased cardiovascular events over the 2010]. Drug-related risk factors were separated course of a year among patients requiring hos- decompensated heart failure, serious arrhyth- Host-related risk factors included modifiable ones (internal environmental disturbances, heart [Schembri et al. 2013]. Because increased car- disease, central nervous system and dysauton- Department of Psychiatry,Memorial University, St diovascular risk persisted over the next year after omy) and those that cannot be modified (older age, female sex, structural heart disease, long QT et al. 2013], the immediate effect of the drug syndrome and ion channel polymorphisms).
did not explain the above findings even though Based on our experience with a case report Therapeutic Advances in Infectious Disease 1 (4) format [Vieweg et al. 2012, 2013a, 2013b; Kogut native cardiac equivalent, the rapid delayed rec- et al. 2013], we seek to organize risk factors to tifier Kþ current, IKr [Finlayson et al. 2004; better help clinicians manage patients requiring Hancox et al. 2008]. Macrolide antibiotics Cardiology and CardiacElectrophysiology, Virginia including clarithromycin have been reported to [Abbott et al. 1999; Volberg et al. 2002; Stanat In the 1970s, the Japanese drug company Taisho et al. 2003; Duncan et al. 2006]. For example, Pharmaceutical developed the macrolide anti- using hERG channel expression in mammalian biotic clarithromycin aiming to improve on (HEK 293) cells, Volberg and colleagues demon- erythromycin’s spectrum of activities, frequency strated IhERG inhibition by six macrolide drugs of of administration and tolerability [Zuckerman, which clarithromycin was the most potent (half 2004]. A branded version was introduced into the Japanese market in 1991 and the US market 32.9 mM), whilst erythromycin exhibited inter- later in the same year. Less than 6 years after mediate potency (IC50 of 72.2 mM) and oleando- its introduction, clarithromycin was linked to mycin was the least potent (IC50 of 339.6 mM) [Volberg et al. 2002]. However, in a separate properties including drug-induced TdP [Kundu study using a similar hERG expression system, et al. 1997; Paar et al. 1997; Sekkarie, 1997].
This linkage is exacerbated by the common reported to be more potent than clarithromycin coprescription of QTc interval prolonging drugs (IC50 values of 38.9 and 45.7 mM, respectively).
in the outpatient setting [Curtis et al. 2003] and In that study both drugs were also reported to the coprescription of drugs blocking CYP3A4 inhibit IhERG when this was elicited with an [Sagir et al. 2003]. Clarithromycin went generic action potential shaped waveform [Stanat et al.
in Europe in 2004 and in the US in mid-2005.
2003], consistent with an ability to reduce thecontribution of IhERG/IKr to action potential repolarization and, hence, the QT interval.
Clarithromycin has been shown to prolong action potential duration (APD) in rabbit cardiac The pharmacokinetics of clarithromycin are tissues in a concentration-dependent fashion similar to those of erythromycin [McConnell (over concentrations ranging between 3 and and Amsden, 1999]. Clarithromycin is rapidly 100 mM) and to reduce native IKr amplitude [Gluais et al. 2003]. For a given drug concentra- Clarithromycin has the greatest bioavailability of tion, APD prolongation was found to be greater any of the macrolides [McConnell and Amsden, for Purkinje fibers than for ventricular myocytes [Gluais et al. 2003], presumably because the basically linear and the steady-state concentra- tion of this metabolite is reached within 3—4 reserve of Purkinje fibers makes them particularly sensitive to hERG/IKr blocking drugs [Gintant,2008; Hancox et al. 2008]. In experiments on The postantibiotic effect of clarithromycin varies intact perfused rabbit hearts, high concentrations of clarithromycin prolonged both monophasic Amsden, 1999]. However, the in vivo significance of this in vitro observation has not been deter- [Milberg et al. 2002]. In the presence of simu- lated hypokalemia, clarithromycin could produce tissue sites extensively. Efficacy is based on main- cellular arrhythmogenic events [early afterdepo- taining a drug concentration above the minimum larizations (EADs)] and TdP [Milberg et al.
inhibitory concentration and clarithromycin is 2002]. Thus, the preclinical literature demon- dosed with a frequency to meet this requirement.
strates that at some concentrations clarithromy-cin can inhibit IhERG/IKr, prolong action potential Clarithromycin as a hERG channel inhibitor repolarization and, under appropriate conditions, A common feature of drugs associated with acquired long QT syndrome and TdP is theirability to produce pharmacological inhibition of An intriguing aspect of clarithromycin’s ability to the activity of the hERG (human Ether-a-go-go inhibit hERG channels is the potential for this Related Gene) potassium ion channel and its action of the drug to vary between individuals.
W. V. R. Vieweg, J. C. Hancox et al.
In 1999, Abbott and colleagues discovered an in Table 1. (A more detailed case narrative accessory protein, MiRP1 (also referred to as appears in the appendix.) Titles and abstracts were independently reviewed by two investigators modifying IhERG properties and drug sensitivity (WVRV and AB). Disagreement was resolved by [Abbott et al. 1999]. A MiRP1 mutation, Q9E- hMiRP1, which was identified in a patient trea-ted who survived clarithromycin-induced TdP and ventricular fibrillation, was found in vitro to We found 15 women, five men and one boy (Table increase markedly hERG’s sensitivity to inhib- 1). Among the 17 adults with reported clarithro- ition by clarithromycin [Abbott et al. 1999].
mycin dose and concurrent QTc interval meas-urement, we found no statistically significant relationship between clarithromycin dose and QTc interval duration (Pearson’s r ¼ À0.086, Multiple regression analysis evaluates the effects p ¼ 0.744; Kendall’s B r ¼ À0.185, p ¼ 0.359; of more than one independent variable on a Spearman’s rho  ¼ À0.223, p ¼ 0.390). These find- dependent variable. However, the assumption is ings did not change for the adults who developed that neither variable changes in the course of ana- TdP (Pearson’s r ¼ À0.093, p ¼ 0.785; Kendall’s lysis. Risk factors associated with drug-induced QTc interval prolongation and TdP may change  ¼ À0.161, p ¼ 0.636). Among adults, major dynamically and the risk factors themselves may risk factors were female sex (15), old age (11) be approximations of more specific factors and heart disease (17). A total of eight adult sub- [Vieweg et al. 2012, 2013a, 2013b; Kogut et al.
jects had all three major risk factors and 14 of the 20 adults had at least two major risk factors. Alladult subjects had at least two risk factors besides clarithromycin. A total of four of the 20 adults chaos, fractals, cellular automata, genetic algo- received cisapride and three received disopyra- rithms and fuzzy logic. They have been brought mide. Three adults were considered to suffer together by Willi-Hans Steeb in the 5th edition of from some aspect of the congenital long QT 2011]. Components likely best describe the inter-action of drug-linked QTc interval prolongation and attendant risk factors to produce TdP In healthy volunteers, the administration of cla- [Vieweg et al. 2012, 2013a, 2013b; Kogut et al.
rithromycin did not lengthen the QTc interval [Van Haarst et al. 1998]. However, plasma cla-rithromycin levels were not reported in this study.
In our study, there was neither parametric nor We conducted a systematic review of case reports nonparametric statistical association between published up to and including 17 April 2013.
drug dose and QTc interval measurement.
Initially, we entered the following MeSH terms:‘clarithromycin and QTc prolongation’ (13) and The finding of congenital long QT syndrome in ‘clarithromycin and torsade’ (10) into Medline.
three (ages 29, 76 and 79 years) of our 21 patients (14.3%) is quite surprising because the prevalence in the general population is approxi- interval prolongation and torsades de pointes (19) mately 1:2000 [Schwartz et al. 2009]. Our find- ing argues strongly for inquiry into a family (‘‘Clarithromycin’’[MeSH] AND (‘‘Long QT history of cardiac arrhythmia, presyncope, syn- Pointes’’[MeSH])) OR (((torsade[ti] OR torsa- degenic[ti] OR torsades[ti] OR torsadogenesis[ti]OR torsadogenic[ti] OR torsadogenicity[ti]) OR qt[ti]) AND clarithromycin[ti]). We searched Among our 20 adult patients (Table 1), four EMBASE (0) and Cochrane (0) only for case received cisapride (Cases 4, 5, 6 and 10) and reports. Only human studies were included.
all four had at least two major risk factors We also reviewed reports from our files and ref- (female sex, old age and heart disease). That is, erence lists yielding a total of 21 cases as shown clinicians may have to take into consideration Therapeutic Advances in Infectious Disease 1 (4) W. V. R. Vieweg, J. C. Hancox et al.
Therapeutic Advances in Infectious Disease 1 (4) W. V. R. Vieweg, J. C. Hancox et al.
other risk factors even when clarithromycin and Pathogenic theories include (1) triangulation cisapride are co-administered. Three of our (short-term variability of action potentials pre- patients (Cases 3, 9 and 14, ages 74, 76 and 76 ceding TdP [Michael et al. 2007]), (2) reverse- years, respectively) received disopyramide and all use dependence (action potential prolongation at slower heart rates [Hondeghem and Snyders, Again, clinicians may have to look beyond the co-administration of clarithromycin and disopyr- [Sauer et al. 2012]), (4) repolarization dispersion amide to more completely explain drug-related [Sauer and Newton-Cheh, 2012]—these four known together as TRIaD [Sauer and Newton- observations highlight the point that these drugs when combined with clarithromycin act synergis- tically to increase QTc interval duration andincrease the risk of subsequent TdP, but may not be the only risk factors in operation.
about risk factors for QTc intervalprolongation and TdP As pointed out by Owens and Ambrose [Owens In 2001, Bednar and colleagues identified 16 risk and Ambrose, 2002], information from spontan- factors for QTc interval prolongation and TdP eous reporting rates (case reports) is not syn- [Bednar et al. 2001]. In 2003, Witchel and cow- orkers described high-risk patients [Witchel et al.
occurring over a specific interval such as a 2003]. In 2003, Viskin and colleagues identified year). However, we believe that if regulatory 12 risk factors [Viskin et al. 2003]. In a study of agencies more vigorously emphasize (perhaps 249 patients, Zeltser and coworkers made the through a reward system) the need for pharma- point most patients at increased risk for QTc ceutical companies and clinicians to report all interval prolongation and TdP have readily iden- major drug-related adverse cardiac events, spon- tifiable risk factors [Zeltser et al. 2003]. The taneous reporting rates for drug-related QTc majority of their 249 patients had at least one interval prolongation and TdP would better risk factor that could be easily identified and approximate incidence rates. If more information 71% had !2 easily identifiable risk factors for unfolds supporting the hypothesis that drug QTc interval prolongation and TdP. In addition, safety related to QTc interval prolongation and most women (female sex being the most common TdP more depends on clinical assessment (such identifiable risk factor) had additional risk factors.
as case reports) than preclinical studies such ashERG analysis, clinicians may have better guid- ance when prescribing drugs and more drugs Owens and Ambrose in their study of TdP asso- may reach the level of phase II and phase III ciated with fluoroquinolones describe the ‘mul- studies ultimately providing a better selection of tiple-hit hypothesis’ in which several factors possible treatments for patients with serious Ambrose, 2002]. Many prescribed drugs includ-ing antibiotics and antipsychotics unfavorably However desirable it may be to have (1) baseline affect IKr kinetics. However, this impact in- EKGs, (2) serum concentrations of nonclarithro- and-of itself rarely explains substantial QTc mycin drugs and (3) genetic information identify- interval prolongation and resultant TdP [Zareba and Lin, 2003]. Combining the list of risk factors syndrome, the clinician is left to decide on the produced by several authors produces the follow- merits and demerits of clarithromycin adminis- ing items [Zareba and Lin, 2003; Sauer and tration based on the presence or absence of Newton-Cheh, 2012]: (1) prolonged QTc inter- more readily available risk factors for QTc inter- val, (2) female sex, (3) advanced age, (4) brady- val prolongation and TdP. We propose that suf- cardia, (5) hypokalemia, (6) hypomagnesemia, ficient information based on case report analysis (7) structural heart disease, (8) cardiac arrhyth- exists to presently identify the triad of (1) female mias, (9) drug combinations including ion chan- sex, (2) old age and (3) heart disease as major risk factors for QTc interval prolongation and reduced repolarization reserve and (11) genetic TdP among patients about to receive clarithro- polymorphisms of gene coding cardiac ion chan- mycin. We believe that the FDA and manufac- nels or enzymes in liver metabolizing drugs.
turer of clarithromycin should provide this Therapeutic Advances in Infectious Disease 1 (4) information in the clarithromycin Black Box The authors declare no conflicts of interest in having all three major risk factors, the more likely clarithromycin administration will link toQTc interval prolongation and TdP.
Abbott, G., Sesti, F., Splawski, I., Buck, M.,Lehmann, M., Timothy, K. et al. (1999) MiRP1 forms The topic discussed in this manuscript is not new IKR potassium channels with hERG and is associated [Raschi et al. 2013], but we believe merits discus- with cardiac arrhythmia. Cell 97: 175—187.
sion from a clinical point of view. Owing to the Abbott Laboratories (2013) BiaxinÕ FilmtabÕ low incidence of TdP, QTc interval prolongation (Clarithromycin Tablets, USP), BiaxinÕ XL FilmtabÕ is used as a surrogate marker of drug-induced (Clarithromycin Extended-Release Tablets), BiaxinÕ TdP risk [Shah, 2005]. Large cohort or popula- Granules (Clarithromycin for Oral Suspension, Usp) tion studies and ‘thorough QT’ investigations on healthy volunteers can index the likelihood and extent of QTc interval prolongation with individ- Alesso, L., Colombo, H., Torre, M. and Herrera, R.
ual drugs, but nonetheless usually provide infor- (2009) Amiodarone/ciprofloxacin/clarithromycin mation on a surrogate marker for TdP rather interaction. Prolonged QT interval and ventriculartachycardia in an elderly patient: case report. Reactions than TdP itself. By contrast, case reports provide Weekly 1272(Issue 1, October): 6—7.
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Zuckerman, J. (2004) Macrolides and ketolides: (2002) Blockade of human cardiac potassium channel azithromycin, clarithromycin, telithromycin. Infect Dis human ether-a-go-go-related gene (hERG) by Appendix: Detailed narrative of case reports linked to clarithromycin-induced/associated QTcinterval prolongation and/or TdP 70-year-old woman was admitted to evaluate syncope after collap- sing at home while watching TV. Past medical history included cor-onary heart disease requiring angioplasty twice (1 year and 3 yearsbefore this presentation), paroxysmal atrial fibrillation, obstructivehypertropic cardiomyopathy and rheumatoid arthritis. Cardiac pro-blems Medications included sublingual nitroglycerin, sotalol, prednisone,hydroxychloroquine and methotrexate. Four days before admission,she presented to the emergency department (ED) complaining ofcough, low-grade fever and a left lung infiltrate. EKG then showednormal sinus rhythm and QT/QTc interval of 440/498 ms without evi-dence of ischemia. She received clarithromycin 250 mg BID for pre-sumed respiratory infection.
On current admission, EKG showed sinus bradycardia (50 beats/minute) and QT/QTc interval of 696/641 msec without evidence ofischemia. Serum potassium was normal. Neither atrial fibrillationnor TdP occurred. Clarithromycin and sotalol were stopped. Overthe next 5 days, QTc interval returned to normal and she was dis-charged to home.
QTc 641 ms; clarithromycin dose 500 mgTdP not documented. Risk factors were female sex, old age, heartdisease, acute medical illness, chronic medical illness, sotalol andclarithromycin.
27-year-old woman presented to the ED with a 3-day history of irre- gular pulse and intermittent palpitations. She was a medical residentand may have been more alert and concerned about bodily changes.
She denied chest pain, dyspnea, diaphoresis, weakness, nausea,vomiting or diarrhea. She gave a history of several weeks of clearrhinorrhea for which she had taken terfenadine 60 mg and phenyl-propanolamine 60 mg each BID for 1 week. She believed she sufferedfrom sinusitis. Previously, she had used terfenadine for allergies withno W. V. R. Vieweg, J. C. Hancox et al.
phenylpropanolamine for 4 days to avoid drug interactions, shestarted clarithromycin 250 mg BID. Palpitations started after the6th dose of clarithromycin. Medical history was free of cardiac, pul-monary, endocrine or psychiatric disease. Review of systems wasotherwise negative and she denied taking drugs, ethanol, tobacco,caffeine or other medications except for oral contraceptives. In theED, her pulse was irregular and telemetry showed many prematureventricular contractions (PVCs) and runs of nonsustained ventriculartachycardia (VT). During these arrhythmias, blood pressure andarterial oxygen saturation remained normal. EKG showed normalsinus rhythm and a QTc interval of 468 ms. Chemistries werenormal and terfenadine was not detected in the serum. She wasadmitted and clarithromycin stopped. Over the next 4 hours, PVCsand brief runs of VT resolved. The next day, echocardiography wasnormal and QTc interval was 420 ms. She remained asymptomaticover the next year even when taking phenylpropanolamine.
QTc 468 ms; clarithromycin dose 500 mgVT did not occur. Risk factors were female sex, acute medicalillness and clarithromycin.
74-year-old woman admitted for evaluation of Helicobacter pylori- related chronic duodenal ulcer. Past medical history included7-year disopyramide (200 mg BID) treatment for tachycardia—bradycardia syndrome with QTc interval never >440 ms.
Admission EKG showed sinus rhythm, right bundle branch block(RBBB), and normal QTc interval. Treatment for H. pylori was startedwith omeprazole (20 mg BID), clarithromycin (250 mg BID) and metro-nidazole (400 mg BID). Renal function was normal. After an unevent-ful hospital course, she collapsed 6 days after admission andventricular fibrillation (VF) was documented. After resuscitation,QTc interval was prolonged (625 ms) with no U-wave present.
Hypokalemia was present (3.0 mmol/l) presumably related to epi-nephrine administration during resuscitation. Disopyramide levelwas at the upper therapeutic level (4.6 mg/ml) with markedly pro-longed half-life (40 hours). Disopyramide was stopped and hypokale-mia corrected. However, QTc interval prolongation persisted untilhospital day 9 and then returned to normal. Two days later she wasdischarged from the ICU and 20 days later from the hospital.
QTc 625 ms; clarithromycin dose 500 mgVF did occur. Risk factors were female sex, old age, heart disease,acute medical illness, chronic medical illness, hypokalemia, diso-pyramide (both directly and as a CYP3A4 blocker) and clarithromy-cin (both directly and as a CYP3A4 blocker).
Case 1: 52-year-old woman with diabetes mellitus, end-stage renal disease, coronary artery disease requiring bypass grafting, diabeticgastroparesis and chronic obstructive lung disease presented withacute bronchitis. Clarithromycin 500 mg BID was started. Other med-ications included transdermal nitroglycerin, iron, erythropoietin, cal-citriol, calcium acetate, ipratropium inhaler and cisapride 10 mg TID.
Hemodialysis was uneventful and she returned home at noon. Sixhours later, she took cisapride just before supper. Shortly after fin-ishing eating, she lost consciousness for a minute recovering spon-taneously. EMS found her awake and in sinus rhythm. On hospitalarrival, Cardioversion restored sinus rhythm and consciousness. EKGshowed sinus rhythm, severe T-wave inversion anteriorly and QTcinterval prolongation (630 ms). Lidocaine was then administeredand she was transferred to the ICU. Cisapride and clarithromycinwere stopped. Cardiac enzymes were normal, serum potassiumwas 3.6 mmol/l, and other chemistries were unremarkable. Nofurther cardiac arrhythmias occurred and lidocaine infusion was Therapeutic Advances in Infectious Disease 1 (4) stopped. Within 36 hours, anterior T-wave inversion returned tonormal. QTc interval slowly returned to normal (440—480 ms).
Cardiac catheterization demonstrated patent bypass grafting withgood filling. Left ventricular ejection fraction was 40%. She was dis-charged with no further cardiac problems on follow up. Manufactureranalysis showed that at 15 hours, the last dose of cisapride produceda serum level of 91.6 ng/ml with an elimination half-life of about 24hours. Following hospital discharge, persistent vomiting returnedrefractory to noncisapride drugs. Cisapride was again given at10 mg TID. A week later morning cisapride level, 15 hours after her6 PM dose, was 14.6 ng/ml. She continued to do well taking 5 mg BID.
QTc 630 ms; clarithromycin dose 1000 mgTdP did occur. Risk factors were female sex, heart disease, acutemedical illness, chronic medical illness, cisapride (directly and as aCYP3A4 blocker) and clarithromycin (directly and as a CYP3A4blocker).
Case 2: 83-year-old man with chronic renal failure (ischemic nephro- pathy) and attendant anemia, coronary artery disease requiringbypass grafting, ischemic cardiomyopathy, sick sinus syndromerequiring pacemaker placement, diffuse atherosclerotic vascular dis-ease, peptic ulcer disease, and gastroesophageal reflux disease pre-sented to his gastroenterologist complaining of a foreign body in hisesophagus while eating. Medications included erythropoietin, furose-mide, alprazolam, amlodipine, ranitidine, iron, temazepam, aspirin,nitroglycerin, Esophagogastroduodenoscopy showed impacted food and diffusegastritis. H. pylori infection was diagnoses and he was given clari-thromycin 500 mg BID. One week later, he presented to the ED withweakness, vomiting and episodes of falling and unconsciousness. Hewas admitted for cardiac monitoring. Physical examination revealed acachectic and chronically ill man who appeared dehydrated.
Chemistries included serum creatinine 4.8 mg/dl, serum potassium4.3 mmol/l and serum magnesium 2.2 mg/dl. Cardiac monitoringshowed nonsustainable episodes of TdP. An earlier EKG showed apaced rhythm of 70 BPM. Cisapride and clarithromycin were stopped.
He received 1 g magnesium sulfate IV. Pacing was increased to 100BPM. He gradually improved and serum creatinine decreased to2.7 mg/dl. He recovered and was discharged.
QTc unknown; clarithromycin dose 1000 mgTdP did occur. Risk factors were old age, heart disease, acutemedical illness, chronic medical illness, cisapride (directly and asa CYP3A4 blocker) and clarithromycin (directly and as a CYP3A4blocker).
53-year-old woman presenting to the ED following two separate automobile accidents. She could not recall events just before eachaccident and ‘may have blacked out twice’. She denied headaches,visual changes, chest pain, dyspnea, sweating or nausea butacknowledged possible light-headedness. She denied experiencingloss of bladder or bowel control before the accidents. She didrecall awakening when observers tried to remove her from her carafter the second accident. The duration of unconsciousness wasunknown. She denied confusion after regaining consciousness. Herhusband stated that her car was sideswiped in mid-afternoon. Later,she struck a parked car and was transported to the ED. In the ED, alower-lip laceration was repaired. Otherwise, her physical findingswere unremarkable. Recently, she had been hospitalized for pneu-monia with findings on echocardiogram of mild concentric left ven-tricular hypertrophy and trace mitral regurgitation. A thallium studywas normal and gastrointestinal work-up revealed hiatal hernia andulcers. Treatment for pneumonia included clarithromycin 500 mg W. V. R. Vieweg, J. C. Hancox et al.
BID. She also took cisapride 20 mg QID. Additional medicationsincluded a clonidine patch, fluoxetine 20 mg daily, omeprazole20 mg daily and prochlorperazine suppositories for nausea. Serumpotassium and magnesium levels were normal. Admission EKGshowed a QTc interval of 456 ms. Two days later it was 396 ms.
Extensive cardiac and neurologic workup of syncope was normal.
Her physicians concluded that she had experiences multiple episodesTdP-induced syncope.
QTc 456 ms; clarithromycin dose 1000 mgTdP assumed but not documented. Risk factors included femalesex, heart disease, fluoxetine, acute medical illness, chronic med-ical illness, cisapride (both directly and as a CYP3A4 blocker) andclarithromycin.
Case 1. 40-year-old male IV drug addict with bronchiectasis and core pulmonale was hospitalized with fulminant bronchopneumonia.
Chemistries showed impaired liver function with absent serologicmarkers for viral hepatitis. EKG showed normal sinus rhythm (80BPM), right axis deviation, right ventricular strain and normal QTcinterval (430 ms). Echocardiography showed dilated pulmonaryartery and severe tricuspid regurgitation. He did not respond to IVpenicillin and gentamicin and treatment was switched to IV ceftazi-dime and vancomycin and oral clarithromycin (500 mg BID). A weeklater, recurrent TdP appeared with degeneration into ventricularfibrillation requiring countershock and cardiopulmonary resuscita-tion. QTc interval was prolonged (670 ms). Serum electrolytes werenormal. Overdrive ventricular pacing controlled the ventriculararrhythmia. Clarithromycin was stopped. A week later, the QTc inter-val was normal. He remained well over the next year.
QTc 670 ms; clarithromycin dose 1000 mgTdP did occur. Risk factors included heart disease, acute medicalillness, chronic medical illness, impaired liver function andclarithromycin.
Case 2. 25-year-old woman with Goodpasture syndrome, end-stage renal failure on hemodialysis and chronic hepatitis was admitted forbronchopneumonia. Serum electrolytes and liver enzymes werenormal. Renal function tests consistent with renal failure. EKGshowed sinus tachycardia (114 BPM) and normal QTc interval(420 ms). Echocardiography showed mild left ventricular dilatationwith a 40% ejection fraction. Treatment included IV ceftazidime, ami-kacin and oral clarithromycin (500 mg BID). One week later, shedeveloped recurrent TdP with seizures and hypotension. QTc intervalwas prolonged (775 ms). After stopping clarithromycin, QTc intervalreturned to normal. No further episodes of TdP occurred and sheremained free of cardiac arrhythmias at 9-month follow up.
QTc 775 ms; clarithromycin dose 1000 mgTdP did occur. Risk factors included female sex, heart disease,acute medical illness, chronic medical illness and clarithromycin.
76-year-old woman referred for presyncope. She had taken disopyr- amide 100 mg TID (QTc interval prolongation 510 ms before admis-sion) to treat supraventricular arrhythmias since her myocardialinfarction 5 years earlier. Additional medications included nitratesand diltiazem 30 mg TID. Five days before presentation, she startedtaking clarithromycin 200 mg BID for upper respiratory infection.
Initial EKG showed QTc interval prolongation (710 ms) and old inferiormyocardial infarction and admission potassium was 2.8 mmol/l andremaining chemistries were normal including cardiac enzymes.
Following admission, several episodes of self-terminating TdPoccurred. On admission, plasma disopyramide level was 3.2 mg/ml(therapeutic range 1—2 mg/ml). All medications were stopped andhypokalemia was corrected. 14 hours after admission, serum Therapeutic Advances in Infectious Disease 1 (4) potassium was 4.3 mmol/l and no further episodes of TdP occurred.
However, QTc interval prolongation (670 ms) persisted. By hospitalday 10, QTc interval was 450 ms.
QTc 710 ms; clarithromycin dose 400 mgTdP did occur. Risk factors were female sex, elderly, heart disease,disopyramide (both directly and as a CYP3A4 blocker), hypokale-mia, acute medical illness and clarithromycin (both directly and asa CYP3A4 blocker).
77-year-old woman presented to ED with 2-week history of dyspnea, cough producing green sputum and sudden worsening of shortnessof breath. Physical examination and chest X-ray was consistent withworsening heart failure and probable left lower pneumonia for whichshe was admitted. Past medical history included heart failure,chronic obstructive pulmonary disease, rheumatic fever as a child,mitral valve replacement, atrioventricular ablation and ventricularpacemaker for atrial fibrillation. Pre-admission medications includedfurosemide 80 mg BID, hydrochloride 25 mg daily, potassium chloride16 mEq BID, captopril 50 mg TID, warfarin, cisapride 10 mg TID,oxazepam 15 mg QHS and budesonide, albuterol, salmeterol andipratropium bromide inhalers. Potassium chloride was reduced to16 mEq daily, captopril reduced to 25 mg TID, cisapride inadvertentlyincreased to 20 mg TID and the other medications continued asrecorded above. Trimethoprim/sulfamethoxazole 10 mg Q8H IV andclarithromycin 500 mg BID were started for pneumonia. AdmissionQTc interval was prolonged (520 ms). One month before, this valuewas normal (440 ms) at a paced rate of 70 BPM. She remained rela-tively stable over the next 48 hours and then was found to be unre-sponsive. She was intubated and transferred to the ICU where serumpotassium was 4.1 mmol/l, serum magnesium was 1.94 mEq/l andserum creatinine was 1.37 mg/dl. Antibiotics and captopril werestopped. Medications included ipratropium 2 ml with albuterol 1 mgQ2H, albuterol 1 ml/h PRN and methylprednisolone 120 mg IV, fol-lowed by 100 mg BID. Shortly after arriving in the ICU, cardiac mon-itoring showed polymorphic ventricular tachycardia (180 BPM).
Repeat serum potassium was 3.3 mmol/l and QTc interval was pro-longed (640 ms) at a paced ventricular rate of 70 BPM. Multiple epi-sodes of ventricular tachycardia continued during the night for whichshe eventually received a lidocaine infusion. Magnesium was givenfor recurrent TdP. On several occasion, electrical cardioversion wasrequired. Lidocaine was stopped. The next morning, the consultingpharmacist hypothesized that the concomitant administration of cisa-pride and clarithromycin may have induced TdP. Both drugs werestopped. Additional magnesium was given, the serum potassiumlevel kept above 4.5 mmol/l, and the pacing rate was increased to80 BPM. She was subsequently discharged from the hospital andthere was no recurrence of the cardiac arrhythmias over the next32 months.
QTc 640 ms; clarithromycin dose 1000 mgTdP did occur. Risk factors were female sex, elderly, heart disease,hypokalemia, acute medical illness, chronic medical illness, cisa-pride (both directly and as a CYP3A4 blocker) and clarithromycin.
Case 1. 78-year-old woman hospitalized because of a syncopal epi- sode. Medications included digoxin, nilvadipine, pravastatin and lofla-zepate. One day before, because of a respiratory infection, she wasstarted on clarithromycin (400 mg daily) and chlorpheniramine (12 mgdaily). On admission, she was mildly anemic. Other chemistries werenormal except for mild hypokalemia (3.3 mmol/l). Admission EKGshowed marked QT interval prolongation (520 msec) at a heart rateof 95 BPM (calculated QTc interval 654 ms—Bazett), right bundlebranch block (RBBB) and atrial fibrillation. She was transferred to W. V. R. Vieweg, J. C. Hancox et al.
the ICU for cardiac monitoring. One hour later, she lost conscious-ness coincident with developing TdP. A temporary pacemaker wasinserted (rate 80 BPM) and magnesium sulfate infused for 4 days.
Echocardiography showed an enlarged left atrium with normal leftventricle and ejection fraction. Chest X-ray showed cardiac enlarge-ment. At the time of hospital discharge 10 days later, the QTc intervalwas normal.
QTc 654 ms; clarithromycin dose 400 mgTdP did occur. Risk factors were female sex, elderly, heart disease,acute medical illness, hypokalemia and clarithromycin.
Case 2. 62-year-old man with idiopathic interstitial pneumonia and chronic hepatitis C was treated with theophylline, cloperastine (coughsuppressant), clarithromycin 400 mg daily and zopiclone (hypnotic).
Soon thereafter, he was rushed to the hospital because of seizuresand cyanosis. Cardiac monitoring showed nonsustained episodes ofTdP. EKG showed normal sinus rhythm (69 BPM), QT interval prolon-gation Chemistries include electrolytes were normal except for mildly ele-vated liver enzymes. Clarithromycin was stopped. He received 2 g ofmagnesium sulfate IV and a temporary pacemaker was placed. ChestX-ray was consistent with interstitial pneumonia and cardiac size wasnormal. Echocardiography was normal. He was discharged with nofurther cardiac arrhythmia. 40 days later, QT interval was 480 ms at aheart rate of 56 BPM (calculated QTc 464 ms).
QTc 600 ms; clarithromycin dose 400 mgTdP did occur. Risk factors were acute medical illness, chronic liverdisease and clarithromycin.
76-year-old woman with history of hypertension, type 2 diabetes mel- litus and stroke was admitted to the hospital with pneumonia.
Baseline Echocardiography showed concentric left ventricular hypertrophywith mild-to-moderate diffuse hypokinesis without ventricular dilata-tion. She received 7 doses of IV erythromycin 500 mg Q6H and thenwas switched to oral clarithromycin 500 mg Q12H. After the 2nd doseof clarithromycin, she developed TdP and then ventricular fibrillationrequiring defibrillation (QTc interval 540 ms). She was hypokalemic(2.8 mmol/l). Mutation to MiRP1 protein was found.
QTc 540 ms; clarithromycin dose 1000 mgTdP did occur. Risk factors were female sex, elderly, heart disease,mutation to MiRP1 protein, acute medical illness, chronic medicalillness, hypokalemia, erythromycin and clarithromycin.
76-year-old woman with history of myocardial infarction, coronary artery bypass grafting, left ventricular dysfunction and symptomatic PVCs suppressed with disopyramide (150 mg BID for previous 19years) was hospitalized because of chronic bronchitis, dehydrationand hypotension. Five days before admission, she started clarithro-mycin 250 mg BID administered by a local community clinic for bron-chitis. Other medications included digoxin 0.25 mg daily (level 1.7 mg/dl), theophylline 200 mg BID, losartan 50 mg BID, furosemide 40 mgdaily, aspirin and bronchodilators.
The initial EKG showed sinus rhythm, left bundle branch block andprolonged QTc interval (498 ms) that had lengthened since the pre-vious QTc interval (477 ms). All medications were stopped except fortheophylline and inhalers. Electrolytes were normal and cardiacenzymes were negative. Several hours after admission, she devel-oped two self-terminating episodes of TdP linked to syncope. At thistime, disopyramide level was in the upper normal range (4.1 mg/ml—normal range 2—5 mg/ml). Electrolytes at this time remainednormal and cardiac enzymes remained negative. Serum creatinineconcentration was 1.8 mg/dl consistent with mild renal impairment.
Therapeutic Advances in Infectious Disease 1 (4) QTc interval had further lengthened (640 ms). Coronary arteriographyshowed a depressed left ventricular unchanged since 1993. Two of three grafts remained patent. 48-hour Holter monitoring showed a 5-beat run of asymptomatic mono-morphic ventricular tachycardia at a slow rate. Electrophysiologicstudies could not induce ventricular tachyarrhythmia. She was dis-charged receiving no further antiarrhythmic treatment.
QTc 640 ms; clarithromycin dose 500 mgTdP did occur. Risk factors were female sex, elderly, heart disease,acute medical illness, chronic medical illness, mild renal failure,disopyramide (both directly and as a CYP3A4 blocker) andclarithromycin.
29-year-woman with recurrent syncope, QTc interval prolongation (680 ms) and documented TdP was diagnosed as having long QT syn-drome. She was treated with clarithromycin shortly before the firstsyncopal episode. No prior EKGs existed. Owing to persisting QTcinterval prolongation more than 6 months after stopping clarithromy-cin and QTc interval prolongation in her uncle, she was diagnosedwith congenital long QT-syndrome. She started a beta-blocker andremained free of symptoms.
QTc 680 ms; clarithromycin dose unknownTdP did occur. Risk factors were female sex, congenital long QTsyndrome, acute medical illness and clarithromycin.
30-year-old man positive for hepatitis C and HIV and enrolled in a methadone detoxification program was admitted for treatment following 10 days of cough, mucopurulent sputum, pleuritic pain,fever and dyspnea. At that time, he had a viral load of 90,000copies/ml and CD4 þ lymphocyte index of 36. Chest X-ray showedan alveolar pattern in both bases consistent with bilateral pneumo-nia. Laboratory testing showed arterial desaturation, anemia, ele-vated serum creatinine (2.4 mg/dl), hyponatremia (129 mmol/l) andpotassium of 5.0 mmol/l. EKG showed sinus tachycardia (100 beats/minute) and normal QTc interval (350 msec). Initial treatmentincluded infusion of two packed red cells and correction of hypona-tremia. IV antibiotics included cefepime (2 g Q8H), clarithromycin(500 mg sulfamethoxazole 1200 mg Q6H). 48 hours later, EKG showed brady- cardia (35 BPM), QTc interval prolongation (580 ms) and ventricularbigeminy. 24 hours later, he developed a self-limited episode ofmonomorphic ventricular tachycardia (150 BPM) in a RBBB config-uration (QRS 160 ms). Clarithromycin and cotrimoxazole werestopped and IV cefepime continued. Cardiac enzymes were normal.
Echocardiography showed a slightly dilated left ventricular anddepressed ejection fraction (23%). Immediately thereafter, no newepisodes of ventricular tachycardia occurred. 4 days later, the QTcinterval was normal (360 ms).
QTc 580 ms; clarithromycin dose 1000 mgMonomorphic ventricular tachycardia did occur. Risk factors wereheart disease, acute medical illness, chronic medical illness, bra-dycardia, methadone, cotrimoxazole (both directly and as a CYP3A4blocker), chronic liver disease and clarithromycin.
80-year-old man presented to the ED with 3 days history of cough and productive sputum. Medical history included coronary artery disease and chronic obstructive pulmonary disease controlled. At admission,white blood cell count was elevated (18,600) and serum creatinine,electrolytes and cardiac enzymes were normal. Initial EKG showedsinus tachycardia and ST segment depression in the lateral leads.
Chest X-ray was inconclusive for pneumonia. He was treated withoral clarithromycin 500 mg BID. After 48 hours, EKG showed QTcinterval prolongation (560 ms) and T-wave inversion in the anterior W. V. R. Vieweg, J. C. Hancox et al.
leads. He remained asymptomatic. An echocardiogram showed nowall motion abnormalities. Clarithromycin was stopped and amoxi-cillin þ clavulanic acid started. One week later, the EKG was normal.
QTc 560 ms; clarithromycin dose 1000 mgTdP did not occur. Risk factors were elderly, heart disease, acutemedical illness, chronic medical illness and clarithromycin.
79-year-old woman presented to the ED with her first syncopal epi- sode. Past medical history included appropriately treated hyperten- sion, hypothyroidism and chronic obstructive pulmonary disease.
Neurological history and examination was unremarkable. Penicillinallergy was noted. Admission EKG showed atrial fibrillation thatreverted to sinus rhythm with first-degree AV block and QTc intervalprolongation (496 ms). A diagnosis of community-acquired pneumo-nia Clarithromycin (250 mg BID) and ceftriaxone were started. Within 24hours of starting antibiotic treatment, she developed brief runs ofparoxysmal ventricular tachycardia/TdP (QTc interval 542 ms) andamiodarone infusion was started. Amiodarone was stopped followingevidence of complete heart block interspersed with paroxysmal ven-tricular tachycardia. Unremarkable studies ensued including serumelectrolytes, coronary arteriography and echocardiography (smallpericardial effusion). Overdrive pacing at 90 BPM was commencedwith a temporary pacing wire. However, the wire dislodged with fail-ure to capture at 6 mV. She was transferred to a tertiary care center.
Clarithromycin was stopped. A permanent DDDR pacemaker wasplaced. A beta-blocker was started. At the time of discharge QTcinterval was prolonged (500 ms).
QTc 542 ms; clarithromycin dose 500 mgTdP did occur. Risk factors were female sex, elderly, heart disease,suspected congenital long QT syndrome, acute medical illness,chronic medical illness, amiodarone and clarithromycin.
50-year-old woman with history of hypertension and depression admitted for cardiac monitoring following two episodes of syncope during preceding 2 days. Chest X-ray was normal. Serum potassiumwas 3.3 mmol/l. She had been treated with clarithromycin for anupper respiratory tract infection. Other medications included HCTZ,fluoxetine and potassium supplement. TdP recurred deteriorating toventricular fibrillation requiring defibrillation. Posterior fascicularblock was noted on the EKG and the QTc interval was 620 ms.
QTc 620 ms; clarithromycin dose unknownTdP did occur. Risk factors were female sex, hypokalemia, acutemedical illness, fluoxetine and clarithromycin.
71-year-old woman was hospitalized with acute respiratory failure and rapid atrial fibrillation. She was allergic to penicillin, smokedand had previously undergone a hysterectomy. On the first day, shereceived amiodarone as a 300 mg bolus followed by a 900 mg/dayinfusion slowing the ventricular rate to less than 100 BPM and thenconverting to sinus rhythm with negative T waves. On day 2, shereceived clarithromycin 1 g/day and ciprofloxacin 1 g/day for commu-nity-acquired pneumonia. On day 3, rapid atrial fibrillation recurredand hemodynamics worsened prompting mechanical ventilation. EKGon day 4 showed sinus or nodal rhythm (58 BPM) and QT intervalprolongation. Sustained ventricular tachycardia developed and wastreated with amiodarone infusion. Ciprofloxacin and clarithromycinwere stopped and ceftriaxone started. On day 5, she had probablenodal rhythm with bradycardia and a QT interval of 640 ms.
Amiodarone dose was decreased and she developed rapid atrialfibrillation. On day 6, she had sinus or atrial rhythm, bradycardia, Therapeutic Advances in Infectious Disease 1 (4) and QT/QTc interval prolongation (630/570 ms).
QTc 570 ms; clarithromycin dose 1000 mg dailySustained ventricular tachycardia did occur. Risk factors werefemale sex, elderly, heart disease, bradycardia, acute medical ill-ness, ciprofloxacin (CYP3A4 inhibitor and directly linked to TdP),amiodarone and clarithromycin (potent CYP3A4 inhibitor anddirectly linked to TdP).
6-year-old boy had started clarithromycin treatment 6 days earlier for atypical pneumonia presented to the pediatric cardiology clinic forevaluation of a heart murmur. 12 hours before presenting to theclinic, he had a syncopal episode. There was no family history ofsyncope or SCD. Vital signs were normal. A 2/6 systolic murmurwas noted in the mesocardiac area. Chemistries were normal. EKGshowed normal sinus rhythm (88 BPM) and QTc interval prolongation(600 ms). Echocardiography was normal. 24-hour Holter monitoringonly showed QTc interval prolongation. Audiometrics were normal.
One week after stopping clarithromycin, QTc interval was normal.
Treating clinicians excluded congenital long QT syndrome.
QTc 600 ms; clarithromycin dose unknownTdP assumed but not documented. Risk factors included acutemedical illness and clarithromycin.

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