Torsade de pointes associated with moxifloxacin: A rare but potentially fatal adverse event

doi:10.1016/S0828-282X(07)70850-4

Canadian Journal of Cardiology

Volume 23, Issue 11, September 2007, Pages 907-908

https://doi.org/10.1016/S0828-282X(07)70850-4 Get rights and content

Torsade de pointes occuring due to a long QT interval is a rare but potentially fatal arrhythmia. Acquired long QT develops most commonly because of drugs that prolong ventricular repolarization. It has been reported that fluoroquinolone antimicrobials prolong the corrected QT interval but rarely cause torsade de pointes. A patient with torsade de pointes risk factors (female sex, advanced age, extreme bradycardia and renal failure) who developed the condition on the fourth day of 400 mg/day of oral moxifloxacin treatment is presented. After the moxifloxacin was stopped, the corrected QT interval normalized and a permanent cardiac pacemaker was implanted. During 11 months of follow-up, arrhythmia did not recur.

Les torsades de pointe attribuables à un intervalle QT long sont des arythmies rares, mais au potentiel fatal. D’ordinaire, les intervalles QT longs se manifestent en raison de médicaments qui prolongent la repolarisation ventriculaire. Il a été signalé que les fluoroquinolones, un antimicrobien, prolongent l’intervalle QT corrigé mais sont rarement responsables de torsades de pointe. On présente le cas d’une patiente ayant des facteurs de risque de torsades de pointe (sexe féminin, âge avancé, bradycardie extrême et insuffisance rénale) qui a souffert de ce trouble après avoir suivi un traitement de 400 mg/jour de moxiflocacine par voie orale pendant quatre jours. Après l’abandon de la moxifloxacine, l’intervalle QT corrigé s’est normalisé, et on a implanté à la patiente un stimulateur cardiaque permanent. L’arythmie ne s’est pas manifestée de nouveau au cours des 11 mois de suivi.

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This chapter explores the potential for antimicrobial drugs to cause QT interval prolongation and torsades de pointes (TdP). Common mechanisms include inhibition of the rapid component of the delayed rectifier potassium current (I_Kr) as well as pharmacokinetic and pharmacodynamic drug-drug interactions. Many antimicrobials agents have the potential to cause TdP and electrocardiogram (ECG) monitoring is recommended in some cases. Attention should also be paid to other risk factors for proarrhythmia.
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Moxifloxacin has been used as a positive control drug on performing QT/QTc studies for new drug candidates, since it possesses a favorable cardiac safety profile despite its QT-interval prolonging action.1,2 Indeed, torsade de pointes was induced neither in previous QT/QTc studies1–3 nor in phase II/III clinical trials4,5; however, there are several case reports describing that moxifloxacin induced torsade de pointes, in which patients were treated with 400 mg/body/day of oral or intravenous moxifloxacin.6–10 Importantly, these patients were confirmed to have such risk factors toward the drug-induced QT prolongation and torsade de pointes as hypertension, chronic renal failure, congestive heart failure, left ventricular dysfunction and coronary artery disease.7–10
We analyzed the effects of intravenously as well as orally administered moxifloxacin on the pharmacokinetic and electrocardiographic variables along with its torsadogenic action using the chronic atrioventricular block cynomolgus monkeys with a cross-over design. Initially, moxifloxacin was intravenously administered in doses of 60 mg/kg/2 h, 60 mg/kg/1 h and 105 mg/kg/1.75 h with an interval of >1 week (n = 3), which provided C_max of 19.7, 25.4 and 37.8 μg/mL, and induced torsade de pointes in 1, 0 and 3 out of 3 animals, respectively. Next, moxifloxacin was orally administered in doses of 10, 30 and 100 mg/kg with an interval of >1 week (n = 6), which provided C_max of 1.8, 4.2 and 8.9 μg/mL, and induced torsade de pointes in 0, 0 and 2 out of 6 animals, respectively. A close analysis of pharmacokinetic and electrocardiographic variables indicates that torsade de pointes was induced in animals that had experienced larger systemic exposure of moxifloxacin and/or greater peak QTcF, although C_max by itself did not necessarily reflect the incidence of torsade de pointes when its administration route was different. These findings may provide a basic guide how to use moxifloxacin in safe for patients with labile repolarization process.
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The incidence of sepsis is increasing, and the condition is now the leading cause of death in general intensive care units. Our review failed to identify studies of the causes of cardiac arrest among infected patients, even though non-cardiac causes represent 15% of out-of-hospital cardiac arrests and though one-third of events have positive blood cultures. Sudden cardiac arrest is the result of local damage to the heart and of the impact of systemic and pulmonary conditions on cardiac performance, and its danger is underestimated. Necropsy findings in sudden death often identify myocarditis as an unexpected cause. The role of hypoxaemia, severe pulmonary thromboembolism with subsequent pulseless cardiac activity, alterations of electrolytes and hydrogen concentrations, distort fluid distribution with reduced pre-load, direct myocyte damage and adverse cardiac effects related to antibiotic use need to be defined. Many cardiac arrests might be preventable. Because cardiopulmonary resuscitation is challenging and usually unsuccessful in patients with sepsis, research is needed to help predict which patients are at risk. Only half of pneumonia patients with cardiac arrest in the ward receive prior ECG monitoring. Telemedicine and non-invasive monitoring in the ward, avoidance of antibiotics associated with prolonged QT syndrome, and adequate haemodynamic resuscitation might be important in preventing in-hospital arrests among patients with infections.
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Prolongation of QT interval is possible with fluoroquinolones, yet the underlying contributing factors have not been elucidated. Two widely used fluoroquinolone drugs were at the focus of this study in rats with/without acute myocardial dysfunction (AMI) induced by isoproterenol. The effects of levofloxacin and ciprofloxacin on the cardiac mRNA expression of rat Kv4.3, Kv1.2 and Nav1.5 mRNAs were determined. Administration of the two antibiotics produced dose-dependent changes in ECG parameters that were more prominent in rats with AMI than healthy rats; this was accompanied by elevations in serum lactate dehydrogenase and creatine kinase-MB. Histopathological examination indicated some loss of striations, edema and fibrotic changes in rats with AMI; however the two antibiotics did not further exacerbate the cardiac histopathology. mRNA expression of the ion channels was altered in rats with AMI and healthy rats. In conclusion, long-term administration of levofloxacin and ciprofloxacin produced deleterious effects on the ECG pattern of rats with/without AMI. The effect was generally baseline-dependent and therefore, rats with AMI showed greater ECG disturbances and increases in cardiac enzymes. Taken together, these data make it advisable to monitor patients with a history of acute AMI requiring treatment with these antibiotics until data from human studies are available.
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We do not really understand why prolongation induces EADs in our system. Rare cases of QT prolongation by therapeutically-relevant doses of moxifloxacin, associated with TdPs, have been reported in the clinic (e.g. Altin et al., 2007; Sherazi, DiSalle, Daubert, & Shah, 2008). Limited by our current dataset, we could not explain the discrepancy of effects of ranolazine that induced EADs in iCells, but no clinical TdPs.
FDSS/μCell is a high-speed acquisition imaging platform (Hamamatsu Ltd., Hamamatsu, Japan) that allows for simultaneous high-throughput reading under controlled conditions. We evaluated the Ca^2 + transients or optical membrane potential changes of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) (iCells) in the presence or absence of 44 pharmacological agents known to interfere with cardiac ion channels (e.g., hERG, I_Ks, NaV_1.5, CaV_1.2). We tested two Ca^2 +-sensitive fluorescence dyes (Codex ACTOne® and EarlyTox®) and a membrane potential dye (FLIPR® membrane potential dye). We were able to quantify and report drug-induced early-after depolarizations (EAD)-like waveforms, cardiomyocyte ectopic beats and changes in beating rate from a subgroup of pharmacological agents acting acutely (within a 1-hour period). Cardiovascular drugs, such as dofetilide and d,l-sotalol, exhibited EAD-like signals at 3 nM and 10 μM, respectively. CNS drugs, such as haloperidol and sertindole, exhibited EAD-like signals and ectopic beats at 30 nM and 1 μM, respectively. Other drugs, such as astemizole, solifenacin, and moxifloxacin, exhibited similar arrhythmias at 30 nM, 3 μM and 300 μM, respectively. Our data suggest that the membrane potential and intracellular Ca^2 + signal are tightly coupled, supporting the idea that the EAD-like signals reported are the accurate representation of an EAD signal of the cardiac action potential. Finally, the EAD-like Ca^2 + signal was well correlated to clinically-relevant concentrations where Torsade de Pointes (TdPs) arrhythmias were noted in healthy volunteers treated orally with some of the compounds we tested, as reported in PharmaPendium®.

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Torsade de pointes associated with moxifloxacin: A rare but potentially fatal adverse eventLes torsades de pointe associées à la moxifloxacine : Une réaction indésirable rare, mais au potentiel fatal

Eur J Pharmacol

Clin Ther

Am J Cardiol

Quinolone-induced QT interval prolongation: A not-sounexpected class effect

J Antimicrob Chemother

Torsades de pointes associated with fluoroquinolones

Pharmacotherapy