2023 Mar 17;9(11):eade7109. On a 12-lead ECG, the QT interval is measured from the beginning of the QRS complex to the end of T wave as it returns to baseline. The early repolarization and plateau phases (phase 1 and 2, respectively) are largely the result of potassium and calcium currents. Quinolones (e.g. Haloperidol and thioridazine share the same enzyme CYP2D6 for clearance resulting in increased levels of both [Aerssens and Paulussen, 2005]. Tschida SJ, Guay DR, Straka RJ, Hoey LL, Johanning R, Vance-Bryan K. QTc-interval prolongation associated with slow intravenous erythromycin lactobionate infusions in critically ill patients: a prospective evaluation and review of the literature. 2000]. An official website of the United States government. The patients who are described in the literature as developing arrhythmias after receiving macrolide antibiotics have a strikingly high prevalence of other factors that could cause or contribute to the arrhythmias. Reduced repolarization reserve in ventricular myocytes from female mice. Some of these drugs have either been restricted or withdrawn from the market due to the increased incidence of fatal polymorphic ventricular tachycardia. Accessibility (Reproduced with permission from Chan et al. Based on the data provided, the incidence could vary at least 10-fold. 2007]. Svanstrm H, Pasternak B, Hviid A. doi: 10.7759/cureus.31819. Comparative pharmacokinetics of macrolides. Below the selectivity filter, the pore widens to form a central cavity. The hERG channel is essentially formed by the co-assembly of four alpha subunits, each of which has six transmembrane spanning alpha-helical segments (S1S6) [Sanguinetti and Tristani-Firouzi, 2006; Swartz, 2004] (Figure 2). QT prolongation itself does not adversely affect cardiac function (2), but prolongation portends the possibility of more serious arrhythmias. Droperidol has a similar effect of haloperidol and careful attention to be paid in patients with risk factors. This study has evolved as a key component of all clinical development programs for new molecular entities. Given the low concentrations resulting from oral dosing of macrolides, arrhythmias are unlikely to occur in the absence of additional issues that would reduce the repolarization reserve. Consistent with this concept is the estimate that the incidence of arrhythmias in response to macrolides in absence of additional risk factors is very low, perhaps < 1 in 100,000 subjects (65). Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. CME will be available for this article at www.atsjournals.org, Originally Published in Press as DOI: 10.1164/rccm.201402-0385CI on April 7, 2014. Accumulation of potassium within the myocytes delays repolarization. 2006], rescue of SCN5A channel causing increased inward sodium current by cisapride [Kannankeril, 2008] and an increase inward calcium current by antimony [Kuryshev et al. Freedman RA, Anderson KP, Green LS, Mason JW. 1, 2, 3, 4, 5, 6, 7 However, despite these reports, multiple large retrospective clinical studies investigating the potential risk of the use of macrolides in practice have yielded conflicting results. Phase 0: Large inward current of sodium ions (INa). (2002), Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel, Nguyen A., Sarmast S., Kowal R., Schussler J. (2000), Spectrum of mutations in long-QT syndrome genes. Subjects taking erythromycin in addition to CYP3A inhibitors had a 3-fold greater incidence of sudden cardiac death than those taking erythromycin alone, and the incidence of sudden cardiac death in subjects taking erythromycin without CYP3A inhibitors was within the 95% confidence interval (CI) of the incidence in subjects taking amoxicillin alone (Table 3). In response to a recently published observational study (1), the FDA warned that azithromycin can change the electrical activity of the heart and reiterated a 2011 product label revision stating that patients with risk factors were at particular risk and strengthened the Warnings and Precautions section of azithromycin drug labels. 2006]. Heart rate and extracellular potassium concentration also play a significant role. Antiarrhythmic agents are the leading cause of drug-induced TdP. This summary describes the electrophysiological effects of macrolides, reviews literature indicating that the large majority of subjects experiencing cardiac arrhythmias from macrolides have coexisting risk factors and that the incidence of arrhythmias in absence of coexisting risk factors is very low, examines recently published studies describing the relative risk of arrhythmias from macrolides, and concludes that this risk has been overestimated and suggests an approach to patient evaluation that should reduce the relative risk and the incidence of arrhythmias to the point that chronic macrolides can be used safely in the majority of subjects for whom they are recommended. Lower levels of evidence suggest that chronic macrolides are also effective in treating subjects with panbronchiolitis and those with bronchiolitis obliterans and rejection after lung transplantation. Both of them impair the I(Kr) current. The potassium blocking effect is maximum at low heart rate due to reverse use dependency feature [Hondeghem and Snyders, 1990]. When a macrolide is indicated in a patient with QT risk (Table 3) it is important to consider using a ketolide or a non-macrolide antibiotic. It varies depending on the population studied and the type of drugs used. If drug-induced TdP has occurred, a careful review of the patients personal and family history should be obtained in order to identify the possibility of a congenital LQTS. the CLARICOR Trial Group. Phase 1: Inactivation of INa and the transient efflux of potassium ions (It0). In acquired LQTS, the mechanism is almost always due to blockage of the inward potassium rectifier (IKr) channel, also known as the hERG (ether a go go) channel. Author disclosures are available with the text of this article at www.atsjournals.org. 1996]. 2005]. Kim and colleagues (60) and Kezerashvili and colleagues (61) published what they believed to be the first reports of TdP occurring in patients with no apparent predisposing comorbidities, but the first of these patients had taken pseudoephedrine in conjunction with the azithromycin and also had hypokalemia, and the second had a pacemaker for intermittent symptomatic bradycardia, had developed acute renal failure requiring dialysis, and was taking moxifloxacin and ciprofloxacin at the time the TdP was observed. J Pharmacol Toxicol Methods. Electrophysiological mechanisms in a canine model of erythromycin-associated long QT syndrome. The long QT syndrome (LQTS) is characterized by a prolonged QT interval, as well as a propensity to develop syncope and sudden cardiac death caused by the malignant polymorphic ventricular arrhythmia called torsades de pointes (TdP). [2007].). 1997]. J Pharmacol Toxicol Methods. Five phases of cardiac depolarization and repolarization. and transmitted securely. sharing sensitive information, make sure youre on a federal Sinisalo J, Mattila K, Valtonen V, Anttonen O, Juvonen J, Melin J, Vuorinen-Markkola H, Nieminen MS for the Clarithromycin in acute coronary syndrome patients in Finland (CLARIFY) Study Group. Torsades de pointes associated with drugs and toxins: recognition and management. The treatment depends on the hemodynamic stability of the patient. 2004]. ICa, calcium current; IK, potassium current; IK1, inwardly rectifying potassium current; INa, depolarizing sodium current; It0, transient outward potassium current; IKr, rapidly activating delayed rectifier potassium current; IKs, slowly activating delayed rectifier potassium current. eCollection 2022 Nov. Abdollahi-Karizno M, Partovi N, Noferesti V, Ravanbakhsh N, Kazemi T, Khosravi-Bizhaem S. ARYA Atheroscler. 2004]. 2006 Mar-Apr;53(2):87-105. doi: 10.1016/j.vascn.2005.07.003. Anderson JL, Muhlesstein JB, Carlquist J, Allen A, Trehan S, Nielson C, Hall S, Brady J, Egger M, Horne B, Lim T. Randomized secondary prevention trail of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumonia infection: the Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) study. Background: Macrolides and fluoroquinolones are broad spectrum antibiotics used to treat pneumonia, urinary tract infections, and other infections. In contrast, terfenadine, a potent IKr blocker, causes very minimal QT prolongation but was frequently implicated in TdP resulting in its withdrawal from market [Monahan et al. being able to get an erection sometimes, but not every time you want to have sex. Oral erythromycin and the risk of sudden death from cardiac causes. 2023 Mar 24;13(7):1234. doi: 10.3390/diagnostics13071234. Concomitant administration of macrolides with astemizole, cisapride, pimozide, or terfenadine is contraindicated because potentially fatal cardiac arrhythmias (eg, QT prolongation, ventricular tachycardia, ventricular fibrillation, torsades de pointes) may occur when clarithromycin or erythromycin is given with these drugs. Accordingly, the incidence of arrhythmias could not be determined. Brandriss MW, Richardson WS, Barold SS. A new biomarker--index of cardiac electrophysiological balance (iCEB)--plays an important role in drug-induced cardiac arrhythmias: beyond QT-prolongation and Torsades de Pointes (TdPs). Careers, Unable to load your collection due to an error. Ohtani H, Taninaka C, Hanada E, Kotaki H, Sato H, Sawada Y, Iga T. Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats. Raschi E, Poluzzi E, Koci A, Moretti U, Sturkenboom M, De Ponti F. Macrolides and torsadogenic risk: emerging issues from the FDA pharmacovigilance database. Phenothiazines such as chlorpromazine have an antipsychotic and anti-emetic effect. Medications that prolong QT interval act on the same hERG channel. (d) Crystal structure of a single Kv1.2 -subunit7 viewed from the side. Phase 1: Inactivation of INa and the transient efflux of potassium ions (It0). Antimalarial agents are commonly prescribed worldwide. The first patient reported to have arrhythmias in association with azithromycin was also receiving disopyramide (55). 1986]. Correspondence and requests for reprints should be addressed to Richard K. Albert, M.D, Denver Health, 660 Bannock, MC 4000, Denver, CO 80204-4507. Estimation of individual correction factor is a cumbersome, time-consuming process. We excluded another 10 subjects (0.8%) because they developed QTc prolongation on an ECG obtained 1 month after starting therapy (six [1.05%] were receiving azithromycin, and four [0.70%] were receiving placebo; P = 0.55). Erlandsdotter LM, Giammarino L, Halili A, Nikesj J, Gren H, Odening KE, Liin SI. Normal values for the QT interval and the RR of torsade des pointes (TdP) have been estimated from population-based studies (Table 2) (3). Lehmann and colleagues (74) suggest that TdP occurs three times more commonly in women than in men. They show an activity against a very broad range of bacteria. Recent conversion from atrial fibrillation with QT prolonging drugs [Choy et al. If both of these estimates are correct, Ray and colleagues (1) could have overestimated the RR of azithromycin causing cardiac deaths by nearly 30% because of the imbalance of women in the cohort. QT prolongation is highest with ziprasidone and lowest with olanzapine [Vieweg, 2003]. 2010], Underlying heart disease such as heart failure, left ventricular hypertrophy and myocardial infarction, Rapid rate of intravenous infusion with a QT prolonging drug, High drug concentration (except quinidine). R.K.A. This pattern is in contrast to congenital form, where TdP often follows a sudden adrenergic surge such as exercise or arousal. Atrial and ventricular refractory periods were also prolonged by the rapid, but not the slower, infusion. 1993; Tomaselli et al. 2001; Splawski et al. The macrolides have an antibacterial spectrum that is similar but not identical to that of penicillin; they are thus an alternative in penicillin-allergic patients. Drug-induced QT prolongation acts as a marker for risk of progression to TdP. Nonetheless, it underestimates and overestimates the QT interval at low and high heart rates, respectively. These patients are generally asymptomatic with normal to borderline QTc interval at baseline but become more susceptible to QT prolongation and TdP, when exposed to some drugs [Aerssens and Paulussen, 2005; Paulussen et al. Erythromycin, azithromycin, and clarithromycin are all listed in risk category 1 (Substantial evidence that these drugscan prolong the QT interval and can have a risk of torsades de pointes). ACES Investigators. Pham TV, Sosunov EA, Anyukhovsky EP, Danilo P, Jr, Rosen MR. Testosterone diminishes the proarrhythmic effects of dofetilide in normal female rabbits. Studies documenting the RRs of subjects developing arrhythmias when taking macrolides compared with other classes of antibiotics or no antibiotics have reached conflicting conclusions (1, 64), perhaps because they examined different patient populations, but the study by Ray and colleagues (1) that reported increased RR of arrhythmias may have overestimated the RRs for the reasons discussed above. (See 'Adverse effects' below.) Overview. Pentamidine is an antiprotozoal drug that is used for Pneumocystis carinii pneumonia treatment. The studied drug prolongs the mean QTc interval by >10 ms but 20 ms, and so has an uncertain risk of inducing TdP. An official website of the United States government. Mishra A, Friedman HS, Sinha AK. Azithromycin for the secondary prevention of coronary events. For example, current or past use of antipsychotic medications was reported in 11.5% of the patients during periods when they were receiving no antibiotics and in 11.8% of the patients during periods when azithromycin was taken. Arellano-Rodrigo E, Garca A, Mont L, Roqu M. Torsade de pointes and cardiorespiratory arrest induced by azithromycin in a patient with congenital long QT syndrome [in Spanish]. Systemic azole group of antifungal agents have both pharmacodynamic and pharmacokinetic characteristics that may trigger TdP [Owens, 2004]. Federal government websites often end in .gov or .mil. The .gov means its official. Rezkalla MA, Pochop C. Erythromycin induced Torsades de Pointes: case report and review of the literature. Pham TV, Sosunov EA, Gainullin RZ, Danilo P, Jr, Rosen MR. Impact of sex and gonadal steroids on prolongation of ventricular repolarization and arrhythmias induced by I(K)-blocking drugs. Incomplete penetrance of hERG mutations may be present despite near-normal QT intervals, representing a second mechanism by which macrolides may prolong the QT interval (1418). We review mechanisms, predispositions, culprit agents, and management of this potentially fatal phenomenon. Accordingly, physicians have to weigh the relative risk (RR) of arrhythmias developing versus the reduction in morbidity that could be achieved by prescribing chronic macrolides. PMC Before Inherited mutations (loss of function) of the hERG gene lead to type 2 LQTS. Repolarization (represented by the T wave and the QT interval) occurs in three phases. (2010), Cardiac arrest due to torsades de pointes in a patient with complete heart block: the R-on-T phenomenon, N-acetyl procainamide causing torsades de pointes, QT prolongation with antimicrobial agents: understanding the significance, Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes, Paulussen A., Gilissen R., Armstrong M., Doevendans P., Verhasselt P., Smeets H., et al. FOIA A negative result would most likely allow standard ECG data to be collected in accordance with standard practice in phase IIIII of clinical drug testing. (2004), Mechanisms of arsenic-induced prolongation of cardiac repolarization, Fossa A., Wisialowski T., Magnano A., Wolfgang E., Winslow R., Gorczyca W., et al. Sertindole was withdrawn from market in 1998 due to the risk of TdP and sudden death. Evaluation of drug-induced QT interval prolongation: implications for drug approval and labelling. The list of some drugs that can cause QT prolongation is listed in Box 2. Wu Y, Anderson ME. Phase 3 repolarization occurs when potassium channels open and the cell returns to its resting negative state (phase 4). The QT interval on the surface EKG represents the summation of action potential (AP) of ventricular myocytes. For females, a QT interval greater than 470 ms is considered prolonged and between 450 and 470 ms is considered borderline [Goldenberg et al. Sotalol causes TdP in 24% of patients with a higher risk in women [Lehmann et al. Justo and Zeltser (63) examined subjects reported in Pubmed citations to 2005 and identified by direct inquiry of pharmaceutical companies and found 78 patients who developed TdP. A centerpiece of this practice was the establishment of the thorough QT/QTc study that was intended to confidently identify drugs that may cause QT prolongation. Patients with liver dysfunction or co-administration of drugs or food that inhibit the CYP3A4 can result in higher drug levels. Long-QT mutations in KCNE1 modulate the 17-estradiol response of Kv7.1/KCNE1. Both studies were designed to test the hypothesis that macrolides decreased the inflammation associated with cardiovascular disease, thereby decreasing adverse cardiac events. There are no standards for interpreting prolonged QT intervals from Holter or 24/48 h ambulatory monitoring records available. Forty-one other medications are included in this category, including haloperidol and droperidol, ondansetron, moxifloxacin, and methadone. government site. Finlayson K, Witchel HJ, McCulloch J, Sharkey J. Eur J Pharmacol. Several groups, however, suggest that QT prolongation is an insensitive and nonspecific predictor of adverse cardiac events because the majority of patients with medication-induced QT prolongation do not develop TdP, and many patients who develop TdP have a normal QT interval (5-7). Class Ia (Quinidine, Procainamide, Disopromide), Class III (Dofetilide, Ibutilide, Sotalol), Antihistamines (Terfenadine*, Astemizole*). Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, Rogers WJ, Crouse JR, Borrowdale SL, Schron E, et al. It is conducted in healthy volunteers once the tolerability and the pharmacokinetics of the drug have been established. Oral macrolide therapy could be considered to reduce exacerbation frequency in adults (50-70 years), with ongoing symptoms despite >80% adherence to high-dose inhaled steroids (>800 g/day) and at least one exacerbation requiring oral steroids in the past year. 8600 Rockville Pike Other factors may play an important role, e.g. Sex differences in the evolution of the electrocardiographic QT interval with age. Figure 1. It conducts a rapid delayed rectifier potassium current (Ikr), a critical current in the phase 3 repolarization of the cardiac action potential [Roden and Viswanathan, 2005]. Drug-induced LQTS is unpredictable in any given individual. In 2001, the FDA Pink Sheet reported 10 cases of QTc-related cardiac events out of 10 million prescriptions of azithromycin (66). Peroperative circulatory arrest after intravenous injection of erythromycin lactobionate [in French], Schoenenberger RA, Haefeli WE, Weiss P, Ritz RF. In their study, the number of cardiovascular deaths within the first 5 days of receiving a prescription for azithromycin was small but greater than what was observed in subjects with no antibiotic use (17/1,102,050 prescriptions of azithromycin vs. 6/1,102,050 episodes of no antibiotics [RR, 2.85; 95% CI, 1.137.24) but was the same as that seen within 5 days of receiving a prescription for penicillin V (RR, 0.93; 95% CI, 0.561.55). A QT study usually results in three clinical scenarios: the studied drug prolongs the mean QTc interval by 10 ms and therefore does not appear to cause TdP (or the increased risk is too small to be detected). Hicks LA, Taylor TH, Jr, Hunkler RJ. Curr Med Chem Cardiovasc Hematol Agents. Prokinetic drugs stimulate GI motility and smooth muscle relaxants suppress the motility. In their resting state, cardiac myocytes have a transmembrane electrical potential of approximately 90 mV. Drug-induced long QT syndrome is characterized by a prolonged corrected QT interval (QTc) and increased risk of a polymorphic ventricular tachycardia known as torsade de pointes (TdP). KVLQT1, HERG, SCN5A, KCNE1, and KCNE2, Stambler B., Wood M., Ellenbogen K., Perry K., Wakefield L., VanderLugt J. Long Q-T syndrome associated with oral erythromycin used in preoperative bowel preparation. (2004), Practice standards for electrocardiographic monitoring in hospital settings: an American Heart Association scientific statement from the Councils on Cardiovascular Nursing, Clinical Cardiology, and Cardiovascular Disease in the Young: endorsed by the International Society of Computerized Electrocardiology and the American Association of Critical-Care Nurses, Eisenhauer M., Eliasson A., Taylor A., Coyne P., Wortham D. (1994), Incidence of cardiac arrhythmias during intravenous pentamidine therapy in HIV-infected patients, El-Sherif N., Caref E, Chinushi M., Restivo M. (1999), Mechanism of arrhythmogenicity of the short-long cardiac sequence that precedes ventricular tachyarrhythmias in the long QT syndrome, International Conference on Harmonisation; guidance on E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs; availability. Ponsonnaille J, Citron B, Richard A, Trolese JF, Chaperon A, Barret B, Gras H. Electrophysiological study of pro-arrhythmogenic effects of erythromycin [in French]. Sci Adv. 2007] that can readily be used in the clinical setting. Slower administration produces lower levels (31), whereas oral administration results in a peak concentration of 2 to 4 mg/L (32). The .gov means its official. John Connett, Richard Casaburi, Jeffrey Curtis, Mark Dransfield, MeiLai Han, Barry Make, and Steve Sharf for making helpful suggestions on a previous draft of this work. Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH, Shimizu W, Schwartz PJ, Stanton M, et al. LQT3 accounts for 810% of cases [Schwartz et al. The role of the positive control is to demonstrate the studys ability (i.e. For example, in patients with a normal baseline QT, amiodarone prolongs the QT interval but very rarely causes TdP [Lazzara, 1989]. Reduced effectiveness and dangers of reverse use dependence, Huang B., Wu C., Hsia C., Yin Chen C. (2007), Jackman W., Friday K., Anderson J., Aliot E., Clark M., Lazzara R. (1988), The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis, Early after depolarizations: mechanism of induction and block. Dopamine receptor antagonists (like metoclopramide, domperidone), serotonin receptor agonists (like cisapride, mosapride, itopride and prucalopride), macrolide antibiotics (like erythromycin) and sincalide are classified as prokinetic agents. Citalopram and escitalopram are also associated with QT prolongation. In the presence of an exaggerated heterogeneity of action potential duration across the myocardium, the ectopic beat can induce reentrant excitation and TdP [Nguyen et al. Permanent pacemakers should be inserted in patients who have chronic bradycardia such as sick sinus syndrome or AV block. Possibility of more serious arrhythmias Holter or 24/48 H ambulatory monitoring records available implications for approval! Accessibility ( Reproduced with permission from Chan et al pharmacokinetic characteristics that may trigger TdP [,. Function ( 2 ):87-105. doi: 10.7759/cureus.31819 serious arrhythmias volunteers once the tolerability and the QT on... Rezkalla MA, Pochop C. erythromycin induced torsades de pointes associated with oral and. Author disclosures are available with the text of this potentially fatal phenomenon a component... Interval with age Adverse effects & # x27 ; below. the incidence of arrhythmias could not be.... 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