Abstract
Cardiac toxicity has been relatively uncommon within the antimicrobial class of drugs, but well described for antiarrhythmic agents and certain antihistamines. Macrolides, pentamidine and certain antimalarials were traditionally known to cause QT-interval prolongation, and now azole antifungals, fluoroquinolones and ketolides can be added to the list. Over time, advances in preclinical testing methods for QT-interval prolongation and a better understanding of its sequelae, most notably torsades de pointes (TdP), have occurred. This, combined with the fact that five drugs have been removed from the market over the last several years, in part because of QT-interval prolongation-related toxicity, has elevated the urgency surrounding early detection and characterisation methods for evaluating non-antiarrhythmic drug classes. With technological advances and accumulating literature regarding QT prolongation, it is currently difficult or overwhelming for the practising clinician to interpret these data for purposes of formulary review or for individual patient treatment decisions.
Certain patients are susceptible to the effects of QT-prolonging drugs. For example, co-variates such as gender, age, electrolyte derangements, structural heart disease, end organ impairment and, perhaps most important, genetic predisposition, underlie most if not all cases of TdP. Between and within classes of drugs there are important differences that contribute to delayed repolarisation (e.g. intrinsic potency to inhibit certain cardiac ion currents or channels, and pharmacokinetics). To this end, a risk stratification scheme may be useful to rank and compare the potential for cardiotoxicity of each drug. It appears that in most published cases of antimicrobial-associated TdP, multiple risk factors are present. Macrolides in general are associated with a greater potential than other antimicrobials for causing TdP from both a pharmacodynamic and pharmacokinetic perspective. The azole antifungal agents also can be viewed as drugs that must be weighed carefully before use since they also have both pharmacodynamic and pharmacokinetic characteristics that may trigger TdP. The fluoroquinolones appear less likely to be associated with TdP from a pharmacokinetic perspective since they do not rely on cytochrome P450 (CYP) metabolism nor do they inhibit CYP enzyme isoforms, with the exception of grepafloxacin and ciprofloxacin.
Nonetheless, patient selection must be carefully made for all of these drugs. For clinicians, certain responsibilities are assumed when prescribing antimicrobial therapy: (i) appropriate use to minimise resistance; and (ii) appropriate patient and drug selection to minimise adverse event potential. Incorporating information learned regarding QT interval-related adverse effects into the drug selection process may serve to minimise collateral iatrogenic toxicity.
Similar content being viewed by others
Notes
The use of trade names is for product identification purposes only and does not imply endorsement.
References
Yoshikawa TT. Epidemiology and unique aspects of aging and infectious diseases. Clin Infect Dis 2000; 30: 931–3
Elming H, Brendorp B, Kober L, et al. QTc interval in the assessment of cardiac risk. Card Electrophysiol Rev 2002; 6(3): 289–94
Roden DM, Lazzara R, Rosen M, et al. Multiple mechanisms in the long-QT syndrome: current knowledge, gaps, and future directions: the SADS Foundation Task Force on LQTS. Circulation 1996 Oct 15; 94(8): 1996–2012
De Ponti F, Poluzzi E, Montanaro N. QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience. Eur J Clin Pharmacol 2000 Apr; 56: 1–18
Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications: report on a policy conference of the European Society of Cardiology. Eur Heart J 2000 Aug; 21(15): 1216–31
Committee on Quality of Health Care in America: Institute of Medicine. To err is human: building a safer health system. Washington, DC: National Academy Press, 2000
Classen DC, Pestotnik SL, Evans RS, et al. Adverse drug events in hospitalized patients: excess length of stay, extra costs, and attributable mortality. JAMA 1997 Jan 22–29; 277(4): 301–6
Schappert SM. Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, 1997: National Center for Health Statistics. Vital Health Stat 13 1999 Nov; (143): i-iv, 1–39
National Association of Chain Drug Stores. 2000 community pharmacy results. Alexandria (VA): National Association of Chain Drug Stores, 2001
Jacubeit T, Drisch D, Weber E. Risk factors as reflected by an intensive drug monitoring system. Agents Actions 1990; 29: 117–25
Witchel HJ, Hancox JC, Nutt DK. Psychotropic drugs, cardiac arrhythmia, and sudden death. J Clin Psychopharmacol 2003 Feb; 23(1): 58–77
Owens Jr RC. Risk assessment for antimicrobial agent-induced QTc interval prolongation and Torsades de Pointes. Pharmacotherapy 2001 Mar; 21(3): 301–19
Curtis LH, Ostbye T, Sendersky V, et al. Prescription of QT-prolonging drugs in a cohort of about 5 million outpatients. Am J Med 2003 Feb 1; 114: 135–41
Bertino JS, Owens Jr RC, Carnes TD, et al. Gatifloxacin-associated corrected QT interval prolongation, torsades de pointes, and ventricular fibrillation in patients with known risk factors. Clin Infect Dis 2002 Mar 15; 34: 861–3
Viskin S. Long QT syndromes and torsade de pointes. Lancet 1999 Nov 6; 354: 1625–33
European Agency for the Evaluation of Medicinal Products (EMEA): ommittee for Proprietary Medicinal Products (CPMP). Points to consider: the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products [online]. Available from URL: http://www.emea.eu.int/pdfs/human/swp/098696en.pdf [Accessed 2003 Mar 10]
McCaig LF, Besser RE, Hughes JM. Antimicrobial drug prescriptions in ambulatory care settings, United States, 1992–2000. Emerg Infect Dis 2003 Apr; 9(4): 432–7
Netter FH. Netter collection of medical illustrations. Vol. 5. Teterboro (NJ): Icon Learning Systems, 1979: 49 (plate #2) [online]. Available from URL: http://65.201.6.68/netterart/ [Accessed 2004 Mar 11]
Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. The ‘Sicilian gambit’: a new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Circulation 1991 Oct; 84(4): 1831–51
Swynghedauw B, Baillard C, Milleiz P. The long QT interval is not only inherited but is also linked to cardiac hypertrophy. J Mol Med 2003 Jun; 81(6): 336–45
Woosley RL, Sale M. QT interval: a measure of drug action. Am J Cardiol 1993 Aug 26; 72(6): 36b–43b
Atiga WL, Calkins H, Lawrence JH, et al. Beat-to-beat repolarization lability identifies patients at risk for sudden cardiac death. J Cardiovasc Electrophysiol 1998 Sep; 9(9): 899–908
Molnar J, Zhang F, Weiss J, et al. Diurnal pattern of QTc interval: how long is prolonged?: possible relation to circadian triggers of cardiovascular events. J Am Coll Cardiol 1996 Jan; 27(1): 76–83
Batchvarov V, Malik M. Measurement and interpretation of QT dispersion. Prog Cardiovasc Dis 2000; 42: 325–44
Gillis AM. Effects of antiarrhythmic drugs on QT interval dispersion: relationship to antiarrhythmic action and proarrhythmia. Prog Cardiovasc Dis 2000 Mar–Apr; 42(5): 385–96
Hohnloser SH. Effect of coronary ischemia on QT dispersion. Prog Cardiovasc Dis 2000 Mar–Apr; 42(5): 351–8
Dessertenne F. Ventricular tachycardia with two variable opposing foci [in French]. Arch Mal Coeur Vaiss 1966 Feb; 59(2): 263–72
Kang J, Wang L, Chen X-L, et al. Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG. Mol Pharmacol 2001; 59: 122–6
Garson Jr A. How to measure the QT interval: what is normal? Am J Cardiol 1993 Aug 26; 72: 14B–6B
Fridericia LS. Die systolendauer im elekrokardiogramm bei normalen menschen und bei herzkranken. Acta Med Scand 1920; 53: 469–86
Hnatkova K, Malik M. ‘Optimum’ formulae for heart rate correction of the QT interval. Pacing Clin Electrophysiol 1999; 22: 1683–7
Al-Khatib SM, Allen LaPointe NM, Kramer JM, et al. What clinicians should know about the QT interval. JAMA 2003; 289: 2120–7
Malik M, Camm AJ. Evaluation of drug-induced QT interval prolongation: implications for drug approval and labeling. Drug Saf 2001; 24(5): 323–51
De Ponti F, Paluzzi E, Cavalli A, et al. Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes. Drug Saf 2002; 25(4): 263–86
Anderson ME, Al-Khatib SM, Roden DM, et al. Cardiac repolarization: current knowledge, critical gaps, and new approaches to drug development and patient management. Am Heart J 2002; 144: 769–81
Moss AJ. Measurement of the QT interval and the risk associated with QTc interval prolongation: a review. Am J Cardiol 1993 Aug 26; 72: 23B-5B
Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol 2000 Jul; 36(1): 1–12
Kubota T, Shimizu W, Kamakura S, et al. Hypokalemia-induced long QT syndrome with an underlying novel missense mutation in S4-S5 linker of KCNQ1. J Cardiovasc Electrophysiol 2000 Sep; 11(9): 1048–54
Sesti F, Abbott GW, Wei J, et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sei U S A 2000 Sep 12; 97(19): 10613–8
Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003; 348: 1866–74
Vincent GM, Timothy K, Fox J, et al. The inherited long QT syndrome: from ion channel to bedside. Cardiol Rev 1999 Jan–Feb; 7(1): 44–55
Wehrens XTH, Vos MA, Doevendans PA, et al. Novel insights in the congenital long QT syndrome. Ann Intern Med 2002; 137: 981–92
Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350: 1013–22
Moss AJ. The QT interval and torsade de pointes. Drug Saf 1999; 21 Suppl. 1: 69–80
Haverkamp W, Monnig G, Schulze-Bahr E, et al. Physician-induced torsade de pointes: therapeutic implications. Cardiovasc Drugs Ther 2002; 16: 101–9
Setzer A, Wray HW. Quinidine syncope: paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation 1964; 30: 17–26
Roden DM, Woosley RL, Primm RK. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am Heart J 1986 Jun; 111(6): 1088–93
Kay GN, Plumb VJ, Arciniegas JG, et al. Torsade de pointes: the long-short initiating sequence and other clinical features: observations in 32 patients. J Am Coll Cardiol 1983 Nov; 2(5): 806–17
Bauman JL, Bauernfeind RA, Hoff JV, et al. Torsades de pointes due to quinidine: observations in 31 patients. Am Heart J 1984 Mar; 107(3): 425–30
Haverkamp W, Martinez RA, Hief C, et al. Efficacy and safety of d,l-sotalol in patients with ventricular tachycardia and in survivors of cardiac arrest. J Am Coll Cardiol 1997 Aug; 30(2): 487–95
Lehmann MH, Hardy S, Archibald D, et al. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 1996 Nov 15; 94(10): 2535–41
Hohnloser SH. Proarrhythmia with class III antiarrhythmic drugs: types, risks, and management. Am J Cardiol 1997 Oct 23; 80(8A): 82G–9G
Frothingham R. Rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. Pharmacotherapy 2001 Dec; 21(12): 1468–72
Owens RCJ, Ambrose PG. Torsades de pointes associated with fluoroquinolones. Pharmacotherapy 2002 May; 22(5): 663–72
De Ponti F, Poluzzi E, Montanaro N. Organising evidence on QT prolongation and occurrence of Torsades de Pointes with non-antiarrhythmic drugs: a call for consensus. Eur J Clin Pharmacol 2001 Feb 14; 57: 185–209
Shaffer D, Singer S, Korvick J. Macrolide and fluoroquinolone associated torsade de pointes: review of the FDA adverse event reporting system [abstract no. A-635]. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2001 Sep 17–20; Toronto, Ontario, Canada. Washington, DC: American Society for Microbiology, 2001: 20
ICH S7B Safety Pharmacology studies for assessing the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. Washington, DC: US Food and Drug Administration, 2002
Ambrose PG, Owens Jr RC. New antibiotics in pulmonary and critical care medicine: focus on advanced generation quinolones and cephalosporins. Semin Respir Crit Care Med 2000; 21(1): 19–32
Volberg WA, Koci BJ, Su W, et al. Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics. J Pharmacol Exp Ther 2002 Jul; 302(1): 320–7
Berlex Laboratories PD. Betapace® (sotalol) tablets: prescribing information. Wayne (NJ): Berlex Laboratories PD, 1998
Kyrmizakis DE, Chimona TS, Kanoupakis EM, et al. QT prolongation and torsades de pointes associated with concurrent use of cisapride and erythromycin. Am J Otolaryngol 2002 Sep–Oct; 23(5): 303–7
Katapadi K, Kostandy G, Katapadi M, et al. A review of erythromycin-induced malignant tachyarrhythmia-torsade de pointes: a case report. Angiology 1997 Sep; 48(9): 821–6
Tschida SJ, Guay DR, Straka RJ, et al. QTc-interval prolongation associated with slow intravenous erythromycin lactobionate infusions in critically ill patients: a prospective evaluation and review of the literature. Pharmacotherapy 1996 Apr; 16(4): 663–74
Rubart M, Pressler ML, Pride HP, et al. Electrophysiological mechanisms in a canine model of erythromycin-associated long QT syndrome. Circulation 1993 Oct; 88 (4 Pt1): 1832–44
Ambrose PG, Owens Jr RC, Grasela D. Antimicrobial pharmacodynamics. Med Clin North Am 2000 Nov; 84(6): 1431–45
Lacy MK, Owens Jr RC, Xu X, et al. Comparison of bactericidal activity after multidose administration of clarithromycin, azithromycin and cefuroxime axetil against streptococcus pneumoniae. Int J Antimicrob Agents 1998 Nov; 10(4): 279–83
Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharma-codynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000 Jan; 38(1): 41–57
Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences. JAMA 1993 Mar 24–31; 269(12): 1513–8
Kivisto KT, Lilja JJ, Backman JT, et al. Repeated consumption of grapefruit juice considerably increases plasma concentrations of cisapride. Clin Pharmacol Ther 1999 Nov; 66(5): 448–53
Desta Z, Zhao X, Shin J-G, et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41(12): 913–58
Center for Drug Evaluation and Research. Preventable adverse drug reactions: a focus on drug interactions [online]. Available from URL: http://www.fda.gov/cder/drug/drugReactions/ default.htm [Accessed 2003 Mar 10]
Goldberg J, Owens Jr RC. Optimizing antimicrobial dosing in the critically ill patient. Curr Opin Crit Care 2002 Oct; 8(5): 435–40
Abbott GW, Sesti F, Splawski I, et al. MiRPl forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999 Apr 16; 97(2): 175–87
Roden DM. Taking the ‘idio’ out of ‘idiosyncratic’: predicting torsades de pointes. Pacing Clin Electrophysiol 1998 May; 21(5): 1029–34
Suchard J. Review: wherefore withdrawal? The science behind recent drug withdrawals and warnings [letter]. Int J Med Toxicol 2001; 4(2): 15
Shaffer D, Singer S, Korvick J, et al. Concomitant risk factors in reports of torsades de pointes associated with macrolide use: review of the United States Food and Drug Administration adverse event reporting system. Clin Infect Dis 2002 Jul 15; 35: 197–200
Leone R, Venegoni M, Motola D, et al. Adverse drug reactions related to the use of fluoroquinolone antimicrobials. Drug Saf 2003; 26(2): 109–20
Morgan Jr TK, Sullivan ME. An overview of class III electrophysiological agents: a new generation of antiarrhythmic therapy. Prog Med Chem 1992; 29: 65–108
Mitcheson JS, Chen J, Lin M, et al. A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci U S A 2000 Oct 24; 97(22): 12329–33
Domagala JM. Structure-activity and structure-side-effect relationships for the quinolone antibacterials. J Antimicrob Chemother 1994 Apr; 33(4): 685–706
Owens Jr RC, Russo R, Wilder M, et al. Review of structuretoxicity relationships of fluoroquinolones [abstract]. Clin Infect Dis 1999 Oct; 29(4): 978
Owens Jr RC. Quinolone structure-activity relationships. Antibiotic Clin 1999; 3 Suppl. 1: 5–12
Iannini PB. Cardiotoxicity of macrolides, ketolides and fluoroquinolones that prolong the QTc interval. Expert Opin Drug Saf 2002; 1(2): 121–8
Arizona Center for Education and Research on Therapeutics [online]. Available from URL: http://www.torsades.org [Accessed 2004 Jan 13]
Arellano-Rodrigo E, Garcia A, Mont L, et al. Torsade de pointes and cardiorespiratory arrest induced by azithromycin in a patient with congenital long QT syndrome. Med Clin (Barc) 2001 Jun; 23: 117 (3): 118–9
Samarendra P, Kumari S. QT prolongation associated with azithromycin/amiodarone combination. Pacing Clin Electrophysiol 2001 Oct; 24: 1572–4
Lee KL, Jim MH, Tang SC, et al. QT prolongation and Torsades de Pointes associated with clarithromycin. Am J Med 1998 Apr; 104(4): 395–6
Piquette RK. Torsade de pointes induced by cisapride/clarithromycin interaction. Ann Pharmacother 1999 Jan; 33(1): 22–6
Sekkarie MA. Torsades de pointes in two chronic renal failure patients treated with cisapride and clarithromycin. Am J Kidney Dis 1997 Sep; 30(3): 437–9
Desta Z, Kerbusch T, Flockhart DA. Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). Clin Pharmacol Ther 1999 Jan; 65(1): 10–20
Kundu S, Williams SR, Nordt SP, et al. Clarithromycin-induced ventricular tachycardia. Ann Emerg Med 1997 Oct; 30(4): 542–4
Paar D, Terjung B, Sauerbruch T. Life-threatening interaction between clarithromycin and disopyramide. Lancet 1997 Feb 1; 349(9048): 326–7
Flockhart DA, Drici MD, Kerbusch T, et al. Studies on the mechanism of a fatal clarithromycin-pimozide interaction in a patient with Tourette syndrome. J Clin Psychopharmacol 2000 Jun; 20(3): 317–24
Hayashi Y, Ikeda U, Hashimoto, et al. Torsades de pointes ventricular tachycardia induced by clarithromycin and disopyramide in the presence of hypokalemia. Pacing Clin Electrophysiol 1999 Apr; 22 (4 Pt 1): 672–4
Vallejo CN, Rodriguez PD, Sanchez HA, et al. Ventricular tachycardia and long QT associated with clarithromycin administration in a patient with HIV infection. Rev Esp Cardiol 2002 Aug; 55(8): 878–81
Choudbury L, Grais IM, Passman RS. Torsades de pointes due to drug interaction between disopyramide and clarithromycin. Heart Dis 1999; 1: 206–7
Kamochi H, Nii T, Eguchi K, et al. Clarithromycin associated with torsade de pointes. Jpn Circ J 1999 May; 63(5): 421–2
Oberg KC, Bauman JL. QT interval prolongation and torsades de pointes due to erythromycin lactobionate. Pharmacotherapy 1995 Nov–Dec; 15(6): 687–92
Woywodt A, Grommas U, Buth W, et al. QT prolongation due to roxithromycin. Postgrad Med J 2000 Oct; 76(900): 651–4
Promphan W, Khongphatthanayothin A, Horchaiprasit K, et al. Roxithromycin induced torsade de pointes in a patient with complex congenital heart disease and complete atrioventricular block. Pacing Clin Electrophysiol 2002; 26(6): 1424–6
Verdun F, Mansourati J, Jobic Y, et al. Torsades de pointe with spiramycin and metiquazine therapy: apropos of a case. Arch Mal Coeur Vaiss 1997 Jan; 90(1): 103–6
Cooper C. Post-marketing safety data. Ketek (telithromycin) for the FDA Anti-infective Drug Products Advisory Committee Meeting, 2003 Jan 8 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/03/slides/3919sl.htm [Accessed 2003 Apr 3]
Ross D. Avenus Pharma. Ketek (telithromycin) briefing document for the FDA Anti-infective Drug Products Advisory Committee Meeting, 2001 Apr 26 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3746b_01_aventis.pdf [Accessed 2003 Jan 10]
FournierP, Pacouret G, Charbonnier B. A new cause of torsades de pointes: combination of terfenadine and troleandomycin. Ann Cardiol Angeiol (Paris) 1993 May; 42(5): 249–52
Singh H, Kishore K, Gupta MS, et al. Ciprofloxacin-induced QTc prolongation. J Assoc Physicians India 2002 Mar; 50: 430–1
Iannini PB, Circiumanu I. Gatifloxacin-induced QTc prolongation and ventricular tachycardia. Pharmacotherapy 2001 Mar; 21(3): 361–2
Cox E. Factive® (gemifloxacin) briefing NDA 21-158. FDA Anti-infective Drug Products Advisory Committee Meeting, 2003 Mar 5 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/03/slides/3931sl.htm [Accessed 2003 Mar 10]
Paltoo B, O’Donoghue S, Mousavi MS. Levofloxacin induced polymorphic ventricular tachycardia with normal QT interval. Pacing Clin Electrophysiol 2001 May; 21(5): 895–7
Samaha FF.QTc interval prolongation and polymorphic ventricular tachycardia in association with levofloxacin [letter]. Am J Med 1999 Nov; 107(5): 528–9
Fedutes BA, Chan-Tompkins NH, Pannala NR, et al. Assessment of levofloxacin’s effects on the QTc interval [abstract no. 611]. In: Program and abstracts of the 40th Annual Meeting of the Infectious Diseases Society of America; 2002 Oct 24–27; Chicago (IL). Alexandria (VA): Infectious Diseases Society of America, 2002: 152
Iannini_PB, Kramer H, Circiumaru I, et al. QTc prolongation associated with levofloxacin [abstract no. 822]. In: Program and abstracts of the 40th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto, Ontario, Canada. Washington, DC: American Society for Microbiology, 2000: 477
Iannini PB, Doddamani S, Byazrova E, et al. Prolongation of QT interval is probably a class effect of fluoroquinolones. BMJ 2001 Jan 6; 322(7277): 46–7
Gandhi PJ, Menezes PA, Vu HT, et al. Fluconazole- and levofloxacin-induced torsades de points in an intensive care unit patient. Am J Health Syst Pharm 2003; 60: 2479–83
Amankwa K, Krishnan SC, Tisdale JE. Torsades de pointes associated with fluoroquinolones: importance of concomitant risk factors. Clin Pharmacol Ther 2004; 75: 242–7
Ball P. Quinolone-induced QT interval prolongation: a not-sounexpected class effect. J Antimicrob Chemother 2000 May; 45(5): 557–9
Jaillon P, Morganroth J, Brumpt I, et al. Overview of electrocardiographic and cardiovascular safety data for sparfloxacin. J Antimicrob Chemother 1996 May; 37 Suppl. A: 161–7
Wassmann S, Nickenig G, Bohm M. Long QT syndrome and torsade de pointes in a patient receiving fluconazole [letter]. Ann Intern Med 1999 Nov 16; 131(6): 797
Tholakanahalli VN, Potti A, Hanley J, et al. Fluconazole-induced torsade de pointes. Ann Pharmacother 2001 Apr; 35(4): 432–4
Khazan M, Mathis AS. Probable case of torsades de pointes induced by fluconazole. Pharmacotherapy 2002 Dec; 22(12): 1632–7
Dorsey ST, Biblo LA. Prolonged QT interval and torsades de pointes caused by the combination of fluconazole and amitriptyline. Am J Emerg Med 2000 Mar; 18(2): 227–9
Pohjola-Sintonen S, Viitasalo M, Toivonen L, et al. Itraconazole prevents terfenadine metabolism and increases risk of torsades de pointes ventricular tachycardia. Eur J Clin Pharmacol 1993; 45(2): 191–3
Cruccu V, Pedretti D, Confalonieri F. A case of pulmonary aspergillosis effectively treated with itraconazole: possible interaction of the antimycotic agent with hydroquinidine. Clin Ther 1995 May; 146(5): 383–9
Romkes JH, Froger CL, Wever EF, et al. Syncopes during simultaneous use of terfenadine and itraconazole. Ned Tijdschr Geneeskd 1997 May; 141(19): 950–3
Hoover CA, Carmichael JK, Nolan Jr PE, et al. Cardiac arrest associated with combination cisapride and itraconazole therapy. J Cardiovasc Pharmacol Ther 1996 Jul; 1(3): 255–8
Zimmermann M, Duruz H, Guinand O, et al. Torsades de Pointes after treatment with terfenadine and ketoconazole. Eur Heart J 1992 Jul; 13(7): 1002–3
Tsai WC, Tsai LM, Chen JH. Combined use of astemizole and ketoconazole resulting in torsade de pointes. J Formos Med Assoc 1997 Feb; 96(2): 144–6
Monahan BP, Ferguson CL, Killeavy ES, et al. Torsades de pointes occurring in association with terfenadine use. JAMA 1990 Dec 5; 264(21): 2788–90
Dumaine R, Roy M-L, Brown AM. Blockade of HERG and Kv1.5 by ketoconazole. J Pharmacol Exp Ther 1998 Aug; 286(2): 727–35
Baildon R, Patterson T, Boucher HW, et al. (2001) NDA 21–266, Vfend (voriconazole) Tablets, and NDA 21–267, Vfend I.V. (voriconazole) for infusion, Pfizer Global Research and Development. Proposed for the treatment of invasive aspergillosis, serious Candida infections, infections caused by Scedosporium spp. and Fusarium spp., rare and refractory infections and empirical treatment of febrile neutropenia. US FDA [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/01/slides/3792s2.htm [Accessed 2003 Mar 10]
Weiner I, Rubin DA, Martinez E, et al. QT prolongation and paroxysmal ventricular tachycardia occurring during fever following trimethoprim-sulfamethoxazole administration. Mt Sinai J Med 1981 Jan–Feb; 48(1): 53–55
Lopez JA, Harold JG, Rosenthal MC, et al. QT prolongation and torsade de pointes after administration of trimethoprim-sulfamethoxazole. Am J Cardiol 1987 Feb 1; 59(4): 376–7
Topol EJ, Lerman BB. Hypomagnesemic torsades de pointes. Am J Cardiol 1983 Dec 1; 52(10): 1367–8
Wharton JM, Demopulos PA, Goldschlager N. Torsade de pointes during administration of pentamidine isethionate. Am J Med 1987 Sep; 83(3): 571–6
Bibler MR, Chou TC, Toltzis RJ, et al. Recurrent ventricular tachycardia due to pentamidine-induced cardiotoxicity. Chest 1988 Dec; 94(6): 1303–6
Pujol M, Carratala J, Mauri J, et al. Ventricular tachycardia due to pentamidine isethionate [letter]. Am J Med 1988 May; 84(5): 980
Mitchell P, Dodek P, Lawson L, et al. Torsades de pointes during intravenous pentamidine isethionate therapy. CMAJ 1989 Jan 15; 140(2): 173–4
Lindsay Jr J, Smith MA, Light JA. Torsades de pointes associated with antimicrobial therapy for pneumonia. Chest 1990 Jul; 8(1): 222–3
Stein KM, Haronian H, Mensah GA, et al. Ventricular tachycardia and torsades de pointes complicating pentamidine therapy of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Am J Cardiol 1990 Oct 1; 66(10): 888–9
Gonzalez A, Sager PT, Akil B, et al. Pentamidine-induced torsade de pointes. Am Heart J 1991 Nov; 122(5): 1489–92
Taylor AJ, Hull RW, Coyne PE, et al. Pentamidine-induced torsades de pointes: safe completion of therapy with inhaled pentamidine. Clin Pharmacol Ther 1991 Jun; 49(6): 698–700
Mani S, Kocheril AG, Andriole VT. Case report: pentamidine and polymorphic ventricular tachycardia revisited. Am J Med Sci 1993 Apr; 305(4): 236–40
Eisenhauer MD, Eliasson AH, Taylor AJ, et al. Incidence of cardiac arrhythmias during intravenous pentamidine therapy in HIV-infected patients. Chest 1994 Feb; 105(2): 389–95
Purkins L, Wood N, Ghahramani P, et al. Pharmacokinetics and safety of voriconazole following intravenous to oral-dose escalation regimens. Antimicrob Agents Chemother 2002 Aug; 46(8): 2546–53
Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes. Ann Pharmacother 1995 Jun; 29(6): 619–24
Thompson D, Oster G. Use of terfenadine and contraindicated drugs. JAMA 1996 May; 275(17): 1339–41
Napolitano C, Priori SG, Schwartz PJ. Torsade de pointes: mechanisms and management. Drugs 1994 Jan; 47(1): 51–65
Zhanel GG, Dueck M, Hogan DJ, et al. Review of macrolides and ketolides: focus on respiratory tract infections. Drugs 2001; 61(4): 443–98
van Haarst AD, van’t Klooster GA, van Gerven JM, et al. The influence of cisapride and clarithromycin on QT intervals in healthy volunteers. Clin Pharmacol Ther 1998 Nov; 64(5): 542–6
Zehender M, Hohnloser S, Just H. QT interval prolonging drugs: mechanisms and clinical relevance of the arrhythmogenic hazards. Cardiovasc Drugs Ther 1991 Apr; 5(2): 515–30
Harris S, Hilligoss DM, Colangelo PM, et al. Azithromycin and terfenadine: lack of drug interaction. Clin Pharmacol Ther 1995 Sep; 58(3): 310–5
Alvarez-Elcoro S, Enzler MJ. The macrolides: erythromycin, clarithromycin, and azithromycin. Mayo Clin Proc 1999 Jun; 74(6): 613–34
Austin KL, Mather LE, Philpot CR, et al. Intersubject and dose-related variability after intravenous administration of erythro-mycin. Br J Clin Pharmacol 1980 Sep; 10(3): 273–9
Nattel S, Ranger S, Talajic M, et al. Erythromycin-induced long QT syndrome: concordance with quinidine and underlying cellular electrophysiologic mechanism. Am J Med 1990 Aug; 89(2): 235–8
Ohtani H, Taninaka C, Hanada E, et al. Comparative pharmaco-dynamic analysis of QT interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin. Chemotherapy 2000; 44: 2630–7
Milberg P, Eckardt L, Hans-Jurgen B, et al. Divergent proar-rhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsades de pointes. J Pharmacol Exp Ther 2002; 303(1): 218–25
Brinker A. Reporting rates for serious cardiac dysrhythmias among fluoroquinolones, azithromycin, clarithromycin, and cefuroxime: Anti-Infective Drugs Advisory Committee, US Food and Drug Administration [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/99/slides/3558sle [Accessed 2003 Apr 10]
Shaffer D, Singer S. Macrolide antibiotics and torsades de pointes postmarketing analysis, 2001 Apr 26. Anti-Infective Drugs Advisory Committee, US Food and Drug Administration [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/01/slides/3746s_02_shaffer_rev.ppt [Accessed 2003 Jan 10]
Smalley W, Shatin D, Wysowski DK, et al. Contraindicated drug use of cisapride: impact of food and drug administration regulatory action. JAMA 2000 Dec 20; 284(23): 3036–9
Iannini P, Stager W, Sharma K, et al. A 24,000 patient trial comparing telithromycin and amoxicillin-clavulanate in the treatment of community acquired respiratory tract infections in a usual care setting [abstract no. LB-240]. In: Abstracts Addendum of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2002 Sep 22–25; San Diego (CA). Washington, DC: American Society for Microbiology, 2002
Demolis J-L, Vacheron F, Cardus S, et al. Effect of single and repeated oral doses of telithromycin on cardiac QT interval in healthy subjects. Clin Pharmacol Ther 2003 Mar; 73(3): 242–52
von Keutz E, Schluter G. Preclinical safety evaluation of moxifloxacin, a novel fluoroquinolone. J Antimicrob Chemother 1999 May; 43 Suppl. B: 91–100
Fogarty C, Grossman C, Williams J, et al. Efficacy and safety of moxifloxacin vs clarithromycin for community-acquired pneumonia. Infect Med 1999; 16: 748–63
Ball P, Mandell L, Niki Y, et al. Comparative tolerability of the newer fluoroquinolone antibacterials. Drug Saf 1999 Nov; 21(5): 407–21
Stahlmann R. Safety profile of the quinolones. J Antimicrob Chemother 1990 Nov; 26 Suppl. D: 31–44
Owens Jr RC, Ambrose PG. Clinical use of the fluoroquinolones. Med Clin North Am 2000 Nov; 84(6): 1447–69
Conder ML, Lawrence JH, Levesque PC, et al. Inhibition of the HERG potassium ion channel by fluoroquinolone antibiotics: correlation with the risk for clinically significant QT interval prolongation [abstract no. 810]. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto, Ontario, Canada. Washington, DC: American Society for Microbiology, 2000: 474
Bischoff U, Schmidt C, Netzer R, et al. Effects of fluoroquinolones on HERG currents. Eur J Pharmacol 2000; 406: 341–3
Stahlmann R, Schwabe R. Safety profile of grepafloxacin compared with other fluoroquinolones. J Antimicrob Chemother 1997; 40 Suppl. A: 83–92
Stahlmann R, Lode H. Toxicity of quinolones. Drugs 1999; 58 Suppl. 2: 37–42
Adamantidis MM, Dumotier BM, Caron JF, et al. Sparfloxacin but not levofloxacin or ofloxacin prolongs cardiac repolarization in rabbit Purkinje fibers. Fundam Clin Pharmacol 1998; 12(1): 70–6
Anderson ME, Mazur A, Yang T, et al. Potassium current antagonist properties and proarrhythmic consequences of quinolone antibiotics. J Pharmacol Exp Ther 2001; 296(3): 806–10
Morganroth J, Talbot GH, Dorr MB, et al. Effect of single ascending, supratherapeutic doses of sparfloxacin on cardiac repolarization (QTc interval). Clin Ther 1999 May; 21(5): 818–28
Dupont H, Timsit JF, Souweine B, et al. Torsades de pointe probably related to sparfloxacin. Eur J Clin Microbiol Infect Dis 1996 Apr; 15(4): 350–1
Thomas SH. Drugs, QT interval abnormalities and ventricular arrhythmias. Adverse Drug React Toxicol Rev 1994; 13(2): 77–102
Von Seggern K, Russo R, Wikler M. A novel approach to postmarketing surveillance: the tequin clinical experience study [abstract no. 2216]. In: Program and abstracts of the 40th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto, Ontario, Canada. Washington, DC: American Society for Microbiology, 2000: 468
Iannini PB, von Seggern K, Wikler MA. Safety of gatifloxacin in patients with cardiovascular disease [abstract no. 2218]. In: Program and abstracts of the 40th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20 Toronto, Ontario, Canada. Washington, DC: American Society for Microbiology, 2000: 469
Brinker A, Staffa J. Concurrent use of selected agents with moxifloxacin: an examination of labelling compliance within 1 year of marketing. Arch Intern Med 2002 Sep 23; 162: 2011–2
Bird N, Lewis A, Montague T, Bygate E, Dixon R. Assessment of the effect of gemifloxacin on QTc interval in healthy volunteers [abstract no. 821]. In: Program and abstracts of the 40th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto, Ontario, Canada. Washington, DC: American Society for Microbiology, 2000: 477
Grasela D, Gajjar A, Bello A, et al. Safety and tolerability and pharmacokinetics of BMS-284756 a novel des-F (6) quinolone following a 14 day oral dose in healthy adult subjects [abstract no. 2260]. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto, Ontario, Canada. Washington, DC: American Society for Microbiology, 2000: 36
Gajjar D, Geraldes M, Russo R, et al. Lack of an effect of intravenous BMS-284756 on the QTc interval in healthy subjects [abstract no. A-633]. In: Program and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2001 Sep 22–25; Chicago (IL). Washington, DC: American Society for Microbiology, 2001: 19
Kahn JB. Quinolone-induced QT interval prolongation: a notso-unexpected class effect. J Antimicrob Chemother 2000 Nov; 46(5): 847–8
Iannini PB. Quinolone-induced QT interval prolongation: a not-so-unexpected class effect. J Antimicrob Chemother 2001 Jun; 47(6): 893–4
White CM, Grant EM, Quintiliani R. Moxifloxacin does increase the corrected QT interval. Clin Infect Dis 2001 Oct 15; 33(8): 1441–2
Paserchia LA, Hewett J, Woosley RL. Effects of ketoconazole on QTc [abstract]. Clin Pharmacol Ther 1994; 55: 146
Albengres E, Le Louet H, Tillement JP. Systemic antifungal agents. Drug interactions of clinical significance. Drug Saf 1998 Feb; 18(2): 83–97
Ghannoum MA, Kuhn DM. Voriconazole-better chances for patients with invasive mycoses. Eur J Med Res 2002 May 31; 7(5): 242–56
Ortho Biotech Inc. Sporanox® (itraconazole) oral solution, Sporanox® (itraconazole) capsules: prescribing information. Raritan (NJ): Ortho Biotech Inc., 2000
Owens RCJ. Fluconazole. Antibiot Clin 1997 Nov–Dec; 1(6): 109–112
Pfizer Pharmaceutical Company. Diflucan® (fluconazole) tablets; Diflucan® (fluconazole) injection: prescribing information. New York: Pfizer Pharmaceutical Company, 1998
Gabel A, Schymik G, Mehmel HC. Ventricular fibrillation due to long QT syndrome probably caused by clindamycin. Am J Cardiol 1999 Mar 1; 83(5): 813–5
Indiana University School of Medicine. Drug interactions [online]. Available from URL: http://www.drug-interactions.com [Accessed 2004 Jan 13]
Acknowledgements
No sources of funding were used to assist in the preparation of this manuscript. The author has no conflicts of interest that are directly relevant to the content of this review.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Owens, R.C. QT Prolongation with Antimicrobial Agents. Drugs 64, 1091–1124 (2004). https://doi.org/10.2165/00003495-200464100-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003495-200464100-00005