Azithromycin: more lethal than chloramphenicol?
Ivan Stratov A C , Justin Denholm B and Stephen J. Kent A
+ Author Affiliations
- Author Affiliations
A Department of Microbiology and Immunology, University of Melbourne, Melbourne, Vic. 3010, Australia.
B Victorian Infectious Diseases Service, Royal Melbourne Hospital, and Department of Medicine, University of Melbourne, Parkville, Vic. 3010, Australia.
C Corresponding author. Email: stratovi@unimelb.edu.au
Sexual Health 10(2) 179-182 https://doi.org/10.1071/SH12128
Submitted: 7 August 2012 Accepted: 18 November 2012 Published: 1 March 2013
Abstract
Azithromycin is commonly used in sexual health and respiratory medicine, often when the diagnosis is presumptive. A recent article by Ray et al. reported that 1 out of 20 000 courses of low-dose azithromycin was associated with (sudden) cardiovascular death (including 1 out of 4000 courses in high-risk cardiovascular patients), ascribing these deaths to azithromycin itself. Here, we critique the actual study and examine conflicting data from randomised control trials, animal studies and observational data.
Additional keywords: cardiovascular health, drugs, mortality rate, presumptive diagnosis.
References
[1] Bradshaw CS, Tabrizi SN, Read TR, Garland SM, Hopkins CA, Moss LM, et al Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure. J Infect Dis 2006; 193 336–45.| Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure.Crossref | GoogleScholarGoogle Scholar | 16388480PubMed |
[2] Cameron ST. Patient-delivered partner therapy for chlamydia: a realistic public health measure in the UK. BJOG 2009; 116 345–6.
| Patient-delivered partner therapy for chlamydia: a realistic public health measure in the UK.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD1M7hsVKktQ%3D%3D&md5=dfcf3c31a2ef5ad23180878c991fb1e4CAS | 19187365PubMed |
[3] Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012; 366 1881–90.
| Azithromycin and the risk of cardiovascular death.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xntlamu7c%3D&md5=1e913010b6b60b7399df56d132492ac2CAS | 22591294PubMed |
[4] Wallerstein RO, Condit PK, Kasper CK, Brown JW, Morrison FR. Statewide study of chloramphenicol therapy and fatal aplastic anemia. JAMA 1969; 208 2045–50.
| Statewide study of chloramphenicol therapy and fatal aplastic anemia.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaF1M7pt1yqtw%3D%3D&md5=47e15d088194575811e6e6740ab9876eCAS | 5818983PubMed |
[5] Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, et al Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case–control study. Lancet 2005; 365 475–81.
| 1:CAS:528:DC%2BD2MXhtlSgt70%3D&md5=a8bf3630ebe4542e2d5e135579c61ce1CAS | 15705456PubMed |
[6] Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, et al ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA 2011; 306 2673–83.
| ADHD medications and risk of serious cardiovascular events in young and middle-aged adults.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xislaktg%3D%3D&md5=5dacdfd9b82d61984593f42c1cdf188dCAS | 22161946PubMed |
[7] Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360 225–35.
| Atypical antipsychotic drugs and the risk of sudden cardiac death.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXnsFCjsg%3D%3D&md5=42723a5611b6f7909afa08a894976a61CAS | 19144938PubMed |
[8] Ray WA, Meredith S, Thapa PB, Hall K, Murray KT. Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharmacol Ther 2004; 75 234–41.
| Cyclic antidepressants and the risk of sudden cardiac death.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXhslenu74%3D&md5=75b6e7a2af83ade7478097b1b06cdbc7CAS | 15001975PubMed |
[9] Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT. Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry 2001; 58 1161–7.
| Antipsychotics and the risk of sudden cardiac death.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XisV2jtw%3D%3D&md5=5f014367c2e1997a19b9f031b54d30f9CAS | 11735845PubMed |
[10] Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med 2004; 351 1089–96.
| Oral erythromycin and the risk of sudden death from cardiac causes.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXntlygsLo%3D&md5=103fad6895e10ca27c400a9a262ba8ceCAS | 15356306PubMed |
[11] Pfizerlabs. Zithromax product information. New York: Pfizer Inc.; 2012.
[12] Wildfeuer A, Laufen H, Leitold M, Zimmermann T. Comparison of the pharmacokinetics of three-day and five-day regimens of azithromycin in plasma and urine. J Antimicrob Chemother 1993; 31 51–6.
| 8396097PubMed |
[13] Bergan T, Jorgensen NP, Olszewski W, Zhang Y. Azithromycin pharmacokinetics and penetration to lymph. Scand J Infect Dis Suppl 1992; 83 15–21.
| 1:STN:280:DyaK3s7ktF2ltg%3D%3D&md5=282f3c32d074603dc3e1b32d71fa4ccaCAS | 1336891PubMed |
[14] Höffler D, Koeppe P, Paeske B. Pharmacokinetics of azithromycin in normal and impaired renal function. Infection 1995; 23 356–61.
| Pharmacokinetics of azithromycin in normal and impaired renal function.Crossref | GoogleScholarGoogle Scholar | 8655206PubMed |
[15] Schoenenberger RA, Haefeli WE, Weiss P, Ritz RF. Association of intravenous erythromycin and potentially fatal ventricular tachycardia with Q-T prolongation (torsades de pointes). BMJ 1990; 300 1375–6.
| Association of intravenous erythromycin and potentially fatal ventricular tachycardia with Q-T prolongation (torsades de pointes).Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK3czitF2ruw%3D%3D&md5=61101d9d372f3046c555043b8b7ab853CAS | 2372583PubMed |
[16] Simkó J, Csilek A, Karaszi J, Lorincz I. Proarrhythmic potential of antimicrobial agents. Infection 2008; 36 194–206.
| Proarrhythmic potential of antimicrobial agents.Crossref | GoogleScholarGoogle Scholar | 18454341PubMed |
[17] Arellano-Rodrigo E, Garcia A, Mont L, Roque M. Torsade de pointes and cardiorespiratory arrest induced by azithromycin in a patient with congenital long QT syndrome. Med Clin (Barc) 2001; 117 118–9.
| 1:STN:280:DC%2BD3MvmsFWntA%3D%3D&md5=a5c13e914497318fb8304f1459cb85f9CAS |
[18] Huang BH, Wu CH, Hsia CP, Yin Chen C. Azithromycin-induced torsade de pointes. Pacing Clin Electrophysiol 2007; 30 1579–82.
| Azithromycin-induced torsade de pointes.Crossref | GoogleScholarGoogle Scholar | 18070319PubMed |
[19] Kezerashvili A, Khattak H, Barsky A, Nazari R, Fisher JD. Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors. J Interv Card Electrophysiol 2007; 18 243–6.
| Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors.Crossref | GoogleScholarGoogle Scholar | 17546486PubMed |
[20] Kim MH, Berkowitz C, Trohman RG. Polymorphic ventricular tachycardia with a normal QT interval following azithromycin. Pacing Clin Electrophysiol 2005; 28 1221–2.
| Polymorphic ventricular tachycardia with a normal QT interval following azithromycin.Crossref | GoogleScholarGoogle Scholar | 16359290PubMed |
[21] Matsunaga N, Oki Y, Prigollini A. A case of QT-interval prolongation precipitated by azithromycin. N Z Med J 2003; 116 U666
| 14615808PubMed |
[22] Russo V, Puzio G, Siniscalchi N. Azithromycin-induced QT prolongation in elderly patient. Acta Biomed 2006; 77 30–2.
| 16856707PubMed |
[23] Samarendra P, Kumari S, Evans SJ, Sacchi TJ, Navarro V. QT prolongation associated with azithromycin/amiodarone combination. Pacing Clin Electrophysiol 2001; 24 1572–4.
| QT prolongation associated with azithromycin/amiodarone combination.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3MnlsVahug%3D%3D&md5=3f1dd6e8e6d0898bdde63d8125e927a5CAS | 11707055PubMed |
[24] Del Rosario ME, Weachter R, Flaker GC. Drug-induced QT prolongation and sudden death. Mo Med 2010; 107 53–8.
| 20222297PubMed |
[25] Baker WL, Couch KA. Azithromycin for the secondary prevention of coronary artery disease: a meta-analysis. Am J Health Syst Pharm 2007; 64 830–6.
| Azithromycin for the secondary prevention of coronary artery disease: a meta-analysis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXkvFenu78%3D&md5=75686b820dda072f8a83a7c027481583CAS | 17420199PubMed |
[26] Cercek B, Shah PK, Noc M, Zahger D, Zeymer U, Matetzky S, et al Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet 2003; 361 809–13.
| Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXitVKmtLw%3D&md5=87bc8b103624ce05fff97610723e38b0CAS | 12642046PubMed |
[27] Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, et al Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005; 352 1637–45.
| Azithromycin for the secondary prevention of coronary events.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXjsFCls78%3D&md5=0ad224837a05edd89bc3d85d1cc1fb53CAS | 15843666PubMed |
[28] Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski JC, Camm AJ. Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation 1997; 96 404–7.
| Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK2szos1emtg%3D%3D&md5=a85529bc1865ccff6be9660320bce11aCAS | 9244203PubMed |
[29] Muhlestein JB, Anderson JL, Carlquist JF, Salunkhe K, Horne BD, Pearson RR, et al Randomized secondary prevention trial of azithromycin in patients with coronary artery disease: primary clinical results of the ACADEMIC study. Circulation 2000; 102 1755–60.
| Randomized secondary prevention trial of azithromycin in patients with coronary artery disease: primary clinical results of the ACADEMIC study.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXnsF2msbg%3D&md5=d3ca11f9a56c88d6746cf8a42a0def94CAS | 11023928PubMed |
[30] O’Connor CM, Dunne MW, Pfeffer MA, Muhlestein JB, Yao L, Gupta S, et al Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA 2003; 290 1459–66.
| Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXntlCms7c%3D&md5=5f3a7d0ebe3c8edf55336cc333afe9d4CAS | 13129985PubMed |
[31] Stone AF, Mendall MA, Kaski JC, Edger TM, Risley P, Poloniecki J, et al Effect of treatment for Chlamydia pneumoniae and Helicobacter pylori on markers of inflammation and cardiac events in patients with acute coronary syndromes: South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA). Circulation 2002; 106 1219–23.
| Effect of treatment for Chlamydia pneumoniae and Helicobacter pylori on markers of inflammation and cardiac events in patients with acute coronary syndromes: South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA).Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XntVKks78%3D&md5=df7593a43de879b294211f57d0e96dbdCAS | 12208796PubMed |
[32] Vainas T, Stassen FR, Schurink GW, Tordoir JH, Welten RJ, van den Akker LH, et al Secondary prevention of atherosclerosis through chlamydia pneumoniae eradication (SPACE trial): a randomised clinical trial in patients with peripheral arterial disease. Eur J Vasc Endovasc Surg 2005; 29 403–11.
| 1:STN:280:DC%2BD2M7hvVajtw%3D%3D&md5=ea1ae9271c767baa12c64ca10d83e9c5CAS | 15749042PubMed |
[33] Ohtani H, Taninaka C, Hanada E, Kotaki H, Sato H, Sawada Y, et al Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats. Antimicrob Agents Chemother 2000; 44 2630–7.
| Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXmvVyqsbo%3D&md5=0a7c6c4ffbe136dc67a6ef944c2d29edCAS | 10991836PubMed |
[34] Milberg P, Eckardt L, Bruns HJ, Biertz J, Ramtin S, Reinsch N, et al Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes. J Pharmacol Exp Ther 2002; 303 218–25.
| Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XnsV2qsLs%3D&md5=8d731bf58b1adc9c358e1c70c42a44caCAS | 12235254PubMed |
[35] Thomsen MB, Beekman JD, Attevelt NJ, Takahara A, Sugiyama A, Chiba K, et al No proarrhythmic properties of the antibiotics moxifloxacin or azithromycin in anaesthetized dogs with chronic-AV block. Br J Pharmacol 2006; 149 1039–48.
| No proarrhythmic properties of the antibiotics moxifloxacin or azithromycin in anaesthetized dogs with chronic-AV block.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28Xht12gsLrF&md5=fef341e79731bf822edebdeafd214cbcCAS | 17088870PubMed |
[36] Fossa AA, Wisialowski T, Duncan JN, Deng S, Dunne M. Azithromycin/chloroquine combination does not increase cardiac instability despite an increase in monophasic action potential duration in the anesthetized guinea pig. Am J Trop Med Hyg 2007; 77 929–38.
| 17984356PubMed |
[37] Darpo B. Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes. Eur Heart J Suppl 2001; 3 K70–80.
| Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXnt12ntL4%3D&md5=ead593c0132e28fb349a7b84760fc57eCAS |
[38] Tisdale JE, Wroblewski HA, Overholser BR, Kingery JR, Trujillo TN, Kovacs RJ. Prevalence of QT interval prolongation in patients admitted to cardiac care units and frequency of subsequent administration of QT interval-prolonging drugs: a prospective, observational study in a large urban academic medical center in the US. Drug Saf 2012; 35 459–70.
| Prevalence of QT interval prolongation in patients admitted to cardiac care units and frequency of subsequent administration of QT interval-prolonging drugs: a prospective, observational study in a large urban academic medical center in the US.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhtFCmsbvP&md5=26bda02533a7daf5e44b8a6d2aa8af10CAS | 22612851PubMed |
[39] Strle F, Maraspin V. Is azithromycin treatment associated with prolongation of the Q-Tc interval? Wien Klin Wochenschr 2002; 114 396–9.
| 1:CAS:528:DC%2BD38XlvFWjtb4%3D&md5=82430b833db2ab8f48314921885e4eb9CAS | 12708094PubMed |
[40] Chung CP, Murray KT, Stein CM, Hall K, Ray WA. A computer case definition for sudden cardiac death. Pharmacoepidemiol Drug Saf 2010; 19 563–72.
| A computer case definition for sudden cardiac death.Crossref | GoogleScholarGoogle Scholar | 20029823PubMed |
[41] Gottlieb SS. Dead is dead – artificial definitions are no substitute. Lancet 1997; 349 662–3.
| Dead is dead – artificial definitions are no substitute.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK2s3jt12mtA%3D%3D&md5=24665f5f03610bd0aeda5af5fa6145f5CAS | 9078192PubMed |
[42] Cazzola M, Santus P, D’Adda A, Pizzolato S, Di Marco F, Centanni S. Acute effects of higher than standard doses of salbutamol and ipratropium on tiotropium-induced bronchodilation in patients with stable COPD. Pulm Pharmacol Ther 2009; 22 177–82.
| Acute effects of higher than standard doses of salbutamol and ipratropium on tiotropium-induced bronchodilation in patients with stable COPD.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXltlegsbw%3D&md5=411c0ab538440f9017f30541ac38e267CAS | 19038356PubMed |
[43] Devasia RA, Jones TF, Collier B, Schaffner W. Compliance with azithromycin versus erythromycin in the setting of a pertussis outbreak. Am J Med Sci 2009; 337 176–8.
| Compliance with azithromycin versus erythromycin in the setting of a pertussis outbreak.Crossref | GoogleScholarGoogle Scholar | 19301451PubMed |
[44] Martinez SM, Kemper CA, Haiduven D, Cody SH, Deresinski SC. Azithromycin prophylaxis during a hospitalwide outbreak of a pertussis-like illness. Infect Control Hosp Epidemiol 2001; 22 781–3.
| Azithromycin prophylaxis during a hospitalwide outbreak of a pertussis-like illness.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD387ksVCrtw%3D%3D&md5=71c0ea79a7c7ac5ff3726e0b0043d234CAS | 11876458PubMed |
