Azithromycin and Levofloxacin Use and Increased Risk of Cardiac Arrhythmia and Death

It has been known that all macrolide antibiotics have a potential risk to cause QT prolongation and resultant torsade de pointes. Among macrolides, azithromycin, with minimal side effects, is considered to be usually better tolerated. In the present article, Rao and colleagues retrospectively investigated the data of 14 million people and defined among them 1.6 million who received the treatment of azithromysin, levofloxacin or amoxicillin, and found that levofloxacin and azithromycin significantly increased not only the mortality but also cardiac arrhythmias when compared with amoxicillin. Azithromycin increased the risks on day 1 to 5, while the risk of levofloxacin could last as long as 10-days.

The main mechanisms underlying the increased risks of arrhythmia and mortality of levofloxacin and azithromycin are their property to prolong the QT duration, and then consequently lead to bradycardia and atrioventricular block, and, through reverse use-dependence, to result in torsade de pointes[1]. Levofloxacin, with its significant effects of QT prolongation, is even regarded as a positive control for the Thorough QT Study of other antibiotic candidates[2]. Previous studies have shown that QT prolongation, regardless of its underlying causes, was associated with an increased mortality in the general population as well as in the people with coronary artery disease[3-4].

Interestingly, azithromycin was not found to be associated with increased risks of death in a previous study by Svanstrom et al[5]. The conflict results may result from the difference in ages between the previous study and the current study. The mean age of the subjects in the study of Rao et al is 56.5 years, older than that (39.7 +-13.9yr) of the subjects in Svanstrom's study. The reasons underlying this unfavorable profile for older people are closely associated with their comparatively complicated clinical profile. On the one hand, older people are more likely to have concomitant diseases like ventricular hypertrophy that may reduce repolarization reserve and render the older people more sensitive to QT-prolonging antibiotics. On the other hand, older people have a reduced creatinine clearance and are more likely to take other drugs, some of which might have certain impact upon the metabolism and kinetics of the antibiotics. Both may significantly raise the concentrations of the antibiotics and therefore potentiate their electrophysiological effects, such as QT prolongation, which, in turn, set the stage for the occurrences of arrhythmias, especially torsade de pointes. So the suggestions in the use of these antibiotics in clinic are to choose, if possible, other alternative antibiotics, or to require, in the absence of alternatives, close monitoring from the start, involving assessment of risk markers before the start of therapy, especially when used in combination with other QT-prolonging drugs.

References
1. Jia S, Lian J, Guo D, Xue X, Patel C, Yang L, et al. Modulation of the Late Sodium Current by ATX-II and Ranolazine Affects the Reverse Use-Dependence and Proarrhythmic Liability of IKr Blockade. British Journal of Pharmacology. 2011; 164(2): 308-316.
2. Taubel J1, Naseem A, Harada T, et al. Levofloxacin Can Be Used Effectively as a Positive Control in Thorough QT/QTc Studies in Healthy Volunteers. British Journal of Clinical Pharmacology, 2010, 69(4): 391-400.
3. Straus SM, Sturkenboom MC, Bleumink GS, Dieleman JP, van der Lei J, de Graeff PA, et al. Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. Eur Heart J. 2005; 26(19):2007-2012.
4. Chugh SS, Reinier K, Singh T,Uy-Evanado A, Socoteanu C, Peters D, et al. Determinants of prolonged QT interval and their contribution to sudden death risk in coronary artery disease: the Oregon Sudden Unexpected Death Study. Circulation. 2009;119(5):663-670.
5. Svanstrom H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013;368(18):1704-1712.

Competing interests: None declared