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Statin toxicity from macrolide antibiotic coprescription: a population-based study of older adults


Background — Clarithromycin and erythromycin inhibit cytochrome P450 isoenzyme 3A4 (CYP3A4), increasing blood concentrations of statins metabolized by CYP3A4, while azithromycin does not.

Objective — To assess outcomes of statin toxicity after co-prescription of either clarithromycin or erythromycin.

Design — Population-based cohort study using four linked healthcare databases.

Setting — Ontario, Canada, from 2003 to 2010.

Patients — Continuous statin users over the age of 65 (mean 74 years) who were co-prescribed either clarithromycin (n=72,591) or erythromycin (n = 3,267) compared to those co-prescribed azithromycin (n = 68,478).

Measurements — The primary outcome was hospital admission with rhabdomyolysis within 30 days of the antibiotic prescription. Secondary outcomes included hospital admission with acute kidney injury and all-cause mortality.

Results — Atorvastatin was the most common statin (73%) followed by simvastatin and lovastatin. Compared to azithromycin, co-prescription for either clarithromycin or erythromycin was associated with a higher risk of hospital admission with rhabdomyolysis (absolute risk increase 0.02% (95% confidence interval (CI) 0.01-0.03) and relative risk (RR) 2.17 (95% CI 1.04 to 4.53)), acute kidney injury (absolute risk increase 1.26% (95% CI 0.58 to 1.95) and RR 1.78 (95% CI 1.49 to 2.14), and a higher risk of all-cause mortality (absolute risk increase 0.25% (95% CI 0.15 to 0.33) and RR 1.56 (95% CI 1.36 to 1.80)). Results were consistent in adjusted analyses and in a subpopulation with laboratory measurements.

Limitations — The codes used to identify rhabdomyolysis were insensitive and the absolute risk increase may be underestimated up to ten fold. The authors only studied older adults.

Conclusion — In older adults co-prescription of either clarithromycin or erythromycin with a CYP3A4 metabolized statin increases the risk of statin toxicity.



Patel AM, Shariff S, Bailey DG, Juurlink DN, Gandhi S, Mamdani M, Gomes T, Fleet J, Hwang YJ, Garg AX. Ann Intern Med. 2013; 158(12):869-76.