Update on the Most Common and Clinically Significant

Macrolides are commonly used to treat a variety of infections. Erythromycin has long been recognized as having numerous highly important drug interactions.¹ Although clarithromycin generally has somewhat less of an effect on the clearance of other drugs, it also has several clinically relevant interactions.^1-3

Here we focus on erythromycinand clarithromycin-drug interactions; the Table lists a number of well-documented examples. Although the older agent troleandomycin has several important interactions, it is rarely used. Dirithromycin is a relatively new macrolide that is generally devoid of interactions.^2,3

In controlled studies, azithromycin has not been associated with clinically significant interactions.^3,4 However, because this macrolide is often used to avoid interactions that occur with erythromycin or clarithromycin, it is important to be aware of the few case reports involving azithromycin and high-risk agents, which we describe here.

MECHANISMS OF MACROLIDE-DRUG INTERACTIONS

Erythromycin and clarithromycin inhibit the cytochrome P-450 (CYP) system and thus reduce hepatic and gut drug metabolism. Athough inhibition of CYP3A4 is the most wellknown effect, these agents also inhibit CYP1A2.⁵ In addition to effects on P-450 isoenzymes, these macrolides may inhibit P-glycoprotein, a drug efflux transporter located at many sites, such as the intestines, kidneys, liver, lymphocytes, and blood-brain barrier. ³ Further research is needed to verify the likely importance of this mechanism for some macrolide-drug interactions.

MANAGEMENT OF MACROLIDE INTERACTIONS

If it is not possible or practical to circumvent erythromycin- or clarithromycin- drug interactions with an alternative agent, appropriate management is essential to enhance patient safety. For each interaction, knowing the time of onset is obviously important. For example, the manifestations of an interaction with theophylline usually take more than 5 days to become evident. Clinical and laboratory monitoring is required while the interacting drugs are given. When the macrolide is discontinued, assess the need to adjust the dosage of the affected drug.

AZITHROMYCIN

Most drug interactions caused by erythromycin and clarithromycin are easily circumvented by the use of azithromycin.^3,4 This widely prescribed antibiotic belongs to the azalide subclass of macrolides.

Rare, isolated clinical observations account for most, if not all, reports of potential azithromycin interactions. Although well-documented case reports are valuable in triggering controlled studies and in validating trial results in young, healthy subjects, controlled investigations are required to establish potential drug interactions.

Case reports of azithromycin drug interactions involve warfarin,^6,7 digoxin,⁸ lovastatin,⁹ cyclosporine,¹⁰ amiodarone,¹¹ and theophylline.¹² Some of these cases had variables that cast doubt as to whether a drug interaction occurred. A potential warfarin interaction has also been questioned.^13,14

Of the drug interactions described in these case reports, perhaps the most likely interaction that may later be verified is with digoxin. Given that one proposed mechanism of the erythromycin and clarithromycin interaction with digoxin is based on antibacterial action (the effect on Eubacterium lentum in the gut), it would be logical that azithromycin may also have an effect on digoxin clearance in some patients.⁸ More than 100 cases of possible interactions with digoxin have been reported to the manufacturer of azithromycin.⁸