Pitfalls in Prescribing: Macrolide-Drug Interactions: Update on the Most Common and Clinically Significant

Macrolides are commonlyused to treat avariety of infections.Erythromycin haslong been recognizedas having numerous highly importantdrug interactions.¹ Althoughclarithromycin generally has somewhatless of an effect on the clearanceof other drugs, it also has severalclinically relevant interactions.^1-3

Here we focus on erythromycinandclarithromycin-drug interactions;the Table lists a number of well-documentedexamples. Although theolder agent troleandomycin has severalimportant interactions, it is rarelyused. Dirithromycin is a relativelynew macrolide that is generally devoidof interactions.^2,3

In controlled studies, azithromycinhas not been associated withclinically significant interactions.^3,4However, because this macrolide isoften used to avoid interactions thatoccur with erythromycin or clarithromycin,it is important to be awareof the few case reports involvingazithromycin and high-risk agents,which we describe here.

MECHANISMS OFMACROLIDE-DRUGINTERACTIONS

Erythromycin and clarithromycininhibit the cytochrome P-450(CYP) system and thus reduce hepaticand gut drug metabolism. Athoughinhibition of CYP3A4 is the most wellknowneffect, these agents also inhibitCYP1A2.⁵ In addition to effects on P-450 isoenzymes, these macrolidesmay inhibit P-glycoprotein, a drug effluxtransporter located at many sites,such as the intestines, kidneys, liver,lymphocytes, and blood-brain barrier.³ Further research is needed toverify the likely importance of thismechanism for some macrolide-druginteractions.

MANAGEMENT OFMACROLIDE INTERACTIONS

If it is not possible or practical tocircumvent erythromycin- or clarithromycin-drug interactions with an alternativeagent, appropriate managementis essential to enhance patientsafety. For each interaction, knowingthe time of onset is obviously important.For example, the manifestationsof an interaction with theophyllineusually take more than 5 days to becomeevident. Clinical and laboratorymonitoring is required while the interactingdrugs are given. When themacrolide is discontinued, assess theneed to adjust the dosage of the affecteddrug.

AZITHROMYCIN

Most drug interactions causedby erythromycin and clarithromycinare easily circumvented by the useof azithromycin.^3,4 This widely prescribedantibiotic belongs to the azalidesubclass of macrolides.

Rare, isolated clinical observationsaccount for most, if not all, reportsof potential azithromycin interactions.Although well-documentedcase reports are valuable in triggering controlled studies and in validatingtrial results in young, healthy subjects,controlled investigations arerequired to establish potential druginteractions.

Case reports of azithromycindrug interactions involve warfarin,^6,7digoxin,⁸ lovastatin,⁹ cyclosporine,¹⁰amiodarone,¹¹ and theophylline.¹²Some of these cases had variablesthat cast doubt as to whether a druginteraction occurred. A potentialwarfarin interaction has also beenquestioned.^13,14

Of the drug interactions describedin these case reports, perhapsthe most likely interaction thatmay later be verified is with digoxin.Given that one proposed mechanismof the erythromycin and clarithromycininteraction with digoxin isbased on antibacterial action (the effecton Eubacterium lentum in thegut), it would be logical that azithromycin may also have an effect ondigoxin clearance in some patients.⁸More than 100 cases of possible interactionswith digoxin have been reportedto the manufacturer ofazithromycin.⁸