Macrolide Antibacterials

Abstract

Macrolide antibiotics can interact adversely with commonly used drugs, usually by altering metabolism due to complex formation and inhibition of cytochrome P-450 IIIA4 (CYP3A4) in the liver and enterocytes. In addition, pharmacokinetic drug interactions with macrolides can result from their antibiotic effect on microorganisms of the enteric flora, and through enhanced gastric emptying due to a motilin-like effect. Macrolides may be classified into 3 different groups according to their affinity for CYP3A4, and thus their propensity to cause pharmacokinetic drug interactions. Troleandomycin, erythromycin and its prodrugs decrease drug metabolism and may produce drug interactions (group 1). Others, including clarithromycin, flurithromycin, midecamycin, midecamycin acetate (miocamycin; ponsinomycin), josamycin and roxithromycin (group 2) rarely cause interactions. Azithromycin, dirithromycin, rikamycin and spiramycin (group 3) do not inactivate CYP3A4 and do not engender these adverse effects. Drug interactions with carbamazepine, cyclosporin, terfenadine, astemizole and theophylline represent the most frequently encountered interactions with macrolide antibiotics. If the combination of a macrolide and one of these compounds cannot be avoided, serum concentrations of concurrently administered drugs should be monitored and patients observed for signs of toxicity. Rare interactions and those of dubious clinical importance are those with alfentanil and sufentanil, antacids and cimetidine, oral anticoagulants, bromocriptine, clozapine, oral contraceptive steroids, digoxin, disopyramide, ergot alkaloids, felodipine, glibenclamide (glyburide), levodopa/carbidopa, lovastatin, methylprednisolone, phenazone (antipyrine), phenytoin, rifabutin and rifampicin (rifampin), triazolam and midazolam, valproic acid (sodium valproate) and zidovudine.

Macrolide Therapy in Chronic Inflammatory Diseases

“…Erythromycin and troleandomycin are the strongest inhibitors of cytochrome CYP 3A4. Clarithromycin shows weak inhibition of CYP 3A4, whereas in vitro studies of azithromycin and diritromycyna show almost no inhibition of the cytochrome [62]. Inhibition of CYP3A4 changed metabolism of many drugs, increasing their concentration in serum and exceeding therapeutic levels and thus is the cause of their toxic effects.…”

Colchicine and macrolides: a cohort study of the risk of adverse outcomes associated with concomitant exposure

“…The adjusted model controlled for age, sex, race, and Charlson comorbidity index. Both clarithromycin and erythromycin have been known to strongly bind and inhibit CYP 3A4/P-gp, while azithromycin has been shown to interfere poorly with cytochrome P450 [ 23 ]. Therefore, we performed a sub-analysis of the colchicine and macrolide exposure consisting of only those encounters with colchicine and clarithromycin or erythromycin (strong CYP3A4 inhibitor exposure).…”

Safety in the selection of oral antibiotic treatment in community infections, beyond COVID-19

“…Las interacciones medicamentosas se relacionan con la capacidad de inhibir o formar complejos con la isoenzima CYP3A4 que tienen eritromicina y en menor medida claritromicina, pero no azitromicina. Los dos primeros potencian los efectos de carbamazepina, corticoides, ciclosporina, digoxina, teofilina, antihistamínicos, benzodiazepinas, ácido valproico y warfarina [37,38].…”