Macrolide drug interactions

The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies.

Recently emerged or substantiated drug interactions:

1-Psychotropic agents:

1- a) Benzodiazepines

Alprazolam, midazolam, temazepam, and triazolam are among the known substrates of CYP 3A4.

In summary, co-administration of a macrolide antibiotic (with the exception of azithromycin) with one of the highly metabolized benzodiazepines mentioned below should be avoided, or the dose of the benzodiazepine should be substantially reduced.

Triazolam: 

Erythromycin and Clarithromycin significantly increased triazolam peak plasma concentrations, prolonged elimination half-life.

The inhibitory effect of clarithromycin was greater than that of erythromycin.

Erythromycin and Clarithromycin are potent inhibitors; In contrast, azithromycin is a weak inhibitor.

Midazolam: 

Erythromycin resulted in undesirably severe and excessively long-lasting hypnotic effects of midazolam.

Erythromycin causes the inhibition of CYP 3A4-mediated metabolism of midazolam.

Clarithromycin reduces the clearance of midazolam.

Alprazolam: 

Erythromycin impairs the metabolic clearance of alprazolam.

1- b) Neuroleptics

Clozapine: is a new antipsychotic agent used in the management of schizophrenia resistant to other neuroleptic medications. 

Erythromycin has been reported to interact with this agent, presumably through inhibition of its metabolic clearance; case-reports of serious side-effects – including seizure, somnolence, disorientation, difficulty in coordination and ambulation – associated with the co-administration of erythromycin and clozapine .This drug combination should therefore be avoided.

Pimozide: 

clarithromycin inhibited the metabolic clearance (CYP3A-mediated) of pimozide resulting in elevation of plasma concentrations, significant prolongation of the QT interval, thereby increasing the risk of pimozide cardio toxicity. Accordingly, this drug association is contraindicated.

2- Cisapride

Erythromycin inhibit the CYP3A4 and, consequently, the metabolism of cisapride causing prolongation of QT intervals, and deaths. 

Clarithromycin seems to exhibit a similar adverse reaction when co-administered with cisapride. 

No studies have been yet reported regarding the potential of the other macrolides for such an interaction with cisapride. 

3- HMG-CoA reductase inhibitors

Erythromycin inhibit CYP 3A4 causing increase in serum level of Simvastatin leading to toxic effect on skeletal muscle that may range from diffuse myalgia and myopathy to severe rhabdomyolysis which is dose –related.

Rhabdomyolysis is a complication known to be associated with concomitant use of lovastatin and erythromycin, clarithromycin or azithromycin. In order to reduce this risk, limiting the daily dose of lovastatin to 20 mg has been advocated.

4- Class IA antiarrhythmic drugs

Erythromycin inhibit clearance of Quinidine through inhibition of CYP 3A4 . Therefore, quinidine concentrations should be monitored closely if quinidine and erythromycin are co-administered

disopyramide-erythromycin or clarithromycin also has the same interaction.

5- Warfarin

erythromycin cause an increase in hypoprothrombinaemic effect of warfarin which is associated with bleeding complications. .

Updated overview of previously well-recognized and clinically relevant drug interactions induced by macrolides

1- Immunosuppressive agents

Cyclosporin is extensively metabolized by CYP 3A pathway so there is considerable potential for interaction with macrolides. This is of particular relevance since cyclosporin has low therapeutic index. 

So when macrolides are used in patients under cyclosporin therapy, trough serum cyclosporin concentrations and serum creatinine concentrations must frequently be monitored to allow appropriate adjustment of the cyclosporin dosage.

Tacrolimus is a new immunosuppressive agent that reacts with macrolides by the same mechanism. 

2- Theophylline

Erythromycin and clarithromycin decreased theophylline clearance. From a practical viewpoint, given the relative unpredictability of the extent of the theophylline–macrolide interaction, it remains necessary to monitor serum theophylline concentrations whatever the macrolide being used, especially in those patients with baseline theophylline concentrations in the upper therapeutic range (15–20 mg l−1).

3- Carbamazepine

Interaction between erythromycin and carbamazepine.

Following oral administration of this macrolide, a two-to fourfold increase in carbamazepine serum concentration is observed. In carbamazepine-treated patients, serious manifestations of toxicity occur within the 3 days of the start of erythromycin therapy. The mechanism underlying this drug interaction is assumed to be the macrolide-induced inhibition of the CYP 3A4 isoform for which carbamazepine is a substrate.

Azithromycin and dirithromycin appear to be free from interaction with carbamazepine.

4- Non-sedating antihistamines

Terfenadine is a non-sedating antihistamine that undergoes nearly complete first-pass biotransformation through CYP 3A4 pathway to form an acid metabolite. In susceptible individuals, accumulation of the parent compound can cause QT interval prolongation that may result in torsade de pointes. Hazardous drug interactions involving this agent and some macrolides have been described. Given that the drug is essentially withdrawn from the market, it will not be discussed further.

Loratadine, another H1-receptor antagonist, is metabolized primarily by CYP 3A4 and, to a lesser extent, by CYP 2D6. Erythromycin reduced the metabolic clearance of loratadine. 

Astemizole drug interactions with terfenadine have been extrapolated to astemizole. Warnings about the concomitant use of terfenadine and macrolides apply also for astemizole.

5- Ergot alkaloids

Clinical ergotism has resulted from the co-administration of ergots and erythromycin. This adverse effect is ascribed to the macrolide-induced inhibition of CYP 3A4, which is responsible for the metabolism of the ergots. 

Accordingly, concomitant use of ergot alkaloids with erythromycin or clarithromycin is contraindicated.

Foods That React With Macrolides

People should be careful, for example, if they are taking erythromycin with vitamin K or vitamin B6, because the interactions between these can deplete the nutritional effects of the vitamins, but your doctor can advise accordingly. Erythromycin can also interact with calcium, digitalis from the foxglove plant and folic acid, so ask your doctor or pharmacist if these appear in your diet. 

In addition, the physiological response to food intake, in particular gastric acid secretion, may reduce the bioavailability of azithromycin capsules, erythromycin stearate or enteric coated.