What are the adverse effects associated with macrolides (macrolide antibiotics)?

From the Guidelines

Macrolide antibiotics can cause several adverse effects, including cardiac effects such as QT interval prolongation, which can lead to potentially fatal arrhythmias, and these effects should be carefully considered when prescribing macrolides, especially in patients with pre-existing cardiac conditions. The most common side effects of macrolides are gastrointestinal disturbances, such as nausea, vomiting, abdominal pain, and diarrhea, which occur in approximately 5-30% of patients 1. Hepatotoxicity can also occur, manifesting as elevated liver enzymes or cholestatic jaundice, particularly with erythromycin. Allergic reactions ranging from mild rashes to severe anaphylaxis may develop. Ototoxicity, presenting as reversible hearing loss or tinnitus, can occur particularly with high doses or in patients with renal impairment.

Some key factors that increase the risk of malignant arrhythmias with macrolides include age >80, female gender, heart disease, use of other QT prolonging medication, reduced drug elimination, bradycardia, prolonged QT interval before therapy, and genetic predisposition 1. The risk of cardiovascular death in patients treated with short, oral antibacterial courses of azithromycin has been reported to be increased in some studies, although the absolute risk is still relatively low, with 85 deaths for each 1 million courses prescribed in the increased risk group 1.

When considering the use of macrolides, particularly for long-term therapy, it is essential to weigh the potential benefits against the risks of adverse effects. For patients with moderate to severe COPD, who have a history of one or more moderate or severe COPD exacerbations in the previous year despite optimal maintenance inhaler therapy, the use of a long-term macrolide to prevent acute exacerbations of COPD may be suggested, but clinicians should be aware of the potential for adverse effects, including cardiovascular side effects and hearing loss 1.

Key points to consider when prescribing macrolides include:

• Carefully evaluating patients for predisposing conditions or medications that may increase the risk of adverse effects
• Monitoring patients for signs of adverse effects, such as cardiac arrhythmias or hearing loss
• Considering alternative therapies or adjusting the dosage or duration of macrolide therapy to minimize the risk of adverse effects
• Educating patients about the potential risks and benefits of macrolide therapy and encouraging them to report any unusual symptoms promptly.

From the FDA Drug Label

Overdosage of clarithromycin can cause gastrointestinal symptoms such as abdominal pain, vomiting, nausea, and diarrhea. Adverse reactions occurred in 12.7% of infants exposed to macrolides and included rash, diarrhea, loss of appetite, and somnolence. Dose-dependent emesis, poor appetite, fecal changes, and reduced body weight were observed in dams at all doses The adverse effects associated with macrolid (clarithromycin) include:

• Gastrointestinal symptoms: abdominal pain, vomiting, nausea, and diarrhea
• Other adverse reactions: rash, diarrhea, loss of appetite, and somnolence
• Maternal toxicity: emesis, poor appetite, fecal changes, and reduced body weight 2 2

From the Research

Adverse Effects of Macrolides

• The most frequently reported adverse effects of macrolides, such as clarithromycin and azithromycin, have been nausea, diarrhea, and abdominal pain 3.
• Macrolide antibiotics, including erythromycin, clarithromycin, and azithromycin, can lead to QT prolongation, which may increase the risk of proarrhythmic effects 4.
• Erythromycin and clarithromycin have been shown to cause early afterdepolarizations (EADs) and torsade de pointes (TdP), whereas azithromycin does not appear to cause these effects 4.
• The new macrolide antibiotics, such as azithromycin and clarithromycin, may offer a lower incidence of adverse gastrointestinal effects compared to erythromycin 5, 6.

Comparison of Adverse Effects

• Azithromycin and clarithromycin have been reported to have fewer gastrointestinal side effects than erythromycin 6, 3.
• Clarithromycin and azithromycin have been shown to be well tolerated by children, with azithromycin having the advantage of shorter treatment regimens and improved tolerance 7.
• The emergence of macrolide resistance with common pathogens, such as Streptococcus pneumoniae, group A streptococci, and H. influenzae, may limit the clinical usefulness of this class of antimicrobial agents in the future 7.

Proarrhythmic Potential

• Macrolide antibiotics have a different proarrhythmic potential despite similar QT prolongation, with erythromycin having the highest potential, followed by clarithromycin, and then azithromycin 4.
• The proarrhythmic potential of macrolides may be related to the pattern of action potential prolongation, with azithromycin causing a rectangular pattern and erythromycin and clarithromycin causing a triangular pattern 4.