What are the side effects of macrolide antibiotics such as azithromycin, clarithromycin, and erythromycin?

Side Effects of Macrolide Antibiotics

Gastrointestinal Effects

Gastrointestinal symptoms are the most common side effects of macrolides, occurring in up to 70% of patients taking erythromycin, with lower rates for clarithromycin and azithromycin. 1

• Macrolides cause GI symptoms through direct interaction with motilin receptors in the gut, not primarily through alterations in gut flora 1
• Common symptoms include nausea, vomiting, abdominal pain, diarrhea, and anorexia 1, 2
• Erythromycin causes the highest rate of GI side effects (up to 70%), while azithromycin and clarithromycin are better tolerated 1
• In FDA-approved labeling, azithromycin causes diarrhea/loose stools in 4-7%, nausea in 3-5%, and abdominal pain in 2-5% depending on dosing regimen 3
• Despite being common, GI symptoms rarely necessitate discontinuation of therapy—in long-term macrolide studies, mild to moderate GI complaints "hardly ever caused study drug discontinuation" 1
• Dose reduction may improve tolerability but may also reduce clinical efficacy 1
• Pseudomembranous colitis can occur during or after treatment 1, 2

Cardiac Effects

Macrolides can prolong the QT interval and cause dangerous cardiac arrhythmias, including ventricular tachycardia and torsades de pointes. 1, 2

• Macrolides directly prolong the QT interval and inhibit metabolism of other proarrhythmogenic drugs through cytochrome P450 inhibition 1
• Risk factors for malignant arrhythmias include: age >80 years, female gender, heart disease, use of other QT-prolonging medications, reduced drug elimination, bradycardia, pre-existing prolonged QT interval, and genetic predisposition 1
• These cardiac events are rare: approximately 85 deaths per 1 million courses prescribed in high-risk populations 1
• Increased cardiovascular death risk has been reported with short courses of azithromycin, particularly in patients with high baseline cardiovascular risk and comorbidity 1
• Prior to initiating therapy, patients should be screened for history of heart disease, previous low serum potassium, slow pulse rate, family history of sudden death, or known prolonged QT interval 1

Hepatotoxicity

• Hepatitis, hepatic dysfunction, and abnormal liver function tests may occur 2
• Asymptomatic transaminase elevation occurs in 1-5% of patients taking macrolides 4
• Cholestatic jaundice has been reported rarely 1, 3
• Fulminant hepatic necrosis has been reported with clarithromycin 5

Ototoxicity

• Reversible sensorineural hearing loss can occur in 15% of patients taking macrolides 4
• Hearing loss occurs chiefly in patients with renal insufficiency and those receiving high doses 2
• Tinnitus and deafness have been reported with azithromycin 3

Allergic and Dermatologic Reactions

• Allergic reactions range from urticaria to anaphylaxis 3, 2
• Skin reactions range from mild eruptions to severe conditions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis 3, 5, 2
• Photosensitivity, rash, pruritus, and angioedema have been reported 3

Neurologic Effects

• Dizziness, headache, vertigo, and somnolence can occur 3, 5
• Convulsions have been reported rarely 3, 2

Other Adverse Effects

• Interstitial nephritis and acute renal failure have been reported coincident with macrolide use 3, 2
• Pancreatitis has been reported rarely 3, 2
• Vaginitis and monilial infections occur in 1-2% of patients 3
• Thrombocytopenia is not listed among recognized adverse events of macrolides in comprehensive safety guidelines 4

Drug-Specific Considerations

Azithromycin has the most favorable side effect profile among macrolides, with lower rates of GI symptoms and no significant cytochrome P450 interactions. 1

• Azithromycin does not inhibit cytochrome P450 enzymes, unlike erythromycin and clarithromycin, reducing drug interaction potential 1
• Clarithromycin and erythromycin are CYP3A inhibitors and can interact with drugs metabolized by this system 1
• Erythromycin has the highest discontinuation rate due to side effects, particularly GI symptoms 1, 6

Clinical Monitoring Recommendations

• Warn patients about GI side effects prior to initiating therapy 1
• Screen for cardiac risk factors before starting macrolides 1
• Consider dose reduction if GI symptoms are intolerable, though this may reduce efficacy 1
• Routine platelet monitoring is not warranted based on current evidence 4
• Monitor liver function, ECG, and hearing in patients on long-term therapy 4