Can Azithromycin Cause Stevens-Johnson Syndrome?
Yes, azithromycin can cause Stevens-Johnson syndrome (SJS), though this is a rare but serious adverse reaction that has been documented in FDA labeling, clinical guidelines, and case reports. 1
FDA-Confirmed Risk
The FDA drug label for azithromycin explicitly warns that "serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens Johnson Syndrome and toxic epidermal necrolysis have been reported rarely in patients on azithromycin therapy," with rare fatalities documented. 1 The label emphasizes that if an allergic reaction occurs, the drug should be discontinued immediately and appropriate therapy instituted, as allergic symptoms may recur even after initial successful treatment due to azithromycin's long tissue half-life. 1
Clinical Guideline Evidence
Multiple authoritative guidelines acknowledge azithromycin as a potential cause of SJS:
American Academy of Dermatology (2016): Lists SJS and toxic epidermal necrolysis among the skin/appendages adverse effects of azithromycin, alongside pruritus and erythema multiforme. 2
Pediatrics Guidelines (2013): Explicitly state that "antibiotics can produce serious allergic reactions such as Stevens-Johnson syndrome," noting that antibiotic-associated adverse events range from mild (diarrhea and rash) to more severe (SJS) to life-threatening (anaphylaxis or sudden cardiac death). 2
Published Case Evidence
A systematic review of macrolide-associated SJS/TEN identified 11 documented cases specifically linked to azithromycin, with patients ranging from 2 to 77 years of age. 3 Time to onset of first symptoms ranged from 1 to 14 days (median: 3 days), and the mortality rate in this case series was 11.1%. 3 Individual case reports have documented azithromycin-induced SJS in both adults and children, including a 62-year-old woman who developed characteristic maculopapular erythematous rash 10 days after starting azithromycin for upper respiratory infection. 4
Clinical Context and Risk Assessment
The absolute risk of azithromycin-induced SJS is very low, but the potential severity—including death—makes recognition critical. 1, 3 This risk must be weighed against azithromycin's known cardiovascular risks (QT prolongation and sudden cardiac death) and the fact that azithromycin is not a first-line antibiotic for most pediatric upper respiratory infections. 2
Key Clinical Pearls
Onset timing: SJS typically develops 1-14 days after azithromycin initiation, with a median of 3 days. 3
Prolonged risk: Due to azithromycin's extended tissue half-life of 68 hours, allergic symptoms may recur even after initial symptomatic treatment and drug discontinuation, requiring prolonged observation. 1
Immediate action required: If SJS is suspected, discontinue azithromycin immediately and institute appropriate supportive therapy. 1
Documentation matters: True hypersensitivity reactions like SJS should be clearly documented as drug allergies, unlike common benign side effects (nausea, diarrhea) which should not be labeled as "allergies." 5
Comparative Risk with Other Antibiotics
While azithromycin can cause SJS, other commonly used antibiotics carry similar or higher risks. Trimethoprim-sulfamethoxazole (TMP/SMX) has a crude relative risk of 172 for severe cutaneous reactions including SJS and toxic epidermal necrolysis, particularly in HIV-positive patients. 2 Erythromycin, another macrolide, also carries documented SJS risk. 2 Even doxycycline has been implicated in fatal cases of SJS/TEN. 6
Bottom line: Azithromycin is a confirmed but uncommon cause of Stevens-Johnson syndrome. Clinicians must maintain vigilance for early signs of severe cutaneous reactions, discontinue the drug immediately if SJS is suspected, and avoid dismissing this rare but potentially fatal adverse effect.