What is the management for a patient with infectious mononucleosis (mono) who develops a rash after taking amoxicillin (amoxicillin)?

Management of Amoxicillin-Associated Rash in Infectious Mononucleosis

Immediately discontinue amoxicillin and do NOT label the patient as penicillin-allergic, as this represents a unique virus-drug interaction rather than a true IgE-mediated allergy. 1, 2, 3

Understanding the Rash Mechanism

• Patients with infectious mononucleosis have a 30-100% chance of developing a non-pruritic morbilliform (maculopapular) rash when given amoxicillin, which is NOT a true drug allergy but rather a transient interaction between the Epstein-Barr virus and the medication. 1, 2

• The FDA label explicitly warns that "a high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash" and states that "amoxicillin should not be administered to patients with mononucleosis." 3

• Recent data shows the actual incidence is approximately 30-33%, significantly lower than the historically reported 80-100% rate from the 1960s. 4, 5

Immediate Management Steps

For mild maculopapular rash (most common presentation):

• Discontinue amoxicillin immediately if the rash is bothersome. 1
• Provide symptomatic treatment with oral antihistamines and topical corticosteroids. 1
• Use acetaminophen or ibuprofen for associated fever or discomfort. 1, 2
• Monitor closely for progression of lesions. 3

If the patient still requires antibiotic therapy for a concurrent bacterial infection:

• Switch to a non-beta-lactam antibiotic (such as a macrolide). 1
• Note that the rash itself does not indicate bacterial infection requiring antibiotics—most mononucleosis cases are self-limiting and do not require antibacterial therapy. 6

Critical Documentation Requirements

Do NOT document this as a penicillin allergy in the medical record. 1, 2

• Patients who develop this rash during mononucleosis can typically take penicillins safely after the EBV infection resolves. 2
• Permanently labeling these patients as penicillin-allergic leads to unnecessary use of broader-spectrum, less effective antibiotics throughout their lifetime. 2
• Over 90% of children with reported amoxicillin rashes during viral illness tolerate the drug on re-exposure. 2

Appropriate documentation should state:

• "Maculopapular rash developed during EBV infection while on amoxicillin—NOT a true penicillin allergy"
• "Patient may use penicillins after resolution of acute EBV infection"

When to Suspect True Drug Allergy (Requires Different Management)

Immediate referral to allergy/immunology is required if the patient develops: 1, 2

• Immediate-onset reactions (within 1 hour): urticaria, angioedema, or anaphylaxis
• Severe cutaneous adverse reactions (SCAR): Stevens-Johnson syndrome, toxic epidermal necrolysis, blistering, skin exfoliation, or mucosal involvement
• Systemic symptoms: DRESS (drug reaction with eosinophilia and systemic symptoms) or serum sickness-like reactions

These severe reactions indicate true drug allergy and require permanent avoidance of penicillins and formal allergy evaluation. 1, 3

Future Antibiotic Selection

• After EBV infection resolves, the patient can safely receive amoxicillin and other penicillins for future infections. 1, 2

• If uncertainty exists about whether the rash was due to mononucleosis or represents a true allergy, consultation with an allergist for direct amoxicillin challenge testing may be helpful. 2

• Direct amoxicillin challenge (single dose under medical observation) is recommended for pediatric patients with past maculopapular rash without systemic symptoms, with only 5-10% reaction rates on rechallenge. 2

Common Pitfalls to Avoid

• Do not avoid penicillins lifelong based solely on this rash—this is the single most important clinical decision point. 1, 2

• Do not perform penicillin skin testing for this type of non-IgE-mediated maculopapular rash, as it has limited utility and poor sensitivity/specificity for delayed reactions. 6, 2

• Do not prescribe antibiotics for uncomplicated mononucleosis in the first place—the guideline for acute sore throat notes that amoxicillin is a poor first choice in older children specifically because of the risk of severe rash among patients with Epstein-Barr virus infection. 1

• Recognize that antibiotic exposure itself may increase overall rash risk in IM children (adjusted odds ratio 1.47), but amoxicillin does not carry higher risk than other antibiotics. 7