How should a rash that develops after amoxicillin (β‑lactam) in a patient with infectious mononucleosis be managed?

Management of Amoxicillin-Associated Rash in Infectious Mononucleosis

Immediately discontinue amoxicillin, provide symptomatic treatment with antihistamines and topical corticosteroids, and do NOT label the patient as penicillin-allergic—this rash represents a unique virus-drug interaction, not a true IgE-mediated allergy. 1, 2

Immediate Clinical Actions

Discontinue the Antibiotic

• Stop amoxicillin immediately upon recognition of the rash, as continuing provides no benefit and may worsen the eruption. 1, 3
• The FDA drug label explicitly states that amoxicillin should not be administered to patients with mononucleosis due to the high percentage who develop erythematous skin rash. 2

Assess for High-Risk Features Requiring Emergency Care

• Transfer to emergency care immediately if any of the following are present: 1
  • Blistering or skin detachment (Stevens-Johnson syndrome/toxic epidermal necrolysis)
  • Mucosal involvement (eyes, mouth, genitals)
  • Angioedema or facial swelling
  • Respiratory compromise (wheezing, stridor, dyspnea)
  • Cardiovascular instability (hypotension, tachycardia)

Symptomatic Management for Benign Rash

• Administer oral antihistamines (e.g., diphenhydramine, cetirizine) for pruritus. 1, 3
• Apply topical corticosteroids (low-to-moderate potency) for localized inflammation. 1, 3
• Use acetaminophen or ibuprofen for associated fever or discomfort. 1, 3
• Monitor for progression over the next 24-48 hours, watching specifically for development of blistering, mucosal lesions, or systemic symptoms. 1

Understanding the Mechanism

This is NOT a True Penicillin Allergy

• Patients with infectious mononucleosis have a 30-100% chance of developing a non-pruritic morbilliform rash when given amoxicillin, representing a unique virus-drug interaction rather than IgE-mediated hypersensitivity. 1, 3
• Recent data shows the actual incidence is approximately 29.5% with amoxicillin (95% CI: 18.52-42.57), significantly lower than the 80-100% historically reported with ampicillin. 4
• The mechanism involves virus-mediated immunomodulation or altered drug metabolism during active EBV infection, not antibody formation against the drug. 5, 6

Rash Characteristics

• The typical presentation is a maculopapular (morbilliform) rash that is generalized and non-pruritic. 1, 7
• The rash can appear even when amoxicillin was administered during EBV's latent phase, manifesting only after clinical onset of infectious mononucleosis. 8
• This reaction is self-limiting and usually resolves within days of discontinuing the antibiotic. 6

Critical Documentation and Future Antibiotic Use

Do NOT Label as Penicillin-Allergic

• Patients should NOT be permanently labeled as "penicillin allergic" based solely on developing this rash during mononucleosis. 1, 3, 2
• Over 90% of children with reported amoxicillin rashes tolerate the drug on re-exposure after the viral infection resolves. 1
• Incorrect labeling leads to unnecessary use of broader-spectrum antibiotics, increased healthcare costs, antimicrobial resistance, and poorer clinical outcomes. 1

Provide Written Documentation

• Document clearly in the medical record that this was a virus-drug interaction specific to EBV infection, not a true drug allergy. 1, 3
• Instruct removal of any penicillin allergy label from electronic health records, pharmacy systems, and outpatient charts. 1
• Provide written confirmation to the patient/family that they are not penicillin-allergic and can safely receive penicillins in the future. 1

Future Beta-Lactam Use

• Patients can safely take penicillins after the EBV infection resolves, as the rash does not indicate permanent drug hypersensitivity. 1, 3
• If uncertainty exists about whether the rash represented a true allergy versus EBV-drug interaction, perform a direct oral amoxicillin challenge (single supervised dose) when the patient next requires antibiotics, typically >1 year after the reaction. 1, 3
• Do NOT perform penicillin skin testing for this delayed morbilliform eruption, as it has limited diagnostic value for non-IgE-mediated reactions. 1

Antibiotic Management During Acute Illness

No Antibiotics Are Indicated for Mononucleosis

• Infectious mononucleosis is a self-limiting viral illness that does not require antibacterial therapy. 1
• If amoxicillin was prescribed for a presumed bacterial infection (e.g., pharyngitis, otitis media) that was actually mononucleosis, the original indication was inappropriate. 1

If Concurrent Bacterial Infection Requires Treatment

• Switch to a non-beta-lactam antibiotic such as a macrolide (azithromycin, clarithromycin) if bacterial infection is confirmed and treatment is necessary. 3
• Note that macrolides can also rarely cause rash in EBV infection (only 2 cases reported with azithromycin), though this is much less common than with beta-lactams. 5
• Other beta-lactams including piperacillin/tazobactam have also been reported to cause rash in mononucleosis and should be avoided. 6

Common Pitfalls to Avoid

• Do not continue amoxicillin "to complete the course" when the original indication was inappropriate—this only increases harm without benefit. 1
• Do not prescribe alternative antibiotics (cephalosporins, macrolides) for viral pharyngitis or upper respiratory infections, as no antibacterial therapy is indicated. 1
• Do not confuse this benign rash with true drug allergy requiring permanent avoidance—only severe reactions (anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis) mandate permanent penicillin avoidance. 1, 3
• Do not order penicillin skin testing for delayed morbilliform rashes, as this test is designed for immediate IgE-mediated reactions and has poor sensitivity/specificity for delayed reactions. 1