What is the appropriate management for a patient with a history of allergies who develops a rash while taking amoxicillin (amoxicillin)?

Management of Amoxicillin-Associated Rash

For patients with a mild maculopapular rash from amoxicillin, discontinue the drug if bothersome, treat symptomatically with oral antihistamines and topical corticosteroids, and do NOT permanently label the patient as penicillin-allergic—over 90% of these patients tolerate amoxicillin on re-exposure and this represents a benign, non-allergic phenomenon in most cases. 1, 2, 3

Immediate Assessment: Distinguish Benign from Severe Reactions

Benign Reactions (Most Common)

• Maculopapular rash is the most common presentation (36% of amoxicillin reactions), typically appearing 5-9 days after starting treatment 1, 2
• These delayed-onset rashes are NOT true IgE-mediated allergies in the vast majority of cases and do not require permanent penicillin avoidance 1, 2
• The maculopapular ampicillin/amoxicillin rash is a benign, non-allergic phenomenon that resolves spontaneously within days without sequelae 3

Severe Reactions Requiring Emergency Care

• Immediately discontinue amoxicillin and seek emergency evaluation if any of the following are present: 1, 4
  • Anaphylaxis (respiratory distress, hypotension, cardiovascular symptoms)
  • Blistering or skin exfoliation
  • Mucosal involvement (eyes, mouth, genitals)
  • Stevens-Johnson syndrome or toxic epidermal necrolysis
  • Angioedema
  • Urticaria with systemic symptoms

Symptomatic Management for Benign Rash

• Discontinue amoxicillin if the rash is bothersome or if the patient is anxious about continuing 1
• Oral antihistamines (e.g., cetirizine, diphenhydramine) for pruritus 1
• Topical corticosteroids for localized inflammation 1
• Acetaminophen or ibuprofen for associated fever or discomfort 1, 2
• If treating an active bacterial infection, consider switching to a non-beta-lactam antibiotic (e.g., macrolide, fluoroquinolone) 1

Special Consideration: Infectious Mononucleosis

• 30-100% of patients with Epstein-Barr virus (mononucleosis) develop a non-pruritic morbilliform rash when given amoxicillin—this is NOT a true drug allergy but a unique virus-drug interaction 1, 2
• These patients should NOT be labeled as penicillin-allergic and can safely receive penicillins after the viral infection resolves 2
• Amoxicillin should not be administered to patients with known mononucleosis 4

Documentation and Allergy Labeling

Do NOT Label as Penicillin-Allergic If:

• The rash was maculopapular without systemic symptoms 1, 2
• The reaction occurred during a viral illness (especially in children) 2
• The patient had infectious mononucleosis at the time of the rash 1, 2

DO Label as Penicillin-Allergic and Refer to Allergy If:

• Anaphylaxis occurred (within 1 hour of ingestion with urticaria, angioedema, respiratory or cardiovascular symptoms) 1, 2
• Severe cutaneous adverse reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome) 1, 4
• Serum sickness-like reaction with fever, arthralgia, and rash 5

Future Antibiotic Selection

For Patients with Benign Maculopapular Rash History:

• Direct oral amoxicillin challenge (single full therapeutic dose under medical observation for 60-90 minutes) is recommended when the patient next requires antibiotics 6, 2, 7
• Over 90% of children and 98% of adults with reported amoxicillin rashes tolerate the drug on re-exposure 2, 8, 9
• Penicillin skin testing has limited utility for non-IgE-mediated maculopapular rashes and should NOT be performed for this indication 2, 7

For Patients with Documented Severe Reactions:

• Avoid all penicillins permanently 1
• Avoid first- and second-generation cephalosporins due to cross-reactivity (approximately 2% risk) 1, 8
• Third-generation cephalosporins with dissimilar R1 side chains may be used with caution or after allergy consultation 6
• Formal allergy evaluation with skin testing is recommended before any beta-lactam use 1

Risk Stratification for Future Penicillin Use

Low-Risk Criteria (Direct Challenge Without Skin Testing):

• Reaction occurred >1 year ago 6, 7
• Benign maculopapular rash or urticaria without systemic symptoms 6, 7
• No anaphylaxis, angioedema, or severe cutaneous reactions 6, 7
• Unknown name of index drug with distant benign rash 6

High-Risk Criteria (Requires Skin Testing Before Challenge):

• Anaphylaxis or angioedema history 6, 7
• Severe cutaneous adverse reactions 6, 7
• Recent reaction (<1 year ago) with systemic symptoms 7
• Multiple beta-lactam hypersensitivities 8

Common Pitfalls to Avoid

• Do not permanently label patients as penicillin-allergic based solely on a maculopapular rash during viral illness—this leads to unnecessary use of broad-spectrum antibiotics, increased healthcare costs, antimicrobial resistance, and increased risk of Clostridioides difficile infection 2, 8
• Do not perform penicillin skin testing for delayed maculopapular rashes—skin testing only identifies IgE-mediated reactions and has poor sensitivity/specificity for delayed, non-IgE-mediated reactions 2, 7
• Do not assume cross-reactivity between penicillins and all cephalosporins—true cross-reactivity is only 2%, much lower than the previously reported 8% 8
• Do not continue amoxicillin in patients with known or suspected mononucleosis—the rash rate is extremely high (30-100%) and amoxicillin is contraindicated in this population 1, 2, 4