What should be done for a patient with infectious mononucleosis who develops a rash after taking penicillin?

Management of Penicillin-Associated Rash in Infectious Mononucleosis

Stop the penicillin immediately and do not label this patient as penicillin-allergic—this is a non-allergic, virus-mediated drug eruption specific to infectious mononucleosis that does not represent true penicillin allergy. 1

Understanding the Mechanism

This rash represents a transient, virus-mediated immune alteration rather than true IgE-mediated penicillin allergy:

• The mechanism involves temporary loss of antigenic tolerance during active Epstein-Barr virus (EBV) infection, creating a reversible delayed-type hypersensitivity reaction to aminopenicillins 1
• This is not an IgE-mediated allergic reaction and does not predict future penicillin allergy 1
• The phenomenon occurs in approximately 30-55% of patients with infectious mononucleosis who receive aminopenicillins, though historical rates were higher (up to 100% in older literature) 1

Immediate Management Steps

Discontinue the penicillin immediately:

• The rash is self-limiting and typically resolves within days to 10 days after stopping the causative antibiotic 2, 3
• No specific treatment is required beyond discontinuation 2
• Symptomatic relief with antihistamines may be provided if pruritus is present 1

Confirm the diagnosis of infectious mononucleosis if not already done:

• Check EBV-specific antibodies (IgM and IgG for acute infection) 2
• Monospot test can provide rapid confirmation 2
• Complete blood count typically shows lymphocytosis with atypical lymphocytes (Downey cells) 4

Critical Point: This is NOT a Penicillin Allergy

Do not document this as a penicillin allergy in the medical record:

• This reaction does not indicate future risk of penicillin allergy once the viral infection resolves 1
• Patients can safely receive penicillin antibiotics in the future without increased risk 1
• Documenting this as an allergy leads to unnecessary avoidance of first-line antibiotics and potential use of broader-spectrum, more expensive, or less effective alternatives 5

Alternative Antibiotic Selection (If Needed)

If continued antibiotic therapy is required for the original infection:

• Avoid all aminopenicillins (ampicillin, amoxicillin) during the acute mononucleosis infection, as these have the highest association with rash 1, 4
• Consider alternative antibiotics based on the indication:
  • For streptococcal pharyngitis: Use cephalexin, azithromycin, or clindamycin 1
  • For other infections: Select based on culture and sensitivity data 6

Important caveat: Other antibiotics including azithromycin, piperacillin/tazobactam, and even non-penicillin antibiotics have been reported to cause similar rashes in infectious mononucleosis, though less frequently than aminopenicillins 2, 7, 1

Patient Education

Counsel the patient explicitly:

• This rash does not mean they are allergic to penicillin 1
• The reaction is specific to having penicillin during active mononucleosis 1
• They can safely receive penicillin antibiotics in the future after recovery from mononucleosis 1
• They should inform future providers about this episode to avoid confusion, but emphasize it was not a true allergy 1

Common Pitfall to Avoid

The most critical error is mislabeling this as penicillin allergy:

• Approximately 90% of patients labeled as penicillin-allergic are not truly allergic 5
• False penicillin allergy labels lead to use of broader-spectrum antibiotics, increased antibiotic resistance, higher costs, and worse outcomes 5
• This specific scenario (aminopenicillin rash during infectious mononucleosis) is a well-recognized non-allergic phenomenon that should never result in a permanent allergy label 1

Future Penicillin Use

When this patient needs penicillin in the future (after mononucleosis has resolved):

• No penicillin skin testing is required 5
• Penicillin can be prescribed normally without special precautions 1
• If there is residual concern, direct oral challenge with amoxicillin can be performed, though this is unnecessary in most cases 5