What is the best course of action for a patient with a positive rapid strep (streptococcal) test, who developed a rash after the fourth dose of penicillin (penicillin), and may have infectious mononucleosis?

Management of Penicillin Rash in Strep Pharyngitis

Stop the penicillin immediately and switch to a non-beta-lactam antibiotic, as this patient likely has infectious mononucleosis causing a drug eruption rather than true penicillin allergy. 1, 2, 3

Understanding the Clinical Scenario

This presentation is classic for infectious mononucleosis (EBV infection) masquerading as strep pharyngitis. The key distinguishing feature is the rash developing after several doses of penicillin—this is pathognomonic for EBV-associated drug eruption, not IgE-mediated penicillin allergy. 1, 2, 3

Why This Matters Clinically

• Patients with infectious mononucleosis develop rash in 80-100% of cases when given aminopenicillins (ampicillin/amoxicillin), and this phenomenon extends to other beta-lactams including penicillin V, piperacillin/tazobactam, and even azithromycin. 2, 3
• This is NOT a true penicillin allergy—it's a transient immune-mediated reaction specific to the combination of EBV infection and beta-lactam exposure. 2, 3
• The rash is self-limiting and resolves within days of stopping the offending antibiotic, without requiring corticosteroids or antihistamines. 3

Immediate Management Algorithm

Step 1: Discontinue Penicillin

• Stop penicillin immediately upon rash development. 3
• Document this as "EBV-associated drug eruption" rather than "penicillin allergy" to avoid unnecessary future avoidance of beta-lactams. 2, 3

Step 2: Confirm Infectious Mononucleosis

• Order heterophile antibody test (monospot) and EBV-specific serology (EBV IgM and IgG). 1, 3
• Look for clinical clues: significant fatigue, palatal petechiae, posterior cervical adenopathy, marked lymphadenopathy, or atypical lymphocytosis ≥20% on CBC. 1
• False-negative monospot tests occur early in infection—if clinical suspicion is high and initial test is negative, repeat in 5-7 days or send EBV serology. 1

Step 3: Switch Antibiotic for Strep Coverage

For confirmed strep pharyngitis requiring continued treatment:

• First choice: Clindamycin 300 mg orally every 6 hours for 10 days (or 20-30 mg/kg/day in 3 doses for children, max 300 mg/dose). 4, 5, 6

  • Provides excellent streptococcal coverage without beta-lactam structure. 4
  • Avoid if local MRSA clindamycin resistance >10%. 4

• Alternative: Azithromycin 500 mg day 1, then 250 mg daily for days 2-5 (or 12 mg/kg once daily for 5 days in children). 4

  • Caution: Azithromycin can also cause rash in EBV, though less commonly than penicillins. 2
  • Use only if clindamycin is contraindicated.

• Do NOT use cephalosporins—cross-reactivity with EBV-associated drug eruption has been reported, though less common than with penicillins. 3

Critical Decision Point: Does This Patient Actually Need Antibiotics?

If infectious mononucleosis is confirmed, the positive rapid strep may represent:

1. Chronic streptococcal carriage with concurrent viral pharyngitis (most likely). 4
2. True co-infection (less common but possible). 4

How to Distinguish Carrier State from True Infection

Clues favoring carrier state: 4

• Patient was "feeling much better" before the rash developed (suggests viral illness already resolving)
• Absence of high fever, severe pharyngeal erythema, or tonsillar exudates
• Presence of viral symptoms: cough, rhinorrhea, conjunctivitis, hoarseness

Clues favoring true strep infection: 4, 7

• Centor criteria: fever history, tonsillar exudates, tender anterior cervical lymphadenopathy, absence of cough
• Scarlatiniform rash (sandpaper texture, different from maculopapular EBV rash)
• Persistent high fever despite several days of appropriate antibiotics

Management Based on Likelihood

If carrier state is likely (patient improving, viral features present):

• Stop all antibiotics—no further strep treatment needed. 4
• Provide supportive care for EBV: adequate hydration, analgesics (acetaminophen or ibuprofen), rest as tolerated. 1
• Do NOT enforce bed rest—activity should be guided by patient's energy level. 1
• Avoid contact/collision sports for 4 weeks due to splenic rupture risk. 1

If true co-infection is likely (persistent fever, classic strep features):

• Complete 10-day course with clindamycin as above. 4
• Continue supportive care for EBV symptoms. 1

Common Pitfalls to Avoid

1. Labeling this as "penicillin allergy"—this creates lifelong unnecessary avoidance of first-line antibiotics. The patient can safely receive penicillins in the future once EBV infection has resolved. 2, 3

2. Prescribing corticosteroids for the rash—unnecessary unless respiratory compromise or severe pharyngeal edema develops. The rash resolves spontaneously with drug discontinuation. 1, 3

3. Continuing antibiotics for strep when EBV is confirmed—most positive strep tests in EBV represent carriage, not true infection. 4

4. Using cephalosporins as "safe alternative"—cross-reactivity with EBV-associated eruption can occur. 3

5. Treating recurrent positive strep cultures after completing therapy—chronic carriers with intercurrent viral infections don't need repeated antibiotic courses unless special circumstances exist (rheumatic fever history, outbreak setting). 4

Follow-Up Recommendations

• Reassess in 24-48 hours to confirm rash is improving after stopping penicillin. 3
• Educate patient that this was NOT a true allergy and penicillins can be used safely in the future. 2, 3
• Warn about prolonged fatigue—myalgias, fatigue, and need for sleep may persist for several months after acute EBV infection resolves. 1
• No routine post-treatment throat culture needed unless patient remains symptomatic or special circumstances exist. 4