What antibiotic should be prescribed for a patient with a positive rapid strep test (Group A streptococcus) and a positive mono spot test (mononucleosis) indicating concurrent mononucleosis infection?

Avoid Amoxicillin and Ampicillin—Use Penicillin V or a First-Generation Cephalosporin

For a patient with concurrent Group A streptococcal pharyngitis and infectious mononucleosis, you should NOT prescribe amoxicillin or ampicillin due to the high risk of a characteristic maculopapular rash; instead, prescribe penicillin V or, if penicillin-allergic, a first-generation cephalosporin like cephalexin. 1

Critical Clinical Context

• Amoxicillin and ampicillin cause a hypersensitivity rash in patients with infectious mononucleosis, occurring in the majority of patients who receive these antibiotics during acute EBV infection 1
• This rash is not a true penicillin allergy but rather a unique drug-virus interaction specific to aminopenicillins (amoxicillin/ampicillin) in the setting of EBV infection 1
• The incidence of concurrent GAS pharyngitis in patients with infectious mononucleosis is only 4%, making routine antibiotic treatment of all IM patients unjustified 2

Treatment Algorithm for This Specific Scenario

Step 1: Confirm Both Diagnoses Are Present

• Positive rapid strep test confirms GAS pharyngitis and requires antibiotic treatment to prevent acute rheumatic fever 3
• Positive monospot confirms infectious mononucleosis, which is typically a clinical diagnosis supported by >40% lymphocytes and >10% atypical lymphocytes on CBC 4

Step 2: Select Appropriate Antibiotic (Avoiding Aminopenicillins)

First-Line Treatment:

• Penicillin V 500 mg orally twice daily for 10 days (adults) or 250 mg four times daily for 10 days 3, 5
• Penicillin V does NOT cause the characteristic rash seen with amoxicillin/ampicillin in IM patients 1
• A full 10-day course is essential to achieve maximal pharyngeal eradication of GAS and prevent acute rheumatic fever 3

For Penicillin-Allergic Patients (Non-Immediate Reactions):

• Cephalexin 500 mg orally twice daily for 10 days (adults) or 20 mg/kg/dose twice daily in children 6
• First-generation cephalosporins have only 0.1% cross-reactivity risk in patients with non-severe, delayed penicillin reactions 6

For Immediate/Anaphylactic Penicillin Allergy:

• Clindamycin 300 mg orally three times daily for 10 days (adults) or 7 mg/kg/dose three times daily in children 6
• Clindamycin has approximately 1% resistance among GAS in the United States and does not cause the IM-associated rash 6

Step 3: Provide Supportive Care for Mononucleosis

• Treatment of IM is supportive only—routine use of antivirals and corticosteroids is not recommended 4
• Restrict athletic activity for 3 weeks from symptom onset to prevent splenic rupture 4
• Acetaminophen or NSAIDs for fever and pharyngeal pain; avoid aspirin in children due to Reye syndrome risk 6

Why This Matters: The Aminopenicillin-EBV Rash

• The rash from amoxicillin/ampicillin in IM patients is a hypersensitivity reaction, not a true IgE-mediated penicillin allergy 1
• This reaction occurs specifically with aminopenicillins (amoxicillin, ampicillin) but NOT with penicillin V or other penicillins 1
• Patients who develop this rash can safely receive penicillin V or other beta-lactams in the future once the IM has resolved 1

Common Pitfalls to Avoid

• Do not empirically treat all IM patients with antibiotics—only 4% have concurrent GAS pharyngitis, and antibiotics do not improve IM symptoms 2
• Do not prescribe amoxicillin or ampicillin when both GAS and IM are present—the rash occurs in the majority of these patients 1
• Do not assume the aminopenicillin rash represents a true penicillin allergy—these patients can receive penicillin V safely 1
• Do not shorten the antibiotic course below 10 days (except azithromycin's 5-day regimen)—this increases treatment failure and rheumatic fever risk 3

Special Consideration: When to Treat the Strep

• Because only 4% of IM patients have concurrent GAS, some experts question whether the positive rapid strep test represents true infection versus colonization 2
• However, given the positive rapid strep test, treatment is indicated to prevent suppurative complications and acute rheumatic fever 3
• Use penicillin V rather than amoxicillin to avoid the characteristic rash while still effectively treating the GAS pharyngitis 1