What is the most likely diagnosis in a 17‑year‑old who developed a rash after a short course of amoxicillin for presumed streptococcal pharyngitis, with a negative monospot test and mild lymphopenia?

Most Likely Diagnosis: Amoxicillin-Associated Rash in the Setting of Viral Pharyngitis

This 17-year-old most likely has a benign maculopapular drug eruption (MDE) from amoxicillin occurring in the context of a concurrent viral infection, not a true IgE-mediated drug allergy. The negative monospot does not exclude all viral causes, and the lymphopenia supports an ongoing viral process rather than bacterial streptococcal infection.

Understanding the Clinical Scenario

Why This Rash Developed

• Aminopenicillins (amoxicillin/ampicillin) cause delayed-onset maculopapular rashes in <7% of patients, compared to only ~2% with penicillin VK, and these reactions are postulated to require the presence of a concurrent viral infection or underlying illness. 1

• The classic example is Epstein-Barr virus (EBV) infection treated with amoxicillin or ampicillin, where 30-100% of patients develop a nonpruritic morbilliform rash. 1 However, a negative monospot does not rule out early EBV (false-negative rate in first week) or other viral pathogens.

• Viruses are the most common cause of acute pharyngitis, including adenovirus, parainfluenza, rhinovirus, respiratory syncytial virus, coxsackievirus, ECHO viruses, and herpes simplex virus. 1 Any of these can trigger amoxicillin rashes.

• The lymphopenia in this patient strongly suggests a viral etiology rather than bacterial streptococcal pharyngitis, which typically shows leukocytosis >12,000/mm³ with neutrophilia. 2

This Is NOT a True Drug Allergy

• These benign cutaneous eruptions are not related to specific IgE antibodies and represent non-immune-mediated reactions that occur when the drug is given during certain viral infections. 1

• Infections are prominent in the development of benign cutaneous eruptions in children and adolescents treated with amoxicillin, resulting in low rates of confirmed true allergy. 1

• Studies of rechallenge testing show reaction rates of only 5-10%, and these were generally no more severe than the historical reactions, confirming that most patients can safely receive amoxicillin again. 1

Differential Diagnosis Considerations

Ruling Out Serious Conditions

• The rash should be characterized: maculopapular exanthem or urticaria without systemic symptoms, blistering, exfoliation, or mucous membrane involvement indicates a benign process. 1

• Absence of respiratory symptoms, cardiovascular symptoms, or anaphylaxis excludes IgE-mediated immediate hypersensitivity. 1

• Late-onset rashes (7-20 days after GAS pharyngitis onset) have been documented in 2% of patients treated with amoxicillin, characterized by maculopapules with symmetrical distribution and propensity for extremities, with good clinical courses and resolution within 14 days. 3

Why the Strep Diagnosis Was Likely Wrong

• Group A streptococcal pharyngitis is primarily a disease of children 5-15 years of age, but even in this age group, only 20-30% of acute pharyngitis cases are actually GAS. 1

• The presence of cough, rhinorrhea, hoarseness, or conjunctivitis strongly suggests viral rather than streptococcal etiology. 1, 2

• Without microbiological confirmation (positive rapid strep test or throat culture), the diagnosis of streptococcal pharyngitis should not be assumed, as clinical features overlap too broadly between viral and bacterial causes. 2

Management Approach

Immediate Actions

• Discontinue amoxicillin immediately. The rash will typically resolve within days to 2 weeks without intervention. 3

• Provide symptomatic treatment only: analgesics (acetaminophen or ibuprofen, avoiding aspirin in adolescents due to Reye syndrome risk), adequate hydration, and reassurance. 1, 2

• Monitor for progression to severe cutaneous adverse reactions (blistering, mucosal involvement, systemic symptoms), though this is extremely unlikely given the benign presentation. 1

Allergy Evaluation and Future Antibiotic Use

• This patient should NOT be labeled as penicillin-allergic based on this presentation alone. 1

• Direct amoxicillin challenge without prior skin testing is recommended for pediatric and adolescent patients with a history of benign cutaneous reaction (MDE or urticaria) not accompanied by systemic symptoms. 1

• If future amoxicillin is needed and there is concern, penicillin skin testing may be performed at the discretion of the clinician, though it is not required and may "overdiagnose" allergy in a small minority. 1

• The benefit of proceeding with testing or direct challenge far outweighs not testing, given that >90% of patients with reported penicillin allergy are not truly allergic. 1

Addressing the Negative Monospot

• A negative monospot does not exclude EBV infection, as heterophile antibodies may not be detectable in the first 1-2 weeks of illness, particularly in younger patients. 2

• If clinical suspicion for infectious mononucleosis remains high (severe pharyngitis, posterior cervical lymphadenopathy, splenomegaly, atypical lymphocytes), consider EBV-specific serology (VCA-IgM, VCA-IgG, EBNA). 2

• However, the specific viral etiology does not change management, as treatment remains supportive regardless. 2

Common Pitfalls to Avoid

• Do not label this patient as penicillin-allergic without proper evaluation, as this leads to unnecessary use of broad-spectrum antibiotics, increased costs, and worse outcomes in future infections. 1

• Do not assume all rashes during antibiotic treatment represent true drug allergy—concurrent viral infections are a major confounding factor, especially in adolescents. 1

• Do not prescribe antibiotics for presumed streptococcal pharyngitis without microbiological confirmation (positive rapid strep test or throat culture), as this leads to overtreatment of viral infections. 1, 2

• Do not perform routine follow-up testing after the rash resolves in an asymptomatic patient, as this is not indicated. 1, 4

Patient and Family Counseling

• Explain that this rash likely represents an interaction between the antibiotic and a viral infection, not a true drug allergy. 1

• Reassure that the rash will resolve on its own within 1-2 weeks and does not indicate a serious condition. 3

• Advise that future use of amoxicillin or penicillin is likely safe, but if there is concern, formal allergy evaluation can be pursued before the next course. 1

• Emphasize that most sore throats are viral and self-limited, resolving within 3-4 days without antibiotics, and that future episodes should be evaluated with proper testing before starting antibiotics. 1