Amoxicillin Rash or The Symptom That Confuses Doctors

A seven-year-old girl arrives at the hospital with a fever, red eyes, swollen lymph nodes, lip redness, and a mysterious rash. At first, doctors suspect a drug reaction. But as the case unfolds, it becomes clear that the diagnosis isn’t so simple. Could it be Kawasaki disease, a viral rash, or something else entirely?

This case was uncovered through the DrugCard platform’s literature monitoring, underscoring the importance of tracking medical literature to identify rare but critical drug safety patterns. Welcome to a classic pharmacovigilance conundrum.

The Confusing Clinical Course: A Case of Shifting Diagnoses

Her journey began two weeks earlier with fever and a diagnosis of acute otitis media, treated with amoxicillin. The fever resolved, and she seemed on the road to recovery briefly. However, four days before hospitalization, new symptoms emerged – cough, sore throat, nasal congestion, and a high fever. This led to another clinic visit, where she was prescribed clarithromycin for suspected acute bronchitis.

Then came the turning point. A generalized, painful, itchy rash erupted, raising red flags. Suspecting a drug reaction, clinicians discontinued clarithromycin, yet the symptoms worsened. Soon after, a new suspicion emerged – Kawasaki disease, leading to hospitalization. But was Kawasaki the true culprit, or was this a case of a misattributed adverse drug reaction?

The Pharmacovigilance Challenge: Antibiotic Rash vs. Underlying Viral Infection

On admission, the girl had a high fever (39.5°C), tachycardia, and lethargy. Clinical signs pointed toward Kawasaki disease, fulfilling five major criteria. Yet, something didn’t quite fit. The rash had distinct characteristics – erythematous papules coalescing into larger patches, accompanied by pain and itching – features atypical for a classic Kawasaki exanthem.

While Kawasaki remained a strong possibility, a deeper investigation into alternative causes was warranted. Blood tests revealed elevated CRP and mild hyponatremia but no leukocytosis. Cultures were negative. Something was missing.

Epstein-Barr Virus and Amoxicillin Rash

A crucial step in differential diagnosis? Serological testing. Results revealed:

EBV viral capsid antigen (VCA)-IgM and VCA-IgG: Positive

Epstein-Barr nuclear antigen (EBNA): Negative

The verdict? An Acute Epstein-Barr virus (EBV) infection. The rash was not an allergic reaction to antibiotics but a well-known phenomenon – amoxicillin rash in latent EBV Infection. 

Cracking the Case: Why EBV Patients Develop Amoxicillin Rash

A well-documented but often misinterpreted event, amoxicillin rash in EBV patients, is not a true allergic reaction. Instead, it represents a non-IgE-mediated immune response triggered when amoxicillin is administered during active EBV infection.

This rash is:

Maculopapular, often confluent, and non-urticarial

Delayed in onset (days after antibiotic initiation)

Self-limiting, resolving as the viral infection subsides

The Takeaways: Pharmacovigilance Lessons from This Case

Beware of misdiagnosing amoxicillin rash as a drug allergy – Many patients labelled as “penicillin-allergic” are not truly allergic but have experienced this transient reaction.

EBV infections can mimic Kawasaki disease – This case emphasizes the importance of serological testing before committing to a Kawasaki diagnosis.

A pharmacovigilance mindset matters – Recognizing atypical patterns in drug reactions prevents mislabeling and improves patient management.

Outcome and Final Thoughts

The patient received IVIG and aspirin for suspected Kawasaki disease but made a full recovery without complications. Had the EBV diagnosis been confirmed earlier, unnecessary concern over antibiotic allergy could have been avoided.

For pharmacovigilance specialists, this case highlights the importance of recognizing non-allergic antibiotic reactions and the need for careful differential diagnosis in pediatric rashes.