A NEW systematic review and meta-analysis reveals that the risk of rash in patients with infectious mononucleosis (IM) who are prescribed aminopenicillins is significantly lower than long believed, challenging decades-old assumptions in clinical practice.
The study analyzed 15 observational studies and 34 case reports comprising over 3,100 patients with IM. Historically, the development of a rash following aminopenicillin administration, particularly ampicillin and amoxicillin, has been considered a hallmark contraindication. However, this research provides a more nuanced understanding of the association. The pooled estimate for rash occurrence after aminopenicillin exposure was 43%, compared to 15% for other antibiotics and 14% with no antibiotics at all.
The study’s findings were strikingly different when analyzed across time. Older studies from 1967 to 1976 showed an 84% rash rate after aminopenicillin use. In contrast, newer studies from 2012 to 2024 reported only an 18% rate. This dramatic decline suggests that previous estimates may have been inflated by confounding factors, including differences in diagnostic accuracy, formulations, or patient populations.
A secondary meta-analysis reinforced the primary findings, showing that aminopenicillin use was associated with a significantly increased risk of rash (odds ratio 5.4; 95% CI 1.8–16.3) compared to no antibiotics. However, the authors emphasize the high heterogeneity (I² = 89%) and note that neither patient age nor study quality reduced this variability.
This study challenges the prevailing belief that aminopenicillins should be categorically avoided in IM patients due to rash risk. While caution is still warranted, particularly in uncertain diagnostic cases, the findings may prompt reconsideration of automatic exclusion of aminopenicillins in this population. Further prospective research could help clarify safe prescribing practices.
Reference:
Vrysis C et al. Rash associated with antibiotic administration in patients with infectious mononucleosis: a systematic review and meta-analysis. Eur J Clin Microbiol Infect Dis. 2025. doi: 10.1007/s10096-025-05189-3. [Online ahead of print]
