Antibiotics Ranked by Risk for Serious Cutaneous Adverse Reactions

Six classes of oral antibiotics were found to present increased risk of serious cutaneous adverse drug reactions (cADR) relative to macrolides, in a population-based study1 of over 21,000 patients requiring emergency department (ED) treatment or hospitalization for cADR from over 3 million receiving outpatient antibiotic prescriptions.

"Although speculation exists that some antibiotics are more likely than others to cause cADRS, no population-based studies have explored this claim," observed Erika Lee, MD, MSc, Division of Clinical Immunology and Allergy, Department of Medicine, University of Toronto, Toronto, Ontario, Canada, and colleagues.

In their earlier review and meta-analysis2 of worldwide prevalence of the rare, but life-threatening Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), antibiotics were implicated for more than one-quarter of the cases worldwide.Among the antibiotic classes, however, they found macrolides associated with lowest risk. The investigators conducted this nested case-control population-based study to ascertain risk of other antibiotic classes relative to the macrolides.

"The present study looked at the class as a whole, but not individual antibiotics in that class," Lee told Contagion."The general approach is that once a patient has a severe allergic reaction to one antibiotic, the whole class is generally avoided due to the risk of cross-reactivity."

The cohort comprised older adults, median age 75 years. This age group is at increased risk for cADRS, Lee and colleagues explain, with several possible contributing factors, including: disproportionately more antibiotic prescriptions than younger people, more exposure to polypharmacy, and more likely to have such comorbidities as kidney insufficiency, liver disease, and malignancies.

Lee and colleagues accessed administrative health databases in Ontario, Canada from April 1, 2002 to March 31, 2022, to identify a cohort of outpatients receiving at least 1 oral antibiotic over that period, and defining the case patients who required ED care or were hospitalized for cADR and who received an antibiotic prescription in the preceding 60 days.Each was matched with up to 4 controls from the same cohort on age, sex, and an antibiotic prescription in the preceding 60 days, but without subsequent cADR.

Patients were excluded if they had received antibiotics from more than 1 class in the 60 days preceding the index date; as well as for prescriptions for other medications associated with serious cADRS in the preceding 90 days, including anticonvulsants, nonsteroidal anti-inflammatory drugs, and allopurinol.

Among a total of 34,114,254 courses of antibiotics, 72,449 were associated with serious cADR requiring ED treatment or hospitalization; a crude rate of 2.12 antibiotic-associated cADRs per 1,000 prescriptions (95% CI, 2.11-2.14).

All antibiotic classes were associated with higher risk for serious cADR than macrolides, with the sulfonamides presenting the highest relative risk (adjusted OR. 2.9; 95% CI, 2.7-3.1). The risk relative to macrolides, in decreasing order are: cephalosporins (aOR, 2.6; 2.5-2.8); "other" antibiotics (aOR, 2.3; 2.2-2.5); nitrofurantoin (aOR, 2.2; 2.1-2.4), penicillins (aOR, 1.4; 1.3-1.5); and fluoroquinolones (aOR, 1.3; 1.2-1.4).

"The finding of nitrofurantoin-associated severe drug allergy is surprising," Lee commented." The only indication for this antibiotic is urinary tract infection (UTI), so it is not as commonly used in the general population compared to other antibiotics that are prescribed for various indications.

In our study that concentrated in older adults, and UTI is one of the most common infections in this age group, we were able to identify this association.It would be interesting to see if this association is reproducible in the general population," Lee suggested.

The investigators advise that "prescribers should preferentially use lower-risk antibiotics when clinically appropriate," Lee elaborated, in discussing the study and findings.

"When prescribing an antibiotic, there are many factors that go through a physician's head to balance the safety and efficacy of the treatment," Lee said. "When there are equally effective options available, our study adds to the knowledge of safety, to consider when selecting an optimal option for the patient."

References

1. Lee EY, Gomes T, Drucker AM, et al. Oral antibiotics and risk of serious cutaneous adverse drug reactions JAMA Online August 8, 2024. doi:10.1001/jama.2024.11437. Accessed August 20, 2024.

2. Lee EY, Knox C, Phillips EJ. Worldwide prevalence of antibiotic-associated Stevens-Johnson and toxic epidermal necrolysis: A systematic review and meta-analysis. JAMA Dermatol 2023. 159(4):384-392.