A recent study published in JAMA highlights the significant risks associated with commonly prescribed oral antibiotics and their link to serious cutaneous adverse drug reactions (cADRs), such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS). These life-threatening hypersensitivity conditions can have mortality rates as high as 20-40% for TEN. Upon ingestion, certain antibiotics are metabolized into reactive metabolites that form complexes with skin proteins, which are then recognized as foreign by the immune system. This recognition triggers the activation of cytotoxic T-cells, leading to the release of pro-inflammatory cytokines and the induction of apoptosis (cell death) in keratinocytes, the skin cells. The widespread cell death results in the detachment of the epidermis, causing the characteristic blistering and necrosis seen in severe cADRs. This immune response not only damages the skin but can also lead to systemic symptoms and life-threatening complications, underscoring the need for careful antibiotic selection to minimize such risks.
The study findings are crucial for guiding safer antibiotic prescribing practices, particularly among elderly populations. Researchers analyzed data from a large-scale cohort of elderly individuals (over 66 years old) in Ontario, Canada, using administrative health records spanning 20 years (2002-2022). The study involved 3,257,181 participants, of which 21,758 experienced antibiotic-related cADRs. These individuals were compared with 87,025 control participants who did not develop cADRs despite antibiotic exposure. The study aimed to investigate the differential risks of cADRs associated with various classes of antibiotics. While previous research has recognized antibiotics as risk factors for cADRs, no study has systematically compared the risks across different antibiotic classes.
The researchers followed a rigorous methodology adhering to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and Reporting of Studies Conducted Using Observational Routinely Collected Health Data Statement for Pharmacoepidemiology (RECORD-PE) guidelines. Participants were included if they were at least 65 years old at the time of enrollment, had comprehensive medical and demographic records, and had been hospitalized for cADRs within 60 days of antibiotic prescription for the case-cohort.
Each cADR case was matched with up to four controls based on age and sex. Patients undergoing multiple simultaneous antibiotic treatments were excluded from the study to avoid confounding factors. The primary outcome was the incidence of serious antibiotic-associated cADRs requiring hospitalization. Macrolides, previously identified as low risk for cADRs, were used as a reference group for comparison with other antibiotic classes. Over the two-decade study period, the researchers identified 34,114,254 antibiotic courses, which were linked to 72,449 serious cADRs, translating to 2.12 cADRs per 1,000 prescriptions. The average time from antibiotic prescription to hospitalization was found to be 14 days.
Penicillins were the most frequently prescribed antibiotics in both the case and control cohorts, accounting for 28.9% of prescriptions, followed by cephalosporins (16.5%), fluoroquinolones (14.8%), nitrofurantoin (8.6%), and sulfonamides (6.2%). Antibiotics not included in these classes were grouped and constituted 6.9% of prescriptions. Statistical analysis revealed that sulfonamides posed the highest risk of cADRs, with an adjusted odds ratio (aOR) of 2.9, corresponding to 3.22 cADRs per 1,000 prescriptions. Cephalosporins followed with an aOR of 2.6, while nitrofurantoin (aOR = 2.2), penicillins (aOR = 1.4), and fluoroquinolones (aOR = 1.3) also demonstrated significant risks. Among the 21,758 cADR cases, 2,852 (13.1%) required hospitalization within 60 days of outpatient antibiotic use, with SJS/TEN being explicitly identified in 50 cases (1.8%). Although in-hospital mortality for all serious cADRs was relatively low (5.3%), the mortality rate for SJS/TEN was notably higher at 20.0%.
Cutaneous drug reactions affect 2-3% of hospitalized patients, with most being mild, self-limiting, and resolving once the offending drug is discontinued. However, severe and potentially life-threatening reactions occur in about 1 in 1000 hospitalized patients. Mortality rates are notably higher for erythema multiforme (EM) major. SJS has a mortality rate of less than 5%, while TEN has a significantly higher rate, ranging from 20-30%, with sepsis being the leading cause of death. Women are more likely than men to experience adverse cutaneous drug reactions, and the incidence increases with age, making elderly patients more susceptible to these reactions.
The study findings underscore the need for medical practitioners to consider the potential cADR risks when prescribing antibiotics, particularly in elderly patients who are more vulnerable to adverse drug reactions due to higher antibiotic consumption, comorbidities, and polypharmacy. Selecting lower-risk antibiotics whenever clinically feasible could reduce the incidence of these severe reactions and improve patient outcomes.
References
- Lee EY, Gomes T, Drucker AM, Daneman N, Asaf A, Wu F, et al. Oral Antibiotics and Risk of Serious Cutaneous Adverse Drug Reactions. JAMA [Internet]. 2024 Aug 8 [cited 2024 Aug 13]; Available from: https://doi.org/10.1001/jama.2024.11437
- Al Aboud DM, Nessel TA, Hafsi W. Cutaneous Adverse Drug Reaction. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Aug 13]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK533000/
- Nayak S, Acharjya B. ADVERSE CUTANEOUS DRUG REACTION. Indian J Dermatol. 2008;53(1):2–8.