A population-based study of more than 3 million older adults in Ontario, Canada, found that commonly prescribed oral antibiotics may be associated with an increased risk of serious cutaneous adverse drug reactions requiring emergency department visits or hospitalization.

In the study, published in JAMA, investigators compared the risk of serious cutaneous adverse drug reactions across different antibiotic classes using macrolides as the reference group. They conducted a nested case-control study using population-based linked administrative data sets for adults aged 66 years or older who received at least one oral antibiotic prescription between April 1, 2002, and March 31, 2022. The study included 21,758 cases who had an emergency department visit or hospitalization for serious cutaneous adverse drug reactions within 60 days of antibiotic prescription, matched with 87,025 controls.

The total cohort comprised 3.3 million older adults with outpatient antibiotic prescriptions. Serious cutaneous adverse drug reactions were identified using International Classification of Diseases, Tenth Revision (ICD-10) codes for drug exanthems as the main diagnosis for emergency department visits or admitting diagnosis for hospitalizations. The investigators used conditional logistic regression to estimate odds ratios, adjusting for factors such as malignancy, chronic kidney disease, chronic liver disease, human immunodeficiency virus (HIV) infection, and health care utilization measures.

Among the key findings were:

• Sulfonamide antibiotics had the highest risk (adjusted odds ratio [OR] = 2.9, 95% confidence interval [CI] = 2.7–3.1), followed by cephalosporins (adjusted OR = 2.6, 95% CI = 2.5–2.8).
• Other antibiotics with increased risk included nitrofurantoin (adjusted OR = 2.2, 95% CI = 2.1–2.4), penicillins (adjusted OR = 1.4, 95% CI = 1.3–1.5), and fluoroquinolones (adjusted OR = 1.3, 95% CI = 1.2–1.4).
• The crude rate of cutaneous adverse drug reaction–related hospital visits was 2.12 per 1,000 antibiotic prescriptions (95% CI = 2.11–2.14).
• Cephalosporins had the highest absolute risk at 4.92 per 1,000 prescriptions (95% CI = 4.86–4.99).

Antibiotic Prescriptions:

• Penicillins: 28.9%
• Cephalosporins: 18.2%
• Fluoroquinolones: 16.5%
• Macrolides: 14.8%
• Nitrofurantoin: 8.6%
• Sulfonamides: 6.2%
• Other antibiotics: 6.9%.

Crude Rates of Serious Cutaneous Adverse Drug Reactions per 1,000 Prescriptions:

• Cephalosporins: 4.92 (95% CI = 4.86–4.99)
• Sulfonamides: 3.22 (95% CI = 3.15–3.28)
• Fluoroquinolones: 2.48 (95% CI = 2.44–2.52)
• Nitrofurantoin: 2.33 (95% CI = 2.28–2.38)
• Penicillins: 1.94 (95% CI = 1.91–1.97)
• Macrolides: 1.80 (95% CI = 1.76–1.84).

Hospitalization Outcomes:

• 13.1% of cases (2,852/21,758) were hospitalized
• Median length of stay: 6 days (interquarticle range [IQR] = 3–13 days)
• 9.6% required critical care unit admission
• 74.1% were discharged home
• Overall in-hospital mortality: 5.3%.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) Subgroup:

• 50 patients (1.8% of hospitalized cases) had SJS/TEN
• 20.0% required critical care or burn unit admission
• In-hospital mortality for SJS/TEN: 20.0%.

Demographic and Clinical Characteristics:

• Median age of cases: 75 years (IQR = 70–82)
• Sex distribution: 64.1% female, 35.9% male
• Urban residence: 76.9% of cases
• Long-term care facility residents: 3.9% of cases.

Comorbidities in cases:

• Malignancy: 20.9%
• Chronic kidney disease: 3.9%
• Chronic liver disease: 0.7%
• HIV infection: 0.1%.

Health Care Utilization (median, IQR) for cases in the year preceding the index date:

• Number of prescribed drugs: 11 (7–15)
• Number of emergency department visits: 1 (0–3)
• Number of physician visits: 18 (10–29).

Antibiotic Prescription Details:

• Median latency period between prescription and hospital visit: 14 days (IQR = 7–35 days)
• Median duration of antibiotic prescription: 7 days (IQR = 7–10 days)
• Total number of antibiotic prescriptions during the study period: 34.1 million.

Hospital Visit Breakdown:

• ED visits only: 86.9% (18,906/21,758 cases)
  • Hospitalizations: 13.1% (2,852/21,758 cases)
  • ED visit rate: 1.85 per 1,000 prescriptions
  • Hospitalization rate: 0.28 per 1,000 prescriptions.

Sensitivity Analyses:

• 30-day latency period: Results were consistent with primary analysis, but with larger effect sizes for all antibiotic classes
• Cases receiving oral steroids within 2 days of discharge: Consistent findings with larger effect sizes
• Stratification by ED visit vs hospitalization: Similar findings, except penicillins showed no increased risk for hospitalized cases (adjusted OR = 1.1, 95% CI = 0.9–1.3)
• Adjustment for apparent infection site: Results remained consistent with the primary analysis.

The investigators concluded that while the absolute risk of antibiotic-associated serious cutaneous adverse drug reactions was relatively low, the findings underscored the importance of judicious antibiotic prescribing, with preferential use of lower-risk antibiotics when clinically appropriate. They noted that this was one of the first studies to provide population-based estimates of relative and absolute risks of serious cutaneous adverse drug reactions following outpatient antibiotic therapy.

Limitations of the study included reliance on ICD-10 codes for case identification, potential underestimation of milder cases not requiring hospital care, and inability to account for genetic susceptibility or over-the-counter medication use.

Conflict of interest disclosures can be found in the study.