Assessment of drug allergy and determination of safe alternative medications: a retrospective observational study.

Background: Drug hypersensitivity reactions (DHRs) represent a major clinical challenge because of their heterogeneous presentations and their impact on future therapeutic choices. Accurate diagnosis and identification of safe alternative medications are essential to optimize patient management and avoid unnecessary drug restrictions. Methods: This retrospective observational study included 541 consecutive patients referred for evaluation of suspected drug hypersensitivity between January 2024 and June 2025. Demographic characteristics, comorbidities, clinical presentations, culprit drugs, and results of skin prick, intradermal, and oral provocation tests were analyzed. Drug classes, reaction phenotypes, and age-related differences were evaluated. Alternative medication challenge protocols were used to identify safe treatment options. Results: The study included 541 patients (70.1% female; mean age 43.9 ± 13.5 years). Non-steroidal anti-inflammatory drugs (NSAIDs) (36.0%) and beta-lactam antibiotics (22.7%) were the most frequently implicated drug classes. Urticaria and angioedema predominated in NSAID-related reactions, whereas beta-lactams and proton pump inhibitors (PPIs) were more commonly associated with anaphylaxis. The frequency of anaphylaxis increased with age and was highest among patients aged 55-64 years. Among 195 patients with isolated NSAID hypersensitivity, 119 (61.0%) demonstrated a cross-reactive pattern involving two or more NSAID groups. Celecoxib was tolerated by all 238 challenged patients with isolated NSAID hypersensitivity or combined NSAID and beta-lactam hypersensitivity. Among 167 patients with beta-lactam hypersensitivity, 104 underwent a standardized alternative non-beta-lactam antibiotic challenge protocol routinely implemented in our clinic, consisting of azithromycin, ciprofloxacin, metronidazole, clindamycin, tetracycline, and sulfamethoxazole-trimethoprim. No adverse reactions were observed with azithromycin or tetracycline, whereas systemic reactions occurred with ciprofloxacin, metronidazole, clindamycin, and sulfamethoxazole-trimethoprim. Tramadol induced urticaria/angioedema in a subset of patients with NSAID-induced or NSAID-exacerbated cutaneous disease but was tolerated by all patients with NSAID-exacerbated respiratory disease. Suspected local anesthetic allergies were not confirmed in any patient. Conclusions: NSAIDs and beta-lactam antibiotics were the leading causes of suspected drug hypersensitivity in this cohort. Systematic allergy evaluation, including skin testing and oral provocation, enabled accurate diagnosis and identification of safe therapeutic alternatives. Celecoxib emerged as a safe alternative for patients with NSAID hypersensitivity, while azithromycin and tetracycline were well tolerated among selected patients with beta-lactam allergy. These findings support the use of structured diagnostic assessment to improve patient safety, prevent unnecessary drug avoidance, and guide evidence-based selection of alternative therapies.