Trimethoprim/sulfamethoxazole-induced phenytoin toxicity in the elderly: a population-based study

center dot Drug interactions are an important and avoidable, yet underappreciated cause of phenytoin toxicity. center dot Trimethoprim (TMP), a potent inhibitor of the CYP2C8 isoenzyme that is commonly administered with sulfamethoxazole (SMX) for the treatment of urinary tract infections, is known to reduce phenytoin clearance by 30%. Given the saturable nature of phenytoin metabolism, decreases in phenytoin clearance of this magnitude may be clinically significant. WHAT THIS STUDY ADDS center dot Prescription of TMP/SMX was associated with a more than doubling of the risk of hospitalization for phenytoin toxicity [adjusted odds ratio 2.11, 95% confidence interval (CI) 1.24, 3.60]. center dot Co-prescription of TMP/SMX and phenytoin is common. In our study, approximately 20% of phenytoin users received at least one prescription for TMP/SMX, thereby being placed at excess risk of phenytoin toxicity. AIMS Pharmacokinetic studies suggest that trimethoprim (TMP) can inhibit the hepatic metabolism of phenytoin, but the clinical relevance of this is uncertain. We studied the risk of phenytoin toxicity following the prescription of trimethoprim/sulfamethoxazole (TMP/SMX), a commonly used antibiotic, among elderly patients receiving phenytoin. METHODS We conducted a population-based, nested case-control study of a cohort of Ontario residents aged 66 years of age or older treated with phenytoin over a 17-year period (April 1 1992 to March 31 2009). Within this group, case patients were those hospitalized with phenytoin toxicity. For each case, we identified up to four control patients from the same cohort, matched for age and sex, and determined the odds ratio (OR) for the association between phenytoin toxicity and receipt of TMP/SMX in the preceding 30 days. RESULTS Among 58 429 elderly patients receiving phenytoin during the study period, we identified 796 case patients hospitalized for phenytoin toxicity and 3148 matched controls. Following multivariable adjustment for potential confounders, we observed a more than doubling of the risk of phenytoin toxicity following the receipt of TMP/SMX [adjusted OR 2.11, 95% confidence interval (CI) 1.24, 3.60]. In contrast, we observed no such risk with amoxicillin, an antibiotic with similar indications but not expected to interact with phenytoin (adjusted OR 1.12, 95% CI 0.64, 1.98). CONCLUSION Among older patients receiving phenytoin, treatment with TMP/SMX is associated with a more than twofold increase in the risk of phenytoin toxicity. When clinically appropriate, alternate antibiotics should be considered for these patients.