A Comparison of Adverse Drug Reactions Between High- and Standard- Dose Trimethoprim-Sulfamethoxazole in the Ambulatory Setting

Background: High-dose trimethoprim-sulfamethoxazole (TMP-SMX) for the empiric treatment of communityacquired methicillin-resistant Staphylococcus aureus skin and soft tissue infections has been evaluated for efficacy, but characterization of adverse reactions is lacking. Methods: To describe adverse reactions associated with high-dose TMP-SMX therapy, a retrospective medical record review of outpatients receiving TMP-SMX was conducted. Each episode (case) of a patient receiving high-dose TMPSMX (at least 4 double-strength tablets per day) was matched by next closest prescription number with a patient (control) receiving standard-dose TMP-SMX. Results: 982 cases were reviewed; 491 in each arm. At least one adverse drug reaction (ADR) occurred in 9.1% of patients. There was a significant difference in the incidence for any ADR between high-dose and standard-dose groups (13.0% vs 5.09%, respectively; p<0.0001). More patients taking high-dose TMP-SMX developed hyperkalemia (3.46% vs 0.81%, p=0.0066), acute renal injury (3.67% vs 1.63%, p=0.044), and rash (1.83% vs 0.20%, p=0.021). Patients receiving high-dose TMP-SMX had significantly higher rates of electrolyte abnormality ADR (5.09% vs 1.63%, p=0.0021), gastrointestinal ADR (5.30% vs 2.24%, p=0.011), renal ADR (3.67% vs 1.63%, p=0.044), central nervous system ADR (2.65% vs 0.81%, p=0.047), and hypersensitivity (2.24% vs 0.41%, p=0.022). Concomitant receipt of an angiotensinconverting enzyme (ACE) inhibitor was a univariate variable associated with hyperkalemia, and advanced age and receipt of high-dose TMP-SMX were independent variables. Conclusion: ADRs such as hyperkalemia are more likely to be associated with the use of high-dose TMP-SMX in the ambulatory setting. Clinicians should use caution when initiating high-dose TMP-SMX and consider laboratory monitoring in patients of advanced age or those receiving concomitant ACE inhibitor therapy.