title: A comparison of adverse drug reactions between high- and standard-dose trimethoprim-sulfamethoxazole in the ambulatory setting.
abstract: BACKGROUND
  High-dose trimethoprim-sulfamethoxazole (TMP-SMX) for the empiric treatment of community-acquired 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 TMP-SMX (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 angiotensin-converting enzyme (ACE) inhibitor was a univariate variable associated with hyperkalemia, and advanced age and receipt of high-dose TMP-SMX were independent variables.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Oklahoma City Veterans Affairs Medical Center, 921 NE 13th Street, Pharmacy Service (119), Oklahoma City, OK 73104, USA.
authors.forename: Ann T
authors.initials: AT
authors.lastname: Nguyen
authors.forename: Chris A
authors.initials: CA
authors.lastname: Gentry
authors.forename: Rona Z
authors.initials: RZ
authors.lastname: Furrh
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000553:Ambulatory Care; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000890:Anti-Infective Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination