Incidence of Hyponatremia with High-Dose Trimethoprim-Sulfamethoxazole Exposure

Am J Med. 2016 Dec;129(12):1322-1328. doi: 10.1016/j.amjmed.2016.07.012. Epub 2016 Aug 16.


Background: Trimethoprim-sulfamethoxazole (TMP-SMX) is a commonly prescribed antibiotic used at high doses for treatment of pneumocystis pneumonia and other infections. Trimethoprim is structurally related to the potassium-sparing diuretic amiloride and has been associated with hyperkalemia and hyponatremia through blocking of epithelial sodium channels in the distal nephron. The incidence of hyponatremia in hospitalized patients treated with high-dose TMP-SMX is unknown.

Methods: We performed a single-center retrospective chart review of all hospitalized patients who received high-dose TMP-SMX (n = 235) from January 2012 to July 2014. Patients with congestive heart failure, cirrhosis, estimated glomerular filtration rate <30 mL/min/1.73 m2, baseline hyponatremia, and those on other medications associated with hyponatremia were excluded. Hyponatremia was defined as a serum sodium level <136 mEq/L.

Results: Analysis was restricted to 76 unique patients who received more than 8 mg/kg/d of TMP for ≥3 days. Mean starting serum sodium at time of TMP-SMX initiation was 138.4 ± 2.1 mEq/L. Fifty-five patients (72.3%) developed hyponatremia while on therapy, of which 43.6% (n = 24) were cases of serum sodium <130 mEq/L. Mean sodium at the time of nadir was 131.6 ± 5.1 mEq/L. Hyponatremia was noted, on average, 5.5 days after initiation of therapy, with more severe hyponatremia development among African American patients. Urine sodium concentrations were available for 40.0% (22/55) of incident hyponatremia cases, with mean urinary sodium of 104.8 ± 55.9 mEq/L. Hyponatremia often resolved within 3 weeks of drug discontinuation.

Conclusions: There is a high incidence (72.3%) of hyponatremia associated with the use of high-dose TMP-SMX among hospitalized patients. This is an overlooked and potentially reversible cause of hyponatremia.

Keywords: ENaC; Hyperkalemia; Hyponatremia; Trimethoprim.

MeSH terms

  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / adverse effects
  • Anti-Bacterial Agents / therapeutic use
  • Female
  • Humans
  • Hyponatremia / chemically induced*
  • Hyponatremia / epidemiology
  • Incidence
  • Inpatients / statistics & numerical data
  • Logistic Models
  • Male
  • Middle Aged
  • New York City / epidemiology
  • Pneumonia, Pneumocystis / drug therapy*
  • Retrospective Studies
  • Trimethoprim, Sulfamethoxazole Drug Combination / administration & dosage*
  • Trimethoprim, Sulfamethoxazole Drug Combination / adverse effects*
  • Trimethoprim, Sulfamethoxazole Drug Combination / pharmacology


  • Anti-Bacterial Agents
  • Trimethoprim, Sulfamethoxazole Drug Combination