Trimethoprim and sulfamethoxazole is an antibiotic combination (Bactrim®) commonly used to treat a variety of infections. In general, such therapy is well tolerated. But trimethoprim has a property which can cause trouble. Structurally and pharmacologically it resembles amiloride. The latter is a potassium sparing diuretic that exerts its effect by blocking the Na channel along the renal tubule, particularly in the cortical collecting tubule.
The renal actions of both amiloride and trimethoprim were of intense interest to our lab. One of the papers we published examining the renal actions of trimethoprim is here: Trimethoprim KI May 1996. It concludes “that from a functional standpoint, trimethoprim is amiloride, and should be used judiciously… in patients with renal insufficiency.”
A study just published in the Archives of Internal Medicine, Trimethoprim-Sulfamethoxazole–Induced Hyperkalemia in Patients Receiving Inhibitors of the Renin-Angiotensin System, examined potassium homeostasis in patient 66 years or older who were receiving continuous therapy with either an ACE (angiotensin converting enzyme) inhibitor or an ARB (angiotensin receptor blocker) and who were treated for 14 days with a variety of antibiotics including the trimethoprim-sulfamethoxazole combination. Not surprisingly, “the use of trimethoprim-sulfamethoxazole was associated with a nearly 7-fold increased risk of hyperkalemia-associated hospitalization (adjusted odds ratio, 6.7; 95% confidence interval, 4.5-10.0). No such risk was found with the use of comparator antibiotics.”
The reason that this finding is not a surprise is this. If you are elderly and you have a disease which requires angiotensin inhibition the odds are that your heart is not what is was and that your renal function is similarly sluggish. Both reduce potassium tolerance, but the kidney has a great reserve that typically prevents hyperkalemia in patients with cardiovascular-renal disease. Inhibiting the renin- angiotensin system with either an ACE inhibitor or an ARB further reduces this reserve. This is because the levels of the potassium losing hormone aldosterone fall when one of its two regulators (the plasma potassium itself is the other) in inhibited. Almost no doctor would hit such a patient with amiloride, but many are not aware that trimethoprim is the same as amiloride. Thus when their elderly patients receiving angiotensin blockade get a urinary tract infection they reflexively prescribe Bactrim® without a thought about potassium homeostasis.
The importance of this paper is that it will remind primary care physicians to be selective in their use of Bactrim®. It’s a very good drug as long as you don’t give it to patients whose potassium balance is precarious.