Trimethoprim and Hyperkalemia: What You Need to Know About the Hidden Risk

Most people think of antibiotics like Bactrim or Septra as simple, safe fixes for infections. But behind that common prescription lies a quiet, dangerous risk: trimethoprim can spike your potassium levels-fast. And in some cases, it can send you to the ER, or worse.

How a Common Antibiotic Raises Potassium Like a Diuretic

Trimethoprim is the active part of the combo drug trimethoprim-sulfamethoxazole (TMP-SMX). It’s used for urinary tract infections, lung infections, and even to prevent pneumonia in people with weak immune systems. But here’s the twist: it doesn’t just kill bacteria. It acts like a potassium-sparing diuretic-exactly like the drug amiloride. That means it blocks sodium channels in your kidneys, which messes with how your body gets rid of potassium.

Normally, your kidneys push excess potassium out in urine. But trimethoprim gets into the kidney tubules at concentrations 10 to 50 times higher than in your blood. There, it shuts down the electrical signal that tells potassium to leave. The result? Potassium builds up. Serum levels can jump 0.5 to 1.5 mmol/L in just 48 to 72 hours. That might not sound like much, but if your normal potassium is 4.2 and it hits 6.0, you’re in danger zone. Above 6.5? That’s cardiac arrest territory.

Who’s at the Highest Risk?

This isn’t a risk for everyone. But for some, it’s a ticking clock.

• People over 65
• Those with kidney problems (eGFR under 60)
• Anyone taking ACE inhibitors (like lisinopril) or ARBs (like losartan)
• Diabetics with chronic kidney disease
• People already on potassium-sparing diuretics like spironolactone

A 2014 JAMA Internal Medicine study found that older adults on ACEIs or ARBs who took TMP-SMX had a 6.7 times higher chance of being hospitalized for high potassium than those on amoxicillin. In patients with three or more risk factors-like age, kidney disease, and an ACEI-the hyperkalemia rate jumped to 32.1%. That’s more than one in three.

Even healthy-looking people aren’t safe. A 2023 case report described an 80-year-old woman with normal kidney function (creatinine 0.7 mg/dL) who developed a potassium level of 7.8 mmol/L-deadly high-just three days after starting a low-dose Bactrim pill for UTI prevention. She had no warning signs. She suffered cardiac arrest.

Why This Risk Is Still Overlooked

Despite being known since the 1980s, this danger is still ignored in clinics. A 2023 survey found only 41.7% of primary care doctors check potassium levels before prescribing trimethoprim to patients on blood pressure meds. Emergency room doctors? Just 32.4% do.

Why? Because it’s not obvious. Patients don’t feel anything until it’s too late. No nausea, no dizziness, no swelling. High potassium doesn’t scream-it whispers. By the time symptoms like muscle weakness or irregular heartbeat show up, the heart is already under stress.

The FDA added a boxed warning for trimethoprim in 2019-but only for people with kidney failure. That leaves out the majority of cases. Most dangerous hyperkalemia events happen in people with normal kidney function who are on ACEIs or ARBs. The European Medicines Agency called this risk “under-recognized,” and they’re right.

What Happens When Potassium Gets Too High?

High potassium doesn’t just cause fatigue. It changes your heart’s electrical rhythm. On an EKG, you’ll see tall, peaked T-waves. Then the QRS complex widens. Then the heart can stop beating entirely.

A 2021 review of 37 case reports found that 78% of severe hyperkalemia cases (potassium above 6.0 mmol/L) happened within 72 hours of starting trimethoprim. The average time to peak potassium? Just 2.3 days. And 43% of those cases needed emergency treatment: calcium gluconate to protect the heart, insulin and glucose to drive potassium into cells, or even dialysis.

The FDA’s adverse event database recorded 43 deaths linked to trimethoprim-induced hyperkalemia between 2010 and 2020. Nearly 70% of those deaths were in patients over 65. Many of them were prescribed the drug for a simple UTI.

What Should You Do Instead?

There are safer alternatives. For urinary tract infections, nitrofurantoin has been shown to carry no increased hyperkalemia risk. For respiratory infections, amoxicillin or doxycycline are usually fine. For Pneumocystis pneumonia prophylaxis in immunocompromised patients, atovaquone or dapsone are options.

Here’s the bottom line: if you’re on an ACEI or ARB, don’t let your doctor reach for Bactrim without asking about potassium. If you’re over 65 or have kidney disease, ask: “Is there a different antibiotic that won’t raise my potassium?”

One pharmacist on Reddit shared that out of 200 TMP-SMX prescriptions she reviewed for patients on blood pressure meds, only 15% ended up with potassium above 5.5. But that’s still 30 people at risk. And it only takes one.

How to Stay Safe If You Must Take It

If your doctor says trimethoprim is your only option, here’s what you need:

1. Check potassium before you start. Don’t assume it’s normal. Get a blood test.
2. Test again at 48-72 hours. That’s when levels peak. Waiting a week is too late.
3. Stop the drug if potassium hits 5.5 or higher. Don’t wait for symptoms.
4. Avoid it entirely if your baseline potassium is above 5.0 or your eGFR is under 30.

Hospitals that added electronic alerts-forcing doctors to check potassium before prescribing trimethoprim-cut hyperkalemia cases by over half. That’s not magic. It’s just doing the basics.

The Bigger Picture

Trimethoprim is still recommended as first-line for Pneumocystis pneumonia in people with HIV or cancer. That’s not changing. But guidelines now say: monitor potassium. Don’t assume safety.

Doctors are starting to use a tool called the TMP-HyperK Score. It looks at your age, baseline potassium, kidney function, and whether you’re on an ACEI or ARB. If three or more factors are present, your risk jumps to over 80%. That’s not guesswork-that’s science.

Every year, 14.7 million TMP-SMX prescriptions are written in the U.S. About 4.2 million go to people over 65. If even half of those patients had potassium checked before and after starting the drug, we could prevent 12,000 to 15,000 hospitalizations annually. That’s not a small number. That’s life-saving.

This isn’t about fear. It’s about awareness. Trimethoprim isn’t evil. But it’s not harmless, either. It’s a drug with a hidden mechanism-one that can quietly turn a simple infection treatment into a cardiac emergency. If you’re taking it, know your potassium. If you’re prescribing it, check it.