What antibiotic is known to cause hyperkalemia?

Trimethoprim-Sulfamethoxazole (TMP-SMX) is the Antibiotic Most Commonly Associated with Hyperkalemia

Trimethoprim-sulfamethoxazole is the primary antibiotic known to cause hyperkalemia through its mechanism of blocking amiloride-sensitive sodium channels in the distal nephron, thereby reducing renal potassium excretion. 1, 2

Mechanism of Hyperkalemia

• Trimethoprim blocks epithelial sodium channels (ENaC) in the distal nephron, similar to potassium-sparing diuretics like amiloride, which impairs potassium excretion 1, 3
• This mechanism is distinct from other antibiotics and occurs even at standard therapeutic doses 2, 3
• The trimethoprim component, not sulfamethoxazole, is responsible for the hyperkalemic effect 1, 3

Incidence and Clinical Significance

• Standard-dose TMP-SMX causes hyperkalemia (K+ >5.0 mEq/L) in approximately 15-26% of treated patients 3, 4
• Severe hyperkalemia (K+ ≥5.5 mEq/L) occurs in 6.5-21% of patients 4, 5
• The mean increase in serum potassium is approximately 1.2 mEq/L, typically occurring 4-5 days after initiating therapy 4
• A hospital encounter with hyperkalemia is 3.36 times more likely with TMP-SMX compared to amoxicillin 6

High-Risk Patient Populations

Patients with renal insufficiency are at dramatically increased risk:

• Those with serum creatinine ≥1.2 mg/dL (106 μmol/L) develop significantly higher peak potassium levels (5.37 vs 4.95 mEq/L in those with normal renal function) 4
• Patients with chronic kidney disease have an 85.7% incidence of electrolyte disorders compared to 17.5% in those with normal renal function 3
• The absolute risk difference increases progressively with declining eGFR: 0.12% for eGFR ≥60 mL/min/1.73 m², 0.42% for eGFR 45-59,0.85% for eGFR 30-44, and 1.45% for eGFR <30 6

Additional high-risk factors include:

• Concurrent use of RAAS inhibitors (ACE inhibitors, ARBs, or mineralocorticoid receptor antagonists) 1
• Advanced age (elderly patients are particularly susceptible) 1
• Diabetes mellitus (though the effect is less pronounced than renal dysfunction) 4
• Higher trimethoprim doses (odds ratio 2.35 per dose increment) 3
• AIDS patients receiving TMP-SMX for Pneumocystis pneumonia prophylaxis or treatment 1, 2

Critical Clinical Warnings

The combination of TMP-SMX with RAAS inhibitors in patients with renal insufficiency is particularly dangerous:

• The American Geriatrics Society specifically warns that TMP-SMX should be used with caution in patients with reduced kidney function taking ACE inhibitors or ARBs due to increased hyperkalemia risk 1
• The combination of RAAS inhibitors and TMP-SMX with unrecognized hyperkalemia has been associated with increased risk of sudden cardiac death 1
• The European Society of Cardiology notes that TMP-SMX is among drugs that decrease potassium excretion and should be carefully monitored in patients on RAAS inhibitors 1

Monitoring Recommendations

• The FDA label mandates close monitoring of serum potassium in patients with underlying disorders of potassium metabolism, renal insufficiency, or those receiving drugs known to induce hyperkalemia 2
• Serum potassium should be checked before initiating therapy and monitored during treatment, particularly in high-risk patients 2, 4
• The British Thoracic Society recommends monthly monitoring of electrolytes (U&Es) during TMP-SMX therapy 1
• Patients should have routine serum potassium monitoring before hospital discharge if treated with TMP-SMX 5

Other Antibiotics Associated with Hyperkalemia

While TMP-SMX is the most significant offender, pentamidine also causes hyperkalemia:

• Pentamidine can cause hyperkalemia, typically after 5-7 days of therapy, along with other electrolyte disturbances 1
• Hyperkalemia from pentamidine is less predictable and occurs in the context of multiple metabolic derangements including hypoglycemia and pancreatitis 1

Penicillin G is listed as a potential cause of hyperkalemia due to its potassium salt formulation, but this is a different mechanism (increased potassium load rather than impaired excretion) 1

Clinical Management

• If hyperkalemia develops, consider alternative antibiotics rather than continuing TMP-SMX, especially in patients with chronic kidney disease 7
• The incidence of hyperkalemia appears consistent across burn patients and general populations, suggesting the effect is primarily pharmacologic rather than disease-specific 5
• Even low-dose TMP-SMX (trimethoprim <80 mg) can cause electrolyte disorders in 9.1% of patients, though standard doses (80-120 mg) increase this to 22.2% 3