Can Bactrim (trimethoprim/sulfamethoxazole) cause acute kidney injury?

Can Bactrim Cause Acute Kidney Injury?

Yes, Bactrim (trimethoprim/sulfamethoxazole) can cause acute kidney injury through multiple mechanisms including direct tubular toxicity, hyperkalemia, and crystalluria, with risk increasing significantly when combined with other nephrotoxic medications or in patients with underlying risk factors. 1, 2

Mechanisms of Kidney Injury

Bactrim causes AKI through several distinct pathways 1:

• Direct tubular toxicity is the primary mechanism of injury 1, 3
• Hyperkalemia occurs due to trimethoprim's potassium-sparing effects, which can indirectly worsen renal function 1, 2
• Crystalluria can develop when fluid intake is inadequate, leading to crystal formation in renal tubules 2
• Interstitial nephritis is rare—in one study, pyuria appeared in only 2 of 37 patients and eosinophiluria was not observed 3

Incidence and Clinical Evidence

The risk of AKI with Bactrim is substantial and higher than previously recognized:

• 11.2% of patients developed AKI (defined as increases in both creatinine and BUN) in a veteran population treated for ≥6 days, with 5.8% judged likely due to the drug and 4.9% possibly due to the drug 3
• Older adults (≥65 years) treated for UTI showed 1.72 times higher odds of AKI within 14 days compared to amoxicillin 4
• One additional patient required dialysis in the veteran study, though most cases resolved promptly after discontinuation 3

High-Risk Patient Populations

Patients with the following characteristics face substantially elevated risk 1, 4, 5:

• Creatinine clearance <15 mL/min: Bactrim is not recommended 1
• Existing acute kidney injury: Use with extreme caution due to risk of further damage and drug accumulation 1
• Hypertension: 2.69 times increased odds of AKI, especially if poorly controlled 3, 5
• Diabetes mellitus: Increased risk, particularly when poorly controlled 3
• Low body mass index: Each unit decrease in BMI increases AKI risk (OR 0.86, meaning lower BMI = higher risk) 5
• Elderly patients: Higher baseline risk translates to greater absolute risk 4

Drug Interactions That Amplify Risk

The "triple whammy" effect and other combinations dramatically increase AKI risk 6, 1:

• Renin-angiotensin system blockers (ACE inhibitors/ARBs): When combined with Bactrim, there are 2 additional admissions with AKI per 1000 UTIs treated 4
• Renin-angiotensin system blockers PLUS spironolactone: Results in 18 additional cases of hyperkalemia and 11 additional AKI admissions per 1000 UTIs treated 4
• Loop diuretics: 2.91 times increased odds of AKI when used concomitantly 5
• Thiazide diuretics: Avoid concurrent use per FDA labeling 2
• Cyclosporine: Marked but reversible nephrotoxicity reported; avoid concurrent use 2

Dose-Related Considerations

Higher doses of Bactrim increase AKI risk 5:

• Each increment in SMX/TMP daily dose increases AKI odds by 1.16 times 5
• High-dose trimethoprim (as used for Pneumocystis jirovecii pneumonia) induces progressive but reversible increases in serum potassium, which can worsen renal function 2

Monitoring Requirements

The FDA mandates specific monitoring for patients receiving Bactrim 2:

• Urinalyses with careful microscopic examination and renal function tests during therapy, particularly for patients with impaired renal function 2
• Complete blood counts and clinical chemistry testing should be done frequently 2
• Serum potassium monitoring is warranted in high-risk patients 2
• Discontinue immediately if significant electrolyte abnormality, renal insufficiency, or reduction in blood cell counts is noted 2

Clinical Pitfalls to Avoid

Several common errors increase the risk of Bactrim-induced AKI:

• Inadequate fluid intake: Patients must maintain adequate hydration to prevent crystalluria and stone formation 2
• Failure to dose-adjust: In renal insufficiency, dosing adjustments are essential 1
• Ignoring drug interactions: Each nephrotoxic medication increases AKI odds by 53%, and this risk compounds with multiple nephrotoxins 1
• Continuing therapy despite warning signs: AKI typically resolves promptly after discontinuation if caught early 3

Alternative Antibiotics in High-Risk Patients

When possible, consider less nephrotoxic alternatives in patients at high risk for AKI 1:

• Fluoroquinolones (ofloxacin, ciprofloxacin) for UTIs, though ciprofloxacin also carries some AKI risk (1.48 times higher odds vs amoxicillin) 1, 4
• β-lactam antibiotics as appropriate alternatives 1
• Nitrofurantoin for uncomplicated UTIs in patients with adequate renal function 4

Absolute Risk in Context

For every 1000 UTIs treated in patients ≥65 years, treatment with trimethoprim instead of amoxicillin results in 4:

• 1-2 additional cases of hyperkalemia in the general population
• 2 additional hospital admissions with AKI in the general population
• 18 additional cases of hyperkalemia in patients taking renin-angiotensin system blockers and spironolactone
• 11 additional AKI admissions in patients taking renin-angiotensin system blockers and spironolactone