What are the dosing considerations for trimethoprim-sulfamethoxazole (TMP-SMX) in patients with chronic kidney disease (CKD)?

From the Guidelines

Trimethoprim-sulfamethoxazole (TMP-SMX) dosing in patients with chronic kidney disease (CKD) should be adjusted based on creatinine clearance, with a recommended dose reduction to 1/2 dose for patients with creatinine clearance 15-30 mL/min and consideration of alternative agents for those with creatinine clearance <15 mL/min. When considering the management of patients with CKD, it is crucial to adjust the dosing of medications that are primarily eliminated by the kidneys to prevent accumulation and potential adverse effects. For TMP-SMX, the usual dosage is 1 double-strength dose orally every 24 hours, but for patients with CKD or end-stage renal disease (ESRD), the dosage needs to be adjusted as indicated in guidelines 1. Key considerations for dosing adjustments include:

• Creatinine clearance 15-30 mL/min: 1/2 dose
• Creatinine clearance <15 mL/min: 1/2 dose or use alternative agent These recommendations are based on the pharmacokinetics of trimethoprim and sulfamethoxazole, which are both primarily eliminated by the kidneys, and the potential for accumulation and adverse effects in renal impairment, as outlined in guidelines for managing CKD in HIV-infected patients 1. Regular monitoring of renal function, electrolytes, and complete blood counts is essential when using TMP-SMX in CKD patients to mitigate potential risks associated with its use in this population.

From the FDA Drug Label

For Patients With Impaired Renal Function When renal function is impaired, a reduced dosage should be employed using the following table: Creatinine Clearance (mL/min)Recommended Dosage Regimen Above 30Usual standard regimen 15-301/2 the usual regimen Below 15Use not recommended

The dosing considerations for trimethoprim-sulfamethoxazole (TMP-SMX) in patients with Chronic Kidney Disease (CKD) are as follows:

• For patients with a creatinine clearance above 30 mL/min, the usual standard regimen is recommended.
• For patients with a creatinine clearance between 15-30 mL/min, the dosage should be reduced to half the usual regimen.
• For patients with a creatinine clearance below 15 mL/min, the use of TMP-SMX is not recommended 2.

From the Research

Dosing Considerations for Trimethoprim-Sulfamethoxazole in CKD

• The pharmacokinetics of trimethoprim-sulfamethoxazole (TMP-SMX) are altered in patients with renal dysfunction, with significant changes occurring when creatinine clearance is less than 30 mL/min 3.
• TMP and SMX disposition are not significantly altered until creatinine clearance is less than 30 mL/min, when SMX metabolites and TMP accumulate and may lead to toxicity 3.
• Renal dysfunction does not preclude the use of TMP-SMX to treat susceptible infections, even when creatinine clearance is less than 15 mL/min, but guidelines for appropriate dosing and monitoring of TMP-SMX therapy in these patients are necessary 3.
• Dosages of drugs cleared renally, such as TMP-SMX, should be adjusted according to creatinine clearance or glomerular filtration rate and should be calculated using online or electronic calculators 4.
• Recommended methods for maintenance dosing adjustments include dose reductions, lengthening the dosing interval, or both 4.

Pharmacokinetics and Dosage Adjustments

• The half-lives of TMP and SMX increase with age and are correlated directly with the level of serum creatinine 5.
• A loading dose of 250 mg of TMP and 1,250 mg of SMZ/m2 is recommended, followed by maintenance doses of 150 mg of TMP and 750 mg of SMZ/m2 every 8 hr for children aged 10 years or younger and every 12 hr for adults with normal renal function 5.
• In renal failure, the dosage interval (hr) should be increased to 12 times the serum creatinine level (mg/dl) (maximum, 48 hr) 5.
• Serum concentrations of TMP and perhaps of N4-acetyl-SMZ should be monitored in patients with severe renal failure 5.

Renal Effects and Adverse Reactions

• Trimethoprim (TMP) can increase serum creatinine and reduce creatinine clearance in patients with renal impairment, particularly in those treated with ciclosporin 6.
• TMP can block tubular secretion of creatinine, which is an important route for creatinine excretion 6.
• Acute kidney injury (AKI) associated with TMP-SMX is more common than previously reported, especially in patients with hypertension and diabetes mellitus 7.
• In nearly all cases of AKI likely due to TMP-SMX, AKI resolved promptly after discontinuation of therapy, but one patient required dialysis 7.