A synergistic combination antibiotic containing trimethoprim and sulfamethoxazole in a 1:5 ratio. Effective against many gram-positive and gram-negative organisms. A first-line agent for uncomplicated urinary tract infections, the drug of choice for Pneumocystis jirovecii pneumonia (PCP) treatment and prophylaxis, and used for MRSA skin infections, Stenotrophomonas, nocardiosis, and toxoplasmosis.
Evidence rating strong. Most-documented uses: first-line for uncomplicated urinary tract infections, treatment and prophylaxis of pcp (pneumocystis jirovecii), treats community-acquired mrsa skin and soft tissue infections. 10 sources indexed (2014–2024), with 4 interaction records on file.
The science
How it works, mechanistically.
Core mechanism
Sequentially inhibits two enzymes in the bacterial folate synthesis pathway. Sulfamethoxazole is a structural analog of para-aminobenzoic acid (PABA) that competitively inhibits dihydropteroate synthase, blocking the incorporation of PABA into dihydrofolic acid. Trimethoprim then inhibits dihydrofolate reductase (DHFR), preventing the reduction of dihydrofolic acid to tetrahydrofolic acid. The sequential blockade at two steps produces synergistic bactericidal activity.
Class
Sulfonamide/Diaminopyrimidine Combination
Dosing
Dosing & protocol.
Common range
1 DS tablet (160/800 mg) every 12 hours; PCP prophylaxis: 1 DS tablet daily or 1 SS tablet daily; PCP treatment: 15-20 mg TMP/kg/day IV divided every 6-8 hours (as prescribed by your physician)
Recommended form
Oral tablets (single-strength, double-strength) or suspension; IV for severe infections
Well absorbed orally (85-100% bioavailability for both components). Can be taken with or without food. Ensure adequate hydration to prevent crystalluria (especially in high-dose therapy).10
Depletions
What it depletes.
Nutrients this medication can lower over time, and what to replace.
Folate
Moderate
Trimethoprim inhibits dihydrofolate reductase and sulfamethoxazole adds antifolate pressure, which can lower functional folate status in susceptible patients.
Replace Folic AcidMonitor CBC + serum folate or RBC folateOnset Usually after prolonged or high-dose therapy, especially with low folate stores
Trimethoprim inhibits dihydrofolate reductase and can cause folate deficiency with prolonged use, particularly in people with marginal folate status, pregnancy, or chronic illness. Methylfolate supplementation can correct this deficiency without interfering with the antibiotic's antibacterial activity, since trimethoprim is highly selective for bacterial dihydrofolate reductase. However, very high folate intake near antibiotic dosing has theoretical potential to reduce antibacterial efficacy in some infections.
Recommendation: Methylfolate supplementation is generally safe during trimethoprim-sulfamethoxazole therapy and is recommended for prolonged courses, pregnancy, or pre-existing folate deficiency. Separate doses by at least 2 hours to be conservative.
Trimethoprim is a folate antagonist that can lower host folate stores during prolonged therapy, particularly in patients with marginal folate intake, pregnancy, or hematologic disease. Folic acid (Vitamin B9) supplementation prevents megaloblastic anemia and is recommended in long courses. Trimethoprim's selectivity for bacterial dihydrofolate reductase means folate supplementation does not meaningfully reduce antibacterial activity in most clinical settings.
Recommendation: Consider folic acid supplementation during prolonged TMP-SMX therapy, in pregnancy, or in patients with hematologic disease. Standard supplemental doses (400 to 1000 mcg per day) are appropriate. Folinic acid is preferred if a significant deficiency develops.
Trimethoprim blocks the epithelial sodium channel (ENaC) in the distal nephron, acting similarly to potassium-sparing diuretics like amiloride. Co-administration with potassium supplements can cause clinically significant hyperkalemia, particularly in older adults, patients with renal impairment, or those on ACE inhibitors, ARBs, or spironolactone. Severe hyperkalemia can cause cardiac arrhythmias and sudden death.
Recommendation: Avoid routine potassium supplementation during trimethoprim-sulfamethoxazole therapy unless directed by a clinician. If supplementation is necessary, monitor serum potassium closely, particularly in older adults or patients with kidney disease.
Probiotic supplementation during trimethoprim-sulfamethoxazole therapy reduces antibiotic-associated diarrhea and helps preserve gut microbiome diversity disrupted by broad-spectrum coverage.
Recommendation: Take probiotics throughout your TMP-SMX course, separated by at least 2 hours from each antibiotic dose. Continue for at least 1 week after the antibiotic ends.
Wu PC, Chen WT, Huang IH et al.. Human Leukocyte Antigens and Sulfamethoxazole/Cotrimoxazole-Induced Severe Cutaneous Adverse Reactions: A Systematic Review and Meta-Analysis. JAMA dermatology. 2024
Keragala KARK, Gunathilaka MGRSS, Senevirathna RMISK et al.. Efficacy and safety of co-trimoxazole in eradication phase of melioidosis; systematic review. Annals of clinical microbiology and antimicrobials. 2023
Wedderburn CJ, Evans C, Slogrove AL et al.. Co-trimoxazole prophylaxis for children who are HIV-exposed and uninfected: a systematic review. Journal of the International AIDS Society. 2023
Faré PB, Memoli E, Treglia G et al.. Trimethoprim-associated hyperkalaemia: a systematic review and meta-analysis. The Journal of antimicrobial chemotherapy. 2022
Burgos RM, Reynolds KM, Williams J et al.. Trimethoprim-Sulfamethoxazole Associated Drug-Induced Liver Injury in Pediatrics: A Systematic Review. The Pediatric infectious disease journal. 2020
Ford N, Shubber Z, Jao J et al.. Safety of cotrimoxazole in pregnancy: a systematic review and meta-analysis. Journal of acquired immune deficiency syndromes (1999). 2014
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