Generic Name

Trimethoprim

Mechanism

• Selective inhibition of bacterial dihydrofolate reductase (DHFR)
• Blocks conversion of dihydrofolate to tetrahydrofolate, essential for purine and pyrimidine synthesis.
• Bacterial DHFR has a higher affinity for TMP than human DHFR, conferring selective toxicity.
• Sparing effect on mammalian cells
• Requires *co‑inhibition* of folate pathways (e.g., with sulfamethoxazole) for potent activity against *Pseudomonas* or *Mycobacterium* species.

Pharmacokinetics

• Absorption: oral tablets are well absorbed; peak plasma concentrations 1–2 h post‑dose.
• Distribution: highly protein‑bound (~85 %); extensive penetration into the urinary tract (urine concentrations 10–30× plasma).
• Metabolism: 25 % hepatic S‑-esterases → 3‑hydroxy‑trimethoprim (inactive); minor glucuronidation.
• Half‑life: 7–10 h (oral); 4–8 h (IV).
• Excretion: primarily renal (80 % unchanged); 20 % biliary.
• Drug interactions: enhances serum potassium (via tubular secretion inhibition); interacts with NSAIDs, ACE inhibitors, ARBs, and lithium.

Indications

• Uncomplicated lower urinary tract infections (single agent).
• Prophylaxis of PCP in HIV/AIDS and other immunocompromised patients (trimethoprim‑sulfamethoxazole combination).
• Intraperitoneal therapy for peritonitis (in select settings).
• Occasionally used for ear, sinus, and skin infections when adjunct to sulfonamides.

Contraindications

• Allergy to trimethoprim, sulfamethoxazole, or other sulfonamides.
• Severe hepatic or renal impairment (dose adjustments required).
• Pregnancy: Category C (use only if benefits outweigh risks).
• Breastfeeding: excreted in milk; avoid if infant is premature or has renal disease.
• G6PD deficiency: risk of hemolysis.
• Hyponatremia / hyperkalemia: monitor electrolytes in elderly and renal patients.

Warnings
• Bone marrow suppression (anemia, leukopenia, thrombocytopenia).
• Skin reactions: Stevens–Johnson syndrome, toxic epidermal necrolysis.
• Hyperkalemia: especially with concomitant potassium‑sparing diuretics or ACE inhibitors.
• Competitive inhibition of creatinine secretion → false‑elevated serum creatinine.

Dosing

Key points
• Do not exceed 1 g/day to avoid toxicity.
• For patients with CrCl <30 mL/min, consider a loading dose of 400 mg BID for the first 24 h, then dose‑reduce.

Adverse Effects

• Common (≤10 %)
• Nausea, vomiting, diarrhea, dyspepsia.
• Skin rash, pruritus, mild fever.
• Hyperuricemia.
• Serious (≤1 %)
• Bone marrow suppression (anemia, neutropenia, thrombocytopenia).
• Severe skin reactions (Stevens–Johnson, toxic epidermal necrolysis).
• Acute interstitial nephritis (rare).
• Hyperkalemia, especially in renal disease or when combined with potassium‑sparing drugs.
• Hemolytic anemia in G6PD‑deficient patients.

Monitoring

• Baseline and periodic CBC (hemoglobin, WBC, platelets).
• Renal function: serum creatinine, BUN, CrCl before initiation, then weekly if therapy >7 days.
• Electrolytes: serum potassium, sodium, chloride.
• Liver function tests if hepatic impairment or prolonged use >10 days.
• Urinalysis if urinary toxicity suspected.

Clinical Pearls

• Synergistic Duo: Trimethoprim pairs with sulfamethoxazole because TMP blocks DHFR and SMX blocks dihydropteroate synthase, achieving bactericidal synergy (tetracycline resistance).
• UTI–Specific: TMP monotherapy achieves high urinary concentrations; ideal for uncomplicated cystitis but not effective against *Proteus* or *Enterobacter* species.
• Copper/Calcium Dependence: Avoid prolonged high‑dose TMP in patients on calcium‑containing antacids or magnesium supplements; may reduce absorption.
• Potassium Scrutiny: TMP can inhibit renin‑mediated tubular secretion of potassium, precipitating hyperkalemia → check K⁺ in elderly, CKD, or patients on ARBs/ACEIs.
• Use in Pregnancy: Due to teratogenic risk, other agents (e.g., nitrofurantoin for UTI) should be preferred; only consider TMP‑SMX if no alternatives and patient is fully informed.
• Monitoring for Hemolysis: In G6PD‑positive patients, give the lowest effective dose and monitor for signs of hemolysis (jaundice, dark urine).
• False Creatinine Elevation: TMP competes with creatinine secretion; serum creatinine may rise without true GFR decline—recalculate CrCl with cystatin‑C if uncertainty.
• Adrenocortical Insufficiency: Co‑administration with high‑dose NSAIDs can exacerbate adrenal suppression in patients with renal disease.

> Bottom line: Trimethoprim is a reliable, oral agent for uncomplicated UTIs, but watch renal function, electrolytes, and complete blood counts. Always pair appropriately with a sulfonamide for broader coverage and PCP prophylaxis.