Sulfonamides and Trimethoprim

Overview

Sulfonamides were among the first synthetic antibiotics (1930s). Trimethoprim-sulfamethoxazole (TMP-SMX) combines two drugs that block sequential steps in bacterial folate synthesis, achieving synergistic bactericidal activity. TMP-SMX remains a first-line agent for UTIs, PCP prophylaxis/treatment, and MRSA skin infections.

Mechanism of Action

Bacteria cannot import folate from the environment and must synthesize it de novo — a pathway absent in humans, making it a selective target.

1. Sulfonamides are structural analogs of para-aminobenzoic acid (PABA) that competitively inhibit dihydropteroate synthase (DHPS), preventing incorporation of PABA into dihydropteroate.
2. Trimethoprim inhibits dihydrofolate reductase (DHFR), preventing reduction of dihydrofolate to tetrahydrofolate (the active cofactor for one-carbon transfer reactions needed for purine and thymidylate synthesis).

Combining them at a 1:5 ratio (TMP:SMX = 1:5) achieves sequential blockade — bactericidal synergy because depletion of both precursor and cofactor is additive.

Clinical Uses

• UTIs: First-line for uncomplicated UTIs where local resistance rates <20%
• PCP (Pneumocystis jirovecii pneumonia): Gold standard treatment (high-dose TMP-SMX) and prophylaxis (standard-dose) in immunocompromised patients (HIV CD4 <200, solid organ transplant)
• MRSA SSTI: TMP-SMX is first-line for community-acquired MRSA skin infections
• Toxoplasma encephalitis: TMP-SMX for prophylaxis; pyrimethamine + sulfadiazine for treatment
• Nocardia, Stenotrophomonas, Listeria: TMP-SMX has clinically useful activity

Adverse Effects

• Hypersensitivity: Rash (5-8%), Stevens-Johnson syndrome, toxic epidermal necrolysis — sulfonamide moiety responsible; ~3% cross-reactivity with other sulfonamide-containing drugs
• Hyperkalemia: TMP blocks ENaC (epithelial sodium channels) in the collecting duct, reducing potassium excretion — especially relevant at high doses or with ACE inhibitors/ARBs
• Increased serum creatinine: TMP competitively inhibits creatinine tubular secretion; raises creatinine without changing GFR (factitious increase)
• Bone marrow suppression: Folate deficiency with prolonged use; supplement folinic acid in high-risk patients
• Crystalluria/nephrotoxicity: Older sulfonamides; less common with modern agents and adequate hydration
• Kernicterus: Sulfonamides displace bilirubin from albumin; contraindicated in neonates and near-term pregnancy

Key Takeaways

• TMP-SMX blocks sequential steps: sulfonamide inhibits DHPS; trimethoprim inhibits DHFR
• First-line for PCP prophylaxis/treatment, community-acquired MRSA skin infections, and uncomplicated UTIs
• Hyperkalemia from TMP's ENaC blockade is particularly important in patients on renin-angiotensin system drugs
• Trimethoprim raises serum creatinine without affecting true GFR via competitive tubular secretion inhibition