Sulfonamides and Trimethoprim
Sulfonamides and trimethoprim block sequential steps in bacterial folate synthesis, achieving synergistic bactericidal activity in combination.
## 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