Sulfamethoxazole and trimethoprim
Sulfamethoxazole
Generic Name
Sulfamethoxazole
Mechanism
- Trimethoprim inhibits bacterial dihydrofolate reductase (DHFR), blocking the conversion of dihydrofolate → tetrahydrofolate.
- Sulfamethoxazole competes with para‑aminobenzoic acid (PABA) for dihydropteroate synthase (DHPS), preventing dihydropteroate formation, the precursor to folic acid.
- By antagonizing two sequential steps in folate biosynthesis, SMX/TMP causes a potent antimicrobial effect even at low concentrations.
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Pharmacokinetics
| Parameter | Typical Values (adult) |
| Absorption | >90 % oral; peak plasma 1–2 h |
| Distribution | Volume of distribution: SMX ≈ 2.4 L/kg, TMP ≈ 1.4 L/kg |
| Protein Binding | SMX ~ 10 %; TMP ~ 20 % |
| Metabolism | Hepatic 2‑hydroxylation (SMX) and 2‑hydroxy‑SMX; TMP largely unchanged |
| Renal Excretion | 70‑80 % unchanged; SMX metabolite 20‑30 % |
| Half‑life | SMX ~5–7 h; TMP ~8–9 h (shorter in healthy adults) |
| Special Populations | Contrast‑enhanced CT may increase SMX half‑life; renal impairment → dose reduction |
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Indications
- Urinary Tract Infection (UTI) (cystitis & pyelonephritis)
- Community‑acquired Pneumonia (CAP)
- Sinusitis & Otitis Media (where sensitivity data support use)
- Clostridioides difficile colitis (especially in combination with metronidazole or vancomycin)
- Pneumocystis jirovecii prophylaxis in HIV/AIDS, transplant recipients, and patients on high‑dose steroids or immunomodulators.
- Leishmaniasis (in combination with paromomycin).
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Contraindications
| Category | Guideline |
| Allergy to sulfonamides | SMX/TMP contraindicated in classic sulfa hypersensitivity (rash, eosinophilia, hemolysis). |
| G6PD deficiency | TMP induces oxidative stress → hemolytic anemia; avoid or carefully monitor. |
| Pregnancy | Category B (animal data) but avoid in 1st trimester if possible; high‑dose TMP can cause neonatal hyperbilirubinemia. |
| Hypertension | TMP may exacerbate resistant hypertension; avoid with other potassium‑sparing agents. |
| Renal or hepatic impairment | Dose adjustment required; avoid in severe CKD (eGFR < 30 mL/min without dose reduction). |
Warnings:
• Drug interactions: Sulfonamides potentiate effects of NSAIDs, diuretics, warfarin, and antiretrovirals.
• Photosensitivity: Protect from sun exposure.
• B12 deficiency: Chronic use can impair absorption; monitor in long‑term prophylaxis.
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Dosing
| Indication | Standard Dose | Frequency | Notes |
| UTI (cystitis) | 1 g SMX + 5 g TMP twice daily | BID | Use 1 : 5 ratio. |
| UTI (pyelonephritis) | 2 g SMX + 10 g TMP twice daily | BID | 7‑10 days. |
| CAP, sinusitis, otitis media | 1 g SMX + 5 g TMP twice daily | BID, 7–10 days | Adjust by renal function. |
| C. difficile | 1 g SMX + 5 g TMP, 5 am/5 pm for 6‑10 days | 2×/day | Alternates with metronidazole/vancomycin. |
| P. jirovecii prophylaxis | 80 mg TMP + 400 mg SMX once daily | QD | Low‑dose prophylaxis (1 g:5 g). |
| Renal impairment | Reduce dose by 50 % in moderate CKD; monitor closely. | Adj. | Tailor to eGFR. |
Administration:
• Oral tablets or suspension.
• Can be given with or without food; avoids GI upset.
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Adverse Effects
| Class | Common | Serious |
| Dermatologic | Mild rash, itching, photosensitivity. | Stevens‑Johnson syndrome, toxic epidermal necrolysis, severe drug‑induced hypersensitivity. |
| Hematologic | Mild anemia, neutropenia. | Agranulocytosis, eosinophilic pneumonia, hemolytic anemia (G6PD). |
| Renal | Urinary frequency, mild pain. | Acute interstitial nephritis, crystalluria, oxalate nephropathy. |
| Metabolic | Nausea, vomiting, diarrhea, abdominal pain. | Hyperkalemia (especially with other K‑retaining drugs). |
| Neurologic | Dizziness. | Rare seizures (dose‑related). |
| Other | Yeast infections (oral & genital), mouth ulcers, B12 deficiency. | – |
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Monitoring
* Renal function: eGFR before and every 2‑3 weeks (if >30 days therapy).
* Serum electrolytes: Na⁺, K⁺, Cl⁻ (baseline, 1‑2 weeks, then monthly).
* Complete Blood Count (CBC): baseline, 1‑2 weeks after start, then periodically.
* Signs of hypersensitivity: rash, fever, eosinophilia.
* B12 levels: particularly in patients requiring long‑term prophylaxis.
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Clinical Pearls
1. Potassium Trap – TMP is a competitive inhibitor of renal tubular Na⁺/K⁺‑ATPase → hyperkalemia. Keep a close eye on patients on ACE inhibitors, ARBs, spironolactone, or NSAIDs.
2. G6PD Deficieny Check – Never give SMX/TMP to an individual with known G6PD deficiency; if unknown, ask about history of hemolytic anemia in response to antimalarials or sulfa drugs.
3. UTI Algorithm – For uncomplicated cystitis in women and uncomplicated pyelonephritis in men, SMX/TMP remains a first‑line choice, but always confirm susceptibility or use local antibiogram if available.
4. Trimethoprim‑Like Effects – Once daily low‑dose prophylaxis for PCP is less toxic than the 2×/day higher dose recommended for treatment, yet still effective if the patient remains adherent.
5. Allergy Cross‑React – Classic sulfa allergy (rash, Stevens‑Johnson) contraindicates SMX/TMP. A mild, non‑severe sulfa allergy (stomach upset or mild rash) may be tolerated with caution.
6. Photography – Even modest sunlight exposure can trigger photosensitivity; patients should apply broad‑spectrum sunscreen during therapy.
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• Key take‑away: SMX/TMP’s dual blockade of folate biosynthesis gives it a broad antibacterial spectrum. Proper dosing based on renal function, vigilant monitoring for hyperkalemia and hypersensitivity, and awareness of contraindications make it a safe, high‑yield therapeutic option for many infections.