Introduction
Sulfamethoxazole/trimethoprim is a fixed-dose combination antimicrobial agent that combines two synthetic antibacterial compounds: sulfamethoxazole (a sulfonamide) and trimethoprim (a diaminopyrimidine). Marketed under various brand names including Bactrim, Septra, and Cotrim, this combination has been widely used since the 1970s for its broad-spectrum activity against various bacterial pathogens. The combination demonstrates synergistic antibacterial effects through sequential blockade of folate metabolism.
Mechanism of Action
Sulfamethoxazole and trimethoprim act at two consecutive steps in the folate biosynthesis pathway of microorganisms. Sulfamethoxazole competitively inhibits the incorporation of para-aminobenzoic acid (PABA) into dihydrofolic acid by competing with PABA for the enzyme dihydropteroate synthase. Trimethoprim binds to and inhibits bacterial dihydrofolate reductase, preventing the reduction of dihydrofolic acid to tetrahydrofolic acid. This sequential dual inhibition effectively blocks the production of tetrahydrofolate, an essential cofactor for bacterial nucleic acid and protein synthesis. The combination is bactericidal against susceptible organisms due to this synergistic mechanism.
Indications
FDA-approved indications include:
- Treatment of urinary tract infections caused by susceptible strains of Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis, and Proteus vulgaris
- Acute otitis media in children caused by susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae
- Acute exacerbations of chronic bronchitis in adults caused by susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae
- Traveler's diarrhea caused by enterotoxigenic E. coli
- Treatment and prophylaxis of Pneumocystis jirovecii pneumonia
- Shigellosis caused by susceptible Shigella flexneri and Shigella sonnei
Off-label uses include treatment of nocardiosis, toxoplasmosis prophylaxis, and community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) skin and soft tissue infections.
Dosage and Administration
Standard adult dosing:- Double strength (DS) tablet (800 mg SMX/160 mg TMP) every 12 hours for 10-14 days for most infections
- PCP treatment: 15-20 mg/kg/day (based on TMP component) in 3-4 divided doses for 14-21 days
- PCP prophylaxis: 1 DS tablet daily or 3 times weekly
- 8-12 mg/kg/day (TMP component) divided every 12 hours
- Based on body weight and indication
- CrCl >30 mL/min: standard dosing
- CrCl 15-30 mL/min: 50% of standard dose
- CrCl <15 mL/min: not recommended
Pharmacokinetics
Absorption: Both components are well absorbed from the GI tract following oral administration. Peak plasma concentrations occur within 1-4 hours post-dose. Bioavailability is approximately 90% for both drugs. Distribution: Widely distributed to body tissues and fluids, including prostate, lungs, bile, and cerebrospinal fluid (CSF achieves 20-50% of serum concentrations). Protein binding: sulfamethoxazole 70%, trimethoprim 45%. Volume of distribution: sulfamethoxazole 0.36 L/kg, trimethoprim 1.2-1.6 L/kg. Metabolism: Sulfamethoxazole is metabolized primarily by N-acetylation and glucuronide conjugation in the liver. Trimethoprim is metabolized to oxide and hydroxylated metabolites. Both demonstrate genetic polymorphism in metabolism. Elimination: Both drugs are eliminated renally. Half-life: sulfamethoxazole 9-11 hours, trimethoprim 8-10 hours. Approximately 80-100% of both drugs is excreted in urine within 72 hours.Contraindications
- Hypersensitivity to sulfonamides, trimethoprim, or any component of the formulation
- Documented megaloblastic anemia due to folate deficiency
- Severe hepatic impairment
- Pregnancy at term and during the nursing period
- Infants less than 2 months of age
- Marked renal impairment (CrCl <15 mL/min)
Warnings and Precautions
Boxed Warning:- fatalities associated with severe reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias
- Hypersensitivity reactions: May cause serious and sometimes fatal hypersensitivity reactions
- Hematologic toxicity: Monitor for thrombocytopenia, leukopenia, megaloblastic anemia, hemolytic anemia
- Electrolyte abnormalities: May cause hyperkalemia, particularly in elderly patients, those with renal impairment, or those on concomitant medications affecting potassium
- Folate deficiency: May exacerbate folate deficiency; caution in elderly, malnourished, or chronic alcohol users
- Renal and hepatic impairment: Requires dosage adjustment and close monitoring
- Photosensitivity: Increased risk of sunburn; advise sun protection
Drug Interactions
Significant interactions:- Warfarin: Increased anticoagulant effect; monitor INR closely
- ACE inhibitors, ARBs: Increased risk of hyperkalemia
- Methotrexate: Increased methotrexate toxicity
- Phenytoin: Increased phenytoin levels
- Oral hypoglycemics: Enhanced hypoglycemic effect
- Cyclosporine: Increased nephrotoxicity risk
- Thiazide diuretics: Increased risk of thrombocytopenia in elderly patients
- Procainamide: Increased procainamide levels
Adverse Effects
Common (≥1%):- Nausea, vomiting, anorexia
- Rash, pruritus
- Headache, dizziness
- Photosensitivity reactions
- Stevens-Johnson syndrome/Toxic epidermal necrolysis
- Agranulocytosis, aplastic anemia, thrombocytopenia
- Hepatotoxicity (elevated transaminases, hepatitis, hepatic necrosis)
- Acute renal failure, interstitial nephritis
- Hyperkalemia, hyponatremia
- Aseptic meningitis
- Hypoglycemia
- QT prolongation
Monitoring Parameters
- Baseline and periodic CBC with differential
- Renal function tests (BUN, creatinine)
- Hepatic function tests
- Electrolytes, particularly potassium
- Signs of hypersensitivity reactions
- Therapeutic response and infection resolution
- Fluid intake and output (maintain adequate hydration)
- For long-term therapy: folate levels, vitamin B12 levels
Patient Education
- Complete the full course of therapy even if feeling better
- Take with food if gastrointestinal upset occurs
- Maintain adequate fluid intake (6-8 glasses of water daily)
- Use sun protection (sunscreen, protective clothing) due to photosensitivity risk
- Report immediately: skin rash, sore throat, fever, unusual bleeding or bruising, yellowing of skin/eyes, dark urine
- Avoid in pregnancy and breastfeeding unless specifically directed by physician
- Inform all healthcare providers of use, particularly before surgery or new prescriptions
- Do not use for viral infections such as common cold or flu
- Be aware of potential interactions with other medications, especially blood thinners and diabetes medications
References
1. Stevens DL, et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):e10-e52. 2. Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. National Institutes of Health. 2023. 3. Sulfamethoxazole and Trimethoprim (Bactrim) Prescribing Information. FDA Label. 4. Gleckman R, et al. Trimethoprim-sulfamethoxazole revisited. Arch Intern Med. 1982;142(5):914-917. 5. Smilack JD. Trimethoprim-sulfamethoxazole. Mayo Clin Proc. 1999;74(7):730-734. 6. Wormser GP, et al. Single-agent therapy for severe bacterial infections: trimethoprim-sulfamethoxazole. Rev Infect Dis. 1982;4(2):562-568. 7. Masters PA, et al. Trimethoprim-sulfamethoxazole revisited. Ann Intern Med. 2003;139(11):922-930.