Usage
Trimethoprim combinations, primarily trimethoprim/sulfamethoxazole (TMP/SMX), also known as co-trimoxazole, are prescribed for various bacterial infections. These include urinary tract infections (UTIs), respiratory tract infections (including Pneumocystis jirovecii pneumonia), otitis media, gastrointestinal infections, skin and soft tissue infections, and certain other infections like toxoplasmosis.
Pharmacological Classification: Antibiotic
Mechanism of Action: TMP/SMX is a synergistic combination of two antibiotics. Trimethoprim inhibits bacterial dihydrofolate reductase, and sulfamethoxazole inhibits bacterial dihydropteroate synthase. Both these enzymes are essential in the bacterial folic acid synthesis pathway. By inhibiting these two sequential steps, TMP/SMX effectively blocks bacterial DNA synthesis, leading to bacterial cell death.
Alternate Names
- Trimethoprim/Sulfamethoxazole (TMP/SMX)
- Co-trimoxazole
- TMP-SMZ or SMZ-TMP
Brand Names: Bactrim®, Septra®, Sulfatrim®, Co-trimoxazole
How It Works
Pharmacodynamics: TMP/SMX exerts a bactericidal effect by disrupting the folic acid synthesis pathway, essential for bacterial DNA synthesis. This leads to impaired cell growth and ultimately, bacterial death.
Pharmacokinetics:
- Absorption: Trimethoprim and sulfamethoxazole are rapidly and almost completely absorbed after oral administration.
- Metabolism: Sulfamethoxazole is partially metabolized in the liver by the CYP2C9 system. Trimethoprim is minimally metabolized.
- Elimination: Both drugs are primarily excreted in the urine, largely unchanged. Trimethoprim is also removed by dialysis.
Mode of Action: TMP/SMX acts by sequential blockade of folic acid synthesis pathway in bacteria.
- Sulfamethoxazole: Inhibits dihydropteroate synthase, preventing the formation of dihydrofolic acid.
- Trimethoprim: Inhibits dihydrofolate reductase, preventing the conversion of dihydrofolic acid to tetrahydrofolic acid.
Elimination Pathways: Primarily renal excretion.
Dosage
Standard Dosage
Adults:
- UTI: 100 mg TMP every 12 hours or 200 mg TMP every 24 hours for 10 days. Alternatively, one double-strength tablet (160 mg TMP/800 mg SMX) every 12 hours for 10-14 days.
- Other Infections: Dosing varies depending on the infection. Consult specific guidelines.
Children:
- Dosing is weight-based, typically 4 mg/kg TMP every 12 hours (up to a maximum of 160 mg TMP) for most infections. Adjust dose for severe infections.
- Pediatric Safety Considerations: Avoid use in neonates less than 6 weeks of age, especially premature infants, due to the risk of kernicterus. Use cautiously in infants younger than 2 months.
Special Cases:
- Elderly Patients: Dose adjustment may be required based on renal function.
- Patients with Renal Impairment: Dosage adjustments are necessary based on creatinine clearance.
- Patients with Hepatic Dysfunction: Caution is advised, though specific dose adjustments are not usually necessary.
- Patients with Comorbid Conditions: Monitor closely for potential interactions, especially in patients with diabetes, folate deficiency, or those receiving other drugs that affect potassium levels (like ACE inhibitors).
Clinical Use Cases
Dosage in these settings should be individualized based on patient factors and the severity of infection. Consult infectious disease specialists for guidance in these situations.
Dosage Adjustments
Refer to the detailed dosing guidelines in the sections above and consider drug monitoring as needed.
Side Effects
Common Side Effects
- Nausea, vomiting
- Loss of appetite
- Rash, itching
- Diarrhoea
- Headache
Rare but Serious Side Effects
- Severe allergic reactions (anaphylaxis)
- Blood disorders (e.g., agranulocytosis, thrombocytopenia, aplastic anemia)
- Clostridioides difficile-associated diarrhea
- Liver damage (hepatitis, jaundice)
- Hyperkalemia
- Stevens-Johnson syndrome, toxic epidermal necrolysis
Long-Term Effects
Potential for bone marrow suppression and folate deficiency with prolonged use.
Adverse Drug Reactions (ADR)
See “Rare but Serious Side Effects”
Contraindications
- Hypersensitivity to trimethoprim or sulfonamides
- Megaloblastic anemia due to folate deficiency
- Marked hepatic impairment
- Severe renal impairment (CrCl <15 ml/min, unless monitored)
- Pregnancy (especially first trimester)
- Neonates < 6 weeks of age
Drug Interactions
- CYP450 Interactions: Sulfamethoxazole is a CYP2C9 inhibitor.
- Other Interactions: ACE inhibitors (increased risk of hyperkalemia), certain diuretics, warfarin, methotrexate, some oral hypoglycemics, dofetilide.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: D (contraindicated, especially in the first trimester)
- Fetal Risks: Increased risk of congenital malformations (neural tube defects, cardiovascular defects) due to folate antagonism.
- Breastfeeding: Small amounts are excreted in breast milk. Generally considered acceptable for short-term use in healthy, term infants, but caution is advised. Avoid use in infants younger than 2 months of age.
Drug Profile Summary
- Mechanism of Action: Inhibits sequential steps in bacterial folic acid synthesis.
- Side Effects: Nausea, vomiting, rash, pruritus, diarrhea; rarely severe allergic reactions, blood disorders, liver damage.
- Contraindications: Hypersensitivity, megaloblastic anemia due to folate deficiency, severe hepatic/renal impairment, pregnancy, neonates <6 weeks.
- Drug Interactions: ACE inhibitors, warfarin, methotrexate, certain diuretics.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy. Use with caution during breastfeeding.
- Dosage: Varies with infection and patient factors. Standard adult dose for UTI is 100-200 mg TMP every 12-24 hours for 10 days.
- Monitoring Parameters: Complete blood count, renal function, liver enzymes, potassium levels (especially with long-term use or in at-risk patients).
Popular Combinations
Trimethoprim/sulfamethoxazole (TMP/SMX). The combination is more effective than either drug alone due to synergistic activity.
Precautions
- Assess renal and hepatic function before and during therapy.
- Monitor for signs of hypersensitivity or blood dyscrasias.
- Supplement with folic acid if necessary.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Trimethoprim Combinations?
A: The standard adult dosage for UTI is 100 mg TMP every 12 hours or 200 mg TMP every 24 hours for 10 days. Pediatric dosing is weight-based (4mg/kg TMP every 12 hours).
Q2: What are the common side effects of Trimethoprim Combinations?
A: Nausea, vomiting, rash, itching, and diarrhea are common.
Q3: What are the contraindications for Trimethoprim Combinations?
A: Hypersensitivity, megaloblastic anemia due to folate deficiency, severe hepatic or renal impairment, pregnancy (especially first trimester), and neonates <6 weeks.
Q4: What are the serious side effects of Trimethoprim Combinations?
A: Severe allergic reactions, blood dyscrasias (e.g., agranulocytosis), liver damage, Stevens-Johnson Syndrome, and hyperkalemia.
Q5: Can Trimethoprim Combinations be used during pregnancy?
A: No, especially during the first trimester due to the risk of congenital malformations.
Q6: How does Trimethoprim Combinations work?
A: TMP/SMX works by blocking two sequential steps in the bacterial folic acid synthesis pathway, inhibiting bacterial growth and leading to cell death.
Q7: What are the important drug interactions with Trimethoprim Combinations?
A: Important interactions include ACE inhibitors (increased risk of hyperkalemia), warfarin, methotrexate, and some oral hypoglycemics.
Q8: What monitoring parameters should be considered when using Trimethoprim Combinations?
A: Complete blood count, renal function, liver function tests, and electrolyte levels, especially potassium.
Q9: What patient education should be provided when prescribing Trimethoprim Combinations?
A: Patients should be advised to complete the full course of therapy, drink plenty of fluids, report any signs of rash or allergic reaction, and avoid sun exposure.
