Usage
Co-trimoxazole is a combination antibiotic used to treat a variety of bacterial infections. It is prescribed for infections like:
- Urinary tract infections (UTIs)
- Acute otitis media (ear infections) in children
- Acute exacerbations of chronic bronchitis
- Shigellosis (bacillary dysentery)
- Traveler’s diarrhea
- Pneumocystis jirovecii pneumonia (PJP), both for treatment and prevention (prophylaxis)
- Toxoplasmosis, both for treatment and prevention
- Nocardiosis
Pharmacological Classification: Antibiotic
Mechanism of Action: Co-trimoxazole works by inhibiting the synthesis of folic acid, a crucial nutrient for bacterial growth and survival. It does this by targeting two different enzymes in the folic acid pathway: sulfamethoxazole inhibits dihydropteroate synthase, and trimethoprim inhibits dihydrofolate reductase. This dual-action mechanism makes it more effective than using either drug alone (synergistic effect) and helps to reduce the development of resistance.
Alternate Names
International Nonproprietary Name (INN): Co-trimoxazole
Other Names: Sulfamethoxazole/Trimethoprim, TMP-SMX, TMP-SMZ
Brand Names: Bactrim, Septra, Cotrim
How It Works
Pharmacodynamics: Co-trimoxazole exerts a bactericidal effect by sequentially blocking two enzymes in the bacterial folic acid synthesis pathway. This synergistic action disrupts the production of essential nucleic acids, ultimately leading to bacterial death. Human cells are not affected because they obtain folic acid from dietary sources rather than synthesizing it.
Pharmacokinetics:
- Absorption: Orally administered co-trimoxazole is well-absorbed from the gastrointestinal tract.
- Metabolism: Primarily hepatic, with sulfamethoxazole undergoing acetylation and glucuronidation, and trimethoprim undergoing oxidation and hydroxylation.
- Elimination: Both components are primarily excreted in the urine, with a small amount excreted in the feces.
- Mode of Action: Inhibits bacterial folic acid synthesis as described above.
- Receptor Binding/Enzyme Inhibition: Co-trimoxazole acts by inhibiting the bacterial enzymes dihydropteroate synthase (by sulfamethoxazole) and dihydrofolate reductase (by trimethoprim).
- Elimination Pathways: Primarily renal excretion, with some hepatic metabolism and fecal excretion.
Dosage
Standard Dosage
Adults:
- Standard dose: 160 mg trimethoprim/800 mg sulfamethoxazole every 12 hours.
- Duration: Variable depending on the infection; typically 5-14 days.
Children:
- Dosage: Calculated based on weight (6 mg trimethoprim/30 mg sulfamethoxazole per kg body weight per day, divided into two doses). Dose should not exceed adult dose
- Safety: Use with caution in infants under 6 weeks old. Avoid in neonates less than 2 months of age.
Special Cases:
- Elderly Patients: Dosage adjustments may be necessary based on renal function. Monitor for hyperkalemia.
- Patients with Renal Impairment: Dosage reduction is needed based on creatinine clearance (CrCl). Not recommended for CrCl <15 mL/min.
- Patients with Hepatic Dysfunction: Caution advised; monitor liver function tests.
- Patients with Comorbid Conditions: Close monitoring is warranted in patients with folate deficiency, G6PD deficiency, or other conditions.
Clinical Use Cases
The standard adult or pediatric dosage applies unless otherwise specified by guidelines or an infectious disease specialist.
- Intubation/Surgical Procedures/Mechanical Ventilation/ICU Use/Emergency Situations: Dosing determined by the specific infection being treated and is often guided by local guidelines and susceptibility patterns.
Dosage Adjustments
As indicated above for renal impairment, hepatic dysfunction, and special populations. Therapeutic drug monitoring may be needed in some situations.
Side Effects
Common Side Effects
- Nausea
- Vomiting
- Diarrhea
- Rash
- Oral thrush
- Vaginal thrush
Rare but Serious Side Effects
- Stevens-Johnson syndrome (SJS)
- Toxic epidermal necrolysis (TEN)
- Drug reaction with eosinophilia and systemic symptoms (DRESS)
- Severe skin reactions
- Bone marrow suppression (leukopenia, thrombocytopenia, anemia)
- Hepatic necrosis
- Hyperkalemia
- Kidney failure
Long-Term Effects
With prolonged use, potential for bone marrow suppression, kidney damage, and antibiotic-associated colitis.
Adverse Drug Reactions (ADR)
As listed above in rare but serious side effects. Any sign of these ADRs requires immediate discontinuation and supportive care.
Contraindications
- Hypersensitivity to sulfonamides or trimethoprim
- Megaloblastic anemia due to folate deficiency
- Infants younger than 2 months of age
- Pregnant women at term and nursing mothers (during the first 6 weeks postpartum, G6PD deficiency, or if the baby is jaundiced).
- Marked liver parenchymal damage
- Severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed
Drug Interactions
Co-trimoxazole has numerous potential drug interactions:
- Warfarin: Increased risk of bleeding.
- Phenytoin: Increased phenytoin levels.
- Sulfonylureas: Increased risk of hypoglycemia.
- Methotrexate: Increased methotrexate toxicity.
- Digoxin: Increased digoxin levels.
- ACE inhibitors: Increased risk of hyperkalemia.
- Diuretics (thiazides): Increased risk of thrombocytopenia and hyperkalemia.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Generally avoided during pregnancy, especially the first trimester and near term. If used during pregnancy, folate supplementation should be considered.
- Fetal Risks: Increased risk of congenital malformations, especially neural tube defects.
- Breastfeeding: Small amounts are excreted in breast milk. Generally not recommended during the first 6 weeks postpartum, in mothers with G6PD deficiency, or if the baby is jaundiced. Avoid in infants <8 weeks of age due to the risk of hyperbilirubinemia
Drug Profile Summary
- Mechanism of Action: Inhibits bacterial folic acid synthesis by blocking dihydropteroate synthase and dihydrofolate reductase.
- Side Effects: Nausea, vomiting, diarrhea, rash, SJS/TEN (rare), bone marrow suppression (rare).
- Contraindications: Sulfonamide hypersensitivity, megaloblastic anemia due to folate deficiency, infants <2 months, pregnancy at term, nursing mothers (certain conditions), marked liver damage, severe renal insufficiency.
- Drug Interactions: Warfarin, phenytoin, sulfonylureas, methotrexate, digoxin, ACE inhibitors, thiazide diuretics.
- Pregnancy & Breastfeeding: Avoided in pregnancy, especially 1st trimester and at term. Small amounts excreted in breast milk; caution advised.
- Dosage: Adults: 160 mg TMP/800 mg SMX every 12 hours. Children: Based on weight (6 mg TMP/30 mg SMX per kg/day divided twice daily). Not recommended for neonates less than 2 months of age.
- Monitoring Parameters: Complete blood count (CBC), renal function tests, liver function tests, electrolyte levels (especially potassium).
Popular Combinations
No commonly used combinations are recommended routinely. If a broader spectrum of coverage is required, an additional antibiotic may be added based on specific clinical circumstances.
Precautions
- General Precautions: Assess renal and hepatic function, monitor CBC, assess for allergies.
- Specific Populations: As outlined above.
- Lifestyle Considerations: Avoid excessive sun exposure due to photosensitivity.
FAQs
Q1: What is the recommended dosage for Co-trimoxazole?
A: Adults: 160 mg TMP/800 mg SMX every 12 hours. Children: Dose based on weight (6mg TMP/30 mg SMX per kg/day divided twice daily).
Q2: What are the common side effects of Co-trimoxazole?
A: Nausea, vomiting, diarrhea, and rash are common.
Q3: Is Co-trimoxazole safe during pregnancy?
A: Generally avoided, especially in the first trimester and near term, due to potential fetal harm.
Q4: Can Co-trimoxazole be used in patients with renal impairment?
A: Yes, but dosage adjustments are necessary based on creatinine clearance. Not recommended if CrCl <15 mL/min.
Q5: What are the serious side effects of Co-trimoxazole?
A: SJS/TEN, bone marrow suppression, hepatic necrosis, hyperkalemia, and renal failure.
Q6: What are the contraindications to Co-trimoxazole use?
A: Hypersensitivity to sulfonamides or trimethoprim, megaloblastic anemia due to folate deficiency, neonates <2 months old, pregnancy near term, certain breastfeeding situations.
Q7: How does Co-trimoxazole interact with warfarin?
A: Increases the risk of bleeding by potentiating warfarin’s anticoagulant effects. Close monitoring of INR is required.
Q8: Can Co-trimoxazole be used to treat a UTI?
A: Yes, Co-trimoxazole is commonly used for uncomplicated UTIs.
Q9: How long should a course of Co-trimoxazole last?
A: Treatment duration varies depending on the infection, typically 5-14 days. The course should be completed even if symptoms resolve earlier.
Q10: How should Co-trimoxazole be administered?
A: Orally, with food or a glass of water, to minimize gastrointestinal upset. An intravenous formulation is available for severe infections.
