COTRIMOXAZOLE/TRIMETHOPRIM+ SULPHAMETHOXAZOLE Use Dose Side effects contraindications

Cotrimoxazole (Trimethoprim + Sulfamethoxazole) Overview

Cotrimoxazole is a combination antibiotic consisting of Trimethoprim and Sulfamethoxazole. This combination works synergistically to inhibit bacterial growth by targeting two steps in the bacterial folic acid synthesis pathway. It is widely used to treat various bacterial infections.

Components:

1. Trimethoprim (TMP): Inhibits dihydrofolate reductase, preventing the conversion of dihydrofolic acid to tetrahydrofolic acid, a critical step in bacterial DNA synthesis.
2. Sulfamethoxazole (SMX): A sulfonamide that inhibits dihydropteroate synthase, preventing the incorporation of para-aminobenzoic acid (PABA) into dihydropteroate, which is a precursor for folic acid synthesis in bacteria.

Mechanism of Action:

Both drugs work together to provide a bactericidal effect by inhibiting sequential steps in the folic acid synthesis pathway:

• Trimethoprim: Inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid.
• Sulfamethoxazole: Inhibits the incorporation of PABA into folic acid.

By targeting two points in the bacterial folate pathway, the combination is more effective and reduces the risk of bacterial resistance.

Uses/Indications:

Cotrimoxazole is used to treat a variety of bacterial infections, including:

1. Urinary Tract Infections (UTIs)
2. Respiratory Infections (e.g., bronchitis, pneumonia caused by Pneumocystis jirovecii)
3. Gastrointestinal Infections (e.g., traveler’s diarrhea)
4. Skin and Soft Tissue Infections (e.g., cellulitis)
5. Nocardiosis
6. Prophylaxis and treatment of Pneumocystis jirovecii pneumonia in immunocompromised patients (such as HIV/AIDS patients).

Dosage:

Cotrimoxazole is available in both oral and intravenous formulations, typically in a fixed ratio of 1:5 (Trimethoprim:Sulfamethoxazole).

• For adults: A standard dose for a UTI would be 160 mg trimethoprim + 800 mg sulfamethoxazole, taken every 12 hours for 7-10 days.
• For children: The dosage is based on body weight, typically 6 mg/kg of trimethoprim and 30 mg/kg of sulfamethoxazole per day.

For serious infections like Pneumocystis jirovecii pneumonia, higher doses and longer durations may be required.

Pharmacokinetics:

• Absorption: Well absorbed orally, with bioavailability near 90%.
• Distribution: Distributed widely in body fluids and tissues, including the lungs, kidneys, and cerebrospinal fluid (CSF).
• Metabolism: Metabolized primarily in the liver.
• Excretion: Mainly excreted via the kidneys.

Side Effects:

Although generally well tolerated, Cotrimoxazole has a range of potential side effects:

1. Gastrointestinal Symptoms: Nausea, vomiting, diarrhea.
2. Allergic Reactions: Rash, fever, pruritus, and more severe hypersensitivity reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis (TEN).
3. Hematologic Effects: Bone marrow suppression leading to anemia, leukopenia, and thrombocytopenia.
4. Renal Effects: Crystalluria, interstitial nephritis.
5. Hyperkalemia: Due to the trimethoprim component, which can reduce potassium excretion in the kidneys.
6. Liver Toxicity: Rarely, hepatotoxicity may occur.

Contraindications:

Cotrimoxazole is contraindicated in:

1. Hypersensitivity to sulfonamides or trimethoprim.
2. Severe liver or renal disease (without dose adjustment).
3. Pregnancy (especially in the first trimester and near term): It can interfere with folic acid metabolism, leading to teratogenic effects.
4. Megaloblastic anemia due to folate deficiency.

Drug Interactions:

Cotrimoxazole can interact with other medications, leading to potential complications:

1. Warfarin: Enhances anticoagulant effects, increasing the risk of bleeding.
2. Phenytoin: Increases the half-life of phenytoin, potentially leading to toxicity.
3. Methotrexate: Competes for renal tubular secretion, increasing toxicity.
4. ACE inhibitors or ARBs: May worsen hyperkalemia.
5. Oral hypoglycemic agents: Enhances the hypoglycemic effect.

Resistance:

Although effective against many bacteria, resistance to Cotrimoxazole is becoming increasingly common, particularly in organisms such as Escherichia coli and Staphylococcus aureus. Resistance mechanisms include mutations in target enzymes and increased production of PABA.

Special Considerations:

• Pediatric Use: Generally safe but requires weight-based dosing.
• Elderly Patients: More prone to side effects, especially hyperkalemia and renal impairment.
• Immunocompromised Patients: Used frequently for prophylaxis in HIV patients to prevent Pneumocystis jirovecii pneumonia.

Conclusion:

Cotrimoxazole is a widely used antibiotic with a broad spectrum of activity, particularly for urinary, respiratory, and gastrointestinal infections. Its effectiveness is enhanced by the synergistic action of its two components. However, its use should be carefully monitored due to the risk of side effects, drug interactions, and emerging resistance patterns.