Cotrimoxazole

1. Drug Name

• Generic Name: Cotrimoxazole

• Brand Names: Bactrim, Septra, Cotrim, and others.

2. Drug Classification

• Class: Antibiotic, Combination (Sulfonamide + Trimethoprim)

• Subclass: None (Combination of two active components: sulfonamide and trimethoprim)

3. Mechanism of Action

• Primary Action: Cotrimoxazole is a fixed-dose combination of sulfamethoxazole (a sulfonamide) and trimethoprim (a dihydrofolate reductase inhibitor). Both drugs act synergistically to inhibit bacterial folic acid synthesis, which is essential for the synthesis of purines and nucleic acids, thereby inhibiting bacterial growth.

  • Sulfamethoxazole: Inhibits the synthesis of dihydropteroate from para-aminobenzoic acid (PABA), thereby preventing the formation of dihydrofolic acid, a precursor to tetrahydrofolic acid.

  • Trimethoprim: Inhibits dihydrofolate reductase, blocking the conversion of dihydrofolic acid to tetrahydrofolic acid, further disrupting folic acid metabolism and inhibiting bacterial DNA synthesis.

• Bactericidal Action: This combination is bactericidal due to the synergistic inhibition of two steps in the folic acid synthesis pathway.

• Spectrum of Activity: Cotrimoxazole has a broad spectrum of activity against both gram-positive and gram-negative organisms. It is effective against Staphylococcus aureus (including MRSA), Escherichia coli, Haemophilus influenzae, Streptococcus pneumoniae, Shigella spp., Salmonella spp., and Pneumocystis jirovecii.

4. Pharmacokinetics

• Absorption: Cotrimoxazole is well absorbed after oral administration. Both sulfamethoxazole and trimethoprim have good oral bioavailability (approximately 85-90%).

• Distribution: Both components of cotrimoxazole are widely distributed throughout the body, including the lungs, liver, kidneys, and cerebrospinal fluid (CSF). The volume of distribution (Vd) for sulfamethoxazole is about 0.6 L/kg, while for trimethoprim, it is about 1.2 L/kg.

• Metabolism:

  • Sulfamethoxazole: Primarily metabolized in the liver by N-acetylation, resulting in inactive metabolites.

  • Trimethoprim: Metabolized in the liver to inactive metabolites. It undergoes both glucuronidation and oxidation.

• Excretion: Both drugs are eliminated by the kidneys, with sulfamethoxazole being excreted in the urine as both unchanged drug and metabolites. Trimethoprim is primarily excreted unchanged in the urine. The half-life (t½) of sulfamethoxazole is 10 hours, while trimethoprim has a half-life of 8-10 hours.

• Special Considerations: Renal impairment can lead to increased plasma concentrations of both drugs, necessitating dose adjustments in patients with compromised renal function. The combination should be used cautiously in patients with impaired renal function.

5. Indications

• Primary Indications:

  • Urinary Tract Infections (UTIs): Effective for the treatment of uncomplicated and complicated UTIs caused by susceptible organisms like E. coli, Klebsiella spp., and Proteus spp.

  • Respiratory Infections: Including pneumonia caused by Pneumocystis jirovecii (PJP), which is a common opportunistic infection in immunocompromised patients, particularly those with HIV/AIDS.

  • Gastrointestinal Infections: Diarrhea caused by Shigella spp., Salmonella spp., and Campylobacter spp.

  • Upper Respiratory Infections: For conditions such as acute otitis media, sinusitis, and bronchitis caused by susceptible bacteria.

  • Staphylococcal Infections: Including skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus (MRSA).

• Off-label Uses:

  • Toxoplasmosis: Cotrimoxazole is sometimes used in the treatment of Toxoplasma gondii infections, especially in immunocompromised patients.

  • Nocardia infections: Used for the treatment of nocardiosis.

• Specific Populations: Effective for treating infections in immunocompromised individuals, particularly those with HIV, as prophylaxis and treatment for Pneumocystis jirovecii pneumonia (PCP).

6. Dosage and Administration

• Adult Dosing:

  • UTIs: 160 mg trimethoprim and 800 mg sulfamethoxazole orally twice daily for 7-10 days.

  • Pneumocystis jirovecii Pneumonia (PCP): 20 mg/kg/day of trimethoprim and 100 mg/kg/day of sulfamethoxazole orally or intravenously in divided doses for 21 days.

  • Acute Exacerbation of Chronic Bronchitis: 160 mg trimethoprim and 800 mg sulfamethoxazole orally every 12 hours for 10-14 days.

  • Toxoplasmosis: 160 mg trimethoprim and 800 mg sulfamethoxazole orally twice daily for 4-6 weeks, as part of combination therapy.

• Pediatric Dosing:

  • UTIs: 8 mg/kg/day trimethoprim and 40 mg/kg/day sulfamethoxazole, divided into two doses.

  • Pneumocystis jirovecii Pneumonia: 5 mg/kg/day trimethoprim and 25 mg/kg/day sulfamethoxazole for 21 days.

• Renal Adjustments: Dosing adjustments are required in patients with renal impairment. In moderate to severe renal dysfunction, the dosing interval may need to be extended, and the dose reduced to avoid drug accumulation.

• Route of Administration: Oral and intravenous (IV) routes are available. Oral administration is preferred for mild to moderate infections, while IV administration is used for more severe infections or when the oral route is not feasible.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to sulfamethoxazole, trimethoprim, or any component of the formulation.

  • Patients with a history of severe hypersensitivity (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis) to sulfonamides.

  • Patients with megaloblastic anemia due to folate deficiency.

  • Pregnancy (especially during the first trimester) and breastfeeding, as the drug can cross the placenta and into breast milk.

• Relative Contraindications:

  • Renal Impairment: Should be used cautiously in patients with renal dysfunction.

  • Hepatic Impairment: Caution is advised in patients with liver disease, especially in those with severe hepatic dysfunction.

8. Warnings and Precautions

• Hematologic Effects: Cotrimoxazole may cause blood dyscrasias, such as leukopenia, thrombocytopenia, and anemia, particularly in patients with pre-existing folate deficiency or in the elderly.

• Skin Reactions: Risk of severe skin reactions like Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and erythema multiforme. Discontinue if any signs of severe skin reactions occur.

• Renal Toxicity: Cotrimoxazole may cause renal impairment, especially in elderly patients or those with pre-existing renal conditions. Renal function should be monitored regularly.

• Hyperkalemia: Trimethoprim can cause hyperkalemia, particularly in patients with renal impairment, and should be used cautiously in patients on potassium-sparing diuretics or ACE inhibitors.

• Sulfonamide Hypersensitivity: Patients with a history of sulfonamide allergy may be at an increased risk for allergic reactions, including rash, fever, and, in severe cases, anaphylaxis.

9. Adverse Effects

• Common Adverse Effects (≥10%):

  • Nausea and vomiting.

  • Rash.

  • Diarrhea.

• Less Common but Clinically Significant:

  • Hematologic Effects: Leukopenia, thrombocytopenia, hemolytic anemia (especially in patients with G6PD deficiency).

  • Liver Toxicity: Elevations in liver enzymes, hepatitis, and jaundice.

• Serious Adverse Reactions:

  • Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): Severe, potentially fatal skin reactions.

  • Renal Failure: Acute kidney injury, particularly in patients with pre-existing kidney disease or dehydration.

  • Hyperkalemia: Potentially life-threatening, particularly in patients with renal impairment or those taking potassium-sparing diuretics.

10. Drug Interactions

• Major Drug Interactions:

  • Warfarin: Cotrimoxazole can increase the anticoagulant effect of warfarin by inhibiting its metabolism, increasing the risk of bleeding.

  • Methotrexate: Increased risk of methotrexate toxicity due to impaired renal excretion when used concurrently with cotrimoxazole.

  • Phenytoin: Cotrimoxazole may increase the plasma concentrations of phenytoin, increasing the risk of toxicity.

• Food-Drug Interactions: There are no significant food interactions, but cotrimoxazole may be taken with or without food.

• Lab Test Interactions: Cotrimoxazole can cause false positive results in tests for urinary glucose and in the Coombs test (direct antiglobulin test).

11. Clinical Pharmacology

• Pharmacodynamics: The combination of sulfamethoxazole and trimethoprim results in synergistic inhibition of bacterial folic acid synthesis. The pharmacodynamic profile of cotrimoxazole is based on its ability to target two separate stages of folate metabolism, leading to enhanced antibacterial activity compared to either drug alone.

• Therapeutic Spectrum: Cotrimoxazole is particularly effective against a wide range of respiratory, gastrointestinal, urinary tract, and systemic infections.

12. Special Populations

• Pregnancy: Category D. Cotrimoxazole is contraindicated during pregnancy, particularly in the first trimester, as it can cause harm to the fetus, including neural tube defects.

• Lactation: Although cotrimoxazole is excreted into breast milk, its use is generally avoided during lactation, especially in infants younger than 2 months due to the potential for kernicterus.

• Geriatrics: Elderly patients may have an increased risk of adverse effects, particularly renal toxicity and hyperkalemia.

• Renal and Hepatic Dysfunction: Dose adjustments are necessary for patients with renal impairment. Cotrimoxazole should be used cautiously in patients with hepatic dysfunction.

13. Therapeutic Uses

• First-Line Therapy:

  • Treatment of uncomplicated and complicated UTIs, respiratory infections, and gastrointestinal infections caused by susceptible organisms.

• Combination Therapy: Can be used in combination with other antibiotics for more severe infections, such as polymicrobial infections or infections in immunocompromised patients.

14. Monitoring and Follow-Up

• Lab Tests: Monitor renal function (serum creatinine, BUN), complete blood count (CBC), and liver enzymes during prolonged therapy.

• Patient Follow-up: Regular follow-up for signs of adverse reactions such as skin rashes, signs of blood dyscrasia, and renal toxicity.

15. Overdose Management

• Symptoms of Overdose: Nausea, vomiting, dizziness, lethargy, and in severe cases, bone marrow suppression and renal failure.

• Treatment Protocols: There is no specific antidote for cotrimoxazole overdose. Supportive care is the mainstay of treatment, including hydration and close monitoring of renal function.

• Supportive Measures: Ensure adequate hydration and renal monitoring. Discontinue the drug if signs of severe toxicity are observed.

16. Patient Counseling Information

• Key Points to Discuss with Patients:

  • Advise patients to take the medication as prescribed and complete the full course of treatment.

  • Inform patients that cotrimoxazole can cause photosensitivity, and they should avoid prolonged sun exposure or use sunscreen.

  • Encourage patients to report any rash, fever, or signs of allergic reactions promptly.

• Signs/Symptoms to Watch For:

  • Symptoms of an allergic reaction (rash, swelling, difficulty breathing).

  • Signs of kidney problems (e.g., decreased urine output, swelling).

  • Severe diarrhea or abdominal pain, especially if related to C. difficile.