CO-TRIMOXAZOLE

Indications

• Urinary tract infections
• Respiratory tract infections
• Gastrointestinal infections
• Pneumocystis pneumonia
• Toxoplasmosis

Dosage

Children: Refer to the BNF for Children for specific dosing information appropriate for paediatric patients, as doses are typically weight-based and vary by age and condition.

Adults: Refer to the BNF for specific dosing information based on the clinical condition being treated, as dosing may vary depending on the severity of the infection and patient characteristics.

Mechanism of action

Sulfamethoxazole inhibits bacterial dihydrofolic acid synthesis due to its structural similarity to para-aminobenzoic acid (PABA). It competitively inhibits dihydropteroate synthase, the enzyme responsible for converting PABA to dihydrofolic acid. This action prevents the synthesis of tetrahydrofolate, leading to the inhibition of bacterial purine and DNA synthesis, resulting in a bacteriostatic effect.

Pharmacodynamics

Sulfamethoxazole is generally bacteriostatic, inhibiting a crucial step in bacterial folate synthesis. It is typically used in combination with trimethoprim, which inhibits the reduction of dihydrofolic acid to tetrahydrofolate. This combination allows for a synergistic effect, reducing the rate of bacterial resistance development compared to using either drug alone. Care should be taken as sulfamethoxazole can cause hypersensitivity reactions, and it may contribute to folate deficiency, particularly in at-risk populations.

Pharmacokinetics

Sulfamethoxazole is well absorbed following oral administration and is widely distributed in body tissues. It has a moderate half-life, necessitating multiple daily doses for sustained therapeutic effect. The drug is metabolized in the liver and excreted primarily via the kidneys, with some metabolites being active. Its excretion can be influenced by renal function, necessitating dose adjustments in patients with compromised kidney function.

Contra-indications

• Hypersensitivity to sulfamethoxazole or other sulfonamides
• Severe liver impairment
• Severe renal impairment
• History of severe adverse reactions to sulfonamides (e.g., Stevens-Johnson syndrome)

Adverse effects

• Rash
• Nausea
• Vomiting
• Diarrhea
• Hematological reactions (e.g., leukopenia, thrombocytopenia)
• Liver toxicity
• Renal toxicity
• Hemolytic anemia in patients with G6PD deficiency
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

Interactions

• Sulfamethoxazole may increase the anticoagulant effect of coumarins
• Concurrent use with other folate antagonists may enhance toxicity
• May interact with methotrexate, increasing the risk of toxicity

Precautions

• Use with caution in patients with a history of hypersensitivity reactions
• Monitor for signs of folate deficiency
• Assess renal and liver function prior to and during treatment
• Discontinue immediately at the first sign of rash or skin reaction

Pregnancy

Sulfamethoxazole is generally not recommended during pregnancy, especially in the first trimester and near term, due to potential risks of teratogenic effects and kernicterus in the newborn.

Breast-feeding

Sulfamethoxazole is excreted in breast milk; caution is advised when administering to nursing mothers due to potential effects on the nursing infant.

Storage

Store at room temperature, away from moisture and heat. Protect from light.

Formulations

• Oral tablets
• Oral suspension
• Injection

Indications

• Urinary tract infections
• Acute otitis media
• Chronic bronchitis exacerbations
• Pneumocystis pneumonia prophylaxis
• Travelers' diarrhea caused by susceptible organisms

Dosage

Children: For paediatric dosing, refer to the BNF for Children for specific indications and age-appropriate dosing.

Adults: Refer to the BNF for specific dosing guidelines based on the condition being treated and patient factors such as renal function.

Mechanism of action

Trimethoprim selectively inhibits dihydrofolate reductase, an enzyme involved in the folate synthesis pathway. By blocking this enzyme, trimethoprim reduces the formation of tetrahydrofolate, a cofactor required for the synthesis of nucleic acids, leading to the inhibition of bacterial growth.

Pharmacodynamics

Trimethoprim demonstrates bactericidal activity against a wide range of gram-positive and gram-negative bacteria. It is particularly effective against urinary tract pathogens, respiratory pathogens, and certain strains of enteric bacteria. Trimethoprim's efficacy is influenced by its concentration at the site of infection and its ability to penetrate bacterial cells.

Pharmacokinetics

Trimethoprim is well absorbed after oral administration, with peak plasma concentrations typically occurring within 1-4 hours. It has a volume of distribution of approximately 0.7 L/kg and is about 45% bound to plasma proteins. Trimethoprim is primarily excreted unchanged in the urine, with a half-life of about 8-10 hours. Renal function significantly affects its clearance, necessitating dose adjustments in patients with renal impairment.

Contra-indications

• Hypersensitivity to trimethoprim or any of its components
• Severe renal impairment
• Pregnancy (especially during the first trimester)
• Concurrent use with methotrexate

Adverse effects

• Nausea
• Vomiting
• Rash
• Itching
• Anemia
• Leukopenia
• Thrombocytopenia
• Elevated liver enzymes
• Hyperkalemia
• Renal impairment

Interactions

• Increased effect of anticoagulants (e.g., warfarin)
• Increased risk of hyperkalemia with potassium-sparing diuretics
• Reduced effectiveness of certain anticonvulsants
• Synergistic effect with sulfamethoxazole (co-trimoxazole)
• May enhance the toxicity of methotrexate

Precautions

• Use with caution in patients with renal impairment
• Monitor renal function and electrolyte levels during treatment
• Consider alternative treatments in patients with folate deficiency
• Use cautiously in patients with a history of asthma or allergic disorders

Pregnancy

Trimethoprim should be avoided in pregnancy, especially in the first trimester due to potential risk of teratogenic effects.

Breast-feeding

Trimethoprim is excreted in breast milk; use caution and monitor the infant for potential side effects.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Oral tablets (e.g., 100 mg, 200 mg)
• Oral suspension (e.g., 200 mg/5 mL)
• Injection (e.g., 100 mg/mL)

Mechanism of action

Sulfamethoxazole is a sulfonamide that inhibits bacterial dihydrofolic acid synthesis due to its structural similarity to an endogenous substrate, para-aminobenzoic acid (PABA). Most bacteria meet their need for folic acid by synthesizing it from PABA, as opposed to Animalia that require exogenous folic acid sources. Sulfamethoxazole competitively inhibits dihydropteroate synthase, the enzyme responsible for bacterial conversion of PABA to dihydrofolic acid. Inhibition of this pathway prevents the synthesis of tetrahydrofolate and, ultimately, the synthesis of bacterial purines and DNA, resulting in a bacteriostatic effect. Sulfonamides are usually bacteriostatic in action. Sulfonamides interfere with the utilization of p-aminobenzoic acid (PABA) in the biosynthesis of tetrahydrofolic acid (the reduced form of folic acid) cofactors in susceptible bacteria. Sulfonamides are structural analogs of PABA and appear to interfere with PABA utilization by competitively inhibiting the enzyme dihydropteroate synthase, which catalyzes the formation of dihydropteroic acid (a precursor of tetrahydrofolic acid) from PABA and pteridine; however, other mechanism(s) affecting the biosynthetic pathway also may be involved. Compounds such as pyrimethamine and trimethoprim, which block later stages in the synthesis of folic acid, act synergistically with sulfonamides. Only microorganisms that synthesize their own folic acid are inhibited by sulfonamides; animal cells and bacteria which are capable of utilizing folic acid precursors or preformed folic acid are not affected by these drugs. The antibacterial activity of the sulfonamides is reportedly decreased in the presence of blood or purulent body exudates. /Sulfonamides/ /Sulfonamides inhibit bacterial growth by preventing para-aminobenzoic acid (PABA) from being incorporated/ into dihydropteroic acid, the immediate precursor of folic acid. Sensitive microorganisms are those that must synthesize their own folic acid; bacteria that can utilize preformed folate are not affected. Bacteriostasis induced by sulfonamides is counteracted by PABA competitively. Sulfonamides do not affect mammalian cells by this mechanism, since they require preformed folic acid and cannot synthesize it. /Sulfonamides/ Sulfonamides are broad-spectrum, bacteriostatic anti-infectives. They are structural analogs of para-aminobenzoic acid and competively inhibit a bacterial enzyme, dihydropteroate synthetase, that is responsible for incorporation of para-aminobenzoic acid into dihydrofolic acid. This blocks the synthesis of dihydrofolic acid and decreases the amount of metabolically active tetrahydrofolic acid, a cofactor for the synthesis of purines, thymidine, and DNA. /Sulfonamides/ The hydroxylamine and nitroso metabolites formed by N4-oxidation of sulfonamides are thought to be involved in the pathogenesis of idiosyncratic reactions to this class of drugs. Idiosyncratic reactions to sulfonamides are characterized by multisystemic toxicity, including hepatitis, nephritis, dermatitis, and blood dyscrasias (aplastic anemia, agranulocytosis). Previously it has been shown that cytochrome p-450 in the liver metabolizes sulfamethoxazole to its hydroxylamine metabolite. In this paper the N4-oxidation of sulfamethoxazole by activated monocytes and neutrophils (human and canine) to form sulfamethoxazole hydroxylamine and nitrosulfamethoxazole is reported. The presumed nitroso intermediate was not detected. Purified myeloperoxidase and prostaglandin H synthase were also capable of mediating the oxidation of sulfamethoxazole. The present studies suggest that myeloperoxidase is responsible for the observed oxidation by phagocytic cells. Oxidation by neutrophils may play a role in agranulocytosis, and oxidation by monocytes may facilitate antigen presentation. Extrahepatic bioactivation of sulfonamides by peroxidases in phagocytic cells and other tissues may be important in determining the range of adverse reactions to sulfonamides

Pharmacodynamics

Sulfamethoxazole is a bacteriostatic sulfonamide antibiotic that inhibits a critical step in bacterial folate synthesis. It is generally given in combination with [trimethoprim], a dihydrofolate reductase inhibitor, which inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid. Studies have shown that bacterial resistance develops more slowly with the combination of the two drugs than with either trimethoprim or sulfamethoxazole alone, as together they inhibit sequential steps in the bacterial folate synthesis pathway. Sulfonamides, including sulfamethoxazole, have been implicated in hypersensitivity reactions - these agents should be discontinued at the first sign of a developing rash, as this may signal the start of a more severe reaction such as Stevens-Johnson syndrome or toxic epidermal necrolysis. Sulfamethoxazole treatment may contribute to folate deficiency and should therefore be used with caution in patients at a higher risk of developing a deficiency. Hemolysis has been observed in patients with glucose-6-phosphate dehydrogenase deficiency who are using sulfamethoxazole/trimethoprim.