SHALPHATRIM SUSPENSION

Indications

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

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines appropriate for children.

Adults: Refer to the BNF for specific dosing guidelines based on the infection being treated.

Mechanism of action

Sulfamethoxazole acts as a competitive inhibitor of dihydropteroate synthase, an enzyme involved in the bacterial folate synthesis pathway. By blocking this enzyme, sulfamethoxazole prevents the conversion of para-aminobenzoic acid (PABA) to dihydropteroic acid, thereby inhibiting the production of folate. This ultimately disrupts nucleic acid synthesis and bacterial growth.

Pharmacodynamics

The antibacterial activity of sulfamethoxazole is dose-dependent and is characterized by its ability to inhibit bacterial growth. It is bacteriostatic, meaning it stops bacteria from multiplying but does not kill them outright. The combination with trimethoprim results in a synergistic effect, leading to enhanced efficacy against certain pathogens.

Pharmacokinetics

Sulfamethoxazole is well-absorbed following oral administration, with peak plasma concentrations typically occurring within 2 to 4 hours. It is widely distributed throughout body tissues and fluids, including the central nervous system. The drug is metabolized in the liver and primarily eliminated via the kidneys. Its half-life ranges from 6 to 12 hours. The presence of trimethoprim can alter the pharmacokinetics of sulfamethoxazole, affecting its efficacy and safety profile.

Contra-indications

• Hypersensitivity to sulfamethoxazole, other sulfonamides or any components of the formulation
• Severe renal impairment
• Porphyria

Adverse effects

• Rash
• Nausea
• Vomiting
• Diarrhea
• Hematologic reactions (e.g., agranulocytosis, aplastic anemia)
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Hepatic toxicity

Interactions

• Anticoagulants (may enhance their effects)
• Methotrexate (may increase toxicity)
• Phenytoin (may displace phenytoin from protein binding sites)
• Diuretics (may increase the risk of nephrotoxicity)

Precautions

• Use with caution in patients with renal impairment
• Monitor blood counts in long-term therapy
• Assess for signs of hypersensitivity
• Avoid use in patients with glucose-6-phosphate dehydrogenase deficiency

Pregnancy

Sulfamethoxazole should be avoided in pregnancy, especially during the first trimester, due to potential teratogenic effects.

Breast-feeding

Sulfamethoxazole is excreted in breast milk; therefore, caution should be exercised when administering to nursing mothers.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Tablets
• Suspension
• Injection

Indications

• Bacterial infections
• Urinary tract infections
• Respiratory tract infections
• Prophylaxis of recurrent urinary tract infections

Dosage

Children: For children aged 6 weeks to 5 months: 4 mg/kg twice daily (max. 200 mg). For children 6 months to 5 years: 4 mg/kg twice daily (max. 200 mg). For children 6–11 years: 4 mg/kg twice daily (max. 200 mg). For children

Adults: 200 mg twice daily.

Mechanism of action

Trimethoprim is a reversible inhibitor of dihydrofolate reductase, an enzyme that catalyzes the formation of tetrahydrofolic acid from dihydrofolic acid. By inhibiting this enzyme, trimethoprim disrupts the biosynthesis of nucleic acids and proteins in bacteria, leading to their growth inhibition. The drug has a significantly higher affinity for bacterial dihydrofolate reductase compared to the mammalian enzyme, ensuring selective antibacterial activity.

Pharmacodynamics

Trimethoprim exerts its antimicrobial effects by disrupting bacterial nucleic acid synthesis. It is effective against various gram-negative bacteria and some coagulase-negative Staphylococcus species. Resistance can develop through mechanisms such as alterations to the bacterial cell wall or overproduction of the target enzyme. Monitoring for potential blood disorders is important during therapy, as rare adverse effects can occur.

Pharmacokinetics

Trimethoprim is well absorbed from the gastrointestinal tract and reaches peak plasma concentrations within 1-4 hours post-administration. It has a volume of distribution that suggests extensive tissue penetration, including into the lungs and kidneys, and is primarily excreted unchanged in the urine. The elimination half-life is approximately 8-10 hours, and dosing adjustments may be necessary in cases of renal impairment.

Contra-indications

• Severe renal impairment
• Known hypersensitivity to trimethoprim or any component of the formulation

Adverse effects

• Diarrhoea
• Nausea
• Headache
• Dizziness
• Fatigue
• Skin reactions
• Vomiting
• Anxiety
• Agranulocytosis
• Eosinophilia
• Photosensitivity reactions
• Thrombocytopenia
• Leukopenia
• Pseudomembranous colitis

Interactions

• Increases exposure to pramipexole
• Increases exposure to treprostinil
• Increases exposure to dopaminergic receptor agonists
• Increases concentration of antiepileptics
• Increases concentration of fosphenytoin
• Increases concentration of phenytoin
• Increases risk of haematological toxicity with azathioprine in renal transplant patients
• Increases concentration of digoxin
• Increases exposure to repaglinide

Precautions

• Caution in patients with renal impairment
• Caution in elderly patients (75 years and over)
• Monitor for signs of blood disorders such as sore throat, fever, and pallor
• Consider local antimicrobial susceptibility patterns before use

Pregnancy

Manufacturer advises avoidance due to potential fetal developmental toxicity observed in animal studies.

Breast-feeding

Manufacturer advises avoidance as trimethoprim is present in milk in animal studies.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets
• Oral suspension
• Injection solution

Mechanism of action

Trimethoprim is a reversible inhibitor of dihydrofolate reductase, one of the principal enzymes catalyzing the formation of tetrahydrofolic acid (THF) from dihydrofolic acid (DHF). Tetrahydrofolic acid is necessary for the biosynthesis of bacterial nucleic acids and proteins and ultimately for continued bacterial survival - inhibiting its synthesis, then, results in bactericidal activity. Trimethoprim binds with a much stronger affinity to bacterial dihydrofolate reductase as compared to its mammalian counterpart, allowing trimethoprim to selectively interfere with bacterial biosynthetic processes. Trimethoprim is often given in combination with sulfamethoxazole, which inhibits the preceding step in bacterial protein synthesis - given together, sulfamethoxazole and trimethoprim inhibit two consecutive steps in the biosynthesis of bacterial nucleic acids and proteins. As a monotherapy trimethoprim is considered bacteriostatic, but in combination with sulfamethoxazole is thought to exert bactericidal activity. Trimethoprim is a bacteriostatic lipophilic weak base structurally related to pyrimethamine. It binds to and reversibly inhibits the bacterial enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with bacterial nucleic acid and protein production. Bacterial dihydrofolate reductase is approximately 50,000 to 60,000 times more tightly bound by trimethoprim than is the corresponding mammalian enzyme. To determine the incidence & severity of hyperkalemia during trimethoprim therapy, 30 consecutive patients with acquired immunodeficiency syndrome receiving high-dose (20 mg/kg/day) trimethoprim were studied; in addition, the mechanism of trimethoprim-induced hyperkalemia was investigated in rats. Trimethoprim increased serum potassium concn by 0.6 mmol/l despite normal adrenocortical function & glomerular filtration rate. Serum potassium levels >5 mmol/l were observed during trimethoprim treatment in 15 of 30 patients. In rats, iv trimethoprim inhibited renal potassium excretion by 40% & increased sodium excretion by 46%. It was concluded that trimethoprim blocks apical membrane sodium channels in the mammalian distal nephron. As a consequence, the transepithelial voltage is reduced & potassium secretion is inhibited. Decreased renal potassium excretion secondary to these direct effects on kidney tubules leads to hyperkalemia in a substantial number of patients being treated with trimethoprim-containing drugs.

Pharmacodynamics

Trimethoprim exerts its antimicrobial effects by inhibiting an essential step in the synthesis of bacterial nucleic acids and proteins. It has shown activity against several species of gram-negative bacteria, as well as coagulase-negative _Staphylococcus_ species. Resistance to trimethoprim may arise via a variety of mechanisms, including alterations to the bacterial cell wall, overproduction of dihydrofolate reductase, or production of resistant dihydrofolate reductase. Rarely, trimethoprim can precipitate the development of blood disorders (e.g. thrombocytopenia, leukopenia, etc.) which may be preceded by symptoms such as sore throat, fever, pallor, and or purpura - patients should be monitored closely for the development of these symptoms throught the course of therapy. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.