Trimethoprim

Question 1

How does Trimethoprim work?

Answer 1

Bacteria are unable to use external sources of folate, so need to make their own for essential functions including DNA synthesis. Trimethoprim inhibits bacterial folate synthesis, slowing bacterial growth (bacteriostatic). It has a broad spectrum of action against Gram-positive and Gram-negative bacteria, particularly enterobacteria, e.g. Escherichia coli. However, its clinical utility is reduced by widespread bacterial resistance. Mechanisms of resistance include reduced intracellular antibiotic accumulation and reduced sensitivity of target enzymes.

Question 2

Indications for Trimethoprim

Answer 2

Trimethoprim is a first choice for uncomplicated urinary tract infections (UTI). Alternatives include nitrofurantoin and amoxicillin.

Co-trimoxazole (trimethoprim combined with sulfamethoxazole) is used for treatment and prevention of pneumocystis pneumonia in people with immunosuppression, e.g. due to HIV infection

Question 3

Contraindications for Trimethoprim

Answer 3

Trimethoprim is contraindicated in the first trimester of pregnancy, because, as a folate antagonist, it is associated with an increased risk of fetal abnormalities (e.g. cardiovascular defects, oral clefts). It should be used cautiously in people with folate deficiency, who are more susceptible to adverse haematological effects. As trimethoprim is mostly excreted unchanged into urine, it is useful in the treatment of urinary tract infections, but is less suitable in renal impairment; if it is used, a dose reduction is necessary. Neonates, the elderly and people with HIV infection are particularly susceptible to adverse effects.

Question 4

Side effects of Trimethoprim

Answer 4

Comon: gastrointestinal upset (nausea, vomiting and sore mouth) and skin rash (3–7%).

Severe hypersensitivity reactions, including anaphylaxis, drug fever and erythema multiforme, occur rarely with trimethoprim, but more commonly with sulfonamides, which limits their use.

As a folate antagonist, trimethoprim can impair haematopoiesis, causing haematological disorders such as megaloblastic anaemia, leucopenia and thrombocytopenia.

Hyperkalaemia and elevation of plasma creatinine concentrations.

Question 5

Interactions of Trimethoprim

Answer 5

Use with potassium-elevating drugs (e.g. aldosterone antagonists, ACE inhibitors, angiotensin receptor blockers) predisposes to hyperkalaemia. Use with other folate antagonists (e.g. methotrexate) and drugs that increase folate metabolism (e.g. phenytoin) increases the risk of adverse haematological effects. Trimethoprim can enhance the anticoagulant effect of warfarin by killing normal gut flora that synthesise vitamin K.

Question 6

Elimination of Trimethoprim

Answer 6

Renal

Trimethoprim also passes the placental barrier and is excreted in human milk

Question 7

Patient information on Trimethoprim

Answer 7

Oral trimethoprim and co-trimoxazole are available as tablets and in suspension.

Explain that the aim of treatment is to get rid of infection and improve symptoms. Encourage the patient to complete the prescribed course. Before prescribing, always check with your patient personally or get collateral history to ensure that they have no allergy to trimethoprim or Septrin® (the brand name for co-trimoxazole). As allergic reactions are common with these antibiotics, it is particularly important to warn them to seek medical advice if a rash or other unexpected symptoms develop. If an allergy develops during treatment, give the patient written and verbal advice not to take this antibiotic in the future and make sure that the allergy is clearly documented in their medical records.