Trimethoprim

Key examples

• Trimethoprim
• Co-trimoxazole

 

Common indications

• 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.

 

Mechanisms of action

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. 

Sulfonamides (e.g. sulfamethoxazole) also inhibit bacterial folate synthesis, but at a different step in the pathway to trimethoprim. Together trimethoprim and sulfamethoxazole cause more complete inhibition of folate synthesis (at least in vitro), making them bactericidal.

 

Important adverse effects

• Trimethoprim most commonly causes 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. 
• It can also cause hyperkalaemia and elevation of plasma creatinine concentrations.

 

Warnings

• 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.

Important interactions

• 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.