Trimethoprim/sulfamethoxazole or co-trimoxazole (BAN) is an antibiotic used in the treatment of a variety of bacterial, fungal and protozoal infections. It consists of 1 part trimethoprim to 5 parts sulfamethoxazole. The drug has been marketed worldwide as generic preparations and under multiple brand names, including Septra (GSK) and Bactrim (Roche). Co-trimoxazole is generally considered bactericidal, although its components are individually bacteriostatic. Its actions are antifolate in nature, inhibiting both de novo folate biosynthesis and metabolism.
Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed. Because it has a higher incidence of adverse effects, including allergic responses (see below), its use has been restricted in many countries to very specific circumstances where its improved efficacy has been demonstrated. It may be effective in a variety of upper and lower respiratory tract infections, renal and urinary tract infections, gastrointestinal tract infections, skin and wound infections, septicaemias, and other infections caused by sensitive organisms. The global problem of advancing antimicrobial resistance has led to a renewed interest in the use of co-trimoxazole more recently.
Its use during pregnancy is contraindicated, although it has been placed in Australian and American pregnancy category C. Despite this its use during the first trimester (during organogenesis) and 12 weeks prior to pregnancy has been associated with an increased risk of congenital malformations, especially malformations associated with maternal folic acid deficiency (which is most likely related to the mechanism of action of co-trimoxazole) such as neural tube defects like spina bifida, cardiovascular malformations (e.g. Epstein's anomaly), urinary tract defects, oral clefts and club foot in epidemiological studies. Its use later on during pregnancy also increases the risk of preterm labour (odds ratio: 1.51) and low birth weight (odds ratio: 1.67). Animal studies have yielded similarly discouraging results. It is also excreted in breast-milk and hence nursing during treatment with co-trimoxazole is generally advised against.
Generally accepted treatment for shigellosis. A recent Cochrane review found that while it is an effective treatment for shigellosis it also produces more significant adverse effects than other antibiotic drugs.
Its use as a prophylactic treatment is supported by one clinical trial involving children with acute lymphoblastic leukaemia. Other than this and one other clinical trial into its efficacy as a treatment for pneumocystis pneumonia, data on its use in both the treatment and prevention of pneumocystis pneumonia is significantly lacking.
Antibacterials like dapsone (increases plasma levels of both drugs), methenamine (increased risk of crystalluria) and rifampicin (as it may lead to an increased plasma level of rifampicin and lower plasma levels of trimethoprim).
Anticoagulants like warfarin and acenocoumarol — anticoagulant effects of either drug is potentiated by this combination.
Antifolates like pyrimethamine, proguanil and methotrexate — increased risk of associated side effects like blood dyscrasis. Folic acid supplementation should be considered. There's a significant risk of megaloblastic anaemia with doses of pyrimethamine in excess of 25 mg/wk.
Antivirals, more specifically, lamivudine (increased plasma concentrations of lamivudine), zalcitabine (increased plasma concentrations of zalcitabine) and zidovudine (increased risk of haematological reactions).
Digoxin — increase in digoxin levels in a proportion of elderly patients.
Diuretics — elderly patients receiving thiazide antidiuretics are at a heightened risk for developing thrombocytopaenia while on co-trimoxazole.
Ciclosporin — patients that have received a kidney transplant and are receiving co-trimoxazole and ciclosporin concomitantly are at an increased risk of having a reversible deterioration in their kidney function.
Potassium aminobenzoate — effects of sulfonamides (like sulfamethoxazole) inhibited.
Laboratory tests; trimethoprim and sulfonamides have been reported to interfere with diagnostic tests, including serum-methotrexate and serum-plasma creatinine levels, also urea, urinary glucose and urobilinogen tests.
Alkalinisation of the urine may reduce the toxicity of sulfamethoxazole, but it may increase the toxic effects of trimethoprim.
Tetrahydrofolate synthesis pathway
The synergy between trimethoprim and sulfamethoxazole was first described in a series of in vitro and in vivo experiments published in the late 1960s. Trimethoprim and sulfamethoxazole have a greater effect when given together than when given separately, because they inhibit successive steps in the folate synthesis pathway. They are given in a one-to-five ratio in their tablet formulations so that when they enter the body their concentration in the blood and tissues is roughly one as to twenty — the exact ratio required for a peak synergistic effect between the two.
Sulfamethoxazole, a sulfonamide, induces its therapeutic effects by interfering with the de novo (that is, from within the cell) synthesis of folate inside microbial organisms such as protozoa, fungi and bacteria. It does this by competing with p-aminobenzoic acid (PABA) in the biosynthesis of dihydrofolate.
Trimethoprim serves as a competitive inhibitor of dihydrofolate reductase (DHFR), hence inhibiting the de novo synthesis of tetrahydrofolate, the biologically active form of folate.
The effects of trimethoprim causes a backlog of dihydrofolate (DHF) and this backlog can work against the inhibitory effect the drug has on tetrahydrofolate biosynthesis; this is where the sulfamethoxazole comes in, its role is in depleting the excess DHF by preventing it from being synthesised in the first place.
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