Trimethoprim

Abstract

Trimethoprim was actually developed as an antimalarial drug but the largest clinical use of this drug has been as a combination with sulphonamide in the treatment of bacterial infections. During recent years, however, more and more has been discussed about the advantages of trimethoprim alone compared to the combination. Trimethoprim is almost completely absorbed and with a dose of 100 mg/day steady-state concentration is achieved on the third day. This concentration is therapeutically sufficient in prophylactic treatment of urinary tract infections. Trimethoprim and its metabolites are almost totally excreted by the kidneys. Less than 4% is excreted in the feces. Trimethoprim cumulates in uremia only when creatinine clearance is less than 10 ml/min. Even in severe renal insufficiency the amount of trimethoprim excreted in the urine is sufficient to cause antimicrobial activity. Synergy in vivo between trimethoprim and sulphonamide is limited because of pharmacokinetic differences of these drugs whose tissue concentrations are not always advantageous for the synergy. The use of trimethoprim alone has mainly been objected because resistant bacterial strains may develop. Trimethoprim does change intestinal flora but trimethoprim resistant strains develop after treatment with trimethoprim alone to a considerably smaller extent than sulphonamide resistant strains develop after treatment with sulphonamide-trimethoprim combination. The frequency of resistant E. coli strains in the urine has not increased in Finland, where trimethoprim alone has been extensively used, during 1972-1977. Trimethoprim can be used in the treatment of acute urinary tract infection in adults. The dosage is then 300-400 mg/day divided into two doses; thus the efficacy is almost equal to that of sulphonamide-trimethoprim, cephalexin or ampicillin. The main area of use is, however, in prophylactic treatment of urinary tract infection with small doses, usually 100 mg in the evening to adults. In long-term treatment trimethoprim is more effective than methenamine salts or nitrofurantoin. Trimethoprim has been successfully used also in the treatment of urinary tract infections in children. Less gastrointestinal side effects and skin rashes have occurred with trimethoprim than with cephalexin, ampicillin, nitrofurantoin or sulphonamide-trimethoprim. On the other hand, hematologic changes occur more frequently with trimethoprim than with cephalexin, ampicillin or nitrofurantoin. 100 mg/day used in long-term therapy is hematologically safe for adults. Trimethoprim should not be used in folic acid deficiency or megaloblastic anemia. Trimethoprim is well tolerated by children. They should, however, be more thoroughly followed.