, Volume 23, Issue 6, pp 405–430 | Cite as

Trimethoprim: A Review of its Antibacterial Activity, Pharmacokinetics and Therapeutic Use in Urinary Tract Infections

  • R. N. Brogden
  • A. A. Carmine
  • R. C. Heel
  • T. M. Speight
  • G. S. Avery
Drug Evaluations


Synopsis: Trimethoprim,1 which has been widely available for several years in combination with sulphamethoxazole as co-trimoxazole, 2 is now available for use alone in the treatment of acute uncomplicated urinary tract infections. Trimethoprim, which is active against a wide range of Gram-positive and Gram-negative aerobic bacteria, is readily absorbed by the oral route and is widely distributed in body fluids and tissues. In therapeutic trials, trimethoprim 200 to 400mg daily has been shown to be comparable in efficacy with co-trimoxazole, ampicillin 2g, cephalexin 2g, oxolinic acid 1.5g and nitrofurantoin 200mg daily in the treatment of acute urinary tract infection. Similarly, in long term prophylaxis of recurrent urinary tract infection, trimethoprim 100mg daily given as a single dose at night was comparable with nitrofurantoin 50 to 100Omg, methenamine 1g, oxolinic acid 375mg or co-trimoxazole (80mg trimethoprim /1400mg sulphamethoxazole) each given as a single daily dose. Emergence of acquired resistance has been infrequent during years of therapeutic use of co-trimoxazole. Nevertheless, results of serial laboratory surveys suggest that resistance to trimethoprim among enterobacteria is increasing. However, at present, there is no conclusive evidence that there will be a more rapid increase following the introduction of trimethoprim for use alone in the treatment of urinary tract infections. At the dosages used, trimethoprim has generally been well tolerated and in studies comparing it with co-trimoxazole overall, skin rashes and gastrointestinal upset have occurred less frequently with trimethoprim than with co-trimoxazole.

Antibacterial Activity: In media containing low levels of thymidine (<0.01μg/ml) trimethoprim at a concentration of 4μg/ml or less, is active in vitro against Staphylococcus aureus, Streptococcus pyogenes, pneumoniae and most strains of Streptococcus faecalis, Haemophilus influenzae, Escherichia coli, Proteus mirabilis and rettgeri (most strains), Morganella morganii, Klebsiella pneumoniae, Salmonella and Shigella species and many strains of Enterobacter, Serratia and Providencia species. The activity against E. coli, Proteus and Klebsiella has been confirmed with urine samples from patients treated with trimethoprim 100mg daily, a dose used for long term prophylaxis of urinary tract infection. Pseudomonas aeruginosa is not susceptible to concentrations of trimethoprim attained in plasma, body tissues or urine after a 100mg dose. Bacteroides fragilis is relatively insensitive to usual therapeutic concentrations of trimethoprim.

A question which surrounds the use of trimethoprim alone in the treatment of urinary tract or other infections is that of the emergence of acquired resistance in the absence of the sulphonamide moiety present in the widely used co-trimoxazole. At-present there is no convincing evidence to suggest that the use of trimethoprim alone in urinary tract infections is associated with a rapid increase in the incidence of bacteria resistant to the drug. However, recent laboratory serial studies of the incidence of resistance to trimethoprim among clinical isolates conducted over adequate periods, indicate a possible increase in the incidence of trimethoprim-resistance in vitro since the widespread use of co-trimoxazole. It is clearly important, therefore, that the levels and mechanisms of trimethoprim-resistance among urinary pathogens be carefully monitored over the next few years subsequent to the therapeutic use of trimethoprim alone.

Pharmacokinetics: Trimethoprim is readily absorbed after oral administration. Mean peak serum concentrations are dose-related and are attained about 2 hours after ingestion. Trimethoprim has a relatively large volume of distribution, averaging about 100L, and is widely distributed in body fluids and tissues. Trimethoprim concentrations higher than in serum are attained in saliva, sputum, lung tissue, prostate gland and fluid. Cerebrospinal fluid concentrations are higher when the meninges are inflamed than when normal, and generally range from 20 to 44% of the corresponding serum concentrations. Trimethoprim concentrations in aqueous humour, middle ear fluid, vaginal fluid and in bone are about half the corresponding plasma concentration sampled at the same time. Trimethoprim is eliminated from the body by renal excretion in patients with normal renal function and is metabolised to a limited extent. Urinary concentrations of the drug are influenced by pH, being elevated by acidification and decreased by alkalinisation. Lack of standardisation of pH and fluid intake has resulted in varying urine concentrations in pharmacokinetic studies, but the mean value is usually between 50 and 210μg/ml in the first 4 to 12 hours after a single 160 to 200mg dose in subjects with normal renal function. The elimination half-life in normal renal function is 8.8 to 17.3 hours, but is prolonged to 2 to 3 times this value in severe renal impairment (creatinine clearance less than 10ml/min). The proportion of trimethoprim excreted by nonrenal mechanisms increases markedly when creatinine clearance is less than 10ml/min.

Therapeutic Trials: In comparisons with co-trimoxazole, ampicillin, cephalexin, sulphafurazole (sulfisoxazole), oxolinic acid and nitrofurantoin, trimethoprim 200 to 400mg daily has been found to be effective in the treatment of acute uncomplicated urinary tract infections caused mainly by E. coli. In studies that have compared trimethoprim alone with a similar dose of trimethoprim plus sulphamethoxazole, also in uncomplicated urinary tract infections, there have been no significant differences between the bacteriological cure rates achieved. Trimethoprim 400mg daily was at least as effective as cephalexin 2g daily or ampicillin 2g daily in hospitalised patients, and pregnant patients, with asymptomatic urinary tract infection, and has been comparable with oxolinic acid 1500mg daily, sulphadiazine 820mg plus trimethoprim 180mg daily or nitrofurantoin 200mg daily. In studies with adequate follow-up, the rate of recurrence of infection was similar after treatment with trimethoprim alone or with other drugs.

Results in treatment of chronic and recurrent urinary tract infection are less encouraging, with trimethoprim tending to be less effective than co-trimoxazole or trimethoprim plus sulphafurazole in the larger and better controlled studies. However, trimethoprim tended to be more effective than cephalexin 1000mg daily in one study in chronic or recurrent infection.

When used as prophylactic treatment in patients with recurrent urinary tract infection, trimethoprim 100mg as a single dose at night has been comparable in efficacy with nitrofurantoin 50 or 100mg, co-trimoxazole (40 to 80mg trimethoprim plus 200 to 400mg sulphamethoxazole), oxolinic acid 375mg or methenamine hippurate 1g, each given as a single dose at night. Treatment with trimethoprim, as with co-trimoxazole and nitrofurantoin, was effective as prophylaxis during the treatment period. The recurrence rate after cessation of treatment was similar for all treatment groups.

Side Effects: At dosages used in the treatment and prophylaxis of urinary tract infection, trimethoprim has generally been well tolerated. The most frequently reported side effects have been gastrointestinal upset, such as nausea, vomiting, anorexia and occasionally diarrhoea, which have occurred in a total of about 6% of patients, and skin rashes and itching which have been reported in about 4% of patients. In comparative studies, the overall incidence of these side effects has been lower with trimethoprim alone than with co-trimoxazole. Despite trimethoprim’s obvious potential to cause megaloblastic changes, generally when used at high dosages, there have been few reports of haematological abnormalities during treatment with trimethoprim alone.

Dosage: The recommended adult dosage of oral trimethoprim is 100mg twice daily in the USA, and 300mg once daily (Wellcome), or 200mg twice daily (others) in the UK and Europe, for 10 to 14 days for the treatment of acute infections of the urinary tract and 100mg once daily at night for long term prophylaxis of urinary tract infection. At these dosages, decrease in dosage should be necessary only in patients whose creatinine clearance is 15ml/min or less to avoid excessive serum concentrations.


Urinary Tract Infection Trimethoprim Nitrofurantoin Cephalexin Sulphonamide 
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Copyright information

© ADIS Press Australasia Pty Ltd 1982

Authors and Affiliations

  • R. N. Brogden
    • 1
  • A. A. Carmine
    • 1
  • R. C. Heel
    • 1
  • T. M. Speight
    • 1
  • G. S. Avery
    • 1
  1. 1.ADIS Drug Information ServicesBirkenhead, Auckland 10New Zealand

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