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Drugs

, 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

Summary

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.

Keywords

Urinary Tract Infection Trimethoprim Nitrofurantoin Cephalexin Sulphonamide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Amyes, S.G.B, and Smith, J.T.: Trimethoprim resistance controlled by a combination of plasmid and chromosomal genes. Genetic Research (Camb.) 29: 35 (1977).CrossRefGoogle Scholar
  2. Amyes, S.G.B.; Emmerson, A.M. and Smith, J.T.: R-factor mediated trimethoprim resistance: Result of two three-month clinical surveys. Journal of Clinical Pathology 31: 850 (1978).PubMedCrossRefGoogle Scholar
  3. Anderson, J.D.; Lacey, R.W.; Lewis, E.L. and Sellin, M.A.: Failure to demonstrate an advantage in combining sulphamethoxazole with trimethoprim in an experimental model of urinary infection. Journal of Clinical Pathology 27: 619 (1974).PubMedCrossRefGoogle Scholar
  4. Anderson, D.M.: Plasmid studies of Salmonella typhimurium phage type 179 resistant to ampicillin, tetracycline, sulphonamides and trimethoprim. Journal of Hygiene 85: 293 (1980).PubMedCrossRefGoogle Scholar
  5. Andrewes, D.A.; Chuter, P.J.; Dawson, M.J.; Eden, B.W.; Moore, R.M.A.; Freestone, D.S. and Morris, C.A.: Trimethoprim and co-trimoxazole in the treatment of acute urinary tract infections: Patient compliance and efficacy. Journal of the Royal College of General Practitioners 31: 274 (1981).PubMedGoogle Scholar
  6. Ardati, K.O.; Thirumoorthi, M.C. and Dajani, A.S.: Intravenous trimethoprim-sulfamethoxazole in the treatment of serious infections in children. Journal of Pediatrics 95: 801 (1979).PubMedCrossRefGoogle Scholar
  7. Avery, G.S.: Trimethoprim-sulphamethoxazole. Drugs 1: 7 (1971).CrossRefGoogle Scholar
  8. Avril, J.L. and Briffod, J.: La resistance des Salmonella aux antibiotiques. Medecine et Maladies Infectieuses 4: 172 (1978).Google Scholar
  9. Bach, M.C.; Finland, M.; Gold, O. and Wilcox, C: Susceptibility of recently isolated pathogenic bacteria to trimethoprim and sulfamethoxazole separately and combined. Journal of Infectious Diseases 128 (Suppl. Nov.): 508 (1973a).PubMedCrossRefGoogle Scholar
  10. Bach, M.C.; Gold, O. and Finland, M.: Absorption and urinary excretion of trimethoprim, sulfamethoxazole and trimethoprim-sulfamethoxazole: Results with single doses in normal young adults and preliminary observations during therapy with trimethoprim-sulfamethoxazole. Journal of Infectious Diseases 128 (Suppl.): 584 (1973b).PubMedCrossRefGoogle Scholar
  11. Bergan, T.; Brodwall, E.K.; Vik-Mo, H. and Anstad, U.: Pharmacokinetics of sulphadiazine, sulphamethoxazole and trimethoprim in patients with varying renal function. Infection 7(Suppl. 4): 382 (1979).CrossRefGoogle Scholar
  12. Bock, J.L. and Pierce, R.: Trimethoprim interference in methotrexate assays. Clinical Chemistry 26: 1570 (1980).Google Scholar
  13. Bohni, E.: Chemotherapeutic activity of the combination of trimethoprim and sulphamethoxazole in infections of mice. Postgraduate Medical Journal 45 (Suppl. Nov.): 18 (1969).PubMedGoogle Scholar
  14. Brooks, M.A.; De Silva, J.A.F. and D’Arconte, L.: Determination of trimethoprim and its N-oxide metabolites in urine of man, dog and rat by differential pulse polarography. Journal of the Pharmaceutical Sciences 62: 1395 (1973).CrossRefGoogle Scholar
  15. Brumfitt, W. and Pursell, R.: Double-blind trial to compare ampicillin, cephalexin, co-trimoxazole and trimethoprim in treatment of urinary infection. British Medical Journal 2: 673 (1972).PubMedCrossRefGoogle Scholar
  16. Brumfitt, W.; Hamilton-Miller, J.M.T. and Grey, D.: Trimethoprim-resistant coliforms (corresp.). Lancet 2: 926 (1977).Google Scholar
  17. Brumfitt, W.; Hamilton-Miller, J.M.T. and Gooding, A.: Resistance of trimethoprim. Lancet 1: 1409 (1980).PubMedGoogle Scholar
  18. Burchall, J.J.: Mechanism of action of trimethoprim-sulphamethoxazole. Journal of Infectious Diseases 128 (Suppl.): 437 (1973).PubMedCrossRefGoogle Scholar
  19. Burman, L.G.: Resistance to trimethoprim (corresp.). Lancet 1: 1409 (1980).PubMedCrossRefGoogle Scholar
  20. Bushby, S.R.M.: Trimethoprim-sulfamethoxazole: In vitro microbiological aspects. Journal of Infectious Diseases 128 (Suppl.): 442 (1973).PubMedCrossRefGoogle Scholar
  21. Clark, A.J.L.; Mouchizadeh, J.; Faunch, R. and McMichael, H.B.: Trimethoprim alone (corresp.). Lancet 1: 1030 (1980).PubMedCrossRefGoogle Scholar
  22. Closson, R.G.: Terminal half-lives of drugs studied in patients with hepatic diseases. American Journal of Hospital Pharmacy 34: 520 (1977).PubMedGoogle Scholar
  23. Cox, C.E. and Montgomery, W.G.: Combined trimethoprimsulfisoxazole therapy of urinary infections. Postgraduate Medical Journal 45: 65 (1969).PubMedCrossRefGoogle Scholar
  24. Craig, W.A. and Kunin, C.M.: Trimethoprim-sulphamethoxazole: Pharmacodynamic effects of urinary pH and impaired renal function. Studies in humans. Annals of Internal Medicine 78: 491 (1973).PubMedGoogle Scholar
  25. Dabhoiwala, N.F.; Bye, A. and Claridge, M.: A study of concentrations of trimethoprim-sulphamethoxazole in human prostate gland. British Journal of Urology 48: 77 (1976).PubMedCrossRefGoogle Scholar
  26. Daikos, G.K.; Kastanakis, S.; Hatjivasiliou, A.E. and Ionnidou, A.: Cerebrospinal fluid levels of trimethoprim. Proceedings of the 7th International Congress on Chemotherapy (Prague) 1: 1109 (1971).Google Scholar
  27. Darrell, J.H.; Garrod, L.P. and Waterworth, P.M.: Trimethoprim: Laboratory and clinical studies. Journal of Clinical Pathology 21: 202 (1968).PubMedCrossRefGoogle Scholar
  28. Datta, N.; Hughes, V.M.; Nugent, M.E. and Richards, H.: Plasmids and transposons and their stability and mutability in bacteria isolated during an outbreak of hospital infection. Plasmid 2: 182 (1979).PubMedCrossRefGoogle Scholar
  29. Datta, N.; Dacey, S.; Hughes, V.; Knight, S.; Richards, H.; Williams, G.; Casewell, M. and Shannon, K.P.: Distribution of genes for trimethoprim and gentamicin resistance in bacteria and their plasmids in a general hospital. Journal of General Microbiology 118: 495 (1980).PubMedGoogle Scholar
  30. Dornbusch, K. and Gezelius, L.: Susceptibility testing to trimethoprim alone and combined with sulphonamides. Chemotherapy (Basel) 26: 418 (1980).Google Scholar
  31. Eatman, F.B.; Maggio, A.C.; Pocelinko, R.; BoxenBaum, H.G.; Geitner, A.; Glover, W.; Macasieb, T.; Holazo, A.; Weinfield, R.E. and Kaplan, S.A.: Blood and salivary concentrations of sulfamethoxazole and trimethoprim in man. Journal of Pharmacokinetics and Biopharmaceutics 5: 615 (1977).PubMedGoogle Scholar
  32. Finlayson, M.C. and Jackson, F.L.: Trimethoprim-resistant Salmonella. Lancet 2: 375 (1978).PubMedCrossRefGoogle Scholar
  33. Fleming, M.P.; Datta, N. and Gruneberg, R.N.: Trimethoprim resistance determined by R-factors. British Medical Journal 1: 726 (1972).PubMedCrossRefGoogle Scholar
  34. Fowle, A.S.E.: Aspects of the pharmacokinetic behaviour of trimethoprim and sulphamethoxazole; in Bernstein and Salter (Eds) Trimethoprim/Sulphamethoxazole in Bacterial Infections, pp.63–72 (Churchill Livingstone, Edinburgh and London 1973).Google Scholar
  35. Fowle, A.S.E. and Bye, A.: Concentrations of trimethoprim and sulphamethoxazole in human prostate fluid. Proceedings of the 7th International Congress of Chemotherapy, Prague 1971, 1: 1289 (1971).Google Scholar
  36. George, R.H. and Healing, D.E.: Thymidine-requiring Haemophilus influenzae and Staphylococcus aureus. Lancet 2: 1081 (1977).PubMedCrossRefGoogle Scholar
  37. Gleckman, R.A.: A co-operative controlled study of the use of trimethoprim-sulfamethoxazole in chronic urinary tract infections. Journal of Infectious Diseases 128: 647 (1973).PubMedCrossRefGoogle Scholar
  38. Gnarpe, H. and Friberg, J.: The penetration of trimethoprim into seminal fluid and serum. Scandinavian Journal of Infectious Diseases, Suppl. 8 (1976).Google Scholar
  39. Greene, B.M.; Thomas, F.E. and Alford, R.H.: Trimethoprim-sulphamethoxazole and brain abscess. Annals of Internal Medicine 82: 812 (1975).PubMedGoogle Scholar
  40. Greenwood, D.: Relevance of in vitro synergy to therapy: does synergy between diaminopyrimidines and sulphonamides operate at concentrations achievable in urine. Journal of Antimicrobial Chemotherapy 5(Suppl. B): 85 (1979).PubMedCrossRefGoogle Scholar
  41. Greenwood, D. and O’Grady, F.: Activity and interaction of trimethoprim and sulphamethoxazole against Escherichia coli. Journal of Clinical Pathology 29: 162 (1976).PubMedCrossRefGoogle Scholar
  42. Grey, D. and Hamilton-Miller, J.M.T.: Sensitivity of Pseudomonas aeruginosa to sulphonamides and trimethoprim and the activity of the combination trimethoprim:sulphamethoxazole. Journal of Medical Microbiology 10: 273 (1977).PubMedCrossRefGoogle Scholar
  43. Grey, D.; Hamilton-Miller, J.M.T. and Brumfitt, W.: Incidence and mechanisms of resistance to trimethoprim in clinically isolated Gram-negative bacteria. Chemotherapy 25: 147 (1979).PubMedCrossRefGoogle Scholar
  44. Grüneberg, E.: The effect of trimethoprim on the activity of sulphonamides and antibiotics in experimental infections. Journal of Infectious Diseases 128 (Suppl. Nov.): 478 (1973).CrossRefGoogle Scholar
  45. Grüneberg, R.N.: The microbiological rationale for the combination of sulphonamides with trimethoprim. Journal of Antimicrobial Chemotherapy 5(Suppl. B): 27 (1979).PubMedCrossRefGoogle Scholar
  46. Grüneberg, R.N. and Bendall, M.J.: Hospital outbreak of trimethoprim resistance in pathogenic coliform bacteria. British Medical Journal 2: 7 (1979).PubMedCrossRefGoogle Scholar
  47. Grüneberg, R.N. and Shaw, E.J.: The influence of antibiotic treatment on resistance patterns of coliform bacilli in childhood urinary tract infection. Medical Microbiology 9: 233 (1976).PubMedCrossRefGoogle Scholar
  48. Guerrant, R.L.; Wood, S.J.; Krongaard, L.; Reid, R.A. and Hodge, R.H.: Resistance among fecal flora of patients taking sulfamethoxazole-trimethoprim or trimethoprim alone. Antimicrobial Agents and Chemotherapy 19: 33 (1981).PubMedCrossRefGoogle Scholar
  49. Hamilton-Miller, J.M.T: Mechanisms and distribution of bacterial resistance to diaminopyrimidines and sulphonamides. Journal of Antimicrobial Chemotherapy 5(Suppl. B): 61 (1979).PubMedCrossRefGoogle Scholar
  50. Hamilton-Miller, J.M.T. and Grey, D.: Resistance to trimethoprim in Klebsiellae isolated before its introduction. Journal of Antimicrobial Chemotherapy 1: 213 (1975).PubMedCrossRefGoogle Scholar
  51. Hamilton-Miller, J.M.T.; Gooding, A. and Brumfitt, W.: Resistance to trimethoprim in 1978–79 compared with 1973–75. Journal of Clinical Pathology 34: 439 (1981).PubMedCrossRefGoogle Scholar
  52. Hande, K.; Gober, J. and Fletcher, R.: Trimethoprim interferes with serum methotrexate assay by the competitive protein binding technique. Clinical Chemistry 26: 1617 (1980).PubMedGoogle Scholar
  53. Hansen, I.B.: The combination trimethoprim-sulphamethoxazole. Antibiotics and Chemotherapy 25: 217 (1978).PubMedGoogle Scholar
  54. Hansen, I.; Neilsen, M.L. and Bertelsen, S.: Trimethoprim in human saliva, bronchial secretion and lung tissue. Acta Pharmacologica et Toxicologica 32: 337 (1973a).PubMedCrossRefGoogle Scholar
  55. Hansen, I.; Nielsen, M.L.; Heerfordt, L.; Henriksen, B. and Bertelsen, S.: Trimethoprim in normal and pathological human lung tissue. Chemotherapy 19: 221 (1973b).PubMedCrossRefGoogle Scholar
  56. Hansen, I.; Neilsen, M.L. and Boss-Nielsen, J.: A new method for homogenization of bone exemplified by measurement of trimethoprim in human bone tissue. Acta Pharmacologica et Toxicologica 37: 33 (1975).PubMedCrossRefGoogle Scholar
  57. Hansson, H.B.; Walder, M. and Juhlin, I.: Susceptibility of Shigellae to mecillinam, nalidixic acid, trimethoprim, and five other antimicrobial agents. Antimicrobial Agents and Chemotherapy 19: 271 (1981).PubMedCrossRefGoogle Scholar
  58. Harbord, R.B. and Grüneberg, R.N.: Treatment of urinary tract infection with a single dose of amoxycillin, co-trimoxazole or trimethoprim. British Medical Journal 283: 1301 (1981).PubMedCrossRefGoogle Scholar
  59. Helle, M.: Trimethoprim in the long term treatment of children’s urine tract infections (translation). Lääkeuutiset 4: 125 (1975).Google Scholar
  60. Hoeffler, U.; Ko, H.L. and Pulverer, G.: Antimicrobial susceptibility of Propionibacterium acnes and related microbial species. Antimicrob. Agents Chemother. 10: 387 (1976).PubMedCrossRefGoogle Scholar
  61. Hoigne, R.; Muller, G. and Schneider, H.R.: A comparison of chemotherapy in patients with urinary tract infections using trimethoprim alone and in combination with sulfamethoxazole (Gantanol). Progress in Antimicrobial and Anticancer Chemotherapy 1: 971 (1970).Google Scholar
  62. Hoppu, K.; Partanen, S. and Koskela, E.: Trimethoprim poisoning (corresp.). Lancet 1: 778 (1980).PubMedCrossRefGoogle Scholar
  63. Howard, A.J.; Hince, C.J. and Williams, J.D.: Antibiotic resistance in streptococcus, pneumoniae and Haemophilus influenzae. British Medical Journal 1: 1657 (1978).PubMedCrossRefGoogle Scholar
  64. Hughes, D.T.D.: Use of combinations of trimethoprim and sulfamethoxazole in the treatment of chest infections. Journal of Infectious Diseases 128 (Suppl.): 701 (1973).PubMedCrossRefGoogle Scholar
  65. Huovinen, P. and Toivanen, P.: Trimethoprim resistance in Finland after five years’ use of plain trimethoprim. British Medical Journal 1: 72 (1980).CrossRefGoogle Scholar
  66. Huovinen, P.; Mantyjarvi, R. and Toivanen, P.: Trimethoprim resistance in three Finnish hospitals. Abstract No. 1234, Paper presented at the 12th International Congress on Chemotherapy, Florence, Italy, July (1981).Google Scholar
  67. Iravani, A.; Richard, G.A. and Baer, H.: Treatment of uncomplicated urinary tract infections with trimethoprim versus sulfisoxazole with special reference to antibody-coated bacteria and faecal flora. Antimicrobial Agents and Chemotherapy 19: 842 (1981).PubMedCrossRefGoogle Scholar
  68. Iwarson, S. and Lidin-Janson, G.: Long-term, low dose trimethoprim prophylaxis in patients with recurrent urinary tract infections. J. Antimicrob. Chemother. 5: 316 (1979).PubMedCrossRefGoogle Scholar
  69. Jordan, G.W.; Krajden, S.F.; Heoprich, P.D.; Wong, G.A.; Peirce, T.H. and Rausch, D.C.: Trimethoprim-sulphamethoxazole in chronic bronchitis. Canadian Medical Association Journal 112: 91 (1975).PubMedGoogle Scholar
  70. Kahn, S.B.; Fein, S.A. and Brodsky, I.: Effects of trimethoprim on folate metabolism in man. Clinical Pharmacology and Therapeutics 9: 550 (1968).PubMedGoogle Scholar
  71. Kaplan, S.A.; Weinfeld, R.E.; Abruzzo, C.W.; McFaden, K.; Jack, M.L. and Weissman, L: Pharmacokinetic profile of trimethoprim-sulfamethoxazole in man. Journal of Infectious Diseases 128 (Suppl.): 547 (1973).PubMedCrossRefGoogle Scholar
  72. Kasanen, A.; Toivanen, P.; Sourander, L.; Kaarsalo, E. and Aantaa, S.: Trimethoprim in the treatment and long-term control of urinary tract infection. Scandinavian Journal of Infectious Diseases 6: 91 (1974a).PubMedGoogle Scholar
  73. Kasanen, A.; Kaarsalo, E.; Hiltunen, R. and Soini, V.: Comparison of long-term low-dosage nitrofurantoin, methenamine hippurate, trimethoprim and trimethoprim-sulphamethoxazole on the control of recurrent urinary tract infection. Annals of Clinical Research 6: 285 (1974b).PubMedGoogle Scholar
  74. Kasanen, A.; Anttila, M.; Elfving, R.; Kahela, P.; Saarimaa, H.; Sundquist, H.; Tikkanen, R. and Toivanen, P.: Trimethoprim: Pharmacology, antimicrobial activity and clinical use in urinary tract infections. Annals of Clinical Research 10(Suppl. 22): 5–35 (1978).Google Scholar
  75. Kasanen, A.; Sundquist, H. and Junnila, S.Y.T.: Trimethoprim in the treatment of acute urinary tract infection. Current Therapeutic Research 25: 202 (1979).Google Scholar
  76. Kasanen, A.; Hajba, A.; Junnila, S.Y.T. and Sundquist, H.: Comparative study of trimethoprim and cephalexin in urinary tract infection. Current Therapeutic Research 29: 477 (1981).Google Scholar
  77. Klimek, J.J.; Bates, T.R.; Nightingale, C.; Lehmann, W.B.; Ziemniak, J.A. and Quintiliani, R.: Penetration characteristics of trimethoprim-sulphamethoxazole in middle ear fluid of patients with serous otitis media. Journal of Pediatrics 96: 1087 (1980).PubMedCrossRefGoogle Scholar
  78. Knothe, H.: The effect of trimethoprim-sulphonamide, trimethoprim and sulphonamide on the occurrence of resistant Enterobacteriaceae in human intestinal flora. Infection 7(Suppl. 4): 321 (1979).CrossRefGoogle Scholar
  79. Koch, U.J.; Schumann, K.P.; Kuchler, R. and Kewitz, H.: Efficacy of trimethoprim, sulfamethoxazole and the combination of both in acute urinary tract infection. Chemotherapy 19: 314 (1973).PubMedCrossRefGoogle Scholar
  80. Koutts, J.; Van der Weyden, M.B. and Cooper, M.: Effect of trimethoprim on folate metabolism in human bone marrow. Australian and New Zealand Journal of Medicine 3: 245 (1973).PubMedCrossRefGoogle Scholar
  81. Kremers, P.; Duvivier, J. and Heusghem, C: Pharmacokinetic studies of co-trimoxazole in man after single and repeated doses. Journal of Clinical Pharmacology 14: 112 (1974).PubMedGoogle Scholar
  82. Kuchler, R. and Koch, U.J.: The in vitro demonstration of the efficacy of trimethoprim as an antibacterial agent in a comparative bacteriological study on the effects of trimethoprim, sulfamethoxazole and the combination trimethoprim /sulfamethoxazole. Chemotherapy (Basel) 18: 242 (1973).Google Scholar
  83. Lacey, R.W.: A critical appraisal of the importance of R-factors in the enterobacteriaceae in vivo. Journal of Antimicrobial Chemotherapy 1: 25 (1975).PubMedCrossRefGoogle Scholar
  84. Lacey, R.W.: Mechanism of action of trimethoprim and sulphonamides: relevance to synergy in vivo. Journal of Antimicrobial Chemotherapy 5(Suppl. B): 75 (1979).PubMedCrossRefGoogle Scholar
  85. Lacey, R.W.; Lord, V.L.; Gunasekera, H.K.W.; Leiberman, P.J. and Luxton, D.E.A.: Comparison of trimethoprim alone with trimethoprim-sulphamethoxazole in the treatment of respiratory and urinary infections with particular reference to selection of trimethoprim resistance. Lancet 1: 1270 (1980b).PubMedCrossRefGoogle Scholar
  86. Lacey, R.W.; Simpson, M.H.C.; Lord, V.L.; Fawcett, C.; Button, E.S.; Luxton, D.E.A. and Trotter, I.S.: Comparison of single-dose trimethoprim with a five-day course for the treatment of urinary tract infection in the elderly. Age and Ageing 10: 179 (1981).PubMedCrossRefGoogle Scholar
  87. Light, R.B.; Ronald, A.R.; Harding, G.K.M.; Dikkema, J.; Thompson, L. and Buckwold, F.J.: Trimethoprim alone in the treatment and prophylaxis of urinary tract infection. Archives of Internal Medicine 141: 1807 (1981).PubMedCrossRefGoogle Scholar
  88. Mabeck, C.E. and Vejlsgaard, R.: Treatment of urinary tract infections with sulphonamide and/or trimethoprim. A preliminary report from a multipractice study. Infection 7(Suppl. 4): 414 (1979).CrossRefGoogle Scholar
  89. McGill, R.E.T.: Trimethoprim-resistant Klebsiella aerogenes. Lancet 2: 156 (1978).PubMedCrossRefGoogle Scholar
  90. Malmborg, A.-S.; Dornbusch, K.; Eliasson, R. and Lindholmer, C: Concentrations of various antibacterials in human seminal plasma; in Danielsson et al. (Eds) Genital Infections and their Complications, pp. 307–312 (Almqvist and Wiksell, Stockholm 1975).Google Scholar
  91. Mannisto, P.T.: Comparison of oxolinic acid, trimethoprim and trimethoprim-sulfamethoxazole in the treatment and long-term control of urinary tract infection. Current Therapeutic Research 20: 645 (1976).PubMedGoogle Scholar
  92. Mannisto, P.; Tuomisto, J.; Saris, N.-E. and Lehtinen, T.: Pharmacokinetic studies with trimethoprim and different doses of sulfadiazine in healthy human subjects. Chemotherapy (Basel) 19: 289 (1973).Google Scholar
  93. Marks, M.I.; Kazemi, M.; Hales, B. and Neims, A.H.: Pharmacokinetic studies of trimethoprim-sulfamethoxazole in children with gastroenteritis. Journal of Infectious Diseases 128 (Suppl): 622 (1973a).PubMedCrossRefGoogle Scholar
  94. Marks, M.I.; Kazemi, M. and MacKay, E.: In vitro sensitivity of Salmonella to ten antimicrobial agents including sulfamethoxazole and trimethoprim, alone and in combination. Antimicrobial Agents and Chemotherapy 4: 555 (1973b).PubMedCrossRefGoogle Scholar
  95. Maskell, R.; Okubadejo, O.A. and Payne, R.H.: Thymine-requiring bacteria associated with co-trimoxazole therapy. Lancet 1: 834 (1976).PubMedCrossRefGoogle Scholar
  96. May, J.R. and Davies, J.: Resistance of Haemophilus influenzae to trimethoprim. British Medical Journal 3: 376 (1972).PubMedCrossRefGoogle Scholar
  97. Miller, R.D. and Salter, A.J.: The passage of trimethoprim/sulphamethoxazole into breast milk and its significance; in Darkos (Ed) Progress in Chemotherapy Vol. 1, pp.687–691 (Hellanic Society for Chemotherapy, 1974).Google Scholar
  98. Moody, M.R. and Young, V.M.: In vitro susceptibility of Pseudomonas cepacia and Pseudomonas maltophilia to trimethoprim and trimethoprim-sulfamethoxazole. Antimicrobial Agents and Chemotherapy 7: 836 (1975).PubMedCrossRefGoogle Scholar
  99. Murray, B.E.; Rensimer, E.R. and Du Pont, H.L.: Emergence of high-level trimethoprim resistance in fecal Escherichia coli during oral administration of trimethoprim or trimethoprim-sulfamethoxazole. New Engl. J. Med. 306: 130 (1982).PubMedCrossRefGoogle Scholar
  100. Muther, R.S. and Bennett, W.M.: Concentration of antibiotics in simple renal cysts. Journal of Urology 124: 596 (1980).PubMedGoogle Scholar
  101. Nielsen, M. and Hansen, I.B.: Trimethoprim in human prostatic tissue and prostatic fluid. Scandinavian Journal of Urology and Nephrology 6: 244 (1972).PubMedCrossRefGoogle Scholar
  102. Nielsen, M.; Hansen, I. and Boos-Nielsen, J.: The penetration of trimethoprim into normal human bone with separate determinations of the concentration in compact bone, spongy bone and bone marrow. Harokeach Hain 16: 54 (1973).Google Scholar
  103. Nolte, H. and Buttner, H.: Pharmacokinetics of trimethoprim and its combination with sulfamethoxazole in man after single and chronic oral administration. Chemotherapy (Basel) 18: 274 (1973).Google Scholar
  104. Norden, C.W. and Keleti, E.: Treatment of experimental staphylococcal osteomyelitis with rifampicin and trimethoprim, alone and in combination. Antimicrobial Agents and Chemotherapy 17: 591 (1980).PubMedCrossRefGoogle Scholar
  105. Oosteslinck, W.; Defoort, R. and Renders, G.: The concentration of sulphamethoxazole and trimethoprim in human prostate gland. British Journal of Urology 47: 301 (1975).CrossRefGoogle Scholar
  106. Pancoast, S.J.; Hyams, D.M. and Neu, H.C.: Effect of trimethoprim and trimethoprim-sulfamethoxazole on development of drug resistant vaginal and fecal floras. Antimicrobial Agents and Chemotherapy 17: 263 (1980).PubMedCrossRefGoogle Scholar
  107. Pearson, N.J.; Towner, K.J.; McSherry, A.M.; Cattell, W.R. and O’Grady, F.: Emergence of trimethoprim-resistant enterobacteria in patients receiving long term co-trimoxazole for the control of intractable urinary tract infection. Lancet 2: 1205 (1979).PubMedCrossRefGoogle Scholar
  108. Pohjanpelto, P.E.J.; Sarmela, T.J. and Raines, T.: Penetration of trimethoprim and sulphamethoxazole in the aqueous humour. British Journal of Ophthalmology 58: 606 (1974).PubMedCrossRefGoogle Scholar
  109. Poskitt, E.M.E.: Clinical problems related to the use of drugs in malnutrition. Proc. Nutrition. Soc. 33: 203 (1974).CrossRefGoogle Scholar
  110. Quayle, A.A. and Hailey, D.M.: Antimicrobial substances in saliva: Sulphamethoxazole and trimethoprim. British Journal of Oral Surgery 11: 60 (1973).PubMedCrossRefGoogle Scholar
  111. Ramal, B.D. and Cottis, L.: Evaluation of in vitro sensitivity testing methods for detecting sulphamethoxazole trimethoprim synergy. Arzneimittel-Forschung 30: 1049 (1980).Google Scholar
  112. Reeves, D.S.: Sulphamethoxazole/trimethoprim: The first two years. Journal of Clinical Pathology 24: 430 (1971).PubMedCrossRefGoogle Scholar
  113. Reeves, D.S. and Wilkinson, P.J.: The pharmacokinetics of trimethoprim and trimethoprim/sulphonamide combinations, including penetration into body tissues. Infection 7(Suppl. 4): 330 (1979).CrossRefGoogle Scholar
  114. Reid, D.W.J.; Caille, G. and Kaufmann, N.R.: Maternal and transplacental kinetics of trimethoprim and sulphamethoxazole separately and in combination. Canadian Medical Association Journal 112: 67s (1975).Google Scholar
  115. Richards, H.; Datta, N.; Sojka, W.J. and Wray, C: Trimethoprim-resistant plasmids and transposons in salmonella. Lancet 2: 1194 (1978).PubMedCrossRefGoogle Scholar
  116. Rieder, J.: Excretion of sulphamethoxazole and trimethoprim into human bile. J. Infec. Dis. 128 (Suppl.): 574 (1973).CrossRefGoogle Scholar
  117. Rieder, J.; Schwartz, D.E.; Fernex, M.; Bergan, T.; Brodwall, E.K.; Blumberg, A.; Cottier, P. and Scheitlin, W.: Pharmacokinetics of the antibacterial combination sulfamethoxazole plus trimethoprim in patients with normal or impaired kidney function in Schonfeld et al. (Eds) Antibiotics and Chemotherapy Vol. 18, pp. 148–198 (Karger, Basel 1974).Google Scholar
  118. Rogers, H.J.; James, C.A.; Morrison, P.J. and Bradbrook, I.D.: Effect of cimetidine on oral absorption of ampicillin and cotrimoxazole (corresp.). Journal of Antimicrobial Chemotherapy 6: 297 (1980).PubMedCrossRefGoogle Scholar
  119. Romero, E. and Perduca, W.: Compatibility groups of R-factors for trimethoprim resistance isolated in Italy. Journal of Antimicrobial Chemotherapy 3(Suppl. C): 35 (1977).PubMedGoogle Scholar
  120. Rosberg, G.: Preventative treatment of urinary tract infections in the case of psychogeriatric patients. Lääkeuutiset 2: 57 (1974).Google Scholar
  121. Salmon, J.D.; Fowle, A.S.E. and Bye, A.: Concentrations of trimethoprim and sulphamethoxazole in aqueous humour and plasma from regimens of co-trimoxazole in man. Journal of Antimicrobial Chemotherapy 1: 205 (1975).PubMedCrossRefGoogle Scholar
  122. Sander, J.; Aandahil, E.; Fellner, H. and Kalstad, S.: The treatment of urinary tract infections in out-patients. A double-blind comparison between trimethoprim and nitrofurantoin. Journal of International Medical Research 9: 181 (1981).PubMedGoogle Scholar
  123. Schwartz, D.E. and Rieder, J.: Pharmacokinetics of sulphamethoxazole + trimethoprim in man and their distribution in the rat. Chemotherapy (Basel) 15: 337 (1970).Google Scholar
  124. Schwartz, D.E. and Ziegler, W.H.: Assay and pharmacokinetics of trimethoprim in man and animals. Postgraduate Medical Journal 45 (Nov): 32 (1969).PubMedCrossRefGoogle Scholar
  125. Schwartz, D.E.; Vetter, W. and Englert, G.: Trimethoprim metabolites in rat, dog and man: Qualitative and quantitative studies. Arzneimittel-Forschung 20: 1867 (1970).PubMedGoogle Scholar
  126. Seneca, H.; Zinsser, H.H. and Uson, A.: Chronic urinary tract infections: Remission rates with trimethoprim and/or sulfamethoxazole or indanyl carbenicillin. New York State Journal of Medicine 74: 494 (1974).PubMedGoogle Scholar
  127. Sharpstone, P.: The renal handling of trimethoprim and sulphamethoxazole in man. Postgraduate Medical Journal 45 (Suppl.): 38 (1969).PubMedGoogle Scholar
  128. Sigel, C.W.; Grace, M.E. and Nichol, C.A.: Metabolism of trimethoprim in man and measurement of a new metabolite. A new fluorescence assay. Journal of Infectious Diseases 128 (Suppl): 580 (1973).PubMedCrossRefGoogle Scholar
  129. Sive, J.; Green, R. anxetz, J.: Effect of trimethoprim on folate-dependent DNA synthesis in human bone marrow. Journal of Clinical Pathology 25: 194 (1972).PubMedCrossRefGoogle Scholar
  130. Sjoholm, I.; Kober, A.; Odar-Cederlof, I. and Borga, O.: Protein binding of drugs in uremic and normal serum: The role of endogenous binding inhibitors. Biochemical Pharmacology 25: 1205 (1976).PubMedCrossRefGoogle Scholar
  131. Smellie, J.M. and Grüneberg, R.N.: The treatment of childhood urinary tract infection with special reference to the use of trimethoprim and talampacillin for prophylaxis; in Losse et al. (Eds) Pyelonephritis Vol. 4, pp. 156–159 (Georg Thieme Verlag, New York, Stuttgart 1980).Google Scholar
  132. Smith, H.W.: Antibiotic-resistant Escherichia coli in market pigs in 1956–1979: The emergence of organisms with plasmidborne trimethoprim resistance. Journal of Hygiene (Camb) 84: 467 (1980).CrossRefGoogle Scholar
  133. Sourander, L.; Saarimaa, H. and Arvilommi, H.: Treatment of sulphonamide-resistant urinary tract infections with a combination of sulphonamide and trimethoprim. Acta Medica Scandinavica 191: 1 (1972).PubMedGoogle Scholar
  134. Spencer, R.C.; Fairclough, D.J. and Cooper, J.: Double-blind clinical trial of trimethoprim v amoxycin in acute symptomatic urinary infection. Abstract of Paper presented at the 12 International Congress of Chemotherapy, Florence, July 1981.Google Scholar
  135. Stamey, T.A. and Condy, M: The diffusion and concentration of trimethoprim in human vaginal fluid. Journal of Infectious Diseases 131: 261 (1975).PubMedCrossRefGoogle Scholar
  136. Stamm, W.E.; Counts, G.W.; Wagner, K.F.; Martin, D.; Gregorg, D.; McKevitt, M.; Turck, M. and Holmes, K.K.: Antimicrobial prophylaxis of recurrent urinary tract infections. Annals of Internal Medicine 92: 770 (1980).PubMedGoogle Scholar
  137. Stamm, W.E.; Counts, G.W.; McKevitt, M.; Turck, M. and Holmes, K.K.: Urinary prophylaxis with trimethoprim and trimethoprim-sulfamethoxazole: Efficacy influence on the natural history of recurrent bacteriuria, and control. Reviews of Infectious Diseases. In press (1982).Google Scholar
  138. Stokes, A. and Lacey, R.W.: Effect of thymidine on activity of trimethoprim and sulphamethazole. Journal of Clinical Pathology 31: 165 (1978).PubMedCrossRefGoogle Scholar
  139. Svedhem, A. and Iwarson, S.: Cerebrospinal fluid concentrations of trimethoprim during oral and parenteral treatment. Journal of Antimicrobial Chemotherapy 5: 717 (1979).PubMedCrossRefGoogle Scholar
  140. Terakado, N.; Ueda, H.; Isayama, Y. and Shigeo, A.: Trimethoprim R plasmids in Escherichia coli isolated from pigs. Microbiology and Immunology 24: 1233 (1980).PubMedGoogle Scholar
  141. Terzian, L.A.; Stahler, N. and Dawkins, A.T.: Differences in drug response of the sporogonous cycles of three strains of Plasmodium falciparum in Anopheles stephensi. Research Communications in Chemical Pathology and Pharmacology 1: 16 (1970).PubMedGoogle Scholar
  142. Then, R.L. and Angehrn, P.: Low trimethoprim susceptibility of anaerobic bacteria due to insensitive dihydrofolate reductases. Antimicrobial Agents and Chemotherapy 15: 1 (1979).PubMedCrossRefGoogle Scholar
  143. Then, R.L. and Hermann, F.: Mechanisms of trimethoprim resistance in enterobacteria isolated in Finland. Chemotherapy 27: 192 (1981).PubMedCrossRefGoogle Scholar
  144. Threlfall, E.J.; Ward, L.R.; Ashley, A.S. and Rowe, B.: Plasmidencoded trimethoprim resistance in multiresistant epidemic Salmonella typhimurium phage types 204 and 193 in Britain. British Medical Journal 280: 1210 (1980).PubMedCrossRefGoogle Scholar
  145. Toivanen, A.; Kasanen, A.; Sundquist, H. and Toivanen, P.: Effect of trimethoprim on the occurrence of drug-resistant coliform bacteria in the fecal flora. Chemotherapy (Basel) 22: 97 (1976).Google Scholar
  146. Towner, K.J.: A clinical isolate of Escherichia coli owing its trimethoprim resistance to a chromosomally-located trimethoprim transposon. Journal of Antimicrobial Chemotherapy 7: 157 (1981).PubMedCrossRefGoogle Scholar
  147. Towner, K.J.: Resistance to trimethoprim amongst urinary tract isolates in the United Kingdom. Reviews of Infectious Diseases. In press (1982).Google Scholar
  148. Towner, K.J.; Pearson, N.J.; Pinn, P. and O’Grady, F.: Increasing importance of plasmid-mediated trimethoprim resistance in enterobacteria: Two six-month clinical surveys. British Medical Journal 280: 517 (1980).PubMedCrossRefGoogle Scholar
  149. Towner, K.J. and Pinn, P.A.: A transferable plasmid conferring only a moderate level of resistance to trimethoprim. FEMS Microbiology (letters) 10: 271 (1981).CrossRefGoogle Scholar
  150. Van Klingeren, B. and Rutgers, A.: Usefulness of commercially available media to MIC-determinations of trimethoprim; in Williams and Geddes (Eds) Chemotherapy Vol. 2, pp.61–64 (Plenum Press, New York and London 1975).Google Scholar
  151. Watson, I.D.; Cohen, H.N.; McIntosh, S.J.; Thompson, J.A. and Shenkin, A.: Synergism between trimethoprim and sulphonamide in urine: Does it exist. Clinical Therapeutics 4: 103 (1981).PubMedGoogle Scholar
  152. Welling, P.G.; Craig, W.A.; Amidon, G.L. and Kunin, C.M.: Pharmacokinetics of trimethoprim and sulfamethoxazole in normal subjects and in patients with renal failure. Journal of Infectious Diseases 128 (Suppl.): 556 (1973).PubMedCrossRefGoogle Scholar
  153. Whitman, E.N.: Effects in man of prolonged administration of trimethoprim and sulfisoxazole. Postgraduate Medical Journal 45 (Suppl.): 46 (1969).PubMedCrossRefGoogle Scholar
  154. Wilson, J.T.; Brown, R.D.; Cherek, D.R.; Dailey, J.W.; Hilman, B.; Jobe, P.C.; Manno, B.R.; Manno, J.E.; Redetzki, H.M. and Steward, J.J.: Drug excretion in human breast milk. Clinical Pharmacokinetics 5: 1 (1980).PubMedCrossRefGoogle Scholar
  155. Ylikorkala, O.; Sjostedt, E.; Jarvinen, P.A.; Tikkanen, R. and Raines, T.: Trimethoprim-sulphonamide combination administered orally and intravaginally in the first trimester of pregnancy: Its absorption into serum and transfer to amniotic fluid. Acta Obstetrica et Gynecologica Scandinavica 52: 229 (1973).CrossRefGoogle Scholar

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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