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. 1991 Sep;35(9):1884–1890. doi: 10.1128/aac.35.9.1884

Pharmacokinetics and adverse effects of 20-mg/kg/day trimethoprim and 100-mg/kg/day sulfamethoxazole in healthy adult subjects.

R C Stevens 1, S C Laizure 1, C L Williams 1, D S Stein 1
PMCID: PMC245286  PMID: 1952863

Abstract

The pharmacokinetics of trimethoprim-sulfamethoxazole were studied in 12 healthy adult subjects receiving trimethoprim at 20 mg/kg of body weight per day and sulfamethoxazole at 100 mg/kg/day, which is the conventional dose for treating Pneumocystis carinii pneumonia (PCP). Daily doses were evenly divided and orally administered every 6 h for 3 days. Trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole concentrations in serum and urine were measured by high-performance liquid chromatography. Five subjects withdrew from the study because of intolerable gastrointestinal and central nervous system toxicities. In the seven subjects that completed the study, the mean maximum serum drug concentrations after the last dose were 13.6 +/- 2.0, 372 +/- 64, and 50.1 +/- 10.9 micrograms/ml for trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole, respectively. The mean half-lives were 13.6 +/- 3.5, 14.0 +/- 2.3, and 18.6 +/- 4.3 h, respectively. Changes in absolute neutrophil count were significantly correlated with the minimum concentrations of trimethoprim and sulfamethoxazole in serum and trimethoprim area under the concentration-time curve (for all three parameters, r2 = 0.6 and P less than 0.05). Our findings add to the evidence that serum drug concentrations in adults following the conventional dose of trimethoprim-sulfamethoxazole for PCP are excessive and contribute to certain adverse reactions. Further studies are indicated in patients to optimize the dosing regimen of trimethoprim-sulfamethoxazole in the treatment of PCP.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Davey R. T., Jr, Masur H. Recent advances in the diagnosis, treatment, and prevention of Pneumocystis carinii pneumonia. Antimicrob Agents Chemother. 1990 Apr;34(4):499–504. doi: 10.1128/aac.34.4.499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Feldman S., Doolittle M., Lott L., Roberson P., Hughes W. T. Similar hematologic changes in children receiving trimethoprim-sulfamethoxazole or amoxicillin for otitis media. J Pediatr. 1985 Jun;106(6):995–1000. doi: 10.1016/s0022-3476(85)80257-2. [DOI] [PubMed] [Google Scholar]
  3. Furio M. M., Weidle P. J., Wordell C. J., Liu H. H. Management of Pneumocystis carinii pneumonia in patients with AIDS and other conditions: experience in a Philadelphia University Teaching Hospital. Pharmacotherapy. 1988;8(4):221–234. doi: 10.1002/j.1875-9114.1988.tb04077.x. [DOI] [PubMed] [Google Scholar]
  4. Golde D. W., Bersch N., Quan S. G. Trimethoprim and sulphamethoxazole inhibition of haematopoiesis in vitro. Br J Haematol. 1978 Nov;40(3):363–367. doi: 10.1111/j.1365-2141.1978.tb05807.x. [DOI] [PubMed] [Google Scholar]
  5. Gordin F. M., Simon G. L., Wofsy C. B., Mills J. Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1984 Apr;100(4):495–499. doi: 10.7326/0003-4819-100-4-495. [DOI] [PubMed] [Google Scholar]
  6. Hughes W. T., Feldman S., Chaudhary S. C., Ossi M. J., Cox F., Sanyal S. K. Comparison of pentamidine isethionate and trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia. J Pediatr. 1978 Feb;92(2):285–291. doi: 10.1016/s0022-3476(78)80028-6. [DOI] [PubMed] [Google Scholar]
  7. Kovacs J. A., Hiemenz J. W., Macher A. M., Stover D., Murray H. W., Shelhamer J., Lane H. C., Urmacher C., Honig C., Longo D. L. Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med. 1984 May;100(5):663–671. doi: 10.7326/0003-4819-100-5-663. [DOI] [PubMed] [Google Scholar]
  8. Kovacs J. A., Masur H. Prophylaxis of Pneumocystis carinii pneumonia: an update. J Infect Dis. 1989 Nov;160(5):882–886. doi: 10.1093/infdis/160.5.882. [DOI] [PubMed] [Google Scholar]
  9. Lau W. K., Young L. S. Trimethoprim-sulfamethoxazole treatment of Pneumocystis carinii pneumonia in adults. N Engl J Med. 1976 Sep 23;295(13):716–718. doi: 10.1056/NEJM197609232951308. [DOI] [PubMed] [Google Scholar]
  10. Lee B. L., Medina I., Benowitz N. L., Jacob P., 3rd, Wofsy C. B., Mills J., 5th Dapsone, trimethoprim, and sulfamethoxazole plasma levels during treatment of Pneumocystis pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). Evidence of drug interactions. Ann Intern Med. 1989 Apr 15;110(8):606–611. doi: 10.7326/0003-4819-110-8-606. [DOI] [PubMed] [Google Scholar]
  11. Medina I., Mills J., Leoung G., Hopewell P. C., Lee B., Modin G., Benowitz N., Wofsy C. B. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med. 1990 Sep 20;323(12):776–782. doi: 10.1056/NEJM199009203231202. [DOI] [PubMed] [Google Scholar]
  12. Sattler F. R., Cowan R., Nielsen D. M., Ruskin J. Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective, noncrossover study. Ann Intern Med. 1988 Aug 15;109(4):280–287. doi: 10.7326/0003-4819-109-4-280. [DOI] [PubMed] [Google Scholar]
  13. Sattler F. R., Remington J. S. Intravenous trimethoprim-sulfamethoxazole therapy for Pneumocystis carinii pneumonia. Am J Med. 1981 Jun;70(6):1215–1221. doi: 10.1016/0002-9343(81)90830-5. [DOI] [PubMed] [Google Scholar]
  14. Shear N. H., Spielberg S. P., Grant D. M., Tang B. K., Kalow W. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med. 1986 Aug;105(2):179–184. doi: 10.7326/0003-4819-105-2-179. [DOI] [PubMed] [Google Scholar]
  15. Siber G. R., Gorham C. C., Ericson J. F., Smith A. L. Pharmacokinetics of intravenous trimethoprim-sulfamethoxazole in children and adults with normal and impaired renal function. Rev Infect Dis. 1982 Mar-Apr;4(2):566–578. doi: 10.1093/clinids/4.2.566. [DOI] [PubMed] [Google Scholar]
  16. Small C. B., Harris C. A., Friedland G. H., Klein R. S. The treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Arch Intern Med. 1985 May;145(5):837–840. [PubMed] [Google Scholar]
  17. Wharton J. M., Coleman D. L., Wofsy C. B., Luce J. M., Blumenfeld W., Hadley W. K., Ingram-Drake L., Volberding P. A., Hopewell P. C. Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective randomized trial. Ann Intern Med. 1986 Jul;105(1):37–44. doi: 10.7326/0003-4819-105-1-37. [DOI] [PubMed] [Google Scholar]
  18. Winston D. J., Lau W. K., Gale R. P., Young L. S. Trimethoprim-sulfamethoxazole for the treatment of Pneumocystis carinii pneumonia. Ann Intern Med. 1980 Jun;92(6):762–769. doi: 10.7326/0003-4819-92-6-762. [DOI] [PubMed] [Google Scholar]

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