Tetrahydrofolate synthesis pathway
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Cotrim

Co-trimoxazole (abbreviated SXT) is a bacteriostatic antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections. The name co-trimoxazole is the International Nonproprietary Name, and has been marketed worldwide under many brand names (GlaxoSmithKline under Septrin®, Hoffmann-La Roche as Bactrim®, and by many other generic pharmaceutical manufacturers). more...

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Synergistic action

Co-trimoxazole exhibits a synergistic antibacterial effect when compared to each of its components administered singly. This is because trimethoprim and sulfamethoxazole inhibit successive steps in the folate synthesis pathway (see diagram below).

Sulfamethoxazole acts as a false-substrate inhibitor of dihydropteroate reductase. Sulfonamides such as sulfamethoxazole are analogues of p-aminobenzoic acid (PABA) and are competitive inhibitors of the enzyme; inhibiting the production of dihydropteroic acid.

Trimethoprim acts by interfering with the action of bacterial dihydrofolate reductase, inhibiting synthesis of tetrahydrofolic acid.

Folic acid is an essential precursor in the de novo synthesis of the DNA nucleosides thymidine and uridine. Bacteria are unable to take up folic acid from the environment (i.e. the infection host) thus are dependent on their own de novo synthesis - inhibition of the enzyme starves the bacteria of two bases necessary for DNA replication and transcription.

Clinical indications

Co-trimoxazole is more effective than either of its components individually in treating bacterial infections. However the degree of benefit for the additonal of the Sulfonamide, was in most cases marginal, but reponsible for its high association will allergic responses (see below). Its widespread use has been restricted in many countries to very specific circumstances where its improved efficacy is 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.

Specific indications for its use include: (Rossi, 2004)

  • treatment and prophylaxis of pneumonia caused by Pneumocystis jiroveci (P. carinii)
  • infections caused by Listeria monocytogenes, Nocardia spp., Stenotrophomonas maltophilia (Zanthomonas maltophilia)
  • melioidosis
  • shigellosis
  • traveller's diarrhoea
  • prophylaxis of cerebral toxoplasmosis in HIV patients
  • Whipple's disease

Safety

There has been some concern about its use, however, since it has been associated with both frequent mild allergic reactions and rare but serious adverse effects including Stevens-Johnson syndrome, myelosuppression, agranulocytosis, as well as severe liver damage (cholostatic hepatosis, hepatitis, liver necrosis, fulminant liver failure) and renal impairment up to acute renal failure and anuria. These side-effects are seen especially in the elderly and may be fatal. (Joint Formulary Committee, 2004)

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Morbidity and survival in advanced AIDS in Rio De Janeiro, Brazil
From Revista do Instituto de Medicina Tropical de Sao Paulo, 7/1/02 by Gadelha, Angela J

SUMMARY

Opportunistic diseases (OD) are the most common cause of death in AIDS patients. To access the incidence of OD and survival in advanced immunodeficiency, we included 79 patients with AIDS treated at Hospital Evandro Chagas (FIOCRUZ) from September 1997 to December 1999 with at least one CD4 count =

Mean follow-up period was 733 days (CI = 683-782). During the study 9 (11.4%) patients died. Survival from AIDS diagnosis was a mean of 2589 days (CI = 2363-2816) and from the date of the CD4 count CD4 =

We found a very low incidence of OD and long survival after CD4

KEYWORDS: AIDS; Morbidity; CD4 counts; Survival.

INTRODUCTION

The introduction of highly active antiretroviral treatment (HAART) has lowered incidence of opportunistic diseases (ODs)2, prolonged survival3,23 and reduced AIDS-related hospital admissions21. HAART has also had a beneficial effect on individuals with advanced immunosuppression3. Little has been done, however, to explore the effects of reconstituting CD4+ cells on OD incidence, especially among patients at an advanced stage of immunodeficiency 16.

Evaluation of the effect of universal distribution of anti-retrovirals free-of-charge in Sao Paulo revealed a 50% reduction in AIDS-related hospital admission and mortality rates18. However, the incidence of AIDSrelated events and the factors that may influence survival following this measure have yet to be evaluated in Brazil.

OBJECTIVES

To identify the factors associated with morbidity and survival in AIDS patients treated with HAART at an advanced stage of immunodeficiency, as compared with before CD4 T cell counts dropped below 100 cells/mm^sup 3^.

PATIENTS AND METHODS

We conducted a bidirectional cohort study at the Evandro Chagas Hospital Research Centre (Centro de Pesquisa Hospital Evandro Chagas, CPqHEC) of the Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, from September 1, 1997 to December 7, 1999. The CPqHEC is an institution that specializes in treating adults with HIV/AIDS or other infectious diseases, and offers reference on clinical and laboratory services.

Inclusion criteria: adult patients with at least an absolute CD4' lymphocyte count of =

Exclusion criteria: individuals monitored for less than 90 days at the end of the study were excluded.

Criterion for defining AIDS and related ODs: the CDC 1993 criterion was adopted4. This study however, did not take account of bacterial pneumonias due to the large number of presumptive diagnoses without bacteriological confirmation.

Data gathering: An initial interview was held to obtain retrospective data on diagnoses of AIDS-indicator diseases, as well as prior antiretroviral treatment. Whenever necessary, this information was complemented by consulting medical records. The monthly prospective evaluation recorded diagnoses of AIDS-related ODs, the antiretroviral treatment used and laboratory data such as plasma HIV1-RNA load and CD4+ cell count, which were repeated every four months.

CD4'T cells were counted by flow cytometry (Epics XL, Coulter Co, FL, USA), using TriTEST CD4 FITC/ CD8 PE/CD3 PerCP monoclonal antibodies (BD Immunocytometry Systems, SJ, CA, USA). Viral load was measured by NucliSens HIV- 1 QT (NASBA Diagnostics, Organon Teknika, Holland) in plasma samples. Both exams were assured by the National Network for CD4 and Viral Load Evaluation, from the National Coordination of Sexual Transmitted Diseases and AIDS, Brazilian Ministry of Health.

ACKNOWLEDGEMENT

We thank to the Day-Hospital team for the special dedication: Liane Braga da Silveira, Luci Alves, Solange Alves da Cruz, Sonilde Mello Fasolo and Marcia Regina Lyra da Silva.

REFERENCES

1. BLUM, S.; SINGH, T.; GIBBONS, J. et al. - Trends in survival among persons with acquired immunodeficiency syndrome in New York City: the experience of the first decade of the epidemic. Amer. J. Epidem., 139: 351-361, 1994.

2. BRODT, H.R.; KAMPS B.S.; GUTE, P. et al. - Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. AIDS, 11: 1731-1738,1997.

3. CAMERON, W.; HEATH-CHIOSI, M.; KRAVICK, S. et al. - Prolongation of life and prevention of AIDS in advanced immunodeficiency with Ritonavir. In: THIRD CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS, Washington, 1996. p. 40.

4. CDC. CENTERS FOR DISEASE CONTROL AND PREVENTION - 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR, 41 (RR-17): 1-19, 1992.

5. CHAISSON, R.E.; KERULY, I.C. & MOORE, R.D. - Race, sex, drug use, and progression of human immunodeficiency virus disease. New Engl. J. Med., 333: 751-756, 1995.

6. CHAISSON, R.E.; GALLANT, I.E.; KERULY, J.C. & MOORE, R.D. - Impact of opportunistic disease on survival in patients with HIV infection. AIDS, 12: 29-33, 1998.

7. DORE, G.; HOY, J.P.; MALLAL, S.A. et al. - Trends in incidence of AIDS illnesses in Australia from 1983 to 1994: the Australian cohort. J. AIDS hum. Retrov., 16: 3943, 1997,

8. FINKELSTEIN, D.M.; WILLIAMS, P.L.; MOLENBERGHS, G. et al. - Patterns of opportunistic infections in patients with HIV infection. J. AIDS hum. Retrov., 12: 38-45, 1996.

9. GADELHA, A.M.J. - Casos notiflcados de AIDS no Municipio do Rio de Janeiro, 1983-1993: anilise de sobrevida. Sao Paulo, 1987. (Tese de Doutorado Universidade de Sao Paulo).

10. LEDERGERBER, B.; EGGER, M. & TELENTI, A. - AIDS-related opportunistic illness and potent antiretroviral therapy. J. Amer. med. Ass., 283: 2653-2654, 2000.

11. LEMP, G.F; PAYNE, S.F; NEAL, D.; TEMELSO, T. & RUTHERFORD, G.W. - Survival trends for patients with AIDS. J. Amer. med. Ass., 263: 402-406, 1990.

12. LIMA, D.B. - Valldaelo do sistema de estigios proposto pela Organiza*io Mundial de Sa6de para infeccao e doenqa pelo HIV em adolescentes e adultos. Rio de Janeiro, Universidade Federal do Rio de Janeiro, 1992.

13. LUO, K.; LAW, M.; KALDOR, J.M.; MCDONALD, A.M. & COOPER, D.A. - The role of initial AIDS-defining illness in survival following AIDS. AIDS, 9: 57-63, 1995.

14. McNAGHTEN, A.D.; HANSON, D.L.; JONES, J.L.; DWORKIN, M.S. & WARD, J.W. - Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis. Adult/Adolescent Spectrum of Disease Group. AIDS, 13: 1687-1695, 1999.

15. MELLORS, JX; RINALDO Jr., C.R.; GUPTA, P. et at. - Prognosis in HIV-I infection predicted by the quantity of virus in plasma. Science, 272: 1167-1170, 1996.

16. MEZZAROMA, L; CARLESIMO, M.; PINTER, E. et aL - Long-term evaluation of Tcell subsets and T-cell function after HAART in advanced stage HIV- I disease. AIDS, 13:1187-1193, 1999.

17. MICHELET, C.; ARVIEUX, C.; FRANCOIS, C. et aL - Opportunistic infections occurring during highly active antiretroviral treatment. AIDS, 12: 1815-1822, 1998.

18. MINISTER]O DA SAUDE, BRASIL - Programs National de Controle de Doencas Sexualmente Transmissfveis/AIDS. Brasilia, Ministerio da Saude, 2000. (www.aids.gov.br).

19. MINISTtRIO DA SAUDE, BRASIL - Contagem de celulas T CD4' e testes de carga viral: principals marcadores laboratoriais para indicacao e monitorizaclo do tratamento anti-retroviral. Brasilia, Unidade de Assistencia e Unidade de Laborat6rio da Coordenaglo National de DST/AIDS, 1998. v. 2000.

20. MOCROFT, A.J.; JOHNSON, M.A.; SABIN, C.A. et aL - Staging system for clinical AIDS patients. Royal Free/Chelsea and Westminster Hospitals Collaborative Group. Lancet, 346: 12-17, 1995.

21. MOUTON, Y.; ALFANDARI, S.; VALETTE, M. et at. - Impact of protease inhibitors on AIDS-defining events and hospitalizations in 10 French AIDS reference centres. Federation National des Centres de Lutte contre le SIDA. AIDS, 11: 101-105, 1997.

22. NOROIIS, M. - Statistical Program for Social Science. Chicago, SPSS, 1995.

23. PALELLA Jr., F.J.; DELANEY, K.M.; MOORMAN, A.C. et al. - Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. New Engl. J. Med., 338: 853-860, 1998.

24. PEDERSEN, C.; GERSTOFT, J.; TAURIS, P. et aL - Trends in survival of Danish AIDS patients from 1981 to 1989. AIDS, 4:1111 -116, 1990.

25. SAAH, A.; HOOVER, D.R.; HE, Y.; KINGSLEY, L. & PHAIR, J.P. - Factors influencing survival after AIDS: report from the Multicenter AIDS Cohort Study (MACS). J. Acquir. Immune Deric. Syndr., 7: 287-295, 1994.

26. SANTORO-LOPES, G.; HARRISON, L.H.; MOULTON, L.H. et al. - Gender and survival after AIDS in Rio de Janeiro, Brazil. J. AIDS hum. Retrov., 19: 403-407, 1998.

27. SCHECHTER, M.T.; CRAIB, KJ; LE, T.N. el al. - Susceptibility to AIDS progression appears early in HIV infection. AIDS, 4: 185-190, 1990.

28. SERC - Statistics and Epidemiology Research Corporation: EGRET. Seattle, User's Manual, 1985.

Received: 5 February 2002

Accepted: 27 June 2002

Angela J. GADELHA(I), Niurea ACCACIO(2), Regina L.B. COSTA(2), Maria Clara GALHARDO(2), Maria Regina COTRIM(2), Rogerio V. DE SOUZA(2), Mariza MORGADO(3), Keyla MARZOCHI(2), Maria Cristina LOURENCO(2) & Valeria C. ROLLA(2)

The program PAPES//Fiocruz supported this work.

(1) Escola Nacional de Saude Publica (ENSP), FIOCRUZ, Rio de Janeiro, RJ, Brazil

(2) Centro de Pesquisa Hospital Evandro Chagas (CPqHEC), FIOCRUZ, Rio de Janeiro, RJ, Brazil

(3) Laboratorio de Imunologia em HIV/AIDS, Instituto Oswaldo Cruz (IOC), FIOCRUZ, Rio de Janeiro, RJ, Brazil

Correspondence to: Dr. Valeria Rolla, Centro de Pesquisa Hospital Evandro Chagas/FIOCRUZ. Av. Brasil 4365, 21045-900 Rio de Janeiro, RJ, Brazil. Email: valeria @cpqhec.fiocruz.br; rolla@unisys.com.br

Copyright Instituto de Medicina Tropical de Sao Paulo Jul/Aug 2002
Provided by ProQuest Information and Learning Company. All rights Reserved

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