Trimethoprim/sulfamethoxazole

Trimethoprim/sulfamethoxazole

Trimethoprim (top) and sulfamethoxazole (bottom)
Combination of
Trimethoprim Dihydrofolate reductase inhibitor
Sulfamethoxazole Sulfonamide antibiotic
Clinical data
Trade names Bactrim, Cotrim, Septra, others
AHFS/Drugs.com monograph
Pregnancy
category
Routes of
administration		 By mouth, intravenous[1]
Legal status
Legal status
Identifiers
CAS Number 8064-90-2
ATC code J01EE01 (WHO)
PubChem CID 358641
DrugBank DB00440
ChemSpider 318412
ChEBI CHEBI:3770
  (verify)

Trimethoprim/sulfamethoxazole (TMP/SMX), also known as co-trimoxazole among other names, is an antibiotic used to treat a variety of bacterial infections.[1] It consists of one part trimethoprim to five parts sulfamethoxazole.[2] It is used for urinary tract infections, MRSA skin infections, travelers' diarrhea, respiratory tract infections, and cholera, among others.[1][2] It may be used both to treat and prevent pneumocystis pneumonia in people with HIV/AIDS. It can be given by mouth or intravenously.[1]

Common side effects include nausea, vomiting, rash, and diarrhea. Severe allergic reactions and Clostridium difficile diarrhea may occasionally occur. Its use near the end of pregnancy is not recommended.[1] It appears to be okay during breastfeeding as long as the baby is healthy.[3] TMP/SMX generally results in bacterial death. It works by blocking the making of folate by the bacteria.[1]

TMP/SMX was first sold in 1974.[4] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[5] It is available as a generic medication and is not very expensive.[2] In the United States it is about 0.40 USD per dose.[1]

Medical uses

Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed.[6] Because it has a higher incidence of adverse effects, including allergic responses, its use has been restricted in many countries to very specific circumstances where its improved efficacy has been demonstrated.[7] 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. The global problem of advancing antimicrobial resistance has led to a renewed interest in the use of co-trimoxazole more recently.[8]

Susceptibility

Organisms against which co-trimoxazole can be effective include:[9][10]

The only notable nonsusceptible organisms are the mycoplasmae[10] and Francisella tularensis (the causative organism of tularaemia).[11][12]

Pregnancy and breast feeding

Its use during pregnancy is contraindicated, although it has been placed in Australian and American pregnancy category C.[9] Despite this, its use during the first trimester (during organogenesis) and 12 weeks prior to pregnancy has been associated with an increased risk of congenital malformations, especially malformations associated with maternal folic acid deficiency (which is most likely related to the mechanism of action of co-trimoxazole) such as neural tube defects such as spina bifida, cardiovascular malformations (e.g. Ebstein's anomaly), urinary tract defects, oral clefts, and club foot in epidemiological studies.[9] Its use later on during pregnancy also increases the risk of preterm labour (odds ratio: 1.51) and low birth weight (odds ratio: 1.67).[13][14] Animal studies have yielded similarly discouraging results.[15] It is also excreted in breast milk and hence nursing during treatment with co-trimoxazole is generally advised against.[9]

Adverse effects

Contraindications

Contraindications include the following:[9][16]

Interactions

Its use is advised against in patients being concomitantly treated with:[9][15][16][17][18][19]

Overdose

Likely signs of toxicity include:[15]

  • Nausea
  • Vomiting
  • Dizziness
  • Headache
  • Mental depression
  • Confusion
  • Bone marrow depression
  • Loss of appetite
  • Colic
  • Drowsiness
  • Unconsciousness

The recommended treatment for overdose includes:[15]

Alkalinisation of the urine may reduce the toxicity of sulfamethoxazole, but it may increase the toxic effects of trimethoprim.[15]

Pharmacology

Tetrahydrofolate synthesis pathway

The synergy between trimethoprim and sulfamethoxazole was first described in the late 1960s.[21][22][23] Trimethoprim and sulfamethoxazole have a greater effect when given together than when given separately, because they inhibit successive steps in the folate synthesis pathway. They are given in a one-to-five ratio in their tablet formulations so that when they enter the body their concentration in the blood and tissues is roughly one-to-twenty — the exact ratio required for a peak synergistic effect between the two.[10]

Sulfamethoxazole, a sulfonamide, induces its therapeutic effects by interfering with the de novo (that is, from within the cell) synthesis of folate inside microbial organisms such as protozoa, fungi and bacteria. It does this by competing with p-aminobenzoic acid (PABA) in the biosynthesis of dihydrofolate.[10]

Trimethoprim serves as a competitive inhibitor of dihydrofolate reductase (DHFR), hence inhibiting the de novo synthesis of tetrahydrofolate, the biologically active form of folate.[10]

The effects of trimethoprim causes a backlog of dihydrofolate (DHF) and this backlog can work against the inhibitory effect the drug has on tetrahydrofolate biosynthesis; this is where the sulfamethoxazole comes in, its role is in depleting the excess DHF by preventing it from being synthesised in the first place.[10]

Pharmacokinetics of co-trimoxazole[9][15]
Component Tmax (hrs) Vd (L) Protein binding t1/2 (hrs) Excretion
Sulfamethoxazole 1-4 20 66% 8-10 Renal
Trimethoprim 1-4 130 42-45% 10 Renal

Society and culture

Approval

Indications for co-trimoxazole
Indication United States
FDA-labelled indication?		 Australia
TGA-labelled indication?		 United Kingdom
MHRA-labelled indication?		 Literature support
Acute infective exacerbation of chronic bronchitis Yes No No Clinical trials are lacking.
Prophylaxis in HIV-infected individuals No No No Effective in one Ugandan study on morbidity, mortality, CD4-cell count, and viral load in HIV infection.[24]
Otitis media Paediatric population only No Yes Clinical trials have confirmed its efficacy in chronic active otitis media[25] and acute otitis media.[26]
Travellers' diarrhoea, treatment & prophylaxis Yes No No Clinical trials have confirmed its efficacy as a treatment for travellers' diarrhoea.[27][28][29]
Urinary tract infection Yes No Yes Clinical trials have confirmed its efficacy in this indication.[10]
Bacterial infections
Acne vulgaris No No No At least one clinical trial supports its use in this indication.[30]
Listeria No Yes No Well-designed clinical trials are lacking.
Melioidosis No Yes No Clinical trials have confirmed its efficacy, with or without adjunctive doxycycline; although, co-trimoxazole alone seems preferable.[31][32][33]
Pertussis (whooping cough) No No No One cochrane review supports its efficacy in preventing the spread of pertussis.[34]
Shigellosis Yes Yes No Generally accepted treatment for shigellosis.[35] A recent Cochrane review found that while it is an effective treatment for shigellosis it also produces more significant adverse effects than other antibiotic drugs.[36]
Staphylococcus aureus infections No No No In vitro and in vivo activity against both non-resistant and methicillin-resistant Staphylococcus aureus (MRSA) infections.[37][38][39][40][41][42][43]
Tuberculosis No No No In vitro and in vivo activity against both nonresistant and MDR strains of TB.[44][45][46]
Whipple's disease No No No Co-trimoxazole is the recommended standard treatment for whipple's disease in some treatment protocols.[47][48][49]
Fungal and protozoal infections
Isosporiasis No No No Clinical trials have confirmed its use in this indication.[50]
Malaria No No No Clinical trials have confirmed its efficacy in both the treatment and prevention of malaria.[51]
Pneumocystis jirovecii pneumonia Yes Yes Yes Its use as a prophylactic treatment is supported by one clinical trial involving children with acute lymphoblastic leukaemia.[52] Other than this and one other clinical trial into its efficacy as a treatment for pneumocystis pneumonia,[53] data on its use in both the treatment and prevention of pneumocystis pneumonia is significantly lacking.
Toxoplasmosis Yes Prevention only Yes Clinical trials have confirmed its prophylactic and therapeutic utility in cases of toxoplasmosis.[54][55][56][57][58][59]
Other indications
Granulomatosis with polyangiitis (formerly Wegener's) No No No Two clinical trials have supported its efficacy in this indication.[60][61]

Trade names

Trimethoprim/sulfamethoxazole may be abbreviated as SXT, TMP-SMX, TMP-SMZ, or TMP-sulfa.

Co-trimoxazole (BAN) is manufactured and sold by many different companies. The following list of brand names is incomplete:

References

  1. 1 2 3 4 5 6 7 8 "Co-trimoxazole". The American Society of Health-System Pharmacists. Retrieved Aug 1, 2015.
  2. 1 2 3 Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 105. ISBN 9781284057560.
  3. ↑ "Sulfamethoxazole / trimethoprim Pregnancy and Breastfeeding Warnings". Retrieved 31 August 2015.
  4. ↑ Oxford Handbook of Infectious Diseases and Microbiology. OUP Oxford. 2009. p. 56. ISBN 9780191039621.
  5. ↑ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  6. ↑ Brumfitt, W; Hamilton-Miller, JM (December 1993). "Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines". Journal of Chemotherapy 5 (6): 465–9. PMID 8195839.
  7. ↑ "Co-trimoxazole use restricted". Drug Ther Bull 33 (12): 92–3. December 1995. doi:10.1136/dtb.1995.331292. PMID 8777892.
  8. ↑ Falagas ME, Grammatikos AP, Michalopoulos A (October 2008). "Potential of old-generation antibiotics to address current need for new antibiotics". Expert Rev Anti Infect Ther 6 (5): 593–600. doi:10.1586/14787210.6.5.593. PMID 18847400.
  9. 1 2 3 4 5 6 7 "Bactrim, Bactrim DS (trimethoprim/sulfamethoxazole) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 13 January 2014.
  10. 1 2 3 4 5 6 7 Wormser, GP; Keusch, GT; Heel, RC (December 1982). "Co-trimoxazole (trimethoprim-sulfamethoxazole): an updated review of its antibacterial activity and clinical efficacy". Drugs 24 (6): 459–518. doi:10.2165/00003495-198224060-00002. PMID 6759092.
  11. ↑ "TULAREMIA" (PDF). Infectious Disease Epidemiology Section. Louisiana Office of Public Health. 17 July 2011. Retrieved 12 February 2014.
  12. ↑ Harik, NS (1 July 2013). "Tularemia: Epidemiology, Diagnosis, and Treatment" (PDF). Pediatric Annals 42 (7): 288–292. doi:10.3928/00904481-20130619-13. PMID 23805970.
  13. ↑ Yang, J; Xie, RH; Krewski, D; Wang, YJ; Walker, M; Wen, SW (May 2011). "Exposure to trimethoprim/sulfamethoxazole but not other FDA category C and D anti-infectives is associated with increased risks of preterm birth and low birth weight" (PDF). International Journal of Infectious Diseases 15 (5): e336–e341. doi:10.1016/j.ijid.2011.01.007. PMID 21345707.
  14. ↑ Santos, F; Sheehy, O; Perreault, S; Ferreira, E; Berard, A (October 2011). "Exposure to anti-infective drugs during pregnancy and the risk of small-for-gestational-age newborns: a case–control study". BJOG 118 (11): 1374–1382. doi:10.1111/j.1471-0528.2011.03041.x. PMID 21749628.
  15. 1 2 3 4 5 6 "BACTRIM®" (PDF). TGA eBusiness Services. Roche Products Pty Limited. 18 September 2012. Retrieved 13 January 2014.
  16. 1 2 3 "Co-Trimoxazole Tablets 80/400mg - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Actavis UK Ltd. 17 October 2012. Retrieved 13 January 2014.
  17. ↑ "BACTRIM DS (sulfamethoxazole and trimethoprim) tablet BACTRIM (sulfamethoxazole and trimethoprim) tablet [AR Scientific, Inc.]". DailyMed. AR Scientific, Inc. June 2013. Retrieved 13 January 2014.
  18. ↑ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.
  19. ↑ Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  20. ↑ Juvet T, Gourineni V, Ravi S, Zarich S. Life-threatening hyperkalemia: a potentially lethal drug combination. Connecticut Medicine [serial online]. September 2013;77(8):491-493. Available from: MEDLINE Complete, Ipswich, MA.
  21. ↑ Bushby SRM, Hitchings GH (1968). "Trimethoprim, a sulphonamide potentiator". Brit J Pharmacol 33 (1): 72–90. doi:10.1111/j.1476-5381.1968.tb00475.x. PMC 1570262. PMID 5301731.
  22. ↑ Böhni E (1969). "Vergleichende bakteriologische untersuchungen mit der Kombination Trimethoprim/Sulfamethoxazole in vitro und in vivo". Chemotherapy 14 (Suppl): Suppl:1–21. doi:10.1159/000220651. PMID 4908562.
  23. ↑ Böhni E (1969). "Chemotherapeutic activity of the combination of trimethoprim and sulfamethoxazole in infections of mice". Postgrad Med J 45 (Suppl): Suppl:18–21. PMID 4902845.
  24. ↑ Mermin, J; Lule, J; Ekwaru, JP; Malamba, S; Downing, R; Ransom, R; Kaharuza, F; Culver, D; Kizito, F; Bunnell, R; Kigozi, A; Nakanjako, D; Wafula, W; Quick, R (October 2004). "Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda". The Lancet 364 (9443): 1428–1434. doi:10.1016/S0140-6736(04)17225-5. PMID 15488218.
  25. ↑ van der Veen, EL; Rovers, MM; Albers, FW; Sanders, EA; Schilder, AG (May 2007). "Effectiveness of trimethoprim/sulfamethoxazole for children with chronic active otitis media: a randomized, placebo-controlled trial" (PDF). Pediatrics 119 (5): 897–904. doi:10.1542/peds.2006-2787. PMID 17473089.
  26. ↑ Leiberman, A; Leibovitz, E; Piglansky, L; Raiz, S; Press, J; Yagupsky, P; Dagan, R (March 2001). "Bacteriologic and clinical efficacy of trimethoprim-sulfamethoxazole for treatment of acute otitis media". Pediatric Infectious Disease Journal 20 (3): 260–264. doi:10.1097/00006454-200103000-00009. PMID 11303827.
  27. ↑ Ericsson, CD; Johnson, PC; Dupont, HL, Morgan DR, Bitsura JA, de la Cabada FJ (February 1987). "Ciprofloxacin or trimethoprim-sulfamethoxazole as initial therapy for travelers' diarrhea. A placebo-controlled, randomized trial". Annals of Internal Medicine 106 (2): 216–220. doi:10.7326/0003-4819-106-2-216. PMID 3541724.
  28. ↑ Ericsson, CD; DuPont, HL; Mathewson, JJ; West, MS; Johnson, PC; Bitsura, JA (January 1990). "Treatment of traveler's diarrhea with sulfamethoxazole and trimethoprim and loperamide". Journal of the American Medical Association 263 (2): 257–261. doi:10.1001/jama.1990.03440020091039. PMID 2403603.
  29. ↑ Rendi-Wagner, P; Kollaritsch, H (March 2002). "Drug Prophylaxis for Travelers' Diarrhea" (PDF). Clinical Infectious Diseases 34 (5): 628–633. doi:10.1086/338640. PMID 11803509.
  30. ↑ Nordin, K; Hallander, H; Fredriksson, T; Rylander, C; et al. (1978). "A clinical and bacteriological evaluation of the effect of sulphamethoxazole-trimethoprim in acne vulgaris, resistant to prior therapy with tetracyclines". Dermatologica 157 (4): 245–53. doi:10.1159/000250840. PMID 150980.
  31. ↑ Chetchotisakd, P; Chaowagul, W; Mootsikapun, P; Budhsarawong, D; Thinkamrop, B (January 2001). "Maintenance therapy of melioidosis with ciprofloxacin plus azithromycin compared with cotrimoxazole plus doxycycline" (PDF). The American Journal of Tropical Medicine and Hygiene 64 (1-2): 24–27. PMID 11425157.
  32. ↑ "Outcomes of patients with melioidosis treated with cotrimoxazole alone for eradication therapy" (PDF). The American Journal of Tropical Medicine and Hygiene 87 (5): 927–932. November 2012. doi:10.4269/ajtmh.2012.12-0136. PMC 3516270. PMID 23033403.
  33. ↑ Chetchotisakd, P; Chierakul, W; Chaowagul, W; Anunnatsiri, S; Phimda, K; Mootsikapun, P; Chaisuksant, S; Pilaikul, J; Thinkhamrop, B; Phiphitaporn, S; Susaengrat, W; Toondee, C; Wongrattanacheewin, S; Wuthiekanun, V; Chantratita, N; Thaipadungpanit, J; Day, NP; Limmathurotsakul, D; Peacock, SJ (November 2013). "Trimethoprim-sulfamethoxazole versus trimethoprim-sulfamethoxazole plus doxycycline as oral eradicative treatment for melioidosis (MERTH): a multicentre, double-blind, non-inferiority, randomised controlled trial". The Lancet 383 (9919): 807–14. doi:10.1016/S0140-6736(13)61951-0. PMC 3939931. PMID 24284287.
  34. ↑ Altunaiji, S; Kukuruzovic, R; Curtis, N; Massie, J (July 2007). "Antibiotics for whooping cough (pertussis)". The Cochrane Database of Systematic Reviews (3): CD004404. doi:10.1002/14651858.CD004404.pub2. PMID 15674946.
  35. ↑ Sureshbabu, J; Venugopalan, P; Abuhammour, W (25 June 2012). Fennelly, G; Windle, ML; Lutwick, LI; Tolan Jr, RW; Steele, RW, ed. "Shigella Infection Medication". Medscape Reference. WebMD. Retrieved 8 January 2014.
  36. ↑ Christopher, PR; David, KV; John, SM; Sankarapandian, V (August 2010). "Antibiotic therapy for Shigella dysentery (Review)" (PDF). The Cochrane Database of Systematic Reviews (8): CD006784. doi:10.1002/14651858.CD006784.pub4. PMID 20687081.
  37. ↑ Grim, SA; Rapp, RP; Martin, CA; Evans, ME (February 2005). "Trimethoprim-Sulfamethoxazole as a Viable Treatment Option for Infections Caused by Methicillin-Resistant Staphylococcus aureus". Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 25 (2): 253–264. doi:10.1592/phco.25.2.253.56956. PMID 15767239.
  38. ↑ Cenizal, MJ; Skiest, D; Luber, S; Bedimo, R; Davis, P; Fox, P; Delaney, K; Hardy, RD (July 2007). "Prospective Randomized Trial of Empiric Therapy with Trimethoprim-Sulfamethoxazole or Doxycycline for Outpatient Skin and Soft Tissue Infections in an Area of High Prevalence of Methicillin-Resistant Staphylococcus aureus" (PDF). Antimicrobial Agents and Chemotherapy 51 (7): 2628–2630. doi:10.1128/AAC.00206-07. PMC 1913240. PMID 17502411.
  39. ↑ LaPlante, KL; Leonard, SN; Andes, DR; Craig, WA; Rybak, MJ (April 2008). "Activities of Clindamycin, Daptomycin, Doxycycline, Linezolid, Trimethoprim-Sulfamethoxazole, and Vancomycin against Community-Associated Methicillin-Resistant Staphylococcus aureus with Inducible Clindamycin Resistance in Murine Thigh Infection and In Vitro Pharmacodynamic Models" (PDF). Antimicrobial Agents and Chemotherapy 52 (6): 2156–2162. doi:10.1128/AAC.01046-07. PMC 2415789. PMID 18411321.
  40. ↑ Pappas, G; Athanasoulia, AP; Matthaiou, DK; Falagas, ME (April 2009). "Trimethoprim-sulfamethoxazole for methicillin-resistant Staphylococcus aureus: a forgotten alternative?". Journal of Chemotherapy 21 (2): 115–126. doi:10.1179/joc.2009.21.2.115. ISSN 1973-9478. PMID 19423463.
  41. ↑ Goldberg, E; Paul, M; Talker, O; Samra, Z; Raskin, M; Hazzan, R; Leibovici, L; Bishara, J (May 2010). "Co-trimoxazole versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteraemia: A retrospective cohort study" (PDF). Journal of Antimicrobial Chemotherapy 65 (8): 1779–1783. doi:10.1093/jac/dkq179. PMID 20507860.
  42. ↑ Cadena, J; Nair, S; Henao-Martinez, AF; Jorgensen, JH; Patterson, JE; Sreeramoju, PV (December 2011). "Dose of Trimethoprim-Sulfamethoxazole To Treat Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus" (PDF). Antimicrobial Agents and Chemotherapy 55 (12): 5430–5432. doi:10.1128/AAC.00706-11. PMC 3232808. PMID 21930870.
  43. ↑ Avery, LM; Steed, ME; Woodruff, AE; Hasan, M; Rybak, MJ (November 2012). "Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus Vertebral Osteomyelitis Cases Complicated by Bacteremia Treated with High-Dose Daptomycin and Trimethoprim-Sulfamethoxazole" (PDF). Antimicrobial Agents and Chemotherapy 56 (11): 5990–5993. doi:10.1128/AAC.01046-12. PMC 3486608. PMID 22869580.
  44. ↑ Forgacs, P; Wengenack, NL; Hall, L; Zimmerman, SK; Silverman, ML; Roberts, GD (November 2009). "Tuberculosis and trimethoprim-sulfamethoxazole" (PDF). Antimicrobial Agents and Chemotherapy 53 (11): 4789–4793. doi:10.1128/AAC.01658-08. PMC 2772331. PMID 19564358.
  45. ↑ Vilchèze, C; Jacobs, WR Jr (October 2012). "The combination of sulfamethoxazole, trimethoprim, and isoniazid or rifampin is bactericidal and prevents the emergence of drug resistance in Mycobacterium tuberculosis" (PDF). Antimicrobial Agents and Chemotherapy 56 (10): 5142–5148. doi:10.1128/AAC.00832-12. PMC 3457372. PMID 22825115.
  46. ↑ Alsaad, N; van Altena, R; Pranger, AD; van Soolingen, D; de Lange, WC; van der Werf, TS; Kosterink, JG; Alffenaar, JW (August 2013). "Evaluation of co-trimoxazole in the treatment of multidrug-resistant tuberculosis". The European Respiratory Journal 42 (2): 504–512. doi:10.1183/09031936.00114812. PMID 23100498.
  47. ↑ Fenollar, F; Raoult, D (January 2001). "Whipple's Disease" (PDF). Clinical and Vaccine Immunology 8 (1): 1–8. doi:10.1128/CDLI.8.1.1-8.2001.
  48. ↑ Ojeda, E; Cosme, A; Lapaza, J; Torrado, J; Arruabarrena, I; Alzate, L (February 2010). "Whipple's disease in Spain: a clinical review of 91 patients diagnosed between 1947 and 2001". Rev Esp Enferm Dig. 102 (2): 108–123. doi:10.4321/s1130-01082010000200006. PMID 20361847.
  49. ↑ Puéchal, X (November 2013). "Whipple’s disease" (PDF). Postgraduate Medical Journal 89 (1057): 659–665. doi:10.1136/postgradmedj-2012-202684rep. PMID 24129033.
  50. ↑ Lagrange-Xélot, M; Porcher, R; Sarfati, C; de Castro, N; Carel, O; Magnier, JD; Delcey, V; Molina, JM (February 2008). "Isosporiasis in patients with HIV infection in the highly active antiretroviral therapy era in France". HIV Medicine 9 (2): 126–30. doi:10.1111/j.1468-1293.2007.00530.x. PMID 18257775.
  51. ↑ Manyando, C; Njunju, EM; D'Alessandro, U; Van Geertruyden, JP (2013). "Safety and Efficacy of Co-Trimoxazole for Treatment and Prevention of Plasmodium falciparum Malaria: A Systematic Review" (PDF). PLoS ONE 8 (2): e56916. doi:10.1371/journal.pone.0056916. PMC 3579948. PMID 23451110.
  52. ↑ Agrawal, AK; Chang, PP; Feusner, J (January 2011). "Twice weekly Pneumocystis jiroveci pneumonia prophylaxis with trimethoprim-sulfamethoxazole in pediatric patients with acute lymphoblastic leukemia". Journal of Pediatric Hematology/Oncology 33 (1): e1–4. doi:10.1097/MPH.0b013e3181fd6fca. PMID 21102354.
  53. ↑ Safrin, S; Finkelstein, DM; Feinberg, J; Frame, P; Simpson, G; Wu, A; Cheung, T; Soeiro, R; Hojczyk, P; Black, JR (May 1996). "Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. ACTG 108 Study Group.". Annals of Internal Medicine 124 (9): 792–802. doi:10.7326/0003-4819-124-9-199605010-00003. PMID 8610948.
  54. ↑ Canessa, A; Del Bono, V; De Leo, P; Piersantelli, N; Terragna, A (February 1992). "Cotrimoxazole therapy of Toxoplasma gondii encephalitis in AIDS patients". European Journal of Clinical Microbiology and Infectious Diseases 11 (2): 125–130. doi:10.1007/BF01967063. PMID 1396726.
  55. ↑ Torre, D; Casari, S; Speranza, F; Donisi, A; Gregis, G; Poggio, A; Ranieri, S; Orani, A; Angarano, G; Chiodo, F; Fiori, G; Carosi, G (June 1998). "Randomized Trial of Trimethoprim-Sulfamethoxazole versus Pyrimethamine-Sulfadiazine for Therapy of Toxoplasmic Encephalitis in Patients with AIDS" (PDF). Antimicrobial Agents and Chemotherapy 42 (6): 1346–1349. PMC 105601. PMID 9624473.
  56. ↑ Muñoz, P; Arencibia, J; Rodríguez, C; Rivera, M; Palomo, J; Yañez, J; Bouza, E (April 2003). "Trimethoprim-Sulfamethoxazole as Toxoplasmosis Prophylaxis for Heart Transplant Recipients" (PDF). Clinical Infectious Diseases 36 (7): 932–933. doi:10.1086/368209. PMID 12652396.
  57. ↑ Béraud, G; Pierre-François, S; Foltzer, A; Abel, S; Liautaud, B; Smadja, D; Cabié, A (April 2009). "Cotrimoxazole for treatment of cerebral toxoplasmosis: an observational cohort study during 1994-2006" (PDF). The American Journal of Tropical Medicine and Hygiene 80 (4): 583–587. PMID 19346380.
  58. ↑ Alavi, SM; Alavi, L (September 2010). "Treatment of toxoplasmic lymphadenitis with co-trimoxazole: double-blind, randomized clinical trial" (PDF). International Journal of Infectious Diseases 14 (Supplement 3): e67–e69. doi:10.1016/j.ijid.2009.11.015. PMID 20194044.
  59. ↑ Patil, HV; Patil, VC; Rajmane, V; Raje, V (January 2011). "Successful treatment of cerebral toxoplasmosis with cotrimoxazole". Indian Journal of Sexually Transmitted Diseases 32 (1): 44–46. doi:10.4103/0253-7184.81255. PMC 3139289. PMID 21799577.
  60. ↑ Valeriano-Marcet, J; Spiera, H (August 1991). "Treatment of Wegener's granulomatosis with sulfamethoxazole-trimethoprim". Archives of Internal Medicine 151 (8): 1649–1652. doi:10.1001/archinte.1991.00400080133026. PMID 1872670.
  61. ↑ Stegeman, CA; Tervaert, JW; de Jong, PE; Kallenberg, CG (July 1996). "Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. Dutch Co-Trimoxazole Wegener Study Group" (PDF). New England Journal of Medicine 335 (1): 16–20. doi:10.1056/NEJM199607043350103. PMID 8637536.
  62. ↑ http://www.vademecum.es/medicamento-septrin+forte_3626
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