Cotrimoxazole (Septrin)

Cotrimoxazole (Septrin) is an approved antibiotic that consists of a mixture of two drugs, trimethoprim and sulphamethoxazole. Both drugs prevent bacteria from reproducing by preventing the production of folic acid (vitamin B9).

The tablet form of cotrimoxazole is most commonly used by people with HIV as prophylaxis against Pneumocystis pneumonia (PCP). It also offers a high level of protection against toxoplasmosis and bacterial infections.1 Cotrimoxazole may also be used to treat Shigella, urinary tract infections, isosporiasis and bronchitis. Intravenous cotrimoxazole is used for treating PCP, Shigella, Salmonella and severe or complicated urinary tract infections. Cotrimoxazole is also available as a suspension for children.

In resource-poor countries, cotrimoxazole can reduce the incidence of a range of opportunistic infections including pneumonia and isosporiasis, even in patients with tuberculosis.2 3 It also has an anti-malarial effect.4 In 2000, the World Health Organization recommended that all HIV-positive patients with CD4 cell counts below 500 cells/mm3 in sub-Saharan Africa take cotrimoxazole to prevent infections. Following a halving of death rates in a large randomised study in an area with high levels of resistance to the drug, this recommendation was modified in November 2004 to include all HIV-infected or -exposed children, until immune restoration has occurred or HIV-negativity is demonstrated.5 Some experts believe that all infected adults should also use the drug.6

In 2006, WHO reinforced this suggestion in a guideline document recommending cotrimoxazole prophylaxis for all infants exposed to HIV infection and all children and adults with CD4 cell counts less than 200cells/mm3. 7 All HIV-exposed infants born to mothers living with HIV must receive cotrimoxazole prophylaxis, starting at four to six weeks of age, or in their first encounter with the health care system, to be administered until the possibility of HIV infection is excluded.

Children from one to four years that are WHO clinical stages 2, 3, or 4 should be treated, regardless of CD4 percentage or any WHO stage and CD4 <25%. Children aged five and older follow adult recommendations.

Prophylaxis with cotrimoxazole should be discontinued if adverse reactions are experienced. Children with a history of grade 4 reactions to cotrimoxazole or other sulfa drugs and children with glucose-6-phosphate dehydrogenase deficiency should be offered dapson as an alternative prophylaxis.

If starting on ART, WHO recommends that cotrimoxazole prophylaxis start two weeks in advance. 

Cotrimoxazole can be used by HIV-positive pregnant women, since the risk of foetal abnormalities is low. In resource-limited settings, the benefits of cotrimoxazole in preventing other infections far exceeds the risk of birth defects.8

In July 1995, the United Kingdom Department of Health announced that cotrimoxazole’s licence was to be restricted since trimethoprim alone is just as effective, although the risk of severe side-effects seems to be similar for either treatment. However, cotrimoxazole remains the recommended drug for PCP and toxoplasmosis treatment and prophylaxis, as well as certain serious infections that are unresponsive to trimethoprim alone. In animal studies, trimethoprim alone is not effective against PCP.

Cotrimoxazole is excreted through the kidneys, so people who have kidney damage may have to take lower doses to avoid the risk of side-effects such as low blood sugar levels.9

The drug may decrease the effectiveness of oral contraceptives. The effectiveness of cotrimoxazole may also be reduced if it is taken alongside vitamin supplements containing folic acid.

Cotrimoxazole can cause a high level of side-effects, especially in the intravenous formulation. The most common reactions are rash, fever, nausea, low white blood cells and liver inflammation. Nausea may be reduced if the drug is taken with food. It should be taken with plenty of water.

Skin rashes due to cotrimoxazole are common among HIV-positive people. These should be taken seriously and treatment stopped or the dose reduced because some people can develop a potentially fatal allergy called Stevens-Johnson syndrome.

People who develop severe allergic reactions to cotrimoxazole appear to be at increased risk of rapid disease progression, for reasons that remain unclear.10 Gradually introducing the drug to the body, through dose escalation reduces the chance of an allergic reaction. These desensitisation regimens are designed to enable people who are allergic to cotrimoxazole to continue to take the drug without problems.

 In some cases, steroids can be given to reduce the allergic responses that can still occur during desensitisation, and some people require two or three attempts at the procedure before it succeeds. Research shows that desensitisation leads to fewer opportunistic infections.11 12

It is generally accepted that most of the side-effects from cotrimoxazole are caused by the sulphamethoxazole component rather than the trimethoprim. Inherited differences make some people more susceptible to this metabolite, possibly explaining why side-effects are more common among Caucasians than people of other ethnic backgrounds.13 14

Resistance to cotrimoxazole may develop, particularly among people who have previously taken the drug for treatment or prevention of PCP, and those who have used pyrimethamine with sulfadoxine (Fansidar) to prevent or treat malaria. Resistance to cotrimoxazole increases a person’s risk of death from PCP. However, people with low-level resistance may still benefit from cotrimoxazole therapy.15

References

  1. Edge MD et al. Community-acquired bacteremia in HIV-positive patients: protective benefit of co-trimoxazole. AIDS 10: 1635-1639, 1996
  2. Mermin J et al. Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV-infection in rural Uganda. Lancet 364: 1428-1434, 2004
  3. Wiktor SZ et al. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Cote d'Ivoire: a randomised controlled trial. Lancet 353: 1469-1475, 1999
  4. Thera M et al. Impact of trimethoprim-sulfamethoxazole prophylaxis on falciparum malaria infection and disease. J Infect Dis 192: 1823-1329, 2005
  5. Chintu C et al. Cotrimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial. Lancet 364: 1865-1871, 2004
  6. Mermin J et al. Should cotrimoxazole prophylaxis be taken by all adults with HIV in Africa? AIDS 19: 845-846, 2005
  7. World Health Organization Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults, Recommendations for a public health health approach. World Health Organization, Geneva, 1-68. Available online at www.who.int/hiv/pub/guidelines/WHO%20CTX.pdf, 2006
  8. Forna F et al. Systematic review of the safety of trimethoprim-sulfamethoxazole for prophylaxis in HIV-infected pregnant women: implications for resource-limited settings. AIDS Rev 8: 24-36, 2006
  9. Strevel EL et al. Severe and protracted hypoglycaemia is associated with co-trimxoazole use. Lancet Infect Dis 6: 178-182, 2006
  10. Veenstra J et al. Rapid disease progression in human immunodeficiency virus type 1-infected individuals with adverse reactions to trimethoprim-sulfamethoxazole prophylaxis. Clin Infect Dis 24: 936-941, 1997
  11. Bachmeyer C et al. Trimethoprim-sulfamethoxazole desensitisation in HIV-infected patients: an open study. AIDS 9: 299-300, 1995
  12. Theodore CM et al. Co-trimoxazole desensitization in HIV-seropositive patients. Int J STD AIDS 9: 158-161, 1998
  13. Pirmohamed M et al. Association anaylysis of drug metabolizing enzyme gene polymorphisms in HIV-positive patients with co-trimoxazole hypersensitivity. Pharmacogenetics 10: 705-713, 2000
  14. Pakianathan MR et al. Hypersensitivity reactions to high-dose co-trimoxazole in HIV-infected Malaysian and Scottish patients. AIDS 13: 1787, 1999
  15. Watera C et al. Feasibility and effectiveness of cotrimoxazole prophylaxis for HIV-1 infected adults attending an HIV / AIDS clinic in Uganda. J Acquir Immune Defic Syndr 42: 373-378, 2006