Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed. Because it has a higher incidence of adverse effects, including allergic responses (see below), its use has been restricted in many countries to very specific circumstances where its improved efficacy has been 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. The global problem of advancing antimicrobial resistance has led to a renewed interest in the use of co-trimoxazole more recently.
Its use during pregnancy is contraindicated, although it has been placed in Australian and American pregnancy category C. 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 like spina bifida, cardiovascular malformations (e.g. Epstein's anomaly), urinary tract defects, oral clefts and club foot in epidemiological studies. 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). Animal studies have yielded similarly discouraging results. It is also excreted in breast-milk and hence nursing during treatment with co-trimoxazole is generally advised against.
Generally accepted treatment for shigellosis. 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.
Its use as a prophylactic treatment is supported by one clinical trial involving children with acute lymphoblastic leukaemia. Other than this and one other clinical trial into its efficacy as a treatment for pneumocystis pneumonia, data on its use in both the treatment and prevention of pneumocystis pneumonia is significantly lacking.
Antibacterials like dapsone (increases plasma levels of both drugs), methenamine (increased risk of crystalluria) and rifampicin (as it may lead to an increased plasma level of rifampicin and lower plasma levels of trimethoprim).
Anticoagulants like warfarin and acenocoumarol — anticoagulant effects of either drug is potentiated by this combination.
Antifolates like pyrimethamine, proguanil and methotrexate — increased risk of associated side effects like blood dyscrasis. Folic acid supplementation should be considered. There's a significant risk of megaloblastic anaemia with doses of pyrimethamine in excess of 25 mg/wk.
Antivirals, more specifically, lamivudine (increased plasma concentrations of lamivudine), zalcitabine (increased plasma concentrations of zalcitabine) and zidovudine (increased risk of haematological reactions).
Digoxin — increase in digoxin levels in a proportion of elderly patients.
Diuretics — elderly patients receiving thiazide antidiuretics are at a heightened risk for developing thrombocytopaenia while on co-trimoxazole.
Ciclosporin — patients that have received a kidney transplant and are receiving co-trimoxazole and ciclosporin concomitantly are at an increased risk of having a reversible deterioration in their kidney function.
Potassium aminobenzoate — effects of sulfonamides (like sulfamethoxazole) inhibited.
Laboratory tests; trimethoprim and sulfonamides have been reported to interfere with diagnostic tests, including serum-methotrexate and serum-plasma creatinine levels, also urea, urinary glucose and urobilinogen tests.
Alkalinisation of the urine may reduce the toxicity of sulfamethoxazole, but it may increase the toxic effects of trimethoprim.
Tetrahydrofolate synthesis pathway
The synergy between trimethoprim and sulfamethoxazole was first described in the late 1960s. 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.
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.
Trimethoprim serves as a competitive inhibitor of dihydrofolate reductase (DHFR), hence inhibiting the de novo synthesis of tetrahydrofolate, the biologically active form of folate.
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.
^Falagas ME, Grammatikos AP, Michalopoulos A (October 2008). "Potential of old-generation antibiotics to address current need for new antibiotics". Expert Rev Anti Infect Ther6 (5): 593–600. doi:10.1586/1478722.214.171.1243. PMID18847400.
^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". BJOG118 (11): 1374–1382. doi:10.1111/j.1471-0528.2011.03041.x. PMID21749628.
^ abcdefg"BACTRIM®" (PDF). TGA eBusiness Services. Roche Products Pty Limited. 18 September 2012. Retrieved 13 January 2014.
^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 Lancet364 (9443): 1428–1434. doi:10.1016/S0140-6736(04)17225-5. PMID15488218.
^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 Journal20 (3): 260–264. doi:10.1097/00006454-200103000-00009. PMID11303827.
^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 Medicine106 (2): 216–220. doi:10.7326/0003-4819-106-2-216. PMID3541724.
^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 Association263 (2): 257–261. doi:10.1001/jama.1990.03440020091039. PMID2403603.
^Nordin, et al., K; Hallander, H; Fredriksson, T; Rylander, C (1978). "A clinical and bacteriological evaluation of the effect of sulphamethoxazole-trimethoprim in acne vulgaris, resistant to prior therapy with tetracyclines". Dermatologica157 (4): 245–53. doi:10.1159/000250840. PMID150980.
^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 Therapy25 (2): 253–264. doi:10.1592/phco.126.96.36.199956. PMID15767239.
^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 Journal42 (2): 504–512. doi:10.1183/09031936.00114812. PMID23100498.
^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/Oncology33 (1): e1–4. doi:10.1097/MPH.0b013e3181fd6fca. PMID21102354.
^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 Medicine124 (9): 792–802. doi:10.7326/0003-4819-124-9-199605010-00003. PMID8610948.
^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 Diseases11 (2): 125–130. doi:10.1007/BF01967063. PMID1396726.
^Böhni E (1969). "Vergleichende bakteriologische untersuchungen mit der Kombination Trimethoprim/Sulfamethoxazole in vitro und in vivo". Chemotherapy14 (Suppl): Suppl:1–21. doi:10.1159/000220651. PMID4908562.
^Böhni E (1969). "Chemotherapeutic activity of the combination of trimethoprim and sulfamethoxazole in infections of mice". Postgrad Med J45 (Suppl): Suppl:18–21. PMID4902845.