Trimethoprim/sulfamethoxazole, sold under the trade names Bactrim, Cotrim (a short form of the British Approved Name, Co-trimoxazole) and Septra, among others, is a fixed-dose combinationantibiotic medication used to treat a variety of bacterial infections.[6] It consists of one part trimethoprim to five parts sulfamethoxazole.It is used to treat urinary tract infections, methicillin-resistant Staphylococcus aureus (MRSA) skin infections, travelers' diarrhea, respiratory tract infections, and cholera, among others.[6] It is used both to treat and prevent pneumocystis pneumonia and toxoplasmosis in people with HIV/AIDS and other causes of immunosuppression.[6] It can be given orally (swallowed by mouth) or intravenous infusion (slowly injected into a vein with an IV).[6]
Trimethoprim/sulfamethoxazole is on the
World Health Organization's List of Essential Medicines
Trimethoprim/sulfamethoxazole generally kills bacteria, by blocking the microorganisms' ability to make and to use folate.[6]
Pneumocystis jirovecii pneumonia
Trimethoprim/sulfamethoxazole (TMP/SMX) is the medicine most commonly used to prevent Pneumocystis jirovecii pneumonia (PCP)[11] People who get Pneumocystis pneumonia have a medical condition that weakens their immune system, like HIV/AIDS, or take medicines (such as corticosteroid, monoclonal antibody and immunosuppressants) that reduce the body's ability to fight bacterial and viral infections.People with HIV/AIDS are less likely to get Pneumocystis pneumonia as a result of antiretroviral therapy (ART). However, Pneumocystis pneumonia is still a substantial public health problem. Most of what is scientifically known about Pneumocystis pneumonia and its treatment comes from studying people with HIV/AIDS.[11]
Susceptibility
Organisms against which trimethoprim/sulfamethoxazole can be effective include:[12]
The only notable nonsusceptible organisms are Pseudomonas aeruginosa, the mycoplasmae and Francisella tularensis (the causative organism of tularaemia).[13][14]
Acinetobacter spp.
Aeromonas spp.
Alcaligenes/Achromobacter spp.
Bartonella henselae
Bordetella pertussis (pertussis)
Pregnancy and breast feeding
Its use during pregnancy is contraindicated, although it has been placed in Australian pregnancy category C.[12] 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.[12] 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).[15][16] Animal studies have yielded similarly discouraging results.[2]
It appears to be safe for use during
Infants
Its use in those less than 2 months of age is not recommended due to the risk of adverse side effects.[18]
Adverse effects
Common side effects include nausea, vomiting, rash, and diarrhea.[6] Severe allergic reactions and Clostridioides difficile infection may occasionally occur.[6] Its use in pregnancy is not recommended.[6][17] It appears to be safe for use during breastfeeding as long as the baby is healthy.[17]
A recent study supported previous case reports that the treatment of teens or young adults with trimethoprim/sulfamethoxazole can cause serious adverse results.The study found that the 30-day risk of developing potentially lethal respiratory failure in patients aged 10 to 25 years who were treated with trimethoprim/sulfamethoxazole was significantly higher than those in this age group who were treated with either amoxicillin or a cephalosporin. These findings supported the FDA warning on using trimethoprim/sulfamethoxazole. Overall, the study suggested that this risk of respiratory failure should be carefully weighed against the benefits of using this trimethoprim/sulfamethoxazole drug combination in individuals 10 to 25 years old.[19]
Antiarrhythmics like amiodarone (increased risk of ventricular arrhythmias) and dofetilide (increased risk of QT interval prolongation)
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
Sulfonylureas — effects enhanced
Phenytoin, half-life of phenytoin is increased
Antifolates like pyrimethamine, proguanil and methotrexate increase the risk of associated side effects like bone marrow toxicity, folic acid supplementation should be considered. A significant risk of megaloblastic anaemia exists 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)
Procainamide and/or amantadine may have their plasma concentrations increased bilaterally or unilaterally.
Clozapine and other antipsychotics — increased risk of haematological side effects
Nucleoside analogue antineoplastics like azathioprine and mercaptopurine — increased risk of haematological toxicity
Digoxin — increase in digoxin levels in a proportion of elderly patients
Diuretics — elderly patients receiving thiazide diuretics are at a heightened risk for developing thrombocytopaenia while on co-trimoxazole
Ciclosporin — patients who 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.
Spironolactone — concurrent use can increase the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron.[22]
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 elevated serum creatinine levels,[23] also urea, urinary glucose and urobilinogen tests.
The recommended treatment for overdose includes:[2]Alkalinisation of the urine may reduce the toxicity of sulfamethoxazole, but it may increase the toxic effects of trimethoprim.[2]
Nausea
Vomiting
Dizziness
Headache
Mental depression
Confusion
Thrombocytopenia
Uremia
Pharmacology
The synergy between trimethoprim and sulfamethoxazole was first described in the late 1960s.[24][25][26] 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.
Tetrahydrofolate is crucial in the synthesis of purines, thymidine, and methionine which are needed for the production of DNA and proteins[27] during bacterial replication.
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.
Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed.[28][29]
Society and culture
Legal status
Brand names
Trimethoprim/sulfamethoxazole may be abbreviated as SXT, SMZ-TMP, TMP-SMX, TMP-SMZ, or TMP-sulfa. The generic British Approved Name (BAN) Co-trimoxazole is used for trimethoprim/sulfamethoxazole manufactured and sold by many different companies.[67]
The following list of brand names is incomplete:
Bactrim, Bactrimel (manufactured by Roche and distributed in Europe)
Bactrom (Venezuela)
Bibactin (manufactured by PPM and distributed in Cambodia and some African countries)
Biseptol
Sumetrolim
Co-trimoxazole (used as generic UK name)
Cotrim
Deprim (AFT Pharmaceuticals)
Diseptyl (Israel)
Graprima Forte Kaplet (manufactured by PT Graha Farma and distributed in Indonesia)
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