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|Trimethoprim||Dihydrofolate reductase inhibitor (16.7%)|
|Sulfamethoxazole||Sulfonamide antibiotic (83.3%)|
|Trade names||Bactrim, Bactrimel, Biseptol, Co-trimoxazole, Cotrim, Septrin, Septra, Sulfatrim, Trisul|
|Pregnancy cat.||C (AU) C (US)|
|Legal status||℞-only (US)|
| (what is this?)
Trimethoprim/sulfamethoxazole or co-trimoxazole (abbreviated SXT, TMP-SMX, TMP-SMZ or TMP-sulfa) is a sulfonamide 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 British Approved Name and has been marketed worldwide under many trade names including Septra (GSK), Bactrim (Roche), and generic preparations. Opinions differ as to whether co-trimoxazole is a bactericidal or a bacteriostatic agent.
Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed. Along with its associated greater incidence of adverse effects including 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. The global problem of advancing antimicrobial resistance has led to a renewed interest in the use of co-trimoxazole more recently.
The British Commission on Human Medicines of the Medicines and Healthcare products Regulatory Agency (MHRA) recommends it can be used to treat or prevent these conditions caused by susceptible organisms:
- lung infections, including pneumonia, caused by Pneumocystis jiroveci (previously known as Pneumocystis carinii)
- infections caused by Toxoplasma (toxoplasmosis) organisms.
It can be used to treat:
- Bladder or urinary tract infections
- Lung infections, such as bronchitis
- Ear infections, such as otitis media
- Nocardiosis, an infection that can affect the lungs, skin and brain.
The following infections have been treated with co-trimoxazole:
- Infections caused by Listeria monocytogenes, Nocardia spp., Stenotrophomonas maltophilia (Xanthomonas maltophilia)
- Staphylococcus saprophyticus infections presenting as urinary tract infection or cystitis
- Susceptible strains of Escherichia coli
- Whipple's disease
- Traveler's diarrhea
- Acne vulgaris
- Treatment and prophylaxis of pneumonia caused by the yeast-like fungus Pneumocystis jirovecii (formerly identified as P. carinii and commonly seen in immunocompromised patients including those suffering from cancer or HIV/AIDS).
There has been some concern about Trimethoprim/sulfamethoxazole's use, however, since it has been associated with frequent mild allergic reactions and serious adverse effects, including Stevens–Johnson syndrome, myelosuppression, mydriasis, agranulocytosis, and severe liver damage (cholestatic hepatosis, hepatitis, necrosis, and fulminant liver failure). Due to displacement of bilirubin from albumin, there is an increased risk of kernicterus in the fetus during the last six weeks of pregnancy. Also, renal impairment up to acute renal failure and anuria have been reported. These side effects are seen especially in the elderly and may be fatal. However, TMP-SMX may elevate creatinine without causing renal damage. This elevation occurs through the inhibition of the tubular secretion of creatinine by the trimethoprim component. Folic acid and folinic acid were found equally effective in reducing the adverse effects of TMP-SMX, so unless new evidence is found for folinic acid that shows it is more effective than the cheaper folic acid, the latter will continue to be the preferred treatment method.
Trimethoprim/sulfamethoxazole may have the following adverse reactions:
- Allergic – Stevens–Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angiodema, drug fever, chills, Henoch–Schönlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria and rash. In addition, periarteritis nodosa and systemic lupus erythematosis have been reported.
- Endocrine – The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides), and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides.
- Gastrointestinal – Hepatitis, including cholestatic jaundice and hepatic necrosis, elevation of serum transaminase and bilirubin, pseudo-membranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, constipation, anorexia.
- Genitourinary – Renal failure, interstitial nephritis, BUN and serum creatinine elevation NOT associated with renal damage, toxic nephrosis with oliguria and anuria, and crystalluria.
- Hematologic – Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrominemia, methemoglobinemia, eosinophilia.
- Metabolic – Hyperkalemia, hyponatremia.
- Musculoskeletal – Arthralgia and myalgia.
- Neurologic – Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, permanent tinnitus, headache.
- Psychiatric – Hallucinations, depression, apathy, nervousness.
- Respiratory System – Cough, shortness of breath, and pulmonary infiltrates.
- Miscellaneous – Weakness, fatigue, insomnia.
Mechanism of action
The synergy between trimethoprim and sulfamethoxazole was first described in a series of in vitro and in vivo experiments published in the late 1960s. Trimethoprim and sulfamethoxazole have a greater effect when given together than when given separately; the reason is because they inhibit successive steps in the folate synthesis pathway.
It is unclear whether this synergy occurs at doses used in humans, because, at the concentrations seen in blood and tissues, the ratio of trimethoprim to sulfamethoxazole is 1:20, which is less than the 1:5 ratio needed in vitro for synergy to occur.
Sulfamethoxazole acts as a false-substrate inhibitor of dihydropteroate synthetase. Sulfonamides such as sulfamethoxazole are analogues of p-aminobenzoic acid (PABA) and, thus, are competitive inhibitors of the enzyme, inhibiting the production of dihydropteroic acid.
Folic acid is an essential precursor in the de novo synthesis of the DNA/RNA nucleosides thymidine and uridine. Bacteria are unable to take up folic acid from the environment (i.e., the infection host) and, 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.
Co-trimoxazole is manufactured and sold by many different companies. Some of the brand names are listed here; this list is not complete.
- Bactrim, Bactrimel (Roche)
- Co-trimoxazole (Sandoz)
- Septrin, Septra (GlaxoSmithKline and formerly Burroughs Wellcome)
- Vactrim (Manufactured and distributed in the country of Laos)
- Bibactin (Manufactured by PPM and distributed in the country of Cambodia and some others African countries)
- Graprima Forte Kaplet (Manufactured by PT Graha Farma, distributed in the country of Indonesia)
- Primotren (Lek (pharmaceutical company) in Slovenia and other countries)
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- briandeer.com Newspaper campaign over adverse events; 1994-