|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 used in the treatment of a variety of bacterial infections. It consists of 1 part trimethoprim to 5 parts sulfamethoxazole.
The name co-trimoxazole is the British Approved Name. The drug has been marketed worldwide as generic preparations and under multiple trade names, including Septra (GSK) and Bactrim (Roche). 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. 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.
The British Commission on Human Medicines, a committee of the Medicines and Healthcare products Regulatory Agency (MHRA), recommends its use to treat or prevent the following conditions caused by susceptible organisms: lung infections, including pneumonia, caused by Pneumocystis jiroveci (previously known as Pneumocystis carinii); and infections caused by Toxoplasma (toxoplasmosis) organisms. It can also 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); and skin and soft tissue infections.
Trimethoprim/sulfamethoxazole is an agent with activity against both gram-positive and gram-negative organisms including:
- Infections caused by Listeria monocytogenes, Nocardia spp., Stenotrophomonas maltophilia (Xanthomonas maltophilia)
- Staphylococcus saprophyticus infections presenting as urinary tract infection or cystitis
- Staphylococcus aureus, including some methicillin-resistant strains
- Susceptible strains of Escherichia coli
- Whipple's disease
- Traveler's diarrhea
- Acne vulgaris.
Trimethoprim/sulfamethoxazole is used for 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 concern about the use of trimethoprim/sulfamethoxazole, 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, it creates an increased risk of kernicterus in the fetus during the last six weeks of pregnancy. Renal impairment, up to acute renal failure, and anuria have also been reported. These side effects are seen especially in the elderly and may be fatal. However, trimethoprim/sulfamethoxazole 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 trimethoprim/sulfamethoxazole, so unless new evidence is found to show that folinic acid is more effective than the cheaper folic acid, the latter will continue to be the preferred treatment. The trophoblasts in the early fetus are sensitive to changes in the folate cycle. A recent study has found a doubling in the risk of miscarriage in women exposed to trimethoprim in early pregnancy.
Trimethoprim/sulfamethoxazole may give rise to 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: 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, 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 for synergy to occur in vitro.
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.
Trimethoprim acts by interfering with the action of bacterial dihydrofolate reductase, inhibiting synthesis of tetrahydrofolic acid. Folic acid is an essential precursor in the de novo synthesis of the DNA/RNA nucleosides thymidine and uridine. Bacteria cannot take up folic acid from the environment (that is, from the infection host) and hence 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. The following list of brand names is incomplete:
- Bactrim, Bactrimel (Roche)
- Co-trimoxazole (Sandoz)
- Septrin (Aspen Pharmacare and formerly GlaxoSmithKline)
- Bactrom (Venezuela)
- Septram (Panama)
- Vactrim (manufactured and distributed in Laos)
- Bibactin (manufactured by PPM and distributed in Cambodia and some African countries)
- Graprima Forte Kaplet (manufactured by PT Graha Farma and distributed in Indonesia)
- Primotren (Lek in Slovenia and other countries).
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