| Combination of | |
|---|---|
| Trimethoprim | Dihydrofolate reductase inhibitor (16.7%) |
| Sulfamethoxazole | Sulfonamide antibiotic (83.3%) |
| Clinical data | |
| Trade names | Bactrim, Bactrimel, Biseptol, Co-trimoxazole, Cotrim, Septrin, Septra, Sulfatrim, Trisul |
| Pregnancy cat. | C(AU) C(US) |
| Legal status | ℞-only (US) |
| Routes | Oral |
| Identifiers | |
| CAS number | 8064-90-2 |
| ATC code | J01EE01 |
| PubChem | CID 358641 |
| ChemSpider | 318412 |
| (what is this?) (verify) |
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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 various generic preparations. Sources differ as to whether co-trimoxazole usually is a bactericide or a bacteriostatic agent.
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Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed.[1] 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.[2] 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 in various settings more recently.[3]
The current British Committee on Safety of Medicines (CSM) guidelines recommend limiting its use to:
Specific indications for its use include:
Being an antibiotic, co-trimoxazole does not have any activity against HIV itself, but it is often prescribed to immunocompromised patients as Pneumocystis jirovecii pneumonia prophylaxis.
There has been some concern about its use, however, since it has been associated with both frequent mild allergic reactions and serious adverse effects, including Stevens–Johnson syndrome, myelosuppression, mydriasis, agranulocytosis, and severe liver damage (cholestatic hepatosis, hepatitis, liver 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. (Joint Formulary Committee, 2004). Both 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:[5]
The synergy between trimethoprim and sulfamethoxazole was first described in a series of in vitro and in vivo experiments published in the late 1960s.[6][7][8] 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 (see diagram below).
It is unclear whether this synergy occurs at doses used in humans,[9] because, at the concentrations seen in blood and tissues, the ratio of trimethoprim to sulfamethoxazole is 1:20,[10] 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.
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 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, but this list is not complete.
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