Co-trimoxazole

drugbox
type = combo
component1 = Trimethoprim
class1 = Dihydrofolate reductase inhibitor (20%)
component2 = Sulfamethoxazole
class2 = Sulfonamide antibiotic (80%)


CAS_number = 8064-90-2
ATC_prefix = J01
ATC_suffix = EE01
PubChem = 358641
DrugBank =
pregnancy_AU = C
pregnancy_US = C
pregnancy_category=
legal_AU =
legal_CA =
legal_UK =
legal_US = Rx-only
legal_status =
routes_of_administration = Oral

Co-trimoxazole (abbreviated SXT, TMP-SMX, TMP-SMZ or TMP-sulfa) is an sulphonamide, antibacterial 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 Septrin (GSK), Bactrim (Roche), and various generic preparations. Sources differ as to whether co-trimoxazole usually is bactericidal or bacteriostatic.

ynergistic action

Co-trimoxazole exhibits a theoretical, although perhaps not a clinical, [cite journal |author=Brumfitt W, Hamilton-Miller JM |title=Limitations of and indications for the use of co-trimoxazole | journal=J Chemother |year=1994 |month=Feb |volume=6 |issue=1 |pages=3–11 |pmid=8071675] synergistic antibacterial effect when compared to each of its components administered singly. This is because trimethoprim and sulfamethoxazole inhibit successive steps in the folate synthesis pathway (see diagram below). They did not exhibit synergistic effects, due to the requirement of a 1 in 5 ratio, which was observed in the laboratory. However, in clinical situations the ratio in the tissue was observed to be 1 in 20, resulting in no synergy.

Sulfamethoxazole acts as a false-substrate inhibitor of dihydropteroate synthetase. Sulfonamides such as sulfamethoxazole are analogues of "p"-aminobenzoic acid (PABA) and 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) 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.

Clinical indications

Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed. [cite journal |author=Brumfitt W, Hamilton-Miller JM |title=Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines | journal=J Chemother |year=1993 |month=Dec |volume=5 |issue=6 |pages=465–9 |pmid=8195839] 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. [cite journal |author= |title=Co-trimoxazole use restricted |journal=Drug Ther Bull |year=1995 |month=Dec | volume=33 |issue=12 |pages=92–3 |pmid=8777892 |url=|doi=10.1136/dtb.1995.331292] 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.

Specific indications for its use include: (Rossi, 2004)
*treatment and prophylaxis of pneumonia caused by "Pneumocystis jirovecii" (formerly identified as "P. carinii") (Commonly seen in immunocompromised patients including those suffering from HIV/AIDS)
*infections caused by "Listeria monocytogenes", "Nocardia" spp., "Stenotrophomonas maltophilia" ("Zanthomonas maltophilia")
*melioidosis
*shigellosis
*traveller's diarrhoea
*prophylaxis of cerebral toxoplasmosis in HIV patients
*Whipple's disease

afety

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, as well as severe liver damage (cholostatic hepatosis, hepatitis, liver necrosis, fulminant liver failure).Fact|date=September 2008 Due to displacement of bilirubin from albumin there is an increased risk of kernicterus in the newborn during the last 6 weeks of pregnancy. Also renal impairment up to acute renal failure and anuria has been reported. These side-effects are seen especially in the elderly and may be fatal. (Joint Formulary Committee, 2004).The folic acid is likely not the best option for the treatment of some adverse effects with associated with TMP-SMX, a better treatment is probably administration of folinic acid.Clarifyme|date=September 2008

In some countries, co-trimoxazole has been withdrawn due to these toxic effects.Fact|date=September 2008

Thus the current British Committee on Safety of Medicines (CSM) guidelines recommend limiting its use to:Fact|date=September 2008
*Pneumocystis pneumonia
*Toxoplasmosis and nocardiosis
*acute exacerbations of chronic bronchitis and infections of the urinary tract where there is good rationale for use
*acute otitis media in children where there is good rationale

References

* Rossi S, editor. Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook; 2004. ISBN 0-9578521-4-2.
* British National Formulary, 51st edition (April 20, 2006). London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2006. ISBN 0853696683
* [http://briandeer.com/bactrim-septra.htm briandeer.com] Newspaper campaign over adverse events; 1994-

Footnotes