Co-trimoxazole

Co-trimoxazole

File:Co-trimoxazole.JPG
Combination of
Trimethoprim	Dihydrofolate reductase inhibitor (16.7%)
Sulfamethoxazole	Sulfonamide antibiotic (83.3%)
Clinical data
Pregnancy category	AU: C US: C (Risk not ruled out)
Routes of administration	Oral
Legal status
Legal status	US: ℞-only
Identifiers
CAS Number	8064-90-2
ATC code	J01EE01 (WHO)
PubChem	CID 358641
ChemSpider	318412

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 bactericidal or bacteriostatic.

Synergistic action

The synergy between trimethoprim and sulphamethoxazole 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 (see diagram below).

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 sulphamethoxazole is 1:20, which is less than the 1:5 ratio needed in vitro for synergy to occur.

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Tetrahydrofolate synthesis pathway

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.

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. 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 in various settings more recently.

Specific indications for its use include:

HIV

Being an antibiotic, co-trimoxazole does not have any activity against HIV itself, but it is often prescribed to immunocompromised patients as Pneumocystis carinii pneumonia prophylaxis.

Bacterial

• infections caused by Listeria monocytogenes, Nocardia spp., Stenotrophomonas maltophilia (Zanthomonas maltophilia)
• Staphylococcus saprophyticus infections presenting as urinary tract infection or cystitis
• melioidosis
• shigellosis
• Whipple's disease
• traveller's diarrhea

Protozoan

• Isosporiasis
• prophylaxis of cerebral toxoplasmosis in HIV patients
• Cyclospora cayetanensis

Fungal

• treatment and prophylaxis of pneumonia caused by Pneumocystis jirovecii (formerly identified as P. carinii and commonly seen in immunocompromised patients including those suffering from cancer or HIV/AIDS)

Safety

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 (cholestatic hepatosis, hepatitis, liver necrosis, fulminant liver failure). 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 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 costlier Folinic acid, Folic acid will continue to be the preferred treatment method.

In some countries, co-trimoxazole has been withdrawn due to these toxic effects.

Thus the current British Committee on Safety of Medicines (CSM) guidelines recommend limiting its use to:

• 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

Trade names

Co-trimoxazole is manufactured and sold by many different companies. Some of the brand names are listed here, but this list is not complete.

• Bactrim®, Bactrimel® (Roche)
• Cotrim®
• Septrin®, Septra® (GlaxoSmithKline and formerly Burroughs Wellcome)
• Sulfatrim®
• Biseptol

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 0-85369-668-3
• briandeer.com Newspaper campaign over adverse events; 1994-

Footnotes

cs:Kotrimoxazol sk:Kotrimoxazol