Co-trimoxazole

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

Co-trimoxazole exhibits a theoretical, although perhaps not a clinical,^[1] 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.

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 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.^[2] 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.^[3] 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:

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^[4]
• prophylaxis of cerebral toxoplasmosis in HIV patients

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 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 (cholostatic 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 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 associated with TMP-SMX; a better treatment is probably administration of folinic acid.

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

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
• briandeer.com Newspaper campaign over adverse events; 1994-