Everything about Trimethoprim-sulfamethoxazole totally explained
Co-trimoxazole (abbreviated SXT, TMP-SMX, TMP-SMZ or TMP-sulfa) is an
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
Septrin (
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,
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 didn't 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 (for example 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. 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.
Specific indications for its use include: (Rossi, 2004)
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's 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
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's good rationale for use
acute otitis media in children where there's good rationaleFurther Information
Get more info on 'Trimethoprim-sulfamethoxazole'.
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