Trimethoprim

Trimethoprim is a dihydrofolate reductase inhibitor, inhibiting the conversion of bacterial dihydrofolic acid to tetrahydrofolic acid, required for the synthesis of some amino acids. Its effects are considerably greater on the cells of micro-organisms than on the mammalian cells.

In vitro trimethoprim has effect on most Gram-positive and Gram-negative aerobic organisms, including enterobacteria such as E. Coli, Proteus, Klebsiella pneumoniae, Streptococcus faecalis, Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus.

It has no effect on Mycobacterium tuberculosis, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Treponema pallidum, Brucella abortis or anaerobic bacteria.

Mechanisms of resistance

Resistance to trimethoprim may be due to several mechanisms. Clinical resistance is often due to plasmid mediated dihydrofolate reductases that are resistant to trimethoprim: such genes may become incorporated into the chromosome via transposons. Resistance may also be due to overproduction of dihydrofolate reductase, changes in cell permeability, or bacterial mutants which are intrinsically resistant to trimethoprim because they depend on exogenous thymidine and thymine for growth. Emergence of resistance to trimethoprim does not appear to be any higher in areas where it is used alone than in areas where trimethoprim is used in combination with sulphonamides. Nonetheless, trimethoprim resistance has been reported in many species, and very high frequencies of resistance have been seen in some developing countries, particularly among Enterobacteriaceae.

Breakpoints

EUCAST clinical MIC breakpoints to separate susceptible (S) pathogens from resistant (R) pathogens are:

^* The activity of trimethoprim is uncertain against enterococci. Hence the wild type population is categorized as intermediate.

Breakpoints for S. pneumoniae and H. Influenzae are not defined.

Trimethoprim is readily absorbed from the gastro-intestinal tract and peak concentrations in the circulation occur about 3 hours after a dose is taken. It is bound to plasma proteins. Tissue concentrations are reported to be higher than serum concentrations with particularly high concentrations occurring in the kidneys and lungs but concentrations in the cerebrospinal fluid are about one half of those in the blood.

About 40 to 50% of a dose is excreted in the urine within 24 hours mainly as unchanged drug, hence patients with impaired renal function, such as the elderly, may require a reduction in dosage due to accumulation. It appears in breastmilk. Urinary concentrations are generally well above the MIC of common pathogens for more than 24 hours after the last dose.

Not relevant.