Trimethoprim: laboratory and clinical studies

Abstract

SYNOPSIS Trimethoprim is a synthetic compound which arrests the step in bacterial purine synthesis immediately succeeding that interfered with by sulphonamides.Acting alone it inhibits the growth of a wide range of bacteria in generally much lower concentrations than sulphonamides. Its action with a sulphonamide is strongly synergic and bactericidal.Studies are described of suitable cultural conditions, methods of testing sensitivity, and acquired resistance.Some clinical results of its use are reported in respiratory tract infections, Gram-negative septicaemia, and urinary tract infections, and further therapeutic possibilities are discussed.

Do Sulphonamide-trimethoprim Combinations Select Less Resistance to Trimethoprim than the Use of Trimethoprim Alone?

“…Whilst the two drugs are said to act by sequential blockade (Darrell, Garrod and Waterworth, 1968), this is not necessarily the explanation for synergy (Webb, 1963;Poe, 1977). When a particular pathway is completely inhibited at a point along it, inhibitors acting at another point may not be able to increase the degree of inhibition.…”

“…After 25 subcultures of a light inoculum ofeach, increase of resistance was not detected but, with a heavy inoculum, each culture yielded resistant variants, most with normal colonial appearance. The virulence of resistant organisms selected by serial transfer in the presence of TMP is not known (Darrell et al, 1968;Breeze, Sims and Stacey, 1975;Grunberg and Beskid, 1977). These findings suggest that there are a few cells in a culture resistant to low concentrations of TMP; these in turn contain a minority of cells resistant to higher concentrations, so that with serial transfer highly resistant derivatives are obtained.…”

“…The biochemical mechanism of this resistance is not known, although it is known to be determined by a cluster of altered genes (Breeze et al, 1975). When a sulphonamide is incorporated into the medium in addition to TMP, the development of this resistance is inhibited (Darrell et al, 1968;Grunberg and Beskid, 1977). However, these manipulations may not represent events within patients treated with TMP and the nature of TMP resistance found in clinical isolates may differ from that in cultures exposed to TMP in vitro.…”

A haematological study of patients receiving long-term treatment with trimethoprim and sulphonamide

“…It has an antibacterial activity which has been established since it was first described by Roth, Falco, Hitchings, and Bushby (1962) and its use in this field is gaining in popularity with the advent of more recent studies (Drew, Hughes, Fowle, and Cassell, 1967a;Darrell, Garrod, and Waterworth, 1968).…”

Relationship between Acute Suppurative Otitis Media and Chronic Secretory Otitis Media: Role of Antibiotics

“…Trimethoprim is seldom used on its own by doctors in our area, but it is commonly used in the form of co-trimoxazole. The sulphonamide in this combination may potentiate the effect of trimethoprim (Darrell et al 1968).…”