Trimethoprim-Sulfamethoxazole: In Vitro Microbiological Aspects

Abstract

The ultimate effect on bacteria of trimethoprim (TMP) and sulfamethoxazole (SMZ) is to deprive them of folate coenzymes; the spectra of in vitro activity of TMP and SMZ are therefore similar although TMP is usually 20–100 times more active than is SMZ. The synergy of TMP and SMZ can be demonstrated in vitro by increases in bacteriostatic and bactericidal activities. There is an optimal ratio for producing these effects, and it corresponds to the ratios of the MIC of each drug when acting alone; however, synergy does occur over a wide range of ratios. The in vitro activity of TMP-SMZ depends on the medium in which it is measured; traces of thymidine will almost completely abolish activity. The size of the inoculum also affects activity. The activity is not affected in vitro or in vivo by the presence of exogenous folates except in the case of Streptococcus faecalis. Resistance to one of the drugs as measured by conventional tests may not abolish synergy; synergy is maximal, however, when the organism is susceptible to both drugs. Multiple studies have confirmed that TMP-SMZ has a wide spectrum of in vitro activity. The only outstanding exception is Pseudomonas aeruginosa. From heavy inocula, resistance to TMP develops rapidly, but the rate is markedly reduced by the presence of SMZ. The retarding effects of the sulfonamide depend on the degree of susceptibility of the organism and become small with highly resistant strains. R-factors conferring resistance to TMP have been identified, although at present they are rare. Susceptibility testing presents no problems provided a suitable medium and a small inoculum are used. A single combined disk containing 1.25 µg of TMP and 23.75 µg of SMZ is adequate for routine tests.