Antagonistic interaction of rifampicin and trimethoprim

Measurements of the steady-state inhibition of specific growth rates by rifampicin and trimethoprim, alone and in combination, showed that these two agents are antagonistic in the inhibition of Klebsiella aerogenes and Streptococcus faecalis. Previous studies, in which inhibition was measured by methods involving relatively long periods of incubation, have shown apparent synergism between rifampicin and trimethoprim in the inhibition of S. faecalis and other bacteria. Populations of S. faecalis contained, at a frequency of about 2×10−5, cells resistant to low concentrations of rifampicin. Such cells were produced with a mutation rate of 1.1×10−5 per cell division. Mutation to low resistance was independent of mutation to high resistance. The concentration of rifampicin required for 50% inhibition of specific growth rate was about 20-fold higher for the mutants than for the parent strain, though both showed the same sensitivity to trimethoprim. Cultures grown from a low inoculum in the presence of low concentrations of rifampicin consisted of more than 90% low-resistance mutants after incubation for 16 h. Addition of trimethoprim to cultures containing rifampicin suppressed the growth of the mutant cells, thus producing the apparent synergism. Tetracycline and chloramphenicol were found to interact independently with rifampicin in the inhibition of specific growth rate of S. faecalis. It is concluded that if the use of rifampicin in combination with a second antibiotic is desirable, the second antibiotic should not be trimethoprim but an inhibitor of protein synthesis such as tetracycline.