MECHANISM OF SULFADIAZINE ENHANCEMENT OF TRIMETHOPRIM ACTIVITY AGAINST SULFADIAZINE-RESISTANT ENTEROCOCCUS-FAECALIS

Sulphadiazine had little or no antibacterial effect against three stra ins of Enterococcus faecalis (MICs of above 3600 mg/L) but it caused a pproximately six-fold increases in bacterial uptake of trimethoprim, i ncreased release of bacterial ATP and produced ultrastructural damage to both the trimethoprim resistant E. faecalis 463 and the trimethopri m sensitive NCTC 5957. MICs of trimethoprim were 0.6, 0.8 and 76.8 mg/ L for E. faecalis NCTC 775, NCTC 5957 and 463 respectively. When log p hase E. faecalis 463 and NCTC 5957 were grown for 4 h in trimethoprim 56 and 0.6 mg/L plus sulphadiazine 320 and 100 mg/L respectively there was an approximate ten-fold and nine-fold increase in uptake of sulph adiazine and a two-fold increase in leakage of ATP. Trimethoprim cause d more damage to the cell wall and cytoplasmic membrane than sulphadia zine but the combination of sulphadiazine plus trimethoprim caused the most cell damage. The increased activity observed with the combinatio n seems very likely to have resulted from the increased uptakes of the antibacterials, which in turn had resulted from the cell wall damage and consequent increased cell permeability caused by each antibacteria l. It is proposed that a markedly subinhibitory concentration of sulph adiazine enhanced the antibacterial activity of trimethoprim against a ll three strains of E. faecalis by this mechanism.