Susceptibility of enterococci to trimethoprim and trimethoprim-sulfamethoxazole

Abstract

The in vitro activities of trimethoprim (TMP), alone and in combination with sulfamethoxazole (SMX), against 131 clinical isolates of enterococci, 126 Streptococcus faecalis isolates, and 5 Streptococcus faecium isolates were determined by a broth microdilution method with Mueller-Hinton broth that was substantially free of inhibitory substances. The geometric mean MIC of TMP for strains of S. faecalis was 0.164 ,g/ml (range, 0.03 to 8 ,g/ml), with a geometric mean MBC of 0.298 ,ug/ml (range, 0.063 to 8 ,ug/ml). Although all strains were resistant to the sulfonamide alone, the inhibitory and bactericidal activities of TMP against strains of S. faecalis were markedly potentiated when TMP was combined in a fixed ratio of 1:19 with SMX; the geometric mean MIC of TMP was reduced to 0.016 ,ug/ml (range, 0.002 to 0.25 ,ug/ml), with a geometric mean MBC of 0.031 ,ug/ml (range, 0.004 to 0.25 ,g/ml). The combination had no synergistic effect against strains of S. faecium; the geometric mean MICs and MBCs of both agents were ca. 0.06 ,ug/ml. The MBC/MIC ratios for TMP and TMP-SMX were .16 for all 131 strains. MICs and MBCs for TMP-SMX were unchanged, and for TMP they decreased when performed in broth supplemented with 50% heat-inactivated pooled human serum. For TMP ind TMP-SMX, the susceptibilities of isolates with high-level resistance to gentamicin or streptomycin were the same as those of isolates pusceptible to <2,000 ,ug of aminoglycoside per ml. These results suggest that tMP-SMX and TMP alone could prove useful in the treatment of serious enterococcal infections, including infections by strains with high-level resistance to aminoglycosides.The enterococci are important pathogens in endocarditis and urinary tract infections and are frequently isolated from polymicrobial infections (11). Because currently used antibiotics are not bactericidal against most strains of enterococci at concentrations readily achievable in the serum, optimal therapy for serious or deep-seated enterococcal infection includes the addition of an aminoglycoside to penicillin, ampicillin, or vancomycin for synergistic, bactericidal activity (20). The combination of a cell wall-active agent plus an atninoglycoside, however, is not synergistic against all strains of enterococci; these strains usually exhibit high-level resistance (MIC, >2,000 ,ug/ml) to the aminoglycoside (4), Recent studies have described clinical isolates of enterococci possessing high-level resistance to all currently available aminoglycosides (14, 15). The optimal therapy for serious infections caused by these strains is unknown.Trimethoprim (TMP) and the fixed-ratio combination of TMP and sulfamethoxazole (SMX) are effective against a broad spectrum of gram-negative and -positive organisms (1). The activities of these agents against enterococci, however, have varied subMtantially among different studies (2,5,12,18,24). These inconsistencies are due primarily to inhibitory substances present within the media that enable many species of bacteria to escape the action of TMP a...

The epidemiology of enterococci

“…Most strains of enterococci are resistant to tetracycline, erythromycin, clindamycin, chloramphenicol and sutfonamides (15,23). Many strains are reported as sensitive to trimethoprim/sulfamethoxazole but this probably represents an in vitro phenomenon, since enterococci have been shown to escape the action of trimethoprim/sulfamethoxazole on addition of folinic acid (24,25,26). Vancomycin and teicoplanin, while highly active against enterococci, are not consistently bactericidal (27,28).…”

Trimethoprim resistance

“…Although TMP does not completely inhibit the growth of chlamydiae in vitro, chlamydial inclusion bodies are abnormally small and reduced in number (37). The antifolate agents appear to be ineffective in the treatment of enterococcal infections, despite the susceptibility in vitro to TMP and the combination of TMP-sulfonamide (20,32,36,93). TMP in combination with sulfonamides is not bactericidal against enterococci, despite the inhibition of growth at low drug concentrations (61).…”

Antibiotic treatment of enterococcal infections

“…dence (1,4). I would therefore be particularly concerned about using trimethoprim-sulfamethoxazole when bactericidal therapy is indicated.…”