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Bactericidal and inhibitory activity of quinupristin/dalfopristin against vancomycin- and gentamicin-resistant
R L Hill1, C T Smith, M Seyed-Akhavani
1Joint Microbiology Research Unit, Dulwich Public Health Laboratory & Medical Microbiology, King's College School of Medicine and Dentistry, London, UK.
Abstract:
There is a need for new agents, or combinations of agents, for the treatment of infections caused by vancomycin- and gentamicin-resistant Enterococcus faecium (VGREF) that may be resistant to all available antimicrobial agents. The early in-vitro activity of quinupristin/dalfopristin (30:70)--an injectable streptogramin--encouraged us to test this agent against VGREF. By broth dilution, the MICs of quinupristin/dalfopristin against 38 isolates of VGREF ranged from 0.06 mg/L to 2.0 mg/L (mode 0.12 mg/L). The addition of 0.5 mg/L of ciprofloxacin significantly reduced the modal MIC of quinupristin/dalfopristin to 0.015 mg/L (P = 5.75 x 10(-8)). Although the addition of 8.0 mg/L of teicoplanin or 4 mg/L of tetracycline did not significantly reduce the modal MIC, the lowest concentration of the MIC range was reduced from 0.06 to 0.015 mg/L. In broth, quinupristin/dalfopristin had slow bactericidal activity against the four strains tested over 48 h, with a 1-2 log10 cfu/mL reduction after 24 h in > 1 mg/L of quinupristin/dalfopristin for two strains and > 8 mg/L for the two other strains. A mixture of quinupristin/dalfopristin in a 70:30 ratio was more bactericidal: against one of the four strains 4-32 mg/L of the combination produced a further 0.5-1.0 log10 reduction in cfu/mL after 24 h and there was a reduction of 6.0 log10 cfu/mL after 48 h for another. By ultracentrifugation, the binding of 32 mg/L quinupristin/dalfopristin to human plasma protein was 90%, and in plasma broth, 32 mg/L of quinupristin/dalfopristin maintained bacteriostatic but not bactericidal activity. There is some useful synergy with ciprofloxacin and tetracycline, and the activity of quinupristin/dalfopristin may be enhanced against some strains by reversing the concentrations of its two components, quinupristin and dalfopristin, as that may occur in vivo.
Insights
New research shows quinupristin/dalfopristin effectively treats vancomycin- and gentamicin-resistant Enterococcus faecium (VGREF). Combining it with ciprofloxacin significantly enhances its antimicrobial activity against these challenging infections.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Emergence of vancomycin- and gentamicin-resistant Enterococcus faecium (VGREF) poses a significant challenge due to limited treatment options.
- The need for novel antimicrobial agents or combinations is critical to combat multidrug-resistant pathogens.
Purpose of the Study:
- To evaluate the in vitro activity of quinupristin/dalfopristin against VGREF isolates.
- To investigate the synergistic effects of quinupristin/dalfopristin in combination with other antimicrobial agents.
Main Methods:
- Broth microdilution assays were employed to determine minimum inhibitory concentrations (MICs).
- Checkerboard assays and time-kill studies assessed synergistic activity and bactericidal/bacteriostatic effects.
- Human plasma protein binding was evaluated using ultracentrifugation.
Main Results:
- Quinupristin/dalfopristin exhibited MICs ranging from 0.06 to 2.0 mg/L against 38 VGREF isolates (modal MIC 0.12 mg/L).
- Ciprofloxacin (0.5 mg/L) significantly reduced the modal MIC to 0.015 mg/L (P = 5.75 x 10(-8)).
- Synergistic activity was observed with ciprofloxacin and tetracycline, enhancing bactericidal effects, particularly at reversed component ratios.
Conclusions:
- Quinupristin/dalfopristin demonstrates promising in vitro activity against VGREF.
- Combination therapy, especially with ciprofloxacin, offers a potential strategy to overcome resistance.
- Further investigation into optimal dosing and in vivo efficacy is warranted.