In Vitro and In Vivo Studies of Oritavancin and Fosfomycin Synergism against Vancomycin-Resistant Enterococcus...

Area of Science:

• Infectious Diseases
• Microbiology
• Pharmacology

Background:

• Vancomycin-resistant enterococci (VRE) infections pose a significant therapeutic challenge due to limited effective treatment options.
• Combination therapies are being explored to overcome antimicrobial resistance, leveraging synergistic drug interactions.

Purpose of the Study:

• To evaluate the in vitro and in vivo efficacy of the combination of oritavancin and fosfomycin against clinical isolates of vancomycin-resistant Enterococcus faecium.
• To assess the synergistic potential and impact on drug susceptibility, biofilm formation, and treatment outcomes in a preclinical model.

Main Methods:

• In vitro susceptibility testing (checkerboard, time-kill assays) and biofilm assays were performed on clinical VRE isolates.
• In vivo efficacy was evaluated using the Galleria mellonella infection model to assess survival rates with combination therapy versus monotherapy.

Main Results:

• The oritavancin + fosfomycin combination demonstrated synergistic effects in 80% of VRE isolates and restored fosfomycin susceptibility in 85% of resistant strains.
• Combination therapy significantly reduced bacterial load compared to monotherapy and prevented regrowth in time-kill assays.
• Synergistic or additive effects were observed in biofilm assays, and in vivo studies showed improved survival rates in Galleria mellonella larvae.

Conclusions:

• The combination of oritavancin and fosfomycin exhibits potent synergistic activity against VRE, including resistant strains and biofilms.
• Preclinical data strongly support the clinical investigation of oritavancin and fosfomycin combination therapy for treating VRE bloodstream infections in humans.