In vivo daptomycin efficacy against experimental vancomycin-resistant Enterococcus faecium endocarditis

Area of Science:

• Infectious Diseases
• Pharmacology
• Microbiology

Background:

• Daptomycin is a first-line treatment for vancomycin-resistant Enterococcus faecium infective endocarditis (IE).
• Optimal daptomycin dosing, especially for strains with minimum inhibitory concentrations (MICs) near the susceptibility breakpoint (4 mg/L), remains under investigation.

Purpose of the Study:

• To evaluate the efficacy of two daptomycin doses (8 mg/kg and 12 mg/kg) in a rabbit model of IE caused by Enterococcus faecium.
• To assess the emergence of daptomycin-resistant mutants under different dosing regimens.

Main Methods:

• A rabbit model of aortic valve IE was established using Enterococcus faecium strains with daptomycin MICs of 2 mg/L (Aus0004) and 4 mg/L (Mut4).
• Rabbits received daptomycin at 8 mg/kg (DAP8) or 12 mg/kg (DAP12), or were untreated (controls).
• Treatment commenced 48 hours post-inoculation and lasted for 5 days, with subsequent analysis of vegetation bacterial load and resistance.

Main Results:

• DAP12 was significantly more effective than DAP8 against the wild-type strain (MIC 2 mg/L), leading to lower bacterial loads and sterile vegetations.
• Both DAP8 and DAP12 showed limited efficacy against the strain with a 4 mg/L MIC (Mut4), with no significant difference between doses.
• Daptomycin-resistant mutants emerged in a substantial proportion of rabbits treated with both DAP8 and DAP12, particularly with the Mut4 strain.

Conclusions:

• The 12 mg/kg daptomycin dose is the most effective strategy against IE caused by wild-type vancomycin-resistant Enterococcus faecium.
• Monotherapy with daptomycin at 8 mg/kg or 12 mg/kg is poorly effective for IE strains with a 4 mg/L MIC, increasing the risk of resistance.
• Reevaluation of the daptomycin susceptibility breakpoint for enterococci is warranted.