Comparative Efficacy of High-Dose Daptomycin Monotherapy versus Combination Therapy for Daptomycin-Resistant...

Infections caused by daptomycin-resistant and vancomycin-resistant Enterococcus faecium (DRE) are a critical clinical challenge with limited therapeutic options. This study aimed to compare the efficacy of high-dose daptomycin monotherapy against combination therapies in a rat model of DRE infective endocarditis (IE).

A clinical DRE isolate (daptomycin MIC, 8 mg/L) was used to establish IE in Wistar rats. After 48  h, the animals were randomized to three-day regimens: saline control, daptomycin 90 mg/kg/day s.c. (D90), daptomycin 125 mg/kg/day s.c. (D125), D90 plus fosfomycin 500 mg/kg/day i.p. (D90F), or D90 plus ceftaroline 40 mg/kg q8 h i.m. (D90C). Efficacy was evaluated by quantifying colony-forming units (CFU) in excised cardiac vegetation.

A strong correlation was observed between higher daptomycin exposure (Cmax/MIC and AUC_{0 -2 4}/MIC) and lower vegetation bacterial density (p < 0.01 for both). High-dose daptomycin monotherapy (D125) was the most effective regimen, resulting in the lowest mean vegetation bacterial load (4.75 log_{1 0} CFU/g). This was significantly lower than the bacterial load in the D90F group (5.62 log_{1 0} CFU/g; p = 0.02) and showed a trend towards superiority over the D90C group (5.87 log_{1 0} CFU/g; p = 0.05).

In this severe DRE infection model, escalating the daptomycin dose was more effective in clearing bacteria from the cardiac vegetation than combining a standard high dose with a synergistic agent. These findings suggest that higher daptomycin exposure may be a viable strategy for managing DRE infections, pending clinical validation.