Comparative Efficacy of High-Dose Daptomycin Monotherapy versus Combination Therapy for Daptomycin-Resistant Enterococcus faecium Endocarditis in a Rat Model

Chia-Jui Yang,1,2 Jann-Tay Wang,3 Jia-Ling Yang,3 Yu-Chung Chuang3 1Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan; 2School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 3Department of Internal Medicine, National Taiwan University Hospital, Taipei, TaiwanCorrespondence: Yu-Chung Chuang, Department of Internal Medicine, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei, 100, Taiwan, Tel +886-2-23123456 ext. 65054, Fax +886-2-23971412, Email [email protected]: 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).Methods: 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.Results: A strong correlation was observed between higher daptomycin exposure (Cmax/MIC and AUC0-24/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 log10 CFU/g). This was significantly lower than the bacterial load in the D90F group (5.62 log10 CFU/g; p = 0.02) and showed a trend towards superiority over the D90C group (5.87 log10 CFU/g; p = 0.05).Conclusion: 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.Plain Language Summary: Infections caused by Enterococcus faecium, a bacterium that is resistant to vancomycin and daptomycin, are very difficult to treat. These infections can affect the heart valves, leading to a serious illness called infective endocarditis. Because very few antibiotics work against this type of bacteria, doctors urgently need better treatment strategies.We carried out this study using rats with heart valve infections caused by a resistant strain of Enterococcus faecium. We tested two approaches: giving higher doses of daptomycin alone, or combining a standard dose of daptomycin with another antibiotic (either fosfomycin or ceftaroline).We found that using a higher dose of daptomycin on its own cleared bacteria from the heart valves more effectively than the combination treatments. The greater the drug exposure, the better the bacterial clearance.These findings suggest that increasing the amount of daptomycin may be more effective than combining it with other drugs in cases of daptomycin-resistant infections. This information could help guide future studies and eventually improve treatment for people with these difficult infections.Keywords: daptomycin, Enterococcus faecium, infective endocarditis, drug resistance, pharmacodynamics