Drug repurposing constitutes a strategy to combat antimicrobial resistance, by using agents with known safety, pharmacokinetics, and pharmacodynamics. Previous studies have implemented new fusidic acid (FA) front-loading-dose regimens, allowing higher serum levels than those achievable with ordinary doses. As susceptibility breakpoints are affected by serum level, we evaluated the repurposing of FA as an antimicrobial product against enterococci. FA minimum inhibitory concentrations (MICs) against standard enterococci strains; Enterococcus faecalis ATCC 29212 and Enterococcus faecium ATCC 27270 were 2 and 4 µg/mL, respectively. The MIC against 98 enterococcal clinical isolates was ≤ 8 µg/mL; all would be susceptible if categorized according to recalculated breakpoints (≥ 16 µg/mL), based on the serum level achieved using the front-loading regimen. FA administration in vivo, using the BALB/c mouse infection model, significantly reduced bacterial burden by two to three log₁₀ units in the liver and spleen of mice infected with vancomycin-susceptible and -resistant strains. Exposure of the standard enterococcal strains to increasing, but not fixed, FA concentrations resulted in resistant strains (MIC = 128 µg/mL), with thicker cell walls and slower growth rates. Only one mutation (M651I) was detected in the fusA gene of the resistant strain derived from serial passage of E. faecium ATCC 27270, which was retained in the revertant strain after passage in the FA-free medium. In conclusion, FA can be repurposed as an antimicrobial drug against enterococci with a low probability of mutational resistance development, and can be employed for treatment of infections attributable to vancomycin-resistant enterococci.

药物再利用是一种通过使用已知安全性、药代动力学和药效学的药物来对抗抗菌素耐药性的策略。先前的研究已经实施了新的夫西地酸（FA）前负荷剂量方案，允许比普通剂量可达到的血清水平更高。由于敏感性断点受血清水平影响，我们评估了 FA 作为肠球菌抗菌产品的重新用途。 FA 对标准肠球菌菌株的最低抑菌浓度 (MIC)；粪肠球菌ATCC 29212 和屎肠球菌ATCC 27270 分别为 2 和 4 µg/mL。针对 98 种肠球菌临床分离株的 MIC ≤ 8 µg/mL；如果根据使用前装方案达到的血清水平重新计算的断点（≥ 16 µg/mL）进行分类，则所有这些都将易受影响。使用 BALB/c 小鼠感染模型进行体内 FA 给药，可将感染万古霉素敏感菌株和耐药菌株的小鼠肝脏和脾脏中的细菌负荷显着减少 2 至 3 log ₁₀个单位。将标准肠球菌菌株暴露于不断增加但不固定的 FA 浓度会产生耐药菌株 (MIC = 128 µg/mL)，其细胞壁较厚，生长速度较慢。屎肠球菌ATCC 27270连续传代衍生的抗性菌株的fus A 基因中仅检测到一个突变 (M651I) ，该突变在无 FA 培养基中传代后保留在回复菌株中。总之，FA可以重新用作针对肠球菌的抗菌药物，产生突变耐药性的可能性较低，并且可以用于治疗万古霉素耐药肠球菌引起的感染。