达托霉素联合头孢洛林治疗由高水平氨基糖苷类耐药及非耐药粪肠球菌所致实验性心内膜炎的体外和体内活性

摘要(中文译文)

需要寻找针对粪肠球菌感染性心内膜炎（EFIE）的标准化治疗之外的有效替代方案。一些体外研究提示，达托霉素与头孢洛林对粪肠球菌具有协同活性。我们旨在评估达托霉素联合头孢洛林对高水平氨基糖苷类耐药（HLAR）和非HLAR粪肠球菌临床分离株的体外和体内活性。使用一组六株与心内膜炎相关的粪肠球菌分离株，在初始标准和高接种量下进行时间-杀菌试验。使用兔实验性EFIE模型，在两个治疗组中采用类人药代动力学模型，在体内比较达托霉素（10 mg/kg/天，静脉注射）与达托霉素（10 mg/kg/天，静脉注射）联合头孢洛林（600 mg，每12小时静脉注射）。在初始标准接种量的时间-杀菌试验中，达托霉素联合头孢洛林对全部三株HLAR和全部三株非HLAR菌株均达到协同作用。在三株HLAR粪肠球菌分离株中的两株观察到杀菌效应。对于HLAR EFAE-188，与单用达托霉素相比，达托霉素联合头孢洛林显著降低了赘生物中的细菌密度（中位密度5.2 vs 6.7 log10 cfu/g；P = 0.028）。对于非HLAR EFAE-468，联合治疗组的赘生物细菌密度低于单用达托霉素组（中位密度5.2 vs 6.8 log10 cfu/g；P = 0.072）。加用头孢洛林在所有病例中均预防了达托霉素耐药粪肠球菌分离株的产生。达托霉素联合头孢洛林是治疗EFIE的一种有前景的替代方案。需要进一步的临床研究来证实这些发现。

Abstract

Effective alternatives to standard of care treatment for E. faecalis infective endocarditis (EFIE) are needed. Some in vitro studies have suggested daptomycin and ceftaroline have synergistic activity against E. faecalis. We aimed to assess the in vitro and in vivo activity of daptomycin in combination with ceftaroline against E. faecalis clinical isolates with and without high-level of aminoglycoside resistance (HLAR). A panel of six endocarditis-associated E. faecalis isolates were used for time-kill assays at initial standard and high inocula. Daptomycin (10 mg/kg/day intravenously) and daptomycin (10 mg/kg/day iv) plus ceftaroline (600 mg q12 hours intravenous) were compared in vivo using a human-like pharmacokinetic model in two treatment groups using the experimental EFIE model in rabbits. The combination of daptomycin plus ceftaroline achieved synergy against all three HLAR and all three non-HLAR strains in time-kill assays at initial standard inoculum. A bactericidal effect was observed in two of the three HLAR E. faecalis isolates. For HLAR EFAE-188, the use of daptomycin plus ceftaroline significantly decreased the bacterial density in vegetations compared with daptomycin alone (median density 5.2 versus 6.7 log10 cfu/g; P = 0.028). For non-HLAR EFAE-468, the bacterial density in vegetations was lower with the combination therapy than with daptomycin alone (median density 5.2 versus 6.8 log10 cfu/g; P = 0.072). Adding ceftaroline prevented the development of daptomycin-resistant E. faecalis isolates in all cases. Daptomycin plus ceftaroline represents a promising alternative for treating EFIE. Further clinical studies are needed to confirm these findings.

如何引用

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