在兔实验性心内膜炎模型中，氯唑西林或磷霉素联合达托霉素的组合对甲氧西林敏感金黄色葡萄球菌（MSSA）的活性比氯唑西林单药治疗或与庆大霉素联合使用更强。
Cloxacillin or fosfomycin plus daptomycin combinations are more active than cloxacillin monotherapy or combined with gentamicin against MSSA in a rabbit model of experimental endocarditis.
作者信息
García-de-la-Mària Cristina, Gasch Oriol, Castañeda Ximena, García-González Javier, Soy Dolors, Cañas Maria-Alexandra, Ambrosioni Juan, Almela Manel, Pericàs Juan M, Téllez Adrián, Falces Carlos, Hernández-Meneses Marta, Sandoval Elena, Quintana Eduard, Vidal Barbara, Tolosana Jose M, Fuster David, Llopis Jaume, Moreno Asuncion, Marco Francesc, Miró Jose M
机构信息
Hospital Clínic - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Hospital Parc Tauli de Sabadell, University Autònoma of Barcelona, Spain.
出版信息
J Antimicrob Chemother. 2020 Dec 1;75(12):3586-3592. doi: 10.1093/jac/dkaa354.
BACKGROUND
In vitro and in vivo activity of daptomycin alone or plus either cloxacillin or fosfomycin compared with cloxacillin alone and cloxacillin plus gentamicin were evaluated in a rabbit model of MSSA experimental endocarditis (EE).
METHODS
Five MSSA strains were used in the in vitro time-kill studies at standard (105-106 cfu/mL) and high (108 cfu/mL) inocula. In the in vivo EE model, the following antibiotic combinations were evaluated: cloxacillin (2 g/4 h) alone or combined with gentamicin (1 mg/kg/8 h) or daptomycin (6 mg/kg once daily); and daptomycin (6 mg/kg/day) alone or combined with fosfomycin (2 g/6 h).
RESULTS
At standard and high inocula, daptomycin plus fosfomycin or cloxacillin were bactericidal against 4/5 and 5/5 strains, respectively, while cloxacillin plus gentamicin was bactericidal against 3/5 strains at standard inocula but against none at high inocula. Fosfomycin, cloxacillin, gentamicin and daptomycin MIC/MBCs of the MSSA-678 strain used in the EE model were: 8/64, 0.25/0.5, 0.25/0.5 and 1/8 mg/L, respectively. Adding gentamicin to cloxacillin significantly reduced bacterial density in vegetations compared with cloxacillin monotherapy (P = 0.026). Adding fosfomycin or cloxacillin to daptomycin [10/11 (93%) and 8/11 (73%), respectively] significantly improved the efficacy of daptomycin in sterilizing vegetations [0/11 (0%), P < 0.001 for both combinations] and showed better activity than cloxacillin alone [0/10 (0%), P < 0.001 for both combinations] and cloxacillin plus gentamicin [3/10 (30%), P = 0.086 for cloxacillin plus daptomycin and P = 0.008 for fosfomycin plus daptomycin]. No recovered isolates showed increased daptomycin MIC.
CONCLUSIONS
The addition of cloxacillin or fosfomycin to daptomycin is synergistic and rapidly bactericidal, showing better activity than cloxacillin plus gentamicin for treating MSSA EE, supporting their clinical use.
背景
在甲氧西林敏感金黄色葡萄球菌（MSSA）实验性心内膜炎（EE）兔模型中，评估了达托霉素单独使用或与氯唑西林或磷霉素联合使用，与单独使用氯唑西林以及氯唑西林加庆大霉素相比的体外和体内活性。
方法
在体外杀菌研究中，使用5株MSSA菌株，接种浓度分别为标准浓度（10⁵ - 10⁶ cfu/mL）和高浓度（10⁸ cfu/mL）。在体内EE模型中，评估了以下抗生素组合：单独使用氯唑西林（2 g/4 h）或与庆大霉素（1 mg/kg/8 h）或达托霉素（6 mg/kg每日一次）联合使用；达托霉素（6 mg/kg/天）单独使用或与磷霉素（2 g/6 h）联合使用。
结果
在标准接种浓度和高接种浓度下，达托霉素加磷霉素或氯唑西林分别对4/5和5/5菌株具有杀菌作用，而氯唑西林加庆大霉素在标准接种浓度下对3/5菌株具有杀菌作用，但在高接种浓度下对任何菌株均无杀菌作用。EE模型中使用的MSSA - 678菌株的磷霉素、氯唑西林、庆大霉素和达托霉素的MIC/MBC分别为：8/64、0.25/0.5、0.25/0.5和1/8 mg/L。与氯唑西林单药治疗相比，氯唑西林加庆大霉素显著降低了赘生物中的细菌密度（P = 0.026）。在达托霉素中添加磷霉素或氯唑西林[分别为10/11（93%）和8/11（73%）]显著提高了达托霉素清除赘生物的疗效[0/11（0%），两种组合的P均<0.001]，并且显示出比单独使用氯唑西林[0/10（0%），两种组合的P均<0.001]和氯唑西林加庆大霉素[3/10（30%），氯唑西林加达托霉素的P = 0.086，磷霉素加达托霉素的P = 0.008]更好的活性。没有回收的分离株显示达托霉素MIC增加。
结论
在达托霉素中添加氯唑西林或磷霉素具有协同作用且杀菌迅速，在治疗MSSA EE方面显示出比氯唑西林加庆大霉素更好的活性，支持它们在临床上的使用。
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