Smith Jordan R, Barber Katie E, Raut Animesh, Aboutaleb Mostafa, Sakoulas George, Rybak Michael J
Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI, USA.
University of California San Diego School of Medicine, La Jolla, CA, USA University of California San Diego Division of Biology, La Jolla, CA, USA.
J Antimicrob Chemother. 2015;70(6):1738-43. doi: 10.1093/jac/dkv007. Epub 2015 Feb 1.
Enterococcus faecalis (Efc) and Enterococcus faecium (Efm) are frequently resistant to vancomycin and β-lactams (BLs). In vitro data suggest synergy between several BLs and glycopeptides or lipopeptides against resistant pathogens. Our objective was to conduct combination MIC and time-kill experiments to evaluate BL synergy with daptomycin against enterococci.
Fifteen Efc and 20 Efm strains were evaluated for daptomycin enhancement via combination MICs. Daptomycin MICs were obtained by microdilution in the absence and presence of ceftaroline, ertapenem, cefepime, ceftriaxone, cefotaxime, cefazolin and ampicillin. Two Efc strains (R6981 and R7808) and one isogenic daptomycin-susceptible/daptomycin-non-susceptible Efm pair (8019/5938) were evaluated in time-kill experiments. Daptomycin at 0.5 × MIC was used in combination with BL at biological free concentration. Strain 5938 was evaluated for enhancement of daptomycin binding in fluorescently labelled daptomycin (BoDipy) experiments.
Ceftaroline reduced daptomycin MIC values the most against all strains. In time-kill experiments, ceftaroline, ertapenem, cefepime, ceftriaxone and ampicillin demonstrated synergy with daptomycin against all strains, cefazolin demonstrated none and cefotaxime demonstrated synergy against only R7808. Bacterial reduction at 24 h was greater for daptomycin + ceftaroline, ertapenem, cefepime, ceftriaxone or ampicillin for all strains compared with any single agent or daptomycin + cefazolin or cefotaxime (P < 0.001). In BoDipy daptomycin experiments, ceftaroline enhanced daptomycin binding most compared with all other agents (P < 0.001).
The data support the potential use of daptomycin/BL combination therapy in infections caused by VRE. Combination regimens, other than those involving cefazolin and cefotaxime, provide better kill compared with daptomycin alone. Further clinical research involving daptomycin combinations is warranted.
粪肠球菌（Efc）和屎肠球菌（Efm）常常对万古霉素和β-内酰胺类药物（BLs）耐药。体外数据表明，几种BLs与糖肽类或脂肽类药物联合使用对耐药病原体具有协同作用。我们的目的是进行联合最低抑菌浓度（MIC）和时间杀菌实验，以评估BLs与达托霉素联合使用对肠球菌的协同作用。
通过联合MIC评估15株Efc和20株Efm菌株对达托霉素的增效作用。在不存在和存在头孢洛林、厄他培南、头孢吡肟、头孢曲松、头孢噻肟、头孢唑林和氨苄西林的情况下，通过微量稀释法获得达托霉素的MIC。在时间杀菌实验中评估2株Efc菌株（R6981和R7808）和1对同基因的对达托霉素敏感/对达托霉素不敏感的Efm菌株（8019/5938）。将0.5×MIC的达托霉素与生物游离浓度的BL联合使用。在荧光标记达托霉素（BODipy）实验中评估5938菌株对达托霉素结合的增强作用。
头孢洛林对所有菌株降低达托霉素MIC值的作用最为明显。在时间杀菌实验中，头孢洛林、厄他培南、头孢吡肟、头孢曲松和氨苄西林与达托霉素联合使用对所有菌株均显示出协同作用，头孢唑林未显示协同作用，头孢噻肟仅对R7808显示出协同作用。与任何单一药物或达托霉素+头孢唑林或头孢噻肟相比，达托霉素+头孢洛林、厄他培南、头孢吡肟、头孢曲松或氨苄西林在24小时时对所有菌株的细菌减少量更大（P<0.001）。在BODipy达托霉素实验中，与所有其他药物相比，头孢洛林增强达托霉素结合的作用最为明显（P<0.001）。
这些数据支持在耐万古霉素肠球菌（VRE）引起的感染中潜在使用达托霉素/BL联合治疗。与单独使用达托霉素相比，除涉及头孢唑林和头孢噻肟的联合方案外，其他联合方案杀菌效果更好。有必要开展进一步涉及达托霉素联合用药的临床研究。
