Impact of Daptomycin Dose Exposure Alone or in Combination with β-Lactams or Rifampin against Vancomycin-Resistant Enterococci in an In Vitro Biofilm Model
Impact of Daptomycin Dose Exposure Alone or in Combination with β-Lactams or Rifampin against Vancomycin-Resistant Enterococci in an In Vitro Biofilm Model
复制标题
DOI：
10.1128/aac.02074-19
复制
发表时间：
2020-05-01
影响因子：
4.9
通讯作者：
Rybak, Michael J.
中科院分区：
文献类型：
--
作者：
Jahanbakhsh, Seyedehameneh;Singh, Nivedita B.;Rybak, Michael J.
屎肠球菌菌株通常对万古霉素和 β-内酰胺具有耐药性。此外，屎肠球菌经常引起生物膜相关感染，并且这些感染难以治疗。在这种情况下，我们研究了单独使用达托霉素 (DAP)（8、10、12 和 14 mg/kg 体重/天）以及联合头孢洛林 (CPT)、氨苄青霉素 (AMP)、厄他培南 (ERT) 和利福平 (RIF) 的给药方案对 2 种产生生物膜的耐万古霉素屎肠球菌临床菌株的活性(VREfm)，即体外生物膜模型中的菌株 S447 和 HOU503。 HOU503 具有常见的 LiaS 和 LiaR 取代，而 S447 缺乏与 LiaFSR 途径相关的突变。 MIC 结果表明，两种菌株均对 DAP 敏感，对 CPT、AMP、ERT 和 RIF 具有抗性。 168 小时药代动力学/药效 (PK/PD) CDC 生物膜反应器模型（模拟人类抗生素暴露）与钛和聚氨酯试样一起使用，以评估抗生素组合的功效。 DAP 12和14对S447具有杀菌活性，但对HOU503缺乏这种效果。 ERT和RIF的添加增强了DAP活性，使得DAP 8和10加上ERT或RIF在168小时时对两种菌株产生杀菌活性。虽然 DAP 8 和 10 加上 CPT 改善了杀灭作用，但它们没有达到针对 S447 的杀菌减少。 AMP、CPT、ERT 或 RIF 的组合导致 DAP 在 168 小时时针对 HOU503 的杀菌活性增强。我们的数据进一步支持 DAP 与 AMP、ERT、CPT 和 RIF 的组合用于治疗由生物膜产生的 VREfm 引起的感染。需要进一步研究 DAP 组合对抗产生生物膜的肠球菌。
Enterococcus faecium strains are commonly resistant to vancomycin and beta-lactams. In addition, E. faecium often causes biofilm-associated infections and these infections are difficult to treat. In this context, we investigated the activity of dosing regimens using daptomycin (DAP) (8, 10, 12, and 14 mg/kg of body weight/day) alone and in combination with ceftaroline (CPT), ampicillin (AMP), ertapenem (ERT), and rifampin (RIF) against 2 clinical strains of biofilm-producing vancomycin-resistant Enterococcus faecium (VREfm), namely, strains S447 and HOU503, in an in vitro biofilm model. HOU503 harbors common LiaS and LiaR substitutions, whereas S447 lacks mutations associated with the LiaFSR pathway. MIC results demonstrated that both strains were susceptible to DAP and resistant to CPT, AMP, ERT, and RIF. The 168-h pharmacokinetic/pharmacodynamic (PK/PD) CDC biofilm reactor models (simulating human antibiotic exposures) were used with titanium and polyurethane coupons to evaluate the efficacy of antibiotic combinations. DAP 12 and 14 achieved bactericidal activity against S447 but lacked such effect against HOU503. Addition of ERT and RIF enhanced DAP activity, allowing DAP 8 and 10 plus ERT or RIF to produce bactericidal activity against both strains at 168 h. While DAP 8 and 10 plus CPT improved killing, they did not reach bactericidal reduction against S447. Combination of AMP, CPT, ERT, or RIF resulted in enhanced and bactericidal activity for DAP against HOU503 at 168 h. Our data provide further support for the use of combinations of DAP with AMP, ERT, CPT, and RIF in infections caused by biofilm producing VREfm. Further research involving DAP combinations against biofilm-producing enterococci is warranted.