Institute of Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany.
InfectoGnostics Forschungscampus Jena e.V., Zentrum für Angewandte Forschung, Jena, Germany.
J Antimicrob Chemother. 2018 Jun 1;73(6):1553-1561. doi: 10.1093/jac/dky051.
Enterococci frequently cause severe biofilm-associated infections such as endocarditis. The combination of ampicillin/ceftriaxone has recently been clinically evaluated as non-inferior compared with the standard therapy of ampicillin/gentamicin for treatment of Enterococcus faecalis endocarditis. Ceftaroline is a novel cephalosporin with enhanced activity against Gram-positive bacteria.
To compare the in vitro effectiveness of the ceftaroline/ampicillin combination with those of gentamicin/ampicillin and ceftriaxone/ampicillin in planktonic and biofilm cultures of clinical E. faecalis isolates.
Synergistic effects at the planktonic level were analysed by chequerboard assays in 20 E. faecalis isolates. Biofilm-eradicating and biofilm-preventing activities of the antibiotics and their combinations were determined by confocal laser scanning microscopy with quantification by quantitative biofilm analysis (qBA) algorithm and cfu/mL determination.
Comparable synergistic effects were observed for both β-lactam combinations in most isolates, in contrast to gentamicin/ampicillin. However, none of the antibiotic combinations succeeded in eradicating mature biofilms. Gentamicin showed promising biofilm-preventing activity, but at concentrations above those clinically tolerable. The β-lactams showed a U-shape dose-response relationship in biofilm prevention. Only exposure to cephalosporins caused alterations in cell morphology, which resulted in cell elongation and reclustering in a concentration-dependent manner. Reclustering was associated with high occurrences of small colony variants (SCVs), especially at high ceftriaxone concentrations.
This study suggests that combinations of cephalosporins or gentamicin with ampicillin may be advantageous only while bacteraemia persists, whereas combinations have no advantage over monotherapy regarding the treatment of mature biofilms. The selection of SCVs at high ceftriaxone concentrations is worth further study.
肠球菌常引起严重的生物膜相关感染，如心内膜炎。氨苄西林/头孢曲松的联合用药最近在临床上被评估为不劣于氨苄西林/庆大霉素标准疗法，可用于治疗粪肠球菌心内膜炎。头孢他啶是一种新型头孢菌素，对革兰氏阳性菌具有增强的活性。
比较头孢他啶/氨苄西林联合用药与庆大霉素/氨苄西林和头孢曲松/氨苄西林在临床粪肠球菌分离株浮游和生物膜培养物中的体外有效性。
通过棋盘微量稀释法分析 20 株粪肠球菌分离株的浮游水平协同作用。通过共聚焦激光扫描显微镜结合定量生物膜分析（qBA）算法和 CFU/mL 测定来确定抗生素及其组合的生物膜清除和生物膜预防活性。
与庆大霉素/氨苄西林相比，大多数分离株中两种β-内酰胺类联合用药均观察到类似的协同作用。然而，没有一种抗生素组合能够成功清除成熟的生物膜。庆大霉素显示出有前景的生物膜预防活性，但浓度高于临床可耐受水平。β-内酰胺类在生物膜预防中呈 U 形剂量反应关系。只有头孢菌素暴露会导致细胞形态发生改变，从而导致细胞伸长和聚集，且这种聚集呈浓度依赖性。聚集与小菌落变异体（SCV）的高发生率相关，尤其是在高浓度头孢曲松时。
本研究表明，头孢菌素或庆大霉素与氨苄西林的联合用药可能仅在菌血症持续存在时具有优势，而与单药治疗相比，联合用药在治疗成熟生物膜方面没有优势。在高浓度头孢曲松时选择 SCV 值得进一步研究。
