Kumaran Dilini, Taha Mariam, Yi QiLong, Ramirez-Arcos Sandra, Diallo Jean-Simon, Carli Alberto, Abdelbary Hesham
Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Centre for Innovation, Canadian Blood Services, Ottawa, ON, Canada.
Front Microbiol. 2018 Feb 5;9:127. doi: 10.3389/fmicb.2018.00127. eCollection 2018.
The inability to effectively treat biofilm-related infections is a major clinical challenge. This has been attributed to the heightened antibiotic tolerance conferred to bacterial cells embedded within biofilms. Lytic bacteriophages (phages) have evolved to effectively infect and eradicate biofilm-associated cells. The current study was designed to investigate the ability of phage treatment to enhance the activity of antibiotics against biofilm-forming . The biofilm positive strain ATCC 35556, the lytic phage SATA-8505, and five antibiotics (cefazolin, vancomycin, dicloxacillin, tetracycline, and linezolid), used to treat infections, were tested in this study. The ability of the SATA-8505 phage to augment the effect of these antibiotics against biofilm-associated cells was assessed by exposing them to one of the five following treatment strategies: (i) antibiotics alone, (ii) phage alone, (iii) a combination of the two treatments simultaneously, (iv) staggered exposure to the phage followed by antibiotics, and (v) staggered exposure to antibiotics followed by exposure to phage. The effect of each treatment strategy on biofilm cells was assessed by enumerating viable bacterial cells. The results demonstrate that the treatment of biofilms with either SATA-8505, antibiotics, or both simultaneously resulted in minimal reduction of viable biofilm-associated cells. However, a significant reduction [up to 3 log colony forming unit (CFU)/mL] was observed when the phage treatment preceded antibiotics. This effect was most pronounced with vancomycin and cefazolin which exhibited synergistic interactions with SATA-8505, particularly at lower antibiotic concentrations. This study provides proof of principle for the ability of phages to augment the activity of antibiotics against biofilms. Our results also demonstrate that therapeutic outcomes can be influenced by the sequence in which these therapeutic agents are administered, and the nature of their interactions. Further investigation into the interactions between lytic phages and antibiotics against various biofilm-forming organisms is important to direct future clinical translation of efficacious antibiotic-phage combination therapeutic strategies.
无法有效治疗生物膜相关感染是一项重大临床挑战。这归因于生物膜内细菌细胞所具有的增强的抗生素耐受性。裂解性噬菌体已进化到能有效感染和根除与生物膜相关的细胞。本研究旨在调查噬菌体治疗增强抗生素对生物膜形成菌活性的能力。本研究测试了生物膜阳性菌株ATCC 35556、裂解性噬菌体SATA - 8505以及用于治疗感染的五种抗生素（头孢唑林、万古霉素、双氯西林、四环素和利奈唑胺）。通过将它们暴露于以下五种治疗策略之一来评估SATA - 8505噬菌体增强这些抗生素对生物膜相关菌细胞作用的能力：（i）单独使用抗生素，（ii）单独使用噬菌体，（iii）两种治疗同时联合使用，（iv）先接触噬菌体再接触抗生素，（v）先接触抗生素再接触噬菌体。通过计数活细菌细胞来评估每种治疗策略对生物膜细胞的影响。结果表明，单独使用SATA - 8505、抗生素或两者同时使用对生物膜相关活细胞的减少作用极小。然而，当噬菌体治疗先于抗生素时，观察到显著减少[高达3个对数集落形成单位（CFU）/mL]。这种效应在万古霉素和头孢唑林上最为明显，它们与SATA - 8505表现出协同相互作用，尤其是在较低抗生素浓度下。本研究为噬菌体增强抗生素对生物膜活性的能力提供了原理证明。我们的结果还表明，治疗效果可受这些治疗剂给药顺序及其相互作用性质的影响。进一步研究裂解性噬菌体与抗生素针对各种生物膜形成菌之间的相互作用对于指导有效的抗生素 - 噬菌体联合治疗策略未来的临床转化很重要。
