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 Staphylococcus aureus. The biofilm positive S. aureus strain ATCC 35556, the lytic S. aureus phage SATA-8505, and five antibiotics (cefazolin, vancomycin, dicloxacillin, tetracycline, and linezolid), used to treat S. aureus infections, were tested in this study. The ability of the SATA-8505 phage to augment the effect of these antibiotics against biofilm-associated S. aureus 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 in vitro study provides proof of principle for the ability of phages to augment the activity of antibiotics against S. aureus 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.
Peri-prosthetic joint infection (PJI) is one of the most serious and dreaded complications after total joint replacement (TJR). Due to an aging population and the constant rise in demand for TJR, the incidence of PJI is also increasing. Successful treatment of PJI is challenging and is associated with high failure rates. One of the main causes for treatment failure is bacterial biofilm formation on implant surfaces and the adherence of biofilm bacteria on tissue and bone next to the implant. Biofilms are protective shields to bacterial cells and possess many unique properties that leads to antibiotic resistance. New therapeutic platforms are currently being explored to breakdown biofilm matrix in order to enhance the efficacy of antibiotics. Bacteriophages (phages) is one of these unique therapeutic platforms that can degrade biofilms as well as target the killing of bacterial cells. Preclinical studies of biofilm-mediated infections have demonstrated the ability of phage to eradicate biofilms and clear infections by working synergistically with antibiotics. There is strong preclinical evidence that phage can reduce the concentration of antibiotics required to treat an infection. These findings support a promising role for phages as a future clinical adjunct to antibiotics. In addition, phage therapy can be personalized to target a specific bacterial strain. Clinical studies using phage therapy are limited in Western literature; but phase I studies have established good safety profile with no adverse outcomes reported. In order to translate phage therapy to treat PJI in clinics, further preclinical testing is still required to study optimal delivery methods as well as the interaction between phage and the immune system in vivo. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1051-1060, 2018.
During the past decade, drug-eluting stents (DES) have been widely used for the treatment of occlusive coronary artery diseases. They are supposed to reduce the incidence of early in-stent restenosis by the elution of highly hydrophobic antiproliferative drugs. Nevertheless, the absence of long-term activity of these devices is responsible for late acute thrombosis probably due to the delayed re-endothelialization of the arterial wall over the bare metallic stent struts. Thus, a new generation of DES with a sustained release of therapeutic agents is required to improve long-term results of these devices. In this article, we report an original functionalization of CoCr vascular devices with a hydrophilic, biocompatible and biodegradable cyclodextrins based polymer which acts as a reservoir for lipophilic drugs allowing the sustained release of antiproliferative drugs. In this setting, polydopamine (PDA), a strong adhesive biopolymer, was applied as a first coating layer onto the surface of the metallic CoCr device in order to promote the strong anchorage of a cyclodextrin polymer. This polymer was generated "in situ" from the methylated cyclodextrins and citric acid as a cross-linking agent through a polycondensation reaction. After optimization of the grafting process, the amount of cyclodextrin polymer coated onto the CoCr device was quantified by colorimetric titrations and the resulting film was characterized by scanning electron microscopy (SEM) investigations. The cytocompatibility of the resulting coated film was assessed by cell proliferation and vitality tests. Finally, the ability of this coated device to act as a drug-eluting system was evaluated with paclitaxel, a strong hydrophobic antiproliferative drug, a reference drug used in current vascular drug-eluting stents.
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