Centre for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany.
BIH Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin; Augustenburger Platz 1 (Südstraße 2), 13353 Berlin, Germany.
Int J Antimicrob Agents. 2020 Dec;56(6):106200. doi: 10.1016/j.ijantimicag.2020.106200. Epub 2020 Oct 17.
Escherichia coli is the most common cause of Gram-negative prosthetic joint infections (PJIs) and ciprofloxacin is the first-line antibiofilm antibiotic. Due to the emergence of fluoroquinolone resistance, management of E. coli PJIs has become challenging and is associated with high treatment failure rates. We evaluated the efficacy of a newly isolated bacteriophage ɸWL-3 as a therapeutic agent in combination with ciprofloxacin, fosfomycin, gentamicin, meropenem or ceftriaxone against biofilm of a ciprofloxacin/ceftriaxone-resistant E. coli strain and the ATCC 25922 reference strain. ɸWL-3 was first characterised in terms of virion morphology, absorption rate, burst size and killing kinetics against both E. coli strains. The tested antibiotics presented high inhibitory concentrations (ranging from 16 to >1024 μg/mL) when tested alone against biofilms. Co-administration of ɸWL-3 with antibiotics improved the antibiotic efficacy against biofilm, especially after staggered exposure, reducing the minimum biofilm bactericidal concentration (MBBC) up to 512 times. The in vivo antimicrobial activity of ɸWL-3/fosfomycin combination against both E. coli strains was assessed in a Galleria mellonella invertebrate infection model. Treatment of infected larvae after lethal doses of E. coli resulted in enhanced survival rates when combinatorial therapy with ɸWL-3/fosfomycin was applied on E. coli ATCC 25922-infected larvae compared with monotherapy, but not for EC1-infected larvae, which we speculated could be due to higher release of endotoxins in a shorter period in EC1-infected larvae exposed to ɸWL-3. Our study provides new insights into the use of bacteriophages and antibiotics in the treatment of biofilm-associated infections caused by antibiotic-resistant bacteria.
大肠杆菌是革兰氏阴性人工关节感染（PJI）最常见的原因，环丙沙星是一线抗生物膜抗生素。由于氟喹诺酮类药物耐药性的出现，大肠杆菌 PJI 的治疗变得具有挑战性，并且与高治疗失败率相关。我们评估了一种新分离的噬菌体ɸWL-3 作为治疗剂与环丙沙星、磷霉素、庆大霉素、美罗培南或头孢曲松联合治疗耐环丙沙星/头孢曲松的大肠杆菌菌株和 ATCC 25922 参考菌株生物膜的疗效。首先，根据噬菌体ɸWL-3 的病毒形态、吸收率、爆发大小和对两种大肠杆菌菌株的杀菌动力学来对其进行特征描述。单独测试时，测试的抗生素对生物膜的抑制浓度较高（范围从 16 到 >1024 μg/mL）。ɸWL-3 与抗生素联合使用可提高抗生素对生物膜的疗效，尤其是在交错暴露后，将最小生物膜杀菌浓度（MBBC）降低了 512 倍。在金蝇无脊椎动物感染模型中评估了噬菌体ɸWL-3/磷霉素组合对两种大肠杆菌菌株的体内抗菌活性。在用致死剂量的大肠杆菌感染幼虫后，用噬菌体ɸWL-3/磷霉素联合治疗感染的幼虫，与单独治疗相比，提高了存活率，但对 EC1 感染的幼虫没有提高，我们推测这可能是由于暴露于噬菌体ɸWL-3 后，EC1 感染的幼虫在较短的时间内释放更多的内毒素。我们的研究为噬菌体和抗生素联合治疗抗生素耐药菌引起的生物膜相关感染提供了新的见解。
