Oechslin Frank, Piccardi Philippe, Mancini Stefano, Gabard Jérôme, Moreillon Philippe, Entenza José M, Resch Gregory, Que Yok-Ai
Department of Fundamental Microbiology, University of Lausanne, Switzerland
Pherecydes Pharma, Romainville, France.
J Infect Dis. 2017 Mar 1;215(5):703-712. doi: 10.1093/infdis/jiw632.
Increasing antibiotic resistance warrants therapeutic alternatives. Here we investigated the efficacy of bacteriophage-therapy (phage) alone or combined with antibiotics against experimental endocarditis (EE) due to Pseudomonas aeruginosa, an archetype of difficult-to-treat infection.
In vitro fibrin clots and rats with aortic EE were treated with an antipseudomonas phage cocktail alone or combined with ciprofloxacin. Phage pharmacology, therapeutic efficacy, and resistance were determined.
In vitro, single-dose phage therapy killed 7 log colony-forming units (CFUs)/g of fibrin clots in 6 hours. Phage-resistant mutants regrew after 24 hours but were prevented by combination with ciprofloxacin (2.5 × minimum inhibitory concentration). In vivo, single-dose phage therapy killed 2.5 log CFUs/g of vegetations in 6 hours (P < .001 vs untreated controls) and was comparable with ciprofloxacin monotherapy. Moreover, phage/ciprofloxacin combinations were highly synergistic, killing >6 log CFUs/g of vegetations in 6 hours and successfully treating 64% (n = 7/11) of rats. Phage-resistant mutants emerged in vitro but not in vivo, most likely because resistant mutations affected bacterial surface determinants important for infectivity (eg, the pilT and galU genes involved in pilus motility and LPS formation).
Single-dose phage therapy was active against P. aeruginosa EE and highly synergistic with ciprofloxacin. Phage-resistant mutants had impaired infectivity. Phage-therapy alone or combined with antibiotics merits further clinical consideration.
抗生素耐药性不断增加，因此需要治疗替代方案。在此，我们研究了噬菌体疗法单独或与抗生素联合使用对实验性心内膜炎（EE）的疗效，该心内膜炎由铜绿假单胞菌引起，是一种难以治疗的感染的典型代表。
体外纤维蛋白凝块以及患有主动脉EE的大鼠分别接受抗铜绿假单胞菌噬菌体鸡尾酒单独治疗或与环丙沙星联合治疗。测定噬菌体药理学、治疗效果和耐药性。
在体外，单剂量噬菌体疗法在6小时内杀死了纤维蛋白凝块中7 log菌落形成单位（CFU）/克。24小时后出现噬菌体抗性突变体，但与环丙沙星联合使用（2.5×最低抑菌浓度）可防止其出现。在体内，单剂量噬菌体疗法在6小时内杀死了赘生物中2.5 log CFU/克（与未治疗的对照组相比，P <.001），且与环丙沙星单药治疗效果相当。此外，噬菌体/环丙沙星联合使用具有高度协同作用，在6小时内杀死了>6 log CFU/克的赘生物，并成功治疗了64%（n = 7/11）的大鼠。噬菌体抗性突变体在体外出现，但在体内未出现，很可能是因为抗性突变影响了对感染性很重要的细菌表面决定因素（例如，参与菌毛运动和脂多糖形成的pilT和galU基因）。
单剂量噬菌体疗法对铜绿假单胞菌EE有活性，且与环丙沙星具有高度协同作用。噬菌体抗性突变体的感染性受损。噬菌体疗法单独或与抗生素联合使用值得进一步临床考虑。
