Porter Stephen B, Johnston Brian D, Kisiela Dagmara, Clabots Connie, Sokurenko Evgeni V, Johnson James R
Minneapolis VA Health Care System, Veterans Health Administration, United States Department of Veterans Affairs, Minneapolis, MN, United States.
Department of Medicine, University of Minnesota, Minneapolis, MN, United States.
Front Microbiol. 2022 Apr 25;13:887799. doi: 10.3389/fmicb.2022.887799. eCollection 2022.
Non-antibiotic measures are needed to reduce the rate of infections due to multidrug-resistant organisms (MDROs), including by eliminating the commensal reservoir that underlies such strains' dissemination and leads to recurrent infections. Here, we tested a cocktail of pre-selected bacteriophages and an engineered microcin C7-producing probiotic Nissle-1917 strain for their ability to reduce gut colonization by an strain from sequence type 131 (ST131)-30R, which is the major clonal group of MDROs among extraintestinal clinical isolates. Although the bacteriophage cocktail was highly effective against ST131-30R strains both and in a murine model of subcutaneous sepsis, it was only weakly and transiently effective against gut colonization by the target ST131-30R strain (0.5 log decrease on + 1: < 0.001; no significant effect on + 4 and beyond). The probiotic strain, while also highly active against ST131-30R , was ineffective against ST131-30R gut colonization despite its abundant presence in feces. Nonetheless, despite failing as decolonizing agents when administered separately, when co-administered the bacteriophage cocktail and probiotic strain exhibited striking synergy against ST131-30R gut colonization. This combinatory effect was most pronounced on + 1 (3.3 log target strain decrease: < 0.001), and persisted until + 7 (0.5 log decrease; < 0.02.). Although by + 10 the ST131-30R load was fully restored, these findings provide proof of concept for combined bacteriophage-plus-probiotic administration to reduce or, possibly, to prevent gut colonization with MDROs in high-risk individuals.
需要采取非抗生素措施来降低多重耐药菌（MDROs）引起的感染率，包括消除作为此类菌株传播基础并导致反复感染的共生菌库。在此，我们测试了一组预先选择的噬菌体和一种工程化的产微菌素C7的益生菌Nissle-1917菌株，看它们是否有能力减少序列类型131（ST131）-30R菌株在肠道的定植，该菌株是肠外临床分离株中MDROs的主要克隆群。尽管噬菌体混合物在体外和皮下脓毒症小鼠模型中对ST131-30R菌株都非常有效，但它对目标ST131-30R菌株在肠道的定植只有微弱且短暂的效果（在第+1天减少0.5个对数：P<0.001；在第+4天及以后无显著效果）。益生菌菌株虽然对ST131-30R也有高度活性，但尽管其在粪便中大量存在，对ST131-30R在肠道的定植却无效。尽管如此，尽管单独给药时作为去定植剂失败了，但噬菌体混合物和益生菌菌株共同给药时，对ST131-30R在肠道的定植表现出显著的协同作用。这种联合效应在第+1天最为明显（目标菌株减少3.3个对数：P<0.001），并持续到第+7天（减少0.5个对数；P<0.02）。尽管到第+10天ST131-30R的负荷完全恢复，但这些发现为联合使用噬菌体和益生菌给药以减少或可能预防高危个体中MDROs在肠道的定植提供了概念验证。
