Bacteriophage Cocktail and Microcin-Producing Probiotic Protect Mice Against Gut Colonization With Multidrug-Resistant Sequence Type 131.

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.