Impact of Phage Therapy on Multidrug-Resistant Escherichia coli Intestinal Carriage in a Murine Model

Introduction: The growing resistance of bacteria to antibiotics is a major global public health concern. An important reservoir of this resistance is the gut microbiota. However, limited data are available on the ability of phage therapy to reduce the digestive carriage of multidrug-resistant bacteria. Materials and methods: Four novel lytic phages were isolated in vitro for efficacy against an extended-spectrum beta-lactamase-producing (ESBL) Escherichia coli strain also resistant to carbapenems through a carbapenemase OXA-48. The first step was to develop models of ESBL E. coli digestive carriage in mice. The second step was to test the efficacy of an oral and rectal phage therapy (a cocktail of four phages or microencapsulated phage) to reduce this carriage. Results: The two most intense models of digestive carriage were obtained by administering amoxicillin (0.5 g center dot L-1) continuously in the drinking water (Model 1) or pantoprazole (0.1 g center dot L-1) continuously in the drinking water, combined with amoxicillin (0.5 g center dot L-1), for the first 8 days (Model 2). Oral administration of the phage cocktail to Model 1 resulted in a transient reduction in the concentration of ESBL E. coli in the faeces 9 days after the bacterial challenge (median = 5.33 x 10(8) versus 2.76 x 10(9) CFU center dot g(-1), p = 0.02). In contrast, in Model 2, oral or oral + rectal administration of this cocktail did not alter the bacterial titre compared to the control (area under the curve, AUC, 3.49 x 10(9); 3.41 x 10(9) and 3.82 x 10(9) for the control, oral and oral + rectal groups, respectively; p-value > 0.8 for each two-by-two group comparison), as well as the administration of an oral microencapsulated phage in Model 1 (AUC = 8.93 x 10(9) versus 9.04 x 10(9), p = 0.81). Conclusions: Oral treatment with amoxicillin promoted digestive carriage in mice, which was also the case for the addition of pantoprazole. However, our study confirms the difficulty of achieving efficacy with phage therapy to reduce multidrug-resistant bacterial digestive carriage in vivo.

Automated summary

The study investigated the efficacy of oral and rectal phage therapy in reducing ESBL E. coli gut carriage in mice. The results showed transient reduction in bacterial concentration with oral phage administration, but no significant change in bacterial titre in certain models, indicating the challenges of phage therapy in reducing carriage of multidrug-resistant bacteria.