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A novel non-antibiotic gut-directed strategy to prevent surgical site infections
John Alverdy, Olga Zaborina, Sanjiv Hyoju, Alexander Zaborin, Rachel Nordgren, Robert Keskey
University of Chicago, Chicago , Illinois, United States

OBJECTIVES: To mimic the human condition, we created a novel model of Surgical Site Infection (SSI) in mice by having them consume a western type diet and exposing them to antibiotics (ABX) (cefoxitin/clindamycin). This model led to SSIs involving drug resistant gram-negative bacteria originating from the gut microbiota. Given that drug resistant gram-negative bacteria causing SSIs are increasing in frequency and resistance to the antibiotics chosen for prophylaxis, we hypothesized that a non-antibiotic virulence suppressing phosphate rich co-polymer (Pi-PEG) can modulate the gut microbiome and prevent SSIs in these mice. The aim of this study was to determine if providing Pi-PEG in the drinking of mice in this model protects against SSIs development in association with modulation of the gut microbiome.
METHODS: Mice consuming a western type diet (high fat/low fiber) were administered parenteral cefoxitin and oral clindamycin prior to surgery and assigned to drinking water containing either 1% PI-PEG or water only. A third group, chow fed (high fiber/low fat) mice NOT administered antibiotics served as controls. All mice underwent incisions in the dorsum (back) under sterile conditions with exposure of the underlying muscle followed by cautery injury and placement of a silk suture in the muscle. All wounds were cultured to confirm sterility at the end of the procedure and the skin closed. 10 days later, all mice were sacrificed and the dorsal muscle site inspected for a grossly visible SSI, with culture for speciation and swabbing for 16S rRNA microbial sequencing. Finally, cecal contents were collected for 16S rRNA analysis of the gut microbiome.

RESULTS: Grossly visible SSIs with culture positivity indicating wound infection in this model was as follows: chow (0%), Western Diet + Antibiotics (60%) and Western Diet + Antibiotics + Pi-PEG (0%) (P<0.001). The main organisms cultured from mice with clinical SSIs were Proteus mirabilis and Enterobacter sp. 16S rRNA sequencing of the cecal contents and surgical wound analyzed by amplicon sequence variant (ASV) to determine strain level concordance between the gut and wound demonstrated that Pi-PEG suppressed SSI-associated bacterial strains in both the gut (cecum) and surgical wound.

FIGURE HERE: ASV analysis demonstrates the distribution and abundance of SSI-associated pathogens with the exact sequence variance in both the cecum and wound. Each dot represents the level of ASV abundance in each sample (cecal content or wound). * P<0.05

CONCLUSION: Given that as many as 50% of the pathogens causing SSIs today display resistance to the antibiotics chosen for prophylaxis, Pi-PEG may represent an alternative to the ever escalating use of broader and more powerful antibiotics. Metatrascriptomic and metabolomics data are pending to further establish causality between the cecal microbiome, Pi-PEG and the SSI pathogens observed in this model. Clinical trial planning is currently under way. <!--![endif]---->

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