Gut-derived circulating bacterial vesicles reduce systemic carbapenem exposure and sustain extraintestinal infections

Abstract Infections frequently persist despite appropriate antibiotic therapy against susceptible pathogens. While unexplained treatment failure is typically linked to the pathogen itself or the local infection environment, we show that spatially distinct colonized resistant populations can undermine systemic therapy. In a 1,028-patient cohort, fecal colonization with carbapenem-resistant Escherichia coli (CREC) independently compromised carbapenem efficacy against susceptible extraintestinal Enterobacterales. Mechanistically, CREC secretes the carbapenemase NDM exclusively via outer membrane vesicles (OMVs). Following intestinal barrier injury, NDM-loaded OMVs translocate into the circulation. These circulating vesicles resist plasma inactivation and accelerate systemic carbapenem clearance, dropping effective drug exposure below therapeutic thresholds to rescue distant susceptible pathogens without genetic transfer. This protection requires porin-mediated antibiotic entry into OMVs and is amplified by carbapenem exposure, which increases vesicles release and enriches NDM cargo. NDM-stable aztreonam-avibactam and non-β-lactam amikacin bypass this vesicle sink and retain in vivo efficacy. Thus, gut microbiota resistance acts as a remote pharmacological sink via circulating bacterial vesicles, compromising antibiotic therapy against distant susceptible pathogens.