Low-Level Antimicrobials in the Medicinal Leech Select for Resistant Pathogens That Spread to Patients

Fluoroquinolones (FQs) and ciprofloxacin (Cp) are important antimicrobials that pollute the environment in trace amounts. Although Cp has been recommended as prophylaxis for patients undergoing leech therapy to prevent infections by the leech gut symbiont , a puzzling rise in Cp-resistant (Cp) infections has been reported. We report on the effects of subtherapeutic FQ concentrations on bacteria in an environmental reservoir, the medicinal leech, and describe the presence of multiple antibiotic resistance mutations and a gain-of-function resistance gene. We link the rise of Cp isolates to exposure of the leech microbiota to very low levels of Cp (0.01 to 0.04 µg/ml), <1/100 of the clinical resistance breakpoint for Using competition experiments and comparative genomics of 37 strains, we determined the mechanisms of resistance in clinical and leech-derived isolates, traced their origin, and determined that the presence of merely 0.01 µg/ml Cp provides a strong competitive advantage for Cp strains. Deep-sequencing the Cp-conferring region of enabled tracing of the mutation-harboring population in archived gut samples, and an increase in the frequency of the Cp-conferring mutation in 2011 coincides with the initial reports of Cp infections in patients receiving leech therapy. The role of subtherapeutic antimicrobial contamination in selecting for resistant strains has received increasing attention and is an important clinical matter. This study describes the relationship of resistant bacteria from the medicinal leech, , with patient infections following leech therapy. While our results highlight the need for alternative antibiotic therapies, the rise of Cp bacteria demonstrates the importance of restricting the exposure of animals to antibiotics approved for veterinary use. The shift to a more resistant community and the dispersion of Cp-conferring mechanisms via mobile elements occurred in a natural setting due to the presence of very low levels of fluoroquinolones, revealing the challenges of controlling the spread of antibiotic-resistant bacteria and highlighting the importance of a holistic approach in the management of antibiotic use.