Abstract
ABSTRACTFluoroquinolones (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 Aeromonas, a puzzling rise in Cp-resistant (Cpr) Aeromonas 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 Cpr Aeromonas 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 Aeromonas. Using competition experiments and comparative genomics of 37 strains, we determined the mechanisms of resistance in clinical and leech-derived Aeromonas isolates, traced their origin, and determined that the presence of merely 0.01 µg/ml Cp provides a strong competitive advantage for Cpr strains. Deep-sequencing the Cpr-conferring region of gyrA enabled tracing of the mutation-harboring Aeromonas population in archived gut samples, and an increase in the frequency of the Cpr-conferring mutation in 2011 coincides with the initial reports of Cpr Aeromonas infections in patients receiving leech therapy.
Highlights
Fluoroquinolones (FQs) and ciprofloxacin (Cp) are important antimicrobials that pollute the environment in trace amounts
We investigated these dynamics in the gut of the medicinal leech, Hirudo verbana, and used this natural system to understand the role of low levels of antimicrobials in enabling resistant bacteria to persist among sensitive strains in their environment
As infections associated with leech therapy may progress to septicemia [8], it has become best practice to treat patients prophylactically with the widely used fluoroquinolone (FQ) ciprofloxacin (Cp), which dramatically reduces the incidence of these wound infections [9]
Summary
Fluoroquinolones (FQs) and ciprofloxacin (Cp) are important antimicrobials that pollute the environment in trace amounts. Because the overuse of antimicrobials in humans and livestock fuels the selection of resistant bacteria, the importance of environmental contamination with antibiotics is receiving increasing attention [1]. Point sources, such as hospital and pharmaceutical industry discharges, can introduce large amounts of antibiotics into the environment. Sartor et al [21] raised the possibility that medicinal leeches were exposed to FQs at the farm where they are raised in France by feeding them on blood derived from FQ-treated poultry This practice could explain the occurrence of resistant Aeromonas isolates causing leech therapy-associated infections, no strain comparisons or FQ measurements were reported [21].
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