title: Antibiotic Selection Pressure Determination through Sequence-Based Metagenomics.
abstract: The human gut forms a dynamic reservoir of antibiotic resistance genes (ARGs). Treatment with antimicrobial agents has a significant impact on the intestinal resistome and leads to enhanced horizontal transfer and selection of resistance. We have monitored the development of intestinal ARGs over a 6-day course of ciprofloxacin (Cp) treatment in two healthy individuals by using sequenced-based metagenomics and different ARG quantification methods. Fixed- and random-effect models were applied to determine the change in ARG abundance per defined daily dose of Cp as an expression of the respective selection pressure. Among various shifts in the composition of the intestinal resistome, we found in one individual a strong positive selection for class D beta-lactamases which were partly located on a mobile genetic element. Furthermore, a trend to a negative selection has been observed with class A beta-lactamases (-2.66 hits per million sample reads/defined daily dose; P = 0.06). By 4 weeks after the end of treatment, the composition of ARGs returned toward their initial state but to a different degree in both subjects. We present here a novel analysis algorithm for the determination of antibiotic selection pressure which can be applied in clinical settings to compare therapeutic regimens regarding their effect on the intestinal resistome. This information is of critical importance for clinicians to choose antimicrobial agents with a low selective force on their patients' intestinal ARGs, likely resulting in a diminished spread of resistance and a reduced burden of hospital-acquired infections with multidrug-resistant pathogens.
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany German Center for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany will80@gmx.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Willmann
authors.affiliation: Center for Bioinformatics, University of Tübingen, Tübingen, Germany.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Hadidi
authors.affiliation: Center for Bioinformatics, University of Tübingen, Tübingen, Germany.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Huson
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany German Center for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Schütz
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany German Center for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany.
authors.forename: Christopher
authors.identifier: http://orcid.org/0000-0003-4107-739X
authors.initials: C
authors.lastname: Weidenmaier
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany German Center for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany.
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Autenrieth
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany German Center for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Peter
mesh_terms: D000328:Adult; D000465:Algorithms; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D044822:Biodiversity; D002939:Ciprofloxacin / Q000494:pharmacology; D004352:Drug Resistance, Microbial / Q000187:drug effects* / Q000235:genetics*; D000069196:Gastrointestinal Microbiome / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D056186:Metagenomics / Q000379:methods*; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012641:Selection, Genetic / Q000187:drug effects; D001618:beta-Lactamases / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin; D001618:beta-Lactamases