title: Pharmacokinetic/pharmacodynamic assessment of the effects of parenteral administration of a fluoroquinolone on the intestinal microbiota: comparison of bactericidal activity at the gut versus the systemic level in a pig model.
abstract: Classical pharmacokinetic/pharmacodynamic studies of antimicrobial agents performed by combining plasma concentrations and minimum inhibitory concentrations (MICs) are often predictive of the activity of a drug against targeted pathogens located at infectious sites closely connected to circulating blood. However, these studies do not predict the impact of parenteral antimicrobial treatment on intestinal bacteria, which could be responsible for transmission of resistance between species or in the environment. The aim of this study was to assess the differential antibacterial activity of a fluoroquinolone against lung and gut bacteria. Plasma and intestinal concentrations of marbofloxacin were assessed in pigs following intramuscular administration, and the in vitro relationship between marbofloxacin concentrations and mean bacterial inoculum growth in standard broth and in sterilised intestinal contents was modelled. It was shown that the increased intestinal exposure to marbofloxacin compared with plasma in pigs was compensated by reduced marbofloxacin activity against Escherichia coli in the contents of the digestive tract compared with in broth. These results showed that marbofloxacin doses used to target pathogens at the lung level would similarly affect the bacterial population of the same size and with a similar MIC located in the small intestine. However, it was shown that the bactericidal activity of marbofloxacin was increased 4- to 7-fold with low (10(5)CFU/mL) compared with high (10(8)CFU/mL) inoculum sizes. This result suggests that much lower marbofloxacin doses than those classically used would potentially eradicate low pulmonary pathogenic inocula while having a minimal impact on the large gut microbiota.
authors.affiliation: INRA, UMR 1331, TOXALIM Research Centre in Food Toxicology, F-31027 Toulouse, France; Université de Toulouse, ENVT, INP, TOXALIM, F-31076 Toulouse, France.
authors.forename: Aude A
authors.initials: AA
authors.lastname: Ferran
authors.forename: Delphine
authors.initials: D
authors.lastname: Bibbal
authors.forename: Terence
authors.initials: T
authors.lastname: Pellet
authors.forename: Michel
authors.initials: M
authors.lastname: Laurentie
authors.forename: Mireille
authors.initials: M
authors.lastname: Gicquel-Bruneau
authors.forename: Pascal
authors.initials: P
authors.lastname: Sanders
authors.forename: Marc
authors.initials: M
authors.lastname: Schneider
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Toutain
authors.forename: Alain
authors.initials: A
authors.lastname: Bousquet-Melou
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001419:Bacteria / Q000187:drug effects*; D024841:Fluoroquinolones / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D041981:Gastrointestinal Tract / Q000382:microbiology*; D007273:Injections, Intramuscular; D007422:Intestines / Q000737:chemistry; D008168:Lung / Q000382:microbiology*; D010949:Plasma / Q000737:chemistry; D013552:Swine
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; C080260:marbofloxacin
keywords: Bactericidal activity; Commensal microbiota; Fluoroquinolone; Inoculum size; Marbofloxacin