title: Low or high doses of cefquinome targeting low or high bacterial inocula cure Klebsiella pneumoniae lung infections but differentially impact the levels of antibiotic resistance in fecal flora.
abstract: The combination of efficacious treatment against bacterial infections and mitigation of antibiotic resistance amplification in gut microbiota is a major challenge for antimicrobial therapy in food-producing animals. In rats, we evaluated the impact of cefquinome, a fourth-generation cephalosporin, on both Klebsiella pneumoniae lung infection and intestinal flora harboring CTX-M-producing Enterobacteriaceae. Germfree rats received a fecal flora specimen from specific-pathogen-free pigs, to which a CTX-M-producing Escherichia coli strain had been added. K. pneumoniae cells were inoculated in the lungs of these gnotobiotic rats by using either a low (10(5) CFU) or a high (10(9) CFU) inoculum. Without treatment, all animals infected with the low or high K. pneumoniae inoculum developed pneumonia and died before 120 h postchallenge. In the treated groups, the low-inoculum rats received a 4-day treatment of 5 mg/kg of body weight cefquinome beginning at 24 h postchallenge (prepatent phase of the disease), and the high-inoculum rats received a 4-day treatment of 50 mg/kg cefquinome beginning when the animals expressed clinical signs of infection (patent phase of the disease). The dose of 50 mg/kg targeting the high K. pneumoniae inoculum cured all the treated rats and resulted in a massive amplification of CTX-M-producing Enterobacteriaceae. A dose of 5 mg/kg targeting the low K. pneumoniae inoculum cured all the rats and averted an outbreak of clinical disease, all without any amplification of CTX-M-producing Enterobacteriaceae. These findings might have implications for the development of new antimicrobial treatment strategies that ensure a cure for bacterial infections while avoiding the amplification of resistance genes of human concern in the gut microbiota of food-producing animals.
authors.affiliation: INRA, UMR1331 TOXALIM, Toulouse, France.
authors.forename: Maleck V
authors.initials: MV
authors.lastname: Vasseur
authors.forename: Michel
authors.initials: M
authors.lastname: Laurentie
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: Rolland
authors.forename: Agnès
authors.initials: A
authors.lastname: Perrin-Guyomard
authors.forename: Jérôme
authors.initials: J
authors.lastname: Henri
authors.forename: Aude A
authors.initials: AA
authors.lastname: Ferran
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Toutain
authors.forename: Alain
authors.initials: A
authors.lastname: Bousquet-Mélou
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D058491:Bacterial Load; D002511:Cephalosporins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D005243:Feces / Q000382:microbiology; D007710:Klebsiella Infections / Q000188:drug therapy*; D007711:Klebsiella pneumoniae / Q000187:drug effects*; D008297:Male; D018410:Pneumonia, Bacterial / Q000188:drug therapy*; D051381:Rats
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C068212:cefquinome