title: Effect of Fidaxomicin versus Vancomycin on Susceptibility to Intestinal Colonization with Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice.
abstract: The use of oral vancomycin or metronidazole for treatment of Clostridium difficile infection (CDI) may promote colonization by health care-associated pathogens due to disruption of the intestinal microbiota. Because the macrocyclic antibiotic fidaxomicin causes less alteration of the intestinal microbiota than vancomycin, we hypothesized that it would not lead to a loss of colonization resistance to vancomycin-resistant enterococci (VRE) and extended-spectrum-β-lactamase-producing Klebsiella pneumoniae (ESBL-Kp). Mice (8 per group) received orogastric saline, vancomycin, or fidaxomicin daily for 5 days at doses resulting in stool concentrations in mice similar to those measured in humans. The mice were challenged with 10(5) CFU of orogastric VRE or ESBL-Kp on day 2 of treatment and concentrations of the pathogens in stool were monitored. The impact of drug exposure on the microbiome was measured by cultures, real-time PCR for selected anaerobic bacteria, and deep sequencing. In comparison to saline controls, oral vancomycin promoted establishment of high-density colonization by VRE and ESBL-Kp in stool (8 to 10 log10 CFU/g; P < 0.001), whereas fidaxomicin did not (<4 log10 CFU; P > 0.5). Vancomycin treatment resulted in significant reductions in enterococci, Bacteroides spp., and Clostridium leptum, whereas the population of aerobic and facultative Gram-negative bacilli increased; deep-sequencing analysis demonstrated suppression of Firmicutes and expansion of Proteobacteria during vancomycin treatment. Fidaxomicin did not cause significant alteration of the microbiota. In summary, in contrast to vancomycin, fidaxomicin treatment caused minimal disruption of the intestinal microbiota and did not render the microbiota susceptible to VRE and ESBL-Kp colonization.
authors.affiliation: Department of Infectious Diseases, Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA Department of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Deshpande
authors.affiliation: Department of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hurless
authors.affiliation: Department of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Cadnum
authors.affiliation: Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Chesnel
authors.affiliation: Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Lihong
authors.initials: L
authors.lastname: Gao
authors.affiliation: Second Genome, Inc., San Bruno, California, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Chan
authors.affiliation: Department of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Sirisha
authors.initials: S
authors.lastname: Kundrapu
authors.affiliation: Department of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Polinkovsky
authors.affiliation: Department of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA Geriatric Research, Education and Clinical Center, Cleveland VA Medical Center, Cleveland, Ohio, USA curtisd123@yahoo.com.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Donskey
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001442:Bacteroides Infections / Q000188:drug therapy / Q000382:microbiology; D003013:Clostridium / Q000187:drug effects / Q000472:pathogenicity; D005243:Feces / Q000382:microbiology; D005260:Female; D000077732:Fidaxomicin; D000068536:Bacillota / Q000187:drug effects / Q000472:pathogenicity; D007422:Intestines / Q000382:microbiology*; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000472:pathogenicity; D051379:Mice; D008826:Microbial Sensitivity Tests; D060888:Real-Time Polymerase Chain Reaction; D014640:Vancomycin / Q000494:pharmacology / Q000627:therapeutic use*; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects* / Q000472:pathogenicity; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D014640:Vancomycin; D001618:beta-Lactamases; D000077732:Fidaxomicin