title: Effect of Surotomycin, a Novel Cyclic Lipopeptide Antibiotic, on Intestinal Colonization with Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice.
abstract: Surotomycin (formerly called CB-183,315) is a novel, orally administered cyclic lipopeptide antibacterial in development for the treatment of Clostridium difficile infection (CDI) that has potent activity against vancomycin-resistant enterococci (VRE) but limited activity against Gram-negative bacilli, including Bacteroides spp. We used a mouse model to investigate the impact of surotomycin exposure on the microbiome, and to test the consequences of the disruption on colonization by vancomycin-resistant enterococci (VRE) and extended-spectrum β-lactamase-producing Klebsiella pneumoniae (ESBL-KP), in comparison with the effects of oral vancomycin and metronidazole. Mice (8 per group) received saline, vancomycin, metronidazole, or surotomycin through an orogastric tube daily for 5 days and were challenged with 10(5) CFU of VRE or ESBL-KP administered through an orogastric tube on day 2 of treatment. The concentrations of the pathogens in stool were determined during and after treatment by plating on selective media. A second experiment was conducted to determine if the antibiotics would inhibit established VRE colonization. In comparison to controls, oral vancomycin promoted VRE and ESBL-KP overgrowth in stool (8 log10 to 10 log10 CFU/g; P < 0.001), whereas metronidazole did not (<4 log10 CFU/g; P > 0.5). Surotomycin promoted ESBL-KP overgrowth (>8 log10 CFU/g; P, <0.001 for comparison with saline controls) but not VRE overgrowth. Surotomycin suppressed preexisting VRE colonization, whereas metronidazole and vancomycin did not. These results suggest that treatment of CDI with surotomycin could reduce levels of VRE acquisition and overgrowth from those with agents such as vancomycin and metronidazole. However, surotomycin and vancomycin may promote colonization by antibiotic-resistant Gram-negative bacilli.
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 & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Chesnel
authors.affiliation: Merck & 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: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects; D007711:Klebsiella pneumoniae / Q000187:drug effects*; D055666:Lipopeptides / Q000494:pharmacology*; D008795:Metronidazole / Q000494:pharmacology; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology*; D014640:Vancomycin / Q000494:pharmacology; D020713:Vancomycin Resistance; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; C574454:CB-183,315; D055666:Lipopeptides; D010456:Peptides, Cyclic; D008795:Metronidazole; D014640:Vancomycin