title: Efficacy of oral ramoplanin for inhibition of intestinal colonization by vancomycin-resistant enterococci in mice.
abstract: Ramoplanin is a glycolipodepsipeptide antibiotic with activity against gram-positive bacteria that is in clinical trials for prevention of vancomycin-resistant Enterococcus (VRE) bloodstream infections and treatment of Clostridium difficile diarrhea. Orally administered ramoplanin suppresses VRE intestinal colonization, but recurrences after discontinuation of treatment have frequently been observed. We used a mouse model to examine the efficacy of ramoplanin for inhibition of VRE colonization and evaluated the etiology of recurrences of colonization. Eight days of treatment with ramoplanin (100 microg/ml) in drinking water suppressed VRE to undetectable levels, but 100% of mice developed recurrent colonization; a higher dose of 500 microg/ml in water was associated with recurrent colonization in 50% of mice. Two of eight (25%) mice treated with the 100-microg/ml dose of ramoplanin had low levels of VRE in their cecal tissues on day 8 despite undetectable levels in stool and cecal contents. Mice that received prior ramoplanin treatment did not develop VRE overgrowth when challenged with 10(7) CFU of oral VRE 1, 2, or 4 days later. In communal cages, rapid cross-transmission and overgrowth of VRE was observed among clindamycin-treated mice; ramoplanin treatment effectively suppressed VRE overgrowth in such communal cages. Ramoplanin treatment promoted increased density of indigenous Enterobacteriaceae and overgrowth of an exogenously administered Klebsiella pneumoniae isolate. These results demonstrate the efficacy of ramoplanin for inhibition of VRE colonization and suggest that some recurrences occur due to reexpansion of organisms that persist within the lining of the colon. Ramoplanin treatment may be associated with overgrowth of gram-negative bacilli.
authors.affiliation: Division of Infectious Diseases, University Hospitals of Cleveland, Case Western Reserve University, Ohio 44106, USA.
authors.forename: Usha
authors.initials: U
authors.lastname: Stiefel
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Pultz
authors.forename: Marion S
authors.initials: MS
authors.lastname: Helfand
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Donskey
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D041221:Candida glabrata / Q000187:drug effects; D002432:Cecum / Q000382:microbiology*; D015169:Colony Count, Microbial; D003428:Cross Infection / Q000382:microbiology; D047630:Depsipeptides; D018562:Disease Transmission, Infectious; D016983:Enterococcus / Q000187:drug effects*; D005243:Feces / Q000737:chemistry / Q000382:microbiology; D005260:Female; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology / Q000635:transmission; D007711:Klebsiella pneumoniae / Q000187:drug effects; D051379:Mice; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020713:Vancomycin Resistance
chemical_list: D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; C041438:ramoplanin