Effect of Parenteral Fluoroquinolone Administration on Persistence of Vancomycin-Resistant Enterococcus faecium in the Mouse Gastrointestinal Tract

Abstract

We examined the effect of subcutaneous fluoroquinolone antibiotic administration on persistence and density of vancomycin-resistant Enterococcus faecium stool colonization in mice. Levofloxacin and ciprofloxacin did not promote colonization in comparison to saline controls, whereas moxifloxacin and gatifloxacin promoted persistent overgrowth in a dose-dependent fashion.In a mouse model and in colonized patients, we have demonstrated that antibiotics with potent in vitro activity against intestinal anaerobes promote persistent high-density colonization with vancomycin-resistant Enterococcus faecium (VRE), whereas antibiotics with minimal antianaerobe activity (including ciprofloxacin) do not (4, 5). Although some fluoroquinolone antibiotics have enhanced in vitro activity against anaerobes (e.g., moxifloxacin and gatifloxacin) (1, 13), studies with human volunteers have demonstrated that none of the currently available agents in this class cause a significant reduction in the density of intestinal anaerobes (2,(6)(7)(8)(9)14). Therefore, we examined the effect of fluoroquinolone antibiotics with various levels of antianaerobe activity on the persistence of VRE stool colonization in mice.The mouse model that we have previously utilized to study the effect of antibiotics on persistence of VRE stool colonization was used (4). Male CF1 mice (Harlan Sprague-Dawley, Indianapolis, Ind.) weighing 25 to 30 g were housed in individual cages and fed rodent chow and water ad libitum. VRE colonization with Enterococcus faecium strain C68 was established in all mice by administering oral vancomcyin (250 g/ liter) in drinking water for 2 days before and 5 days after esophageal instillation of 10 8 CFU of VRE in 0.5 ml (4). After discontinuation of oral vancomycin, mice were begun on twice-daily subcutaneous injections of saline (negative controls) or antibiotics for 15 days. Three different doses of the fluoroquinolone antibiotics were studied: a low dose equal to the usual human dose administered over a 24-h period (milligrams of antibiotic per gram of body weight); a medium dose of 5 times the low dose, and a human-equivalent dose of 12 times the usual human dose calculated by the technique of Freireich et al. (11). The dose of levofloxacin was based on the 750-mg-per-day human dose. Gatifloxacin and moxifloxacin were administered only at the lower two dosages because the highest dosage of these agents resulted in significant subcutaneous tissue irritation. The dosages included ciprofloxacin at 0.4, 2, and 4.8 mg/day; levofloxacin at 0.375, 1.875, and 4.7 mg/day; gatifloxacin at 0.2 and 1 mg/day; and moxifloxacin at 0.2 and 1 mg/day. Clindamycin at 1.4 mg/day promoted persistent high-density colonization in previous experiments and was included as a positive control (4).Four mice were included in each experimental group, and the experiments were performed twice (eight mice per group). Stool samples were collected prior to starting subcutaneous antibiotics and then on days 5, 10, and 15 of antibiotic therapy. To measure the de...

Probiotics and Intestinal Colonization by Vancomycin-Resistant Enterococci in Mice and Humans

“…Eight out of eight mice who had received prior oral vancomycin became colonized with VRE, with counts ranging from 3.2 ϫ 10 6 to 8.3 ϫ 10 9 CFU/g of feces on D9 (48 h after VRE inoculation) ( Fig. 1), similar to the observations of Donskey et al (1). These levels of VRE fecal concentration persisted for 9 days, including 2 days after vancomycin was stopped, and then rapidly declined to reach a level of 10 3 to 10 4 CFU/g of feces on D26, which was maintained in five mice up to D80 (Fig.…”

Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans

“…Although previous studies have demonstrated that antibiotic treatment can lead to increased colonization of the intestine by VRE (17,34), to our knowledge, the prevalence of VRE relative to other intestinal microbes has not been previously determined. To address this question, untreated and ampicillin-treated mice were infected with 10 8 CFUs of VRE.…”

Effect of Fidaxomicin versus Vancomycin on Susceptibility to Intestinal Colonization with Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice

“…Several pathogens were studied here, including E. faecium C68, a previously described VanB-type clinical VRE isolate (7). K. pneumoniae P62 is a clinical isolate that produces an SHV type extendedspectrum ␤-lactamase (ESBL).…”

“…K. pneumoniae P62 is a clinical isolate that produces an SHV type extendedspectrum ␤-lactamase (ESBL). Both organisms have been used in previous mouse model studies (7,8).Susceptibility testing. Broth dilution MICs of the test antibiotics for the test organisms were determined using standard methods for susceptibility testing of aerobic bacteria (9).…”