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Analytical Procedures

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

Abhishek Deshpande, Kelly Hurless, Jennifer L. Cadnum, Laurent Chesnel, Lihong Gao, Luisa Chan, Sirisha Kundrapu, Alexander Polinkovsky, Curtis J. Donskey
Abhishek Deshpande
aDepartment of Infectious Diseases, Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
bDepartment of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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Kelly Hurless
bDepartment of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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Jennifer L. Cadnum
bDepartment of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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Laurent Chesnel
cMerck and Co., Inc., Kenilworth, New Jersey, USA
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Lihong Gao
cMerck and Co., Inc., Kenilworth, New Jersey, USA
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Luisa Chan
dSecond Genome, Inc., San Bruno, California, USA
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Sirisha Kundrapu
bDepartment of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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Alexander Polinkovsky
bDepartment of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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Curtis J. Donskey
bDepartment of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
eGeriatric Research, Education and Clinical Center, Cleveland VA Medical Center, Cleveland, Ohio, USA
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DOI: 10.1128/AAC.02590-15
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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 105 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.

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Effect of Fidaxomicin versus Vancomycin on Susceptibility to Intestinal Colonization with Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice
Abhishek Deshpande, Kelly Hurless, Jennifer L. Cadnum, Laurent Chesnel, Lihong Gao, Luisa Chan, Sirisha Kundrapu, Alexander Polinkovsky, Curtis J. Donskey
Antimicrobial Agents and Chemotherapy Jun 2016, 60 (7) 3988-3993; DOI: 10.1128/AAC.02590-15

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Effect of Fidaxomicin versus Vancomycin on Susceptibility to Intestinal Colonization with Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice
Abhishek Deshpande, Kelly Hurless, Jennifer L. Cadnum, Laurent Chesnel, Lihong Gao, Luisa Chan, Sirisha Kundrapu, Alexander Polinkovsky, Curtis J. Donskey
Antimicrobial Agents and Chemotherapy Jun 2016, 60 (7) 3988-3993; DOI: 10.1128/AAC.02590-15
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