Repurposing niclosamide for intestinal decolonization of vancomycin-resistant enterococci

• Published in: International journal of antimicrobial agents 2018-06, Vol.51 (6), p.897-904
• Main Authors: Mohammad, Haroon, AbdelKhalek, Ahmed, Abutaleb, Nader S., Seleem, Mohamed N.
• Format: Article
• Language: English
• Subjects: Animals; Anthelmintic; Anti-Bacterial Agents - therapeutic use; Antibiotics; Decolonization; Depsipeptides - therapeutic use; Drug Repositioning; Feces - microbiology; Humans; Intestines - microbiology; Linezolid - therapeutic use; Mice; Microbial Sensitivity Tests; Niclosamide - therapeutic use; Oxyclozanide - pharmacology; Rafoxanide - pharmacology; Repurposing; Resistance; Salicylanilide; Salicylanilides - pharmacology; Vancomycin - pharmacology; Vancomycin Resistance; Vancomycin-Resistant Enterococci - drug effects; Vancomycin-Resistant Enterococci - growth & development
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2018.02.003

•Niclosamide, an anthelmintic, is evaluated as a decolonizing agent for enterococci.•Niclosamide has antibacterial activity against Enterococcus faecium but not Enterococcus faecalis.•Vancomycin-resistant E. faecium (VRE) was unable to form resistance to niclosamide.•Niclosamide significantly reduced VRE shedding in faeces of colonized mice.•Niclosamide significantly decreased VRE in the caeca and ilea of infected mice. Enterococci are commensal micro-organisms present in the gastrointestinal tract of humans. Although normally innocuous to the host, strains of enterococcus exhibiting resistance to vancomycin (VRE) have been associated with high rates of infection and mortality in immunocompromised patients. Decolonization of VRE represents a key strategy to curb infection in highly-susceptible patients. However, there is a dearth of decolonizing agents available clinically that are effective against VRE. The present study found that niclosamide, an anthelmintic drug, has potent antibacterial activity against clinical isolates of vancomycin-resistant Enterococcus faecium (minimum inhibitory concentration 1–8 µg/mL). E. faecium mutants exhibiting resistance to niclosamide could not be isolated even after multiple (10) serial passages. Based upon these promising in-vitro results and the limited permeability of niclosamide across the gastrointestinal tract (when administered orally), niclosamide was evaluated in a VRE colonization-reduction murine model. Remarkably, niclosamide outperformed linezolid, an antibiotic used clinically to treat VRE infections. Niclosamide was as effective as ramoplanin in reducing the burden of vancomycin-resistant E. faecium in the faeces, caecal content and ileal content of infected mice after only 8 days of treatment. Linezolid, in contrast, was unable to decrease the burden of VRE in the gastrointestinal tract of mice. The results obtained indicate that niclosamide warrants further evaluation as a novel decolonizing agent to suppress VRE infections.