In Vivo Efficacy Studies of Clofazimine against CDAD in Hamster Model

DESCRIPTION provided by applicant CDC identified in a report C difficile CD associated disease CDAD as andquot urgent public health threatandquot responsible for at least deaths annually A primary factor for origin of CDAD is exposure to broad spectrum antibiotics causing a disruption of normal intestinal bacterial flora unchecked growth of CD and its toxins causing serious inflammatory damage to colon wall Recent emergence and spread of a more virulent strain of CD NAP B is accompanied by a decrease in efficacy of current drug regimens of metronidazole MET and vancomycin leading at times to fatal conditions Recent RFI from NIAID HHS NIH NIAID BAA shows an urgent need for a therapeutic agent that can overcome the re occurrence problems arising from either emergence of resistant strains of CD and or from ingestion and growth of new spores in a hospital setting It is both incentive and cost prohibitive for major pharmaceuticals to invest in discovery and development of new antimicrobial agents with low return on investment leaving repurposing of generics as a favorite choice Based on over yrs of work on tuberculosis TB with clofazimine CFM antibiotic the PI tested in detail and found its activity to be excellent against many strains of D including NAP B in culture and not so for a majority of normal flora of the gut This data led us to examine the properties of CFM to treat CDAD and found to be worth exploring These are CFM has over forty yearsandapos history of safe use in lepromatous leprosy and multidrug resistant TB treatment It has also been used against Crohnandapos s disease an inflammatory condition of the intestine as well as other autoimmune conditions Its bactericidal activity appears to preclude the emergence of resistant mutants of targeted bacteria It has exhibited promising pharmacological and toxicological data for human use Half life of days even after a single dose and upto days after a course of treatment could protect against reinfection with new spores in a hospital These properties make CFM great candidate to explore its efficacy in a CDAD animal model To this end we need non dilutive SBIR phase I funding to do Pharmacokinetic study to identify drug formulation and lowest delivery dose that would optimize bioavailability of CFM in the gut lumen establish conditions of animal model for CDAD in our hands especially to determine minimal amount of CD NAP B spores to kill all clindamycin treated animals followed by testing pre selected doses of preselected formulation of CFM on CDAD animals to show improvement in survival Acceptable data would lead to SBIR phase II study to Optimize Dose time to treat before or after CD challenge to achieve survival for over days in animal model a goal to do initial clinical trials during this Phase II period PUBLIC HEALTH RELEVANCE Investigate potential of Clofazimine CFM used for over years to treat leprosy and MTB DR to treat C difficile CD associated disease CDAD an andquot Urgent Public Health Threatandquot We found CFM to be differentially active against CD in culture as compared to other gut microbes and at this stage propose to investigate its efficacy in animal model