CDC identified in a 2013 report, C. difficile (CD) associated disease (CDAD) as "urgent public health threat" responsible for at least 14,000 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 (NAP1/027/B1) 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-15-037) 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 20 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 NAP1/027/B1 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: 1) CFM has over forty years' history of safe use in lepromatous leprosy and multidrug- resistant TB treatment; 2) It has also been used against Crohn's disease, an inflammatory condition of the intestine, as well as other autoimmune conditions; 3) Its bactericidal activity appears to preclude the emergence of resistant mutants of targeted bacteria; 4) It has exhibited promising pharmacological and toxicological data for human use; 5) Half-life of 8-10 days even after a single dose, and upto 70 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: 1) Pharmacokinetic study to identify drug formulation and lowest delivery dose that would optimize bioavailability of CFM in the gut lumen; 2) establish conditions of animal model for CDAD in our hands especially to determine minimal amount of CD NAP1/027/B1 spores to kill all clindamycin treated animals; followed by 3) testing 3 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 100% survival for over 27 days in animal model, a goal to do initial clinical trials during this Phase II period.
Public Health Relevance Statement: Public Health Relevance: Investigate potential of Clofazimine CFM (used for over 40 years to treat leprosy and MTB-DR) to treat C. difficile (CD) associated disease (CDAD) an "Urgent Public Health Threat". 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.
NIH Spending Category: Antimicrobial Resistance; Biodefense; Digestive Diseases; Emerging Infectious Diseases; Infectious Diseases
Project Terms: Acids; Address; Affect; Animal Disease Models; Animal Diseases; Animal Model; Animals; Antibiotics; antimicrobial drug; Autoimmune Diseases; Autoimmune Process; Bacteria; bactericide; base; Bioavailable; Biological Availability; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clindamycin; Clinical Trials; Clostridium difficile; Colon; Combined Modality Therapy; Control Groups; cost; Crohn's disease; Data; Development; Diarrhea; Disease; Disease model; Dose; Drug Controls; Drug Formulations; Drug Kinetics; Drug vehicle; Elderly; Epidemic; Equipment and supply inventories; Exhibits; Exposure to; fecal transplantation; Formulation; Funding; Generic Drugs; Goals; Growth; Half-Life; Hamsters; Hospitals; Human; human data; Immunization; in vitro activity; in vivo; Incentives; Incidence; Individual; Infection; Inflammatory; Ingestion; Intestines; Investments; Killings; Lead; Left; Length; Lepromatous Leprosy; Leprosy; Measures; Mesocricetus auratus; Metronidazole; Microbe; Modeling; Morbidity - disease rate; mortality; Multidrug-Resistant Tuberculosis; mutant; National Institute of Allergy and Infectious Disease; new growth; Oral; Pharmaceutical Preparations; pharmacokinetic model; Pharmacologic Substance; Pharmacology and Toxicology; Phase; phase 2 study; Phase II Clinical Trials; prevent; Probiotics; Property; prophylactic; Pseudomembranous Colitis; Public Health; public health relevance; Recording of previous events; Recurrence; Regimen; Reporting; Reproduction spores; Resistance; resistant strain; Rosa; Safety; Small Business Innovation Research Grant; Span 40; Staging; Survival Rate; Symptoms; Systemic infection; Testing; Therapeutic; Therapeutic Agents; Time; Toxic Megacolon; Toxin; Tuberculosis; tuberculosis drugs; tuberculosis treatment; United States National Institutes of Health; Vancomycin; Virulent; Work
