R01AI150685

Characterizing Vancomycin-Resistant C. difficile Strains at Two Geographically Distinct Locations - Project Summary

Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea and death worldwide. As a result, the U.S. CDC has classified C. difficile (CD) as an urgent public health threat. Recent guidelines from the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America recommended oral vancomycin or fidaxomicin for both non-severe and severe CDI cases. Because of the high cost of fidaxomicin, vancomycin is now the drug of choice, making it the most important antibiotic for the treatment of CDI.

The foundation for this work is based on our recent discovery of CD strains in patients from Texas and Kenya exhibiting reduced susceptibility to both metronidazole and vancomycin. We examined diarrhea CDI stools from 438 patients from Texas and 98 from Kenya for the presence of metronidazole- and vancomycin-non-susceptible CD isolates. Of the stools from Houston, 114/438 (26%) grew CD isolates that were not susceptible to vancomycin, 128/438 (29%) to metronidazole, and 97/438 (22%) to both metronidazole and vancomycin. Among the Kenyan patients, 66/98 (67%) were not susceptible to vancomycin, 83/98 (85%) to metronidazole, and 57/98 (58%) to both antibiotics. Alarmingly, many of the isolates from both locations showed levels of non-susceptibility to these antibiotics that far exceeded their known MICs.

Whole-genome sequencing showed the presence of homologs of VANA and VANB gene clusters, common mediators of high-level vancomycin resistance in many hospital-associated pathogens. Until now, such high-level vancomycin non-susceptibility has not been reported in CD strains. The spread of CD strains resistant to vancomycin, a front-line antibiotic for this life-threatening pathogen, will have serious clinical and public health implications. This underscores an urgent need for a comprehensive analysis of the circulating strains, mechanisms of resistance, and how it impacts clinical outcomes to help inform clinical decisions.

Our preliminary evidence strongly supports the hypothesis that vancomycin non-susceptible CD strains may be widespread in the CDI patient population and that strains circulating on the African continent may be genetically different from strains circulating in North America. To investigate this hypothesis, we will:

(I) Assess the proportion of CDI patients from Texas and Kenya infected with vancomycin non-susceptible strains and compare the infecting strains;
(II) Characterize the genetic elements associated with vancomycin non-susceptibility; and
(III) Prospectively follow CDI patients infected with vancomycin non-susceptible strains to assess disease severity, clinical outcome, and rate of recurrence of the infection following treatment.

Due to the current importance of vancomycin in CDI treatment, the proposed research will have a major impact on clinical decisions. Importantly, the genetic elements responsible for high-level vancomycin non-susceptibility in CD strains and how it impacts disease severity, clinical outcome, and treatment will be established. This will provide insight into the extent of resistance and open up new avenues for long-term preventative and interventional strategies to mitigate deaths associated with this life-threatening pathogen.

University Of Texas Health Science Center At Houston

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Houston, Texas 770303870 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 384% from $702,187 to $3,395,135.