R01AI182167

ANIMAL MODELS TO DEVELOP NEW REGIMENS FOR S. AUREUS IMPLANT-ASSOCIATED INFECTIONS - STAPHYLOCOCCUS AUREUS IS THE LEADING CAUSE OF SERIOUS DEEP-SEATED OSTEOARTICULAR AND IMPLANT- ASSOCIATED INFECTIONS. S. AUREUS ORTHOPEDIC IMPLANT-ASSOCIATED INFECTIONS ARE DIFFICULT TO TREAT, REQUIRING SURGERY AND / OR PROLONGED SYSTEMIC ANTIBIOTICS (WEEKS-MONTHS). THEY ARE ALSO ASSOCIATED WITH EXTENDED DISABILITY AND REHABILITATION, CONTRIBUTING TO WORSE OVERALL OUTCOMES. ALTHOUGH INFECTION RATES OF ORTHOPEDIC IMPLANT-ASSOCIATED INFECTIONS HAVE REMAINED AT 1-2% AFTER PRIMARY AND 3-6% AFTER REVISION ARTHROPLASTY, INPATIENT COSTS AVERAGE $25,000-$107,000 PER CASE, AND AN ANNUAL HEALTHCARE BURDEN OF $3 BILLION IN THE U.S. ALONE. THE INCREASING PREVALENCE OF METHICILLIN-RESISTANT S. AUREUS (MRSA) IN THE U.S. AND WORLDWIDE, POSES YET ANOTHER CHALLENGE FOR THE TREATMENT OF THESE INFECTIONS, REQUIRING PROLONGED INTRAVENOUS ANTIBIOTICS. WE HAVE DEVELOPED ANIMAL MODELS OF S. AUREUS ORTHOPEDIC IMPLANT-ASSOCIATED INFECTIONS THAT REPLICATE KEY PATHOLOGICAL FEATURES OF HUMAN DISEASE AS WELL AS NOVEL, CLINICALLY TRANSLATABLE POSITRON EMISSION TOMOGRAPHY (PET) BIOIMAGING FOR HOLISTIC, NONINVASIVE LONGITUDINAL MEASUREMENTS IN LIVE SUBJECTS - BACTERIA-SPECIFIC DETECTION OF S. AUREUS INFECTIONS [11C-PARA-AMINOBENZOIC ACID (PABA), SELECTIVELY METABOLIZED VIA THE BACTERIAL FOLATE PATHWAY] AND 11C-RIFAMPIN, 18F-LINEZOLID, 18F-SUTEZOLID, ALL CHEMICALLY IDENTICAL TO THE PARENT ANTIBIOTIC, TO MEASURE ANTIBIOTIC AREA UNDER THE CURVE (AUC). RECENTLY, WE CONDUCTED FIRST-IN-HUMAN 11C-PABA (ORDONEZ ET AL. JCI INSIGHT 2022) AND 11C-RIFAMPIN (GORDON ET AL. SCI TRANSL MED. 2021) PET STUDIES IN HEALTHY VOLUNTEERS AND NEWLY IDENTIFIED PATIENTS WITH S. AUREUS ORTHOPEDIC IMPLANT INFECTIONS, RESPECTIVELY. WE SHOW THAT RIFAMPIN BONE EXPOSURES ARE SUBSTANTIALLY LOWER THAN PREVIOUSLY THOUGHT (BASED ON SINGLE TIME-POINT BIOPSY STUDIES). PHARMACOKINETIC MODELING OF THIS RICH PET DATA ENABLED THE DEVELOPMENT OF OPTIMIZED, SHORTER RIFAMPIN-BASED TREATMENTS FOR S. AUREUS ORTHOPEDIC IMPLANT INFECTIONS, WHICH AMELIORATED THE DEVELOPMENT OF ANTIBIOTIC RESISTANT BACTERIA, REDUCED MUTATIONS CONFERRING BACTERIAL PERSISTENCE, AND MITIGATED ADVERSE BONE REMODELING. HERE, WE WILL LEVERAGE OUR EXPERTISE IN BIOIMAGING, PHARMACOLOGY AND ANIMAL MODEL APPROACHES TO PERFORM COMPREHENSIVE PROOF-OF-PRINCIPLE STUDIES AND GAIN MECHANISTIC INSIGHTS INTO THE INTERPLAY OF SPATIOTEMPORALLY COMPARTMENTALIZED ANTIBIOTIC EXPOSURES (RIFAMPIN, LINEZOLID AND SUTEZOLID) AND BACTERIAL EVOLUTION / ACQUIRED DRUG RESISTANCE (ADR) DURING ANTIBIOTIC TREATMENTS, TO ESTABLISH RELAPSE-FREE CURE FOR S. AUREUS ORTHOPEDIC IMPLANT INFECTIONS. INTEGRATION OF FINDINGS FROM ANIMAL AND HUMAN STUDIES WILL ENABLE US TO REFINE OUR MODELS AND ADDRESS CLINICALLY RELEVANT CHALLENGES. KNOWLEDGE GAINED FROM THESE STUDIES WILL NOT ONLY PROVIDE UNIQUE MECHANISTIC INSIGHTS INTO BACTERIAL EVOLUTION AND ADR AND INFORM THE DEVELOPMENT OF NOVEL, SHORT, ORAL-ONLY THERAPEUTIC (ANTIBIOTIC) REGIMENS FOR S. AUREUS ORTHOPEDIC IMPLANT INFECTIONS, BUT WILL ALSO BE A MAJOR STRIDE TOWARDS DEVELOPING PRECISION MEDICINE TOOLS FOR AT-RISK PATIENTS WITH COMPLICATED S. AUREUS INFECTIONS.

The Johns Hopkins University

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]

Maryland United States

State-Wide

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