Near patient molecular diagnostics test for infections

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ABSTRACT Currently, there are no FDA cleared molecular-based tests for urinary tract infection (UTI) pathogen identification and antimicrobial susceptibility testing to replace the 'gold standard' of dipstick urinalysis and urine culturing. All pathogen identification tests still rely on clinical isolates from urine cultures, largely unchanged from Koch's postulates developed in the 19th century as general guidelines to identify pathogens. What has changed over time, however, is the dramatic and progressive emergence of antibiotic resistance among these pathogens. Data from the Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN) indicate that 70% of the pathogens isolated from hospital-acquired infections (HAIs) now are resistant to at least 2 major classes of antibiotics. Recent developments in molecular diagnostic testing for multidrug resistant (MDR) pathogens can provide a sensitive, specific, and real-time solution to support active surveillance-driven infection control interventions, but these PCR-based tests can only be performed on simple specimen matrices such as swabs or positive blood culture media (1:10 blood-to-broth ratio). No molecular-based method is cleared by the FDA to test directly on urine or whole blood samples. The goal of this Commercialization Readiness Pilot (CRP) Grant is to accelerate the commercialization effort of the program outcome from our NIAID SBIR R44AI088756 project titled “An Integrated Diagnostic System for Rapid Antimicrobial Susceptibility Testing (AST)”. We propose technical assistance on regulatory strategy development and cost-effective manufacturing, as well as later stage research and development activities on independent replication of key studies in compliance with FDA requirements and ISO 13485 standards. The goal of our NIAID Advanced Technology SBIR project is to develop and validate RAST (rapid antimicrobial susceptibility testing), an integrated and compact diagnostic system that enables clinicians direct point-of-care (POC) with an evidence-based selection of antibiotics for treatment of acute bacterial infections. Our first compact automated system is capable of rapid pathogen identification (ID) and AST directly from patient's samples with evidenced-based information to start patient-specific antimicrobial treatment. It is expected to obtain a CE Mark after the coming ISO 13485 surveillance certification audit in February 2016. However, the FDA clearance is hindered by: (1) no molecular-based predicate test cleared by the FDA for urinary tract infections (UTI), (2) the low cost of conventional dipstick urinalysis tests, and (3) the lack of fresh urine specimens through a multi- site clinical feasibility study. We will overcome these hurdles through the following aims: TECHNICAL ASSISTANCE Aim 1: Obtain a risk-based classification of the Class II device through a de novo request with external regulatory assistance from NSF International (an international certification organization) in 18 months Aim 2: Reduce the cost of goods sold of <$3 for cartridge and <$5k for system with external manufacturing development assistance LATE STAGE RESEARCH AND DEVELOPMENT ACTIVITIES Aim 3: Conduct a multi-center clinical performance study and demonstrate >95% clinical sensitivity/specificity and >95% susceptibility categorical agreement In this study, we focus on validating the rapid UTI diagnostic device according to federal regulations 21 CFR 866.2660 (microorganism differentiation and identification device), 21 CFR 866.1640 (antimicrobial susceptibility test powder), and 21 CFR 866.1645 (fully automated, short-term incubation cycle antimicrobial susceptibility testing system). The FDA product codes for such systems are “JSS” and “LON.” The regulatory strategy will be finalized in Aim 1 (Regulatory) for preparation of the clinical protocol and multicenter clinical performance study in Aim 3 (Clinical study) that will utilize the cost-effective system and consumables optimized in Aim 2 (Manufacturing).