Antimicrobial resistance is a growing health problem in the United States with more than two million people are infected annually and >23,000 deaths. A major challenge in antibiotic-resistant bacterium-mediated bloodstream infections (BSI) is diagnosis: by the time doctors identify the bacteria species to refine treatment, it can b too late. Indeed, the current gold standard for bacteria detection, blood culture, takes days to get a result while other molecular diagnosis methods such as PCR are often not sensitive enough to directly detect bacteria that occur at low concentrations in blood (1-100 CFU/mL). We have developed a platform technology called Integrated Comprehensive Droplet Digital Detection (IC 3D). This system is able to rapidly (1-3 h) and selectively detect bacteria from milliliters (mLs) of unprocessed whole blood at single-cell sensitivity in a one-step, and culture- and amplification-free reaction. The proposed study aims to develop and validate new IC 3D tests for rapid detection of carbapenem-resistant Enterobacteriaceae (CRE) and extended spectrum beta lactamase (ESBL) because of their critical importance as Gram-negative pathogens for which few antimicrobials are active. We will also work with our industrial partners including ISS Inc, Dolomite Microfluidics and BioVenture Services (BVS), LLC to develop and validate an integrated, automated, portable IC 3D system and to perform product development activities towards future clinical approval. Specifically, we will 1) isolate and optimize DNAzyme sensors that specifically detect ESBLs and CREs (Aim 1), 2) Integrate and validate the IC 3D for rapid, single CRE and ESBL detection in blood (Aim 2), and 3) Validate the IC 3D for CRE and ESBL detection from clinical specimens (Aim 3). By the conclusion of this study, we will have developed and validated 1) a novel IC 3D diagnostic assay for rapid CRE and ESBL detection, and 2) a first generation instrument, which are ready for FDA submission and commercialization.

Public Health Relevance

Antimicrobial resistance is a growing health problem in the United States with more than two million people are infected annually and >23,000 deaths. We propose to develop an 'Integrated Comprehensive Droplet Digital Detection (IC 3D)' system that can rapidly detect antimicrobial resistant bacteria in blood. This new technology will direct early therapy and enable better antimicrobial stewardship and therefore have the potential to increase the survival and decrease the financial costs.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1)
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Ritchie, Alec
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University of California Irvine
Schools of Pharmacy
United States
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Li, Yiyan; Yang, Xing; Zhao, Weian (2017) Emerging Microtechnologies and Automated Systems for Rapid Bacterial Identification and Antibiotic Susceptibility Testing. SLAS Technol 22:585-608
Labanieh, Louai; Nguyen, Thi N; Zhao, Weian et al. (2015) Floating Droplet Array: An Ultrahigh-Throughput Device for Droplet Trapping, Real-time Analysis and Recovery. Micromachines (Basel) 6:1469-1482
Zhang, Kaixiang; Kang, Dong-Ku; Ali, M Monsur et al. (2015) Digital quantification of miRNA directly in plasma using integrated comprehensive droplet digital detection. Lab Chip 15:4217-26