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Real-time Assessment of Antimicrobial Concentrations for Personalized Treatment of Infectious Diseases

Description:

 
 

PROPOSALS ACCEPTED: Phase I and DP2. Please see the 16.2 DoD Program Solicitation and the DARPA 16.2 Direct to Phase II Instructions for DP2 requirements and proposal instructions.

TECHNOLOGY AREA(S): Biomedical, Materials/Processes

OBJECTIVE: Develop a real-time device capable of measuring small-molecule antibiotic drug concentrations from a small quantity of blood in less than 30 minutes. The application of this technology would be improved and personalized antibiotic administration, which would diminish the likelihood of the development of antimicrobial resistance.

DESCRIPTION: There is an urgent DoD need to optimize antimicrobial dosing to address the prevalence of drug-resistant pathogens and the increase of minimum inhibitory concentrations (MICs) of antimicrobials. Recent evidence suggests that current antimicrobial dosing may be inadequate for some critically ill patients. Specifically, variable metabolism of antibiotics due to the patient’s current state of illness, as well as heterogeneity among patients in the metabolism and antimicrobials, lead to substantial fluctuations in levels. The ability to measure drug concentrations in near real-time would greatly facilitate treatment and reduce the risk of administering suboptimal doses of antimicrobials. Unfortunately, the reliance on laboratory-scale equipment such as high-performance liquid chromatography (HPLC) to quantify drug concentrations precludes measurement at the point of care.

PHASE I: Develop a benchtop breadboard device to demonstrate feasibility of approach. Deliverables will include a detailed device design plan, regulatory plan, Phase II commercialization strategy, and Phase I final report.

PHASE II: Compare the performance of the breadboard device developed in Phase I with gold standard testing (e.g., HPLC) to determine the performance characteristics of the system in an in vitro and in vivo small animal model. Modify the approach to ensure that the device meets the minimum specifications outlined below. In addition, develop and implement a design-for-manufacturability strategy. Deliverables will include ten standalone prototype devices suitable for user evaluation, and Phase II final report.

The device prototype will be required to meet the following specifications:

 

• Antimicrobials of Interest: Amphotericin; Voriconazole; Colistin; Gentamicin; Meropenem (1 specimen per test)

 

• Specimen Matrix: Blood (< 50 µL drop)

 

• Limit of Detection: Dependent on drug (specify & justify in proposal)

 

• Dynamic Range: Dependent on drug (specify & justify in proposal)

 

• Error and Uncertainty: Specify & justify in proposal (compared to gold standard measurement and across multiple measurements)

 

• Test Turnaround Time (TAT): < 30 minutes

 

• Ease of Use: Low complexity; < 5 steps by user with one timed step requiring < 5 minutes of user intervention

 

• User Interface: Results displayed on screen with capability to save and recall previous results

 

• Power: AC and battery (> 8 hour lifetime; > 15 tests between charges)

 

• Training: Minimal; instructions and graphical aides sufficient for user operation

 

• Storage: Reagents do not require cold-chain and shelf stable > 12 months

 

• Form Factor: Handheld device for sample preparation and measurement

 

• Communications Interface: USB with computer for data upload/download

The ultimate device may be comprised of a disposable component containing the reagents and a non-disposable component (e.g., pumps, power supply, electronics etc.). The device form factor should be suitable for use at the point of care by a nurse or physician, similar to commercially available glucose meters. Sample preparation by the user should be minimal and all reagents required should be self-contained within a disposable component and not require refrigeration. The device should accept specimens from the patient using standard clinical methods (e.g., finger prick or venous whole blood).

PHASE III DUAL USE APPLICATIONS: A clear plan towards FDA approval for the device should be implemented and additional testing to meet FDA requirements will be completed. Additional funding may be provided by DoD sources, but the awardee must also look toward other government or civilian funding sources to continue the process of translation and commercialization. If successful, this device would have clinical utility in both civilian and military settings. Acquisition customers include the US Army Medical Research and Materiel Command (MRMC) and Defense Health Agency (DHA).

REFERENCES:

  • Akers, KS. Colistin Pharmacokinetics in Burn Patients during Continuous Venovenous Hemofiltration. Antimicrobial Agents and Chemotherapy 59, 46-52 (2015).
  • Ferguson, BS. Real-Time, Aptamer-Based Tracking of Circulating Therapeutic Agents in Living Animals. Science Translational Medicine 5, 213ra165 (2013).
  • Wong, G. How do we use therapeutic drug monitoring to improve outcomes from severe infections in critically ill patients? BMC Infectious Diseases 14, 288-299 (2014).

KEYWORDS: Therapeutic drug monitoring; point-of-care test; drug concentration; biosensor; personalized medicine

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