Description:
OBJECTIVE: Develop a miniaturized, point of care, analyzer for rapidly determining peak and trough concentrations of antibiotics and antifungals in blood and serum to provide for real-time therapeutic drug monitoring in fixed and field medical treatment facilities. DESCRIPTION: Antibiotics are one of the most commonly prescribed and therapeutically monitored drugs in clinical practice. Due to issues related to efficacy and toxicity, select groups of antibiotics (e.g. aminoglycosides, glycopeptides) and antifungals (e.g azoles) are typically monitored for peak and trough concentrations in serum. Aminoglycosides, such as gentamicin, tobramycin and amikacin, are frequently used to treat potentially life threatening gram negative infection in wounded soldiers. Vancomycin, a glycopeptide, is the most frequently prescribed drug to treat methicillin resistant Staphylococcus aureus infections. Currently, these drugs are therapeutically monitored by commercially available platforms and tests. While commercial systems can determine peak and trough concentrations of many antibiotics and antifungals, they are generally large, require an inventory of several different individual assays, and have turn-around-times (TAT) that not conducive to real-time monitoring. These shortcomings make these systems less than ideal for the monitoring of drugs at deployed medical treatment facilities, which require smaller devices, smaller inventories of tests and more rapid TAT. A small, rapid, drug generic (e.g. STAT test) point-of-care like device is needed that can determine peak and trough concentrations of antibiotics and other therapeutic drugs in real-time so that medical practitioners can make more accurate decision on dosing and toxicity of administered drugs. PHASE I: During this Phase I, the contractor will develop and demonstrate a prototype, point-of-care analyzer for rapidly determining concentrations of antibiotics in liquids to provide for real-time therapeutic drug monitoring of a variety of drugs. The analyzer envisioned should have the following characteristics. The analyzer should have minimal processing steps, or preferably be autoprocessing capable. It should be capable of providing a resultant drug concentration in less than 60 minutes of sample receipt, including all sample preparation time. The analyzer should be a single device capable of identifying a wide range of drugs at both low (e.g.<0.1 g/ml) and high concentrations (>100 g/ml). It should have a user friendly interface and be capable of resulting out drug identification and concentration in a format that is easy to read and understand. The analyzer should be no larger than 24 cubic inches in dimension and preferably be smaller than 12 cubic inches. The specific deliverables of this Phase I award will be 1) the contractor will develop a prototype analyzer matching the above description and 2) will determine the feasibility of the analyzer for identifying and defining the detectable concentration ranges for vancomycin and tobramycin in a simple sample matrix, such as phosphate buffered saline. Technical Readiness Level (TRL) level at the end of Phase I should be TRL4. PHASE II: The contractor will further develop and optimize the prototype, point-of-care analyzer for determining concentrations of a variety of antibiotics and antifungals in complex matrices. The contractor will demonstrate the ability of analyzer to identify the following antibiotics and antifungals in blood and serum: vancomycin, teicoplanin, telavancin tobramycin, gentamicin, amikacin, arbekacin, colistin, amphotericin B, itraconazole, fluconazole, voriconazole, posaconazole, and flucytosine; and will define the detectable concentration ranges for each drug in these matrices. Contractor is highly encouraged to demonstrate analyzer"s ability to identify and define concentration ranges of other antibiotics and antifungals and other drugs. During PHASE II, the contractor is expected to develop and implement the all the preclinical work needed to advance the prototype analyzer into clinical development. At the end of PHASE II, it is envisioned that the contractor will have conducted a pre-investigation device exemption (IDE) communication with the Food and Drug Administration (FDA), completed all the necessary preclinical studies, and obtained approvals for protocols required for moving the analyzer into clinical studies enroute to FDA clearance. TRL level at the end of Phase II should be TRL5. PHASE III: During PHASE III, the contractor will design, develop and execute required clinical studies to support a 510(k) submission to the FDA to obtain clearance for the analyzer. The envisioned endstate for PHASE III is an analyzer that is FDA cleared to determine and monitor peak and trough concentrations for vancomycin, tobramycin, gentamicin, amikacin, colistin, itraconazole, voriconazole, posaconazole, and flucytosine. Contractor is highly encouraged to obtain FDA clearance for determining the peak and trough concentrations of other antibiotics, antifungals and drugs. TRL level at the end of Phase III should be TRL8. REFERENCES: 1. Begg EJ, Barclay ML and Kirlpatrick CMJ. The therapeutic monitoring of antimicrobial agents. Br J Clin Pharmacol. 2001;52 Suppl 1:35S-43S. 2. Goodwin ML and Drew RH. Antifugal serum concentration monitoring: an update. J Antimicrob Chemother. 2008 Jan;61(1):17-25. 3. Cooks RG, Manicke NE, Dill AL, Ifa DR, Eberlin LS, Costa AB, Wang H, Huang GM and Ouyang Z. New ionization methods and miniature mass spectrometers for biomedicine: DESI imaging for cancer diagnostics and paper spray ionization for therapeutic drug monitoring. Faraday Discussions, 2011, 149, 247-267 4. Touw DJ, Neef C, Thomson AH and Vinks AA. Cost-Effectiveness of Therapeutic Drug Monitoring. Current controversies in shock and resuscitation. Ther Drug Monit.2005 Feb;27(1):10-7. 5. Avent ML, Rogers BA, Cheng AC and Paterson DL. Current use of aminoglycosdes: indications, pharmacokinetics and monitoring for toxicity. Intern Med J. 2011 Jun;41(6):441-9. 6. Rybak MJ, Lomaestro BM, Rotschafer JC, Moellering RC Jr, Craig WA, Billeter M, Dalovisio JR, Levine DP. Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2009 Nov; 29(11):1275-9.
