Quantitation of Anti-Infectious Disease Molecules Utilizing Paper Spray Mass Spectrometry

Abstract

Suboptimal dosing of anti-microbial agents increases the likelihood of therapeutic failure and resistance. Dosing optimization, while an attractive approach to combat these issues, is difficult to implement due to the different pharmacokinetics of each individual. These limitations highlight the inadequacies of a “standardized” dosing strategy. Therapeutic drug monitoring (TDM) provides a tailored treatment for individuals while avoiding adverse side effects from compounds with a narrow therapeutic window where elevated concentrations of a drug cause organ toxicity. This strategy involves accurately measuring the concentration of the analyte and interpreting the results based on pharmacokinetic parameters. Clinicians then draw conclusions regarding dose adjustment for their patient. However, TDM is expensive and difficult to perform because measurements occur in biofluids. Rapid and robust methods are necessary to quantify antimicrobial agents at the institutional level to guide patient care toward improved outcomes in serious infection. Paper spray ionization (PS), an emerging ambient ionization technique for clinical settings, demonstrations a wide versatility both in analyte variety and applications. This technique offers a rapid, accurate method to analyze these compounds with low rates of false positives even when multiplexing. The work herein explains the method development of assays for TDM of various antimicrobial agents. Chapters two and three describe ways to improve the quantitative capability of paper spray through substrate pre-treatment, modification, and manipulation of key factors. Chapter four describes real-world applications for paper spray utility in clinical settings with the cross-validation of antifungal agents against a “gold standard” method. The final chapter, while not clinical based, describes the method development process for a LC-MS/MS assay to detect urobilinoids in fly guts.