March 16, 2023
Faculty of Pharmacy, Keio University
A research group led by Wataru Tashiro, a fourth-year student in the Doctoral Programs at the Graduate School of Pharmaceutical Sciences, Keio University, along with Associate Professor Kazuaki Taguchi and Professor Kazuaki Matsumoto of the Faculty of Pharmacy at the same university, has established a new PK/PD evaluation method based on fecal kinetics for poorly absorbed antimicrobial agents, to which conventional pharmacokinetics/pharmacodynamics (PK/PD) evaluation methods cannot be applied.
Clostridioides difficile ( C. difficile ) is a drug-resistant bacterium recognized as a high-threat-level pathogen worldwide. C. difficile causes C. difficile infection (CDI), with diarrhea as its main symptom. CDI clinical practice guidelines in various countries position fidaxomicin (FDX) and vancomycin (VCM) as first-line drugs for treatment. However, since the dosage and administration of these drugs are largely based on experience and lack a strong scientific basis, their use can lead to treatment difficulties and concerns about the emergence of further drug-resistant bacteria.
Typically, the development of antimicrobial agents involves conducting PK/PD analysis based on drug concentrations in the blood to determine the optimal PK/PD parameters and their target values for each therapeutic agent, which then informs the dosage and administration for patients with infectious diseases. However, because FDX and VCM are not absorbed from the gastrointestinal tract and exert their effects directly on C. difficile in the intestine, they could not be analyzed using conventional PK/PD evaluation methods.
This research group has newly established a PK/PD analysis method for poorly absorbed antimicrobial agents based on fecal drug concentrations and has determined the optimal fecal PK/PD parameters and their target values for treating CDI with the poorly absorbed CDI therapeutics FDX and VCM. Furthermore, using the fecal drug concentrations when standard doses of FDX or VCM were administered to CDI patients and the obtained target fecal PK/PD parameter values for FDX and VCM, the group identified the minimum inhibitory concentration (MIC) of C. difficile at which efficacy can be expected—that is, the breakpoint MIC. The breakpoint MIC is an indicator for evaluating the action of antimicrobial agents and serves as useful basic data when selecting an antimicrobial agent for CDI patients.
The results of this research are expected to contribute to the proper use of poorly absorbed antimicrobial agents in CDI patients and to promote the development of new, evidence-based antimicrobial agents using this method.
This research was published in the international academic journal "Clinical Microbiology and Infection" on December 24, 2022 (Central European Time).
For the full press release, please see below.