Antibiotic Distribution and Recovery in Tissue

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Antimicrobial resistance imposes an important health and economic burden with the threat of a future without effective antibiotics requiring major changes to contemporary healthcare provision. Therefore, the discovery and development of novel mechanism of action agents able to treat resistant infections is a key urgent need. Gepotidacin is a first in class, novel triazaacenaphthylene antibacterial that is being developed by GSK. Due to its novel mechanism of action, gepotidacin is active in vitro against most target pathogens carrying resistance determinants to established antibacterials, including fluoroquinolones. Gepotidacin has broad gram-positive activity and selective gram-negative activity and is currently under development as a treatment for infections caused by N. gonorrhoeae (urogenital gonorrhoea) and E. coli (acute uncomplicated urinary tract infections), including isolates resistant to existing classes of antimicrobials. To explore the potential of gepotidacin to treat infections caused by N. gonorrhoeae or E. coli at other body sites, the AB-DiRecT consortium will conduct a tissue distribution study in tonsil and prostate after single oral dose of gepotidacin in healthy (non-infected) subjects undergoing elective tonsillectomy or prostatectomy. Microdialysis will be used to measure gepotidacin levels in tissue following surgery and PBPK, PopPK and PKPD models will be built to understand the tissue penetration of gepotidacin to characterize exposure response and to evaluate different dose regimens. Difference between infected and healthy tissue will be explored in an animal prostatitis infection model where gepotidacin PK in plasma and tissue will be determined using microdialysis. Overall the data generated in AB-DiRecT may support the potential for clinical trials to determine the efficacy of gepotidacin for the treatment for pharyngeal N. gonorrhoeae infections and / or prostatitis caused by E. coli.