Sadouki, Zahra; (2024) Approaches to improved dosing of antibiotic combinations for the treatment of complex gram-negative bacterial infections. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Infections caused by multi drug resistant (MDR) gram negative bacteria in critically ill patients and complex clinical settings present challenges to the selection of appropriate antimicrobial dosing. Antibacterial therapy aims to achieve target bacterial killing and suppression of re-emergence and resistance. International standards of in vitro dynamic concentration methods for determining the attainment of these endpoints against unconventional antimicrobial regimens do not exist. Therefore, approaches of improving dosing of repurposed antibiotic combinations to provide improved understanding of the pharmacodynamics (PD) of the drug-drug interactions were explored. For example, semimechanistic modelling of in vitro static time kill experiments conducted found meropenem and gentamicin both lower the IC50 of ciprofloxacin and prevent re-growth and resistance. Thus, providing therapeutic options to be explored for the treatment of gram-negative bacteria at Royal Free London NHS Foundation Trust (RFL). This thesis also applied dynamic in vitro infection models to investigate the PD responses. A Prisma systematic review on the use of the hollow fibre infection model (HFIM) found wide variability in reporting of both engineering and biological parameters. Therefore, this thesis developed published guidelines for suggested minimum standards of reporting to develop robust international HFIM methodology. This thesis applied the HFIM in two clinical settings. Firstly, a simulated exposure of Ceftazidime-Avibactam 2.5g with Aztreonam 2g proposed regimen to be administered to a patient prior to orthotopic liver transplantation (OLT). Results demonstrated slow killing dynamics with three eight hourly infusions required to supress the XDR E. coli bacterial load below the limit of detection (LOD). This provided the rationale for altered antimicrobial administration for this patient. Secondly this thesis simulated exposures in the HFIM of antibiotic regimens to be administered into the OrganOxmetra™, a normothermic liver preservation device shown in RCTs to increase the liver donor. HFIM data showed in vitro activity of both fifteen times less meropenem dosing than standard protocol or a β-lactam free combination therapy were both sufficient at maintaining CFU/mL below the LOD. Thus, this provided rationale for improved dosing and updated the local protocol to meet best clinical practise. In summary this thesis details the applications and considerations of different approaches to determine in vitro antibacterial activity to inform antibacterial combination dosing for complex gram-negative bacterial infections and systems.

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