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Abbott Group

Pharmacodynamic Profiling of Antimicrobials

Overview

Developing robust and clinically relevant pharmacokinetic (PK) / pharmacodynamic (PD) models will enable us to engage in independent antimicrobial in vitro research and foster new collaborations with the biopharmaceutical industry on drug discovery, dosing and licensing. Our research outcomes will develop tools and an understanding of how to rationally optimise antimicrobial therapy in vulnerable patients. This will raise the standard of clinical care by establishing robust evidence, based on PK/PD principles, for personalised treatment regimens in patients. The broader scope of this work is to influence health policy in relation to antimicrobial licensing, susceptibility, indication and dosing recommendations.

Dr Iain Abbott is an early-career researcher, infectious diseases physician, and clinical microbiologist with expertise in urinary tract infection (UTI) PD in vitro modelling and a track record of securing major research grants, including an NHMRC EL-1 Investigator Grant and a U.S. FDA contract. He is also the Infection and Microbiome theme leader for the Monash University Bladder and Kidney Health Discovery Program. Ideally placed across the professional fields of clinical medicine, diagnostic microbiology and fundamental research, our research group is perfectly positioned to address complex clinical problems identified at the bedside, examine these questions in the research laboratory, and then translate the results back again to the patient.

Group Leader

Research areas

Our “iOASIS” research program focuses on the in-vitro optimisation of antimicrobials for superbug infections. Broadly across the different projects, our research aims are to:

Define optimised dosing for essential and new antimicrobials used in the treatment of common infections, such as urinary tract infections (UTIs), using dynamic PK/PD experimental systems
Characterise the impact of antimicrobial exposure on the emergence of resistance as determined by whole-genome sequencing and phenotypic antimicrobial susceptibility testing.
Evaluate clinical antimicrobial dosing schedules that integrates maximal efficacy with lowest risk for emergence of AMR using advanced mathematical PD modelling techniques.

UTIs are extremely common, affecting >400-million people worldwide annually. The burden of UTIs is increasing globally and is complicated by rising rates of antimicrobial resistance (AMR). UTIs are the most common infectious disease affecting our ageing population, and one of the most frequent healthcare-associated infections, particularly in patients with urinary catheters. Severe infections are a frequent cause of sepsis presentations to the Emergency Department. One in four women will have recurrent infections, representing a substantial global healthcare problem, with negative consequences for quality of life, mental health, socialising, engagement with work and daily activities, and sexual wellbeing.

There is a clear and pressing need for the development of effective oral antibiotics for the treatment of uncomplicated urinary tract infections (UTIs) caused by multidrug-resistant (MDR) uropathogens. New oral agents, such as gepotidacin and tebipenem provide optimism for the future antibiotic armamentarium, but development of resistance proportional to their use remains a concern. Current recommended oral antibiotic for UTIs, such as nitrofurantoin, fosfomycin tromethamine, ciprofloxacin and amoxicillin-clavulanate, and pivmecillinam have limited urinary pharmacokinetic (PK) and pharmacodynamic (PD) data to inform UTI-specific susceptibility breakpoints and dosing schedules that correlate with clinical and microbiological outcomes.

Our work examines how PK/PD investigations can advance the treatment options for patients with UTIs to provide a pathway for UTI drug development, inform susceptibility breakpoints, and optimise dosing schedules to prevent the emergence of resistance and preserve antibiotic activity for the future.

Projects

Bridging the gap between urinary tract infection PK/PD in vitro models and the optimization of antibiotic selection, dosing strategies, clinical breakpoints, and novel drug development
Funding
- US FDA 3-year contract (29 Sep 2023 – 28 Sep 2026)
Synopsis
To address the FDA Broad Agency Announcement (BAA-23-00123; III-B-1b), we examine opportunities to advance the methodology of uncomplicated UTI in vitro PK/PD modelling. We ensure a patient-focused agenda by embedding clinical links within our UTI drug development framework. We will leverage our unique dynamic bladder infection model (developed by our team) to evaluate the utility of such models to derive urine-specific antibacterial PK/PD parameters to drug development for uncomplicated UTIs. This work will characterize and model host and uropathogen variables within a simulated urinary environment to rationally optimize therapy for uncomplicated UTIs and forge a pathway for new drug development and evaluation.
This proposal outlines three connected Work Packages (WP) that will establish the urine-specific PK/PD parameters against Escherichia coli uropathogens for two common first-line oral antibiotics (nitrofurantoin and fosfomycin tromethamine) and two common second-line antibiotics (amoxicillin-clavulanate and ciprofloxacin).
- WP-1: Assess bacterial kill and emergence of resistance within a dynamic bladder infection model against contemporary E. coli uropathogens sourced from an expanded uropathogen biobank.
- WP-2: Determine urine-specific susceptibility breakpoints and optimise clinical dosage regimens through mechanism-based mathematical predictive models.
- WP-3: Clinical correlation and validation study in patients prescribed antibiotics for uncomplicated UTIs.
Innovating diagnostics, antibiotic treatment, and prevention strategies for urinary tract infections
Funding
- NHMRC EL-1 Investigator Grant (1 Jan 2025 – 31 Dec 2029)
Synopsis
Preclinical pharmacokinetic (PK) and pharmacodynamic (PD) infection models play a critical role in optimising clinical dosage regimens, susceptibility breakpoint determination, and “go or no go” drug development decisions. However, there are no established methods for deriving urine-specific antibiotic PK/PD parameters to support UTI-specific antibiotic susceptibility testing and the development of new UTI antibiotics active against multidrug resistant (MDR) uropathogens. Furthermore, data are lacking to support the translation of UTI PK/PD research to human studies.
This project will implement an innovative, bladder infection modelling platform that will provide a comprehensive bench-to-bedside approach to optimise diagnosis, antibiotic treatment, and prevention of uncomplicated UTIs. This will provide a pathway for future UTI drug development.
This work will address the clear and pressing need for improved diagnostics and the development of effective oral antibiotics for the treatment of MDR uropathogens. By implementing strategies that differentiate infections from colonisation, optimise therapy, prevent recurrence, and minimise unnecessary antibiotic will be of paramount importance both for individuals and the community.
Aims
- Develop novel UTI diagnostics that applies modern laboratory methods.
- Optimise oral antibiotic treatment using a dynamic bladder infection in vitro model.
- Investigate the role of the urobiome and bacteriophage-antimicrobial combinations in managing recurrent infections.
Phage-Antimicrobial Synergy targeting Escherichia coli and Klebsiella pneumoniae (PHASEK)
Funding
JPIAMR – Interventions moving forward to promote action to counteract the emergence and spread of bacterial and fungal resistance and to improve treatments (1 Apr 2025 – 31 Mar 2028)
Synopsis
Multidrug-resistant (MDR) bacterial infections constitute a major challenge, resulting in significant morbidity and mortality. One of the cornerstones of the management of AMR infections is development of antimicrobials. In recent years several novel antimicrobials have been developed, but the emergence of resistance has already been described, and novel approaches are needed to improve the efficacy of current treatment regimens, while preventing development of resistance.
Bacteriophages are viruses that selectively target bacteria, causing lysis of bacterial cells. Phage therapy has emerged as a potential tool to mitigate the effects of AMR. The possibility of using phages in combination with antimicrobials is largely unexplored although our evidence, and that of others, suggests that phages can improve the efficacy of antibiotics. However, there is limited knowledge about how to combine them, how this works in vitro and in vivo including impacts on the immune system.
This project is aimed at generating pivotal information on how to optimally combine phages and antimicrobials by using several infection models – in silico, in vitro, ex vivo cell culture, patient-derived organoid models, and murine animal models. We will also investigate the emergence of phage resistance and development of antibodies in animals receiving long-term treatment with phages. This project explores the utility of phage-antimicrobial combinations in various infection models and will direct roadmaps for clinical use.

Research project partners

Martha Clokie, University of Leicester, United Kingdom (Coordinator)
Christian Giske, Karolinska Institutet, Sweden (Partner)
Li Deng, Helmholtz Zentrum Muenchen - German Research Center for Environmental Health (GmbH), Germany (Partner)
Fabrice Pirot, Civils Hospices of Lyon, FRIPHARM, Pharmacy / Université Claude Bernard Lyon, France (Partner)
Iain Abbott, Monash University, Australia (Partner)
Alasdair MacGowan, North Bristol NHS Trust, United Kingdom (Partner)
Krystyna Dabrowska, Hirszfeld Institute of Immunology and Experimental Therapy in Wroclaw, Poland (Partner)

Work packages

WP1: Assemble a comprehensive phage library (UK, Sweden, Germany, France, Poland)
WP2: In vitro efficacy of phages (UK)
WP3: In vivo efficacy of phages & phage resistance (Germany)
WP4: In vitro phage-antimicrobial interaction (UK)
WP5: Phage formulations (France)
WP6: Pneumonia infection models (Sweden)
WP7: Bladder infection models (Australia)
WP8: Immunological studies (Poland)

Publications

For a full list of publications please visit Google Scholar

Department of Infectious Diseases

Medicine, Nursing and Health Sciences

Abbott Group

Pharmacodynamic Profiling of Antimicrobials

Overview

Group Leader

Research areas

Projects

Funding

Synopsis

Funding

Synopsis

Aims

Funding

Synopsis

Research project partners

Work packages

Publications