Elke van Gorp
Antimicrobials are a precious resource that need to be protected by preventing the rapid emergence of resistance. Hospitalised patients and the critically unwell are those at most risk of dying as a consequence of AMR, yet how to optimise and individually tailor their antimicrobial therapy is desperately lacking translatable data to influence antimicrobial treatment guidelines. The treatment of multidrug-resistant (MDR) bacterial infections often requires consideration for personalised, off-label use of currently available antimicrobials and the pioneering use of newly developed agents. Conceptually this requires a multifaceted approach that details the patient factors, antimicrobial properties and the characteristics of the infecting pathogen.
Our research directly translates patient antimicrobial and microbiological data into preclinical laboratory-based models, which, in turn, informs rational approaches in the design of clinical antimicrobial dosing studies and treatment guidelines. 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.
Developing robust and clinically relevant laboratory PK/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.
iOASIS: 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 and severe hospital infections 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.
Our dynamic bladder infection in vitro model enables a novel approach for the pharmacodynamic profiling of antimicrobials for the treatment of urinary tract infections (UTIs). Millions of people, particularly healthy women, are affected worldwide every year, with 1 in 2 women subsequently expected to have a recurrence within 12-months of an initial UTI. Inadequate treatment risks progression to an ascending infection leading to acute pyelonephritis, bacteraemia and sepsis. In an era of increasing antimicrobial resistance, it is critical to provide optimised antimicrobial treatment.
We use a multi-compartmental in-vitro model that can simulate the processes of antimicrobial gastrointestinal absorption, distribution into systemic circulation and excretion into the bladder. In-vivo drug distribution PK equations can be integrated into a mathematical model that incorporates two consecutive first-order processes, with the antibiotic dose, the flow rate and compartment volumes used as the variables. The aim of the dynamic in-vitro model is to provide a means to demonstrate the relationship between urinary fosfomycin exposures and the microbiological effect, as well as detailing the emergence of resistance.
Previously, we examined the efficacy of oral fosfomycin in a wide variety of different exposures and target pathogens and our group continues to expand testing to other antimicrobials (both new and old) that are indicated for UTIs and Gram-negative infections. Thereby, we are able to provide unique insights into antimicrobial activity at the site of infection, establish evidence of laboratory UTI clinical breakpoints, and inform optimised dosing schedules.