Introduction: Daptomycin is a key antibiotic for multidrug-resistant Gram-positive infections, but its substantial inter-individual pharmacokinetic variability and exposure-related efficacy and toxicity make optimal dosing challenging, particularly in elderly patients. Age-related changes in renal function may further alter daptomycin exposure, increasing the risk of underexposure or toxicity. Population pharmacokinetic (PopPK) models provide the foundation for model-informed […]
Nick Holford Prize
Mechanism-based mathematical modelling predicts the impact of resistance mechanisms present in Pseudomonas aeruginosa on meropenem effectiveness
Background: Mechanism-based mathematical models (MBMs) address limitations of PK/PD indices, such as the time unbound antibiotic concentration exceeds the pathogen’s MIC (fT>MIC). Meropenem (MEM) is commonly used against Pseudomonas aeruginosa (PA) infections, however resistance mechanisms reduce its effectiveness. We developed a novel MBM to 1) characterise the full time-course of bacterial killing and resistance emergence in seven isogenic PA strains […]
Mechanism-based modelling of the response from hypermutable cystic fibrosis Pseudomonas aeruginosa isolates to inhaled aztreonam and tobramycin dosing regimens simulated in a dynamic biofilm model
Background Hypermutable, resistant and biofilm forming Pseudomonas aeruginosa proves challenging to treat in patients with cystic fibrosis (CF). Understanding biofilm killing and regrowth is important for the selection of effective antibiotic dosing regimens. Aim To develop a mechanism-based model (MBM) which characterises the time-course of planktonic and biofilm bacteria in response to aztreonam and tobramycin […]
Time Course of Procalcitonin Concentration Following Birth and Surgery
Introduction: Procalcitonin plasma concentration (PCT) has been suggested as a biomarker for acute infection (usually bacterial). Concentrations increase rapidly within 4-6 hours of infection [1]. However PCT also increases following events such as birth and surgery without any known infection [2, 3]. It is important to understand the time course of PCT following these events […]
Cefazolin pharmacokinetics and extent of device binding during cardiopulmonary bypass
Introduction: Cefazolin is administered routinely for antibiotic prophylaxis during cardiac surgery. However there is uncertainty in determining the correct dose due to the impact of critical illness and the cardiopulmonary bypass (CPB) machine on drug pharmacokinetics (PK). Aims: To quantify cefazolin adsorption to the CPB machine device and incorporate this into a population PK model […]
A population pharmacokinetic model of once daily intravenous busulfan in paediatrics characterising time-dependent clearance
Aims: To characterise the pharmacokinetics of busulfan in paediatrics and investigate changes in clearance over a 4-day treatment course of once daily intravenous therapy. Methods: A population pharmacokinetic model was developed using NONMEM®, based on first-order conditional estimation with interaction, in patients ≤18 years receiving once daily intravenous busulfan for haematopoietic stem cell transplant (HSCT) who had […]
External evaluation of population pharmacokinetic models of tacrolimus in adult heart transplant recipients
Background. Numerous population pharmacokinetic (popPK) models of tacrolimus (TAC) in adult transplant recipients have been published. However, data on the accuracy of Bayesian forecasting with concomitant azole therapy or extrapolation to other transplant cohorts are scarce. Aims. To externally validate the predictive performances of relevant popPK models of TAC in adult heart transplant (HTX) recipients […]
The Influence of Genotype on Warfarin Dose Predictions
Background & Aims: Warfarin is the most commonly prescribed oral anticoagulant worldwide, however, a narrow therapeutic range poses a barrier to safe and effective therapy. Common methods to predict warfarin dose requirements are biased at the extremes. When evaluated by simulation, Bayesian dose forecasting using a theory-based warfarin PKPD model achieves unbiased and precise dose predictions […]
Total and unbound mycophenolic acid pharmacokinetics before and after kidney transplantation
Background: An increased incidence of acute rejection is seen with underexposure to mycophenolic acid (MPA) in the initial week post kidney transplantation, particularly in high immunological risk patients (1,2). Up to 25% of individuals in contemporary drug regimens are below the proposed therapeutic range at this time (3), and these individuals cannot be identified a […]
Mechanism-based PK/PD modelling approach to optimise combination dosage regimens against multidrug-resistant clinical isolates of Pseudomonas aeruginosa and in-vivo evaluation in a murine thigh infection model
Aims: Pseudomonas aeruginosa (Pa) is an opportunistic Gram-negative pathogen that is prevalent in bloodstream, wound and respiratory infections and has a high propensity to become multidrug-resistant. Our primary aim was to systematically evaluate synergistic killing and suppression of resistance of Pa by combinations of carbapenem plus aminoglycoside (AGS) antibiotics. Secondly, we sought to propose optimised […]