Pharmacokinetic-Pharmacodynamic study on antibiotics in critically ill patients receiving renal replacement therapy: amikcin, co-amoxiclav and teicopanin

Background The treatment of critically-ill septic patients on renal replacement therapy (RRT) requires optimal antibiotics dosing to reduce mortality and bacterial resistance. Currently the evidence for optimal antibiotic dosing in critical care patients receiving RRT is lacking. Current doses of the study antibiotics used are potentially subtherapeutic. We aim to study antibiotic pharmacokinetics and pharmacodynamics (PKPD) in critically-ill patients on RRT to recommend the optimal dosage of three commonly used antibiotics: amikacin, co-amoxiclav and teicoplanin. Research questions: What is the impact of critical illness and renal replacement therapy on the PKPD of the antibiotics: amikacin, co-amoxiclav and teicoplanin? What is the optimal antibiotic dose of the study drugs for treating sepsis in critically-ill patients receiving RRT? Aim To develop the optimal antibiotic dose needed for critically-ill patients with sepsis on RRT for amikacin, co- amoxiclav and teicoplanin. Objectives · To carry out a systematic review and meta-analysis on the pharmacokinetics and pharmacodynamics of the study antibiotics · To design and carry out an experimental model for in-vitro investigation of PKPD of the study antibiotics during RRT · To conduct an observational study to investigate the PKPD of the antibiotic study drugs in critically ill patients on RRT · To build a PKPD population model and simulation for optimal antibiotic dosing of the study drugs Methods The systematic review and meta-analysis will evaluate PKPD studies on the study drugs; data will be pooled from studies which have clinical data that permits analysis of relevant covariates. The experimental lab-based project will utilise crystalloid fluids infused with the study drugs in a RRT machine to investigate the clearance during RRT stages; this will allow us to calculate the drug clearance by the RRT machine without confounding patient factors. In addition, the lab-based project will inform the sampling times for the observational study. The observational study is a non-interventional study based on patients already receiving the study drugs and RRT. Samples of blood, urine and effluent will be assayed to determine the volume of distribution and drug clearance. Statistical analysis using PKPD modelling techniques will be built using Non-linear Mixed- effects Modelling (NONMEM®7.5). This will be used to produce simulations for recommending optimal dosages for the study drugs. Timelines for delivery Year 1: Complete the systematic review and meta-analysis and publish. Carry out lab-based study. Year 2: Publish lab-based study protocol. Ethical approval gained and study site opening for observational clinical study. Complete recruitment for observational study and begin sample analysis. Year 3: PK modelling and simulation. Write up thesis, disseminate and publish findings. Anticipated impact and dissemination The results will be disseminated across critical care and antimicrobial multidisciplinary networks via publication, meetings, seminars and conferences. We will publish the research in peer reviewed journals, and we will work with patient representatives to co-author a document for sharing the outcomes with patient and public forums. The patient and public groups will inform the dissemination strategy. The impact of this study will provide evidence for optimal dosing of the study antibiotics potentially optimising patient care.