Improving antibiotic dosing in critically ill Australian Indigenous patients with severe sepsis

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Sepsis is a major health issue in the Australian Indigenous population. Unfortunately, the high ratesof mortality and morbidity caused by sepsis or severe sepsis in this population have notsignificantly reduced over recent decades. Research into the role of optimisation of antibiotictherapy for improving patient outcomes is certainly an important area of need. In other patientpopulations, there is increasing evidence of an improvement of clinical cure rates and survival inpatients with severe sepsis when antibiotic dosing results in therapeutic concentrations, that is,achieves pharmacokinetic/pharmacodynamic (PK/PD) targets. However, numerous PK changescaused by the altered physiology associated with critical illness may reduce the likelihood of sucheffective dosing.Previous studies have identified a number of physiological characteristics in the AustralianIndigenous population which suggest that interethnic PK differences are likely in comparison withthe non-Indigenous. As most PK data of antibiotics were obtained from healthy Caucasianvolunteers, whether these data can be extrapolated to the critically ill Indigenous patients requiresinvestigation.The aims of this thesis are to describe the PK of meropenem, ceftriaxone, vancomycin andpiperacillin in severely septic Indigenous patients; compare the PK with existing data from nonIndigenouspatients; design optimised dosing regimens for each of the study antibiotics; andquantify the variation in renal function of critically ill Indigenous patients.This thesis consists of nine Chapters:Chapter one provides an overview of the current clinical challenges encountered in antibiotic dosingin critically ill patients. It also discusses specific physiological characteristics of AustralianIndigenous patients which may lead to different PK compared with non-Indigenous comparators.Chapter two comprises of a narrative review which discusses the PK/PD factors that should beconsidered when prescribing antibiotics to critically ill patients. This Chapter summarises datawhich describe an improvement in clinical outcome when antibiotics achieve PK/PD targets. ThisChapter concludes to support an individualised approach to dosing antibiotics as opposed to the‘one dose fits all’ approach that is common to clinical practice. Chapter three incorporates a systematic review which investigates the published data describingdifferences in antibiotic PK between different ethnic groups. No reports on PK in IndigenousAustralians were found. The predominant data described differences in PK between the Asian andCaucasian ethnicities. Typically, Asian subjects manifested higher antibiotic concentrations forantibiotics that have significant hepatic metabolism, are substrates to p-glycoprotein or other formsof active transport and/or have high alpha-1-acid glycoprotein binding.Chapter four incorporates a study which described the renal function of critically ill AustralianIndigenous patients. This study found a numerically higher incidence of augmented renal clearance(ARC) in the Indigenous patients and a similar rate of acute kidney injury (AKI) when comparedwith the non-Indigenous patients. The study also found that major surgery, male sex and youngerage were each associated with the presence of ARC.Chapter five includes a population PK study aiming to optimise meropenem dosing in critically illAustralian Indigenous patients. No significant interethnic differences in meropenem PK betweenthe Indigenous (n=6) and Caucasian (n=5) patients were observed and CrCL was found to be thestrongest determinant of dosing requirements.Chapter six includes a population PK study aiming to optimise piperacillin dosing in critically illAustralian Indigenous patients. CrCL was found to be the most important determinant ofappropriate dosing regimens. When compared with other published data, a slightly lower meanpiperacillin CL was observed.Chapter seven includes a PK study aiming to optimise ceftriaxone dosing in critically ill AustralianIndigenous patients. The unbound trough concentration for the first and second dosing intervalsexceeds the minimum inhibitory concentration (MIC) of all typical target pathogens, supporting theempiric dosing regimen of 1 g 12-hourly. Ceftriaxone CL and Vd in this study were generally lowerthan previously published data in critically ill non-Indigenous patients.Chapter eight includes a population PK study aiming to optimise vancomycin dosing in critically illAustralian Indigenous patients. Loading dose requirements were found to be heavily dependent onweight and CrCL. Maintenance doses were highly dependent on CrCL. These results provide aframework for effective dosing of vancomycin in these patients.Chapter nine provides a summary of all findings obtained from the five research projects conductedand recommendations for the implementation of these findings in the clinical setting. The Chapteralso includes a discussion of potential future research directions.The overall results of this thesis do not support any significant interethnic PK differences formeropenem or vancomycin between the Indigenous compared with the non-Indigenouscomparators. However, a slightly lower drug CL was observed for ceftriaxone and piperacillin inthe Indigenous patients, and lower of Vd in the ceftriaxone. These differences observed are unlikelyto affect the dosing of these antibiotics. Nonetheless, it is concluded that dose individualisation isnecessary to maximise PK/PD target attainment in the patients that are critically ill.