| Summary: | Background: Sepsis is a common reason for admission to adult, paediatric or neonatal intensive care and mortality remains high. Evidence of increased pharmacokinetic (PK) variability in critically ill adults compared to non-critically ill has raised concerns about antimicrobial target attainment and dosing strategies. Paediatric data is lacking. Aims: 1. Summarise published data on the PK of commonly used antibiotics across all age groups, in healthy and critically ill populations. 2. Describe the PK of commonly used antibiotics in patients receiving treatment in adult, paediatric and neonatal intensive care and describe the effect of age on antibiotic PK. 3. Describe attainment of pharmacokinetic/pharmacodynamic (PK/PD) targets for antibiotics in critically ill patients of all ages and outline associations between PK/PD target attainment and clinical outcome. Methods: 1. Systematic review of PK data in adult, paediatric and neonatal populations. 2. Prospective, observational study of the PK of 10 commonly used antimicrobials in critically ill adults, children and neonates. 3. Population-PK techniques (NONMEM) to model antibiotic PK and PK/PD target attainment in critical illness, using data from all age groups. Inclusion of a maturation function to model the effect of age on PK parameters Results: 1. Parameters from 143 studies were pooled to estimate PK maturation- decline through life. There was marked uncertainty in parameter estimates. 2. PK study of 230 critically ill participants (300 antibiotic prescriptions) and 1283 PK samples. Age range 24-weeks post-menstrual age to 90-years. 3. Population-PK models of 10 antibiotics using all age groups. Maturation-decline function describes changes in PK through life well. Only 74% of antibiotic courses achieved minimum PK/PD targets. Paediatric participants had lower target attainment than adults. Conclusion: Age need not be a barrierto inclusion in a PK trial. A new standard method for modelling PK maturation throughout life has been proposed that could be used in future age-inclusive PK studies. The first age-inclusive PK models of beta-lactams have been presented with the PK of intravenous benzylpenicillin and clarithromycin described for the first time in critically ill populations. Standard doses fail to achieve PK/PD targets in critically ill adults, children and neonates.
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