Baker, E

Barker, C

Johnston, A

Kipper, K

Lonsdale, DO

Philips, B

Rhodes, A

Sharland, M

Standing, J

English

St George's Online Research Archive

O0808 Standard beta-lactam doses fail to achieve PK/PD targets in critically ill patients of all ages, with children particularly at risk: results from the ABDose studyDagan Lonsdale*1 2, Karin Kipper1 3 4, Charlotte Barker1, Atholl Johnston4 5, Barbara Philips1 6, Andrew Rhodes6, Emma Baker1 2, Mike Sharland1 7, Joe Standing1 8 91St George's, University of London, Infection and Immunity, United Kingdom, 2St George's Hospital, Clinical Pharmacology, United Kingdom, 3University of Tartu, Institute of Chemistry, Tartu, Estonia, 4Analytical Services International Ltd, United Kingdom, 5Barts and the London School of Medicine and Dentistry, Queen Mary Univeristy of London, West Smithfields Campus, Clinical Pharmacology, United Kingdom, 6St George's Hospital, Intensive Care Medicine, United Kingdom, 7St George's Hospital, Paediatric infectious diseases, United Kingdom, 8University College London, Institute of Child Health , United Kingdom, 9Great Ormond Street Hospital, Pharmacy, United KingdomBackground: There is a growing body of evidence from critically-ill adults that standard doses of beta-lactams fail to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets associated with successful treatment(1). Data is lacking for many antibiotics in children and neonates. We aimed to describe antibiotic PK and PK/PD target attainment in an age inclusive study (ABDose) of beta-lactams in critically-ill adults, children and neonates.Materials/methods: Study participants were adults, children and neonates admitted to intensive care and receiving one or more of eight beta-lactams as part of standard treatment. Following informed consent or assent, blood samples were obtained at predefined time-points between doses. Plasma was frozen at -80°C and concentrations were measured retrospectively using ultra-high-performance liquid chromatography tandem mass spectrometry. Population-PK modelling was undertaken using non-linear mixed-effects modelling software (NONMEM v7.3, Icon plc). Minimum PK/PD targets of time with free concentration above the minimum inhibitory concentration (MIC) of the target pathogen (fT>MIC) at 50% and 100% of the dosing interval were used, alongside more conservative targets of concentration >4xMIC(1). Ethical approval was provided by the national research ethics committee, London (14/LO/1999).Results: 216 participants (144 adults, 51 children, 21 neonates) provided 1283 samples for analysis. Allometric scaling and organ maturation functions were used to produce age inclusive pharmacokinetic models for each drug. The range of doses received by adults was greater than children and neonates, e.g. benzylpenicillin 10–34mg/kg adults vs 47–55mg/kg neonates (median 17mg/kg vs 50mg/kg). Only 73% of antibiotic courses achieved 50%fT>MIC. There was marked heterogeneity in the %fT>MIC in adults (Figure 1). Paediatric participants were significantly less likely to achieve the lowest PK/PD target compared to adults (49% vs 74% achieving 50%fT>MIC, p<0.01 Chi-squared). Conclusions: Current dosing regimens fail to achieve recognised PK/PD targets for a large proportion of critically ill patients. Children appear particularly vulnerable to under-dosing. The standard, “one size fits all” dosing in adults contributes to a failure to achieve PK/PD targets. To our knowledge, ABDose is the first study to demonstrate that antibiotic PK data from adults, children and neonates can be modelled simultaneously by using scaling and maturation functions. Roberts et al.(2014).Clinical Infectious Diseases5(8):1072-1083

Standard beta-lactam doses fail to achieve PK/PD targets in critically ill patients of all ages, with children particularly at risk: results from the ABDose study

http://openaccess.sgul.ac.uk/112215/1/O0808_abstract.pdf

Standard beta-lactam doses fail to achieve PK/PD targets in critically ill patients of all ages, with children particularly at risk: results from the ABDose study

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