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Roberts J.A.,University of Queensland | Roberts J.A.,Royal Brisbane and Womens Hospital | Stove V.,Ghent University | De Waele J.J.,Ghent University | And 19 more authors.
International Journal of Antimicrobial Agents | Year: 2014

The aims of this study were to describe the variability in protein binding of teicoplanin in critically ill patients as well as the number of patients achieving therapeutic target concentrations. This report is part of the multinational pharmacokinetic DALI Study. Patients were sampled on a single day, with blood samples taken both at the midpoint and the end of the dosing interval. Total and unbound teicoplanin concentrations were assayed using validated chromatographic methods. The lower therapeutic range of teicoplanin was defined as total trough concentrations from 10 to 20 mg/L and the higher range as 10-30 mg/L. Thirteen critically ill patients were available for analysis. The following are the median (interquartile range) total and free concentrations (mg/L): midpoint, total 13.6 (11.2-26.0) and free 1.5 (0.7-2.5); trough, total 11.9 (10.2-22.7) and free 1.8 (0.6-2.6). The percentage free teicoplanin for the mid-dose and trough time points was 6.9% (4.5-15.6%) and 8.2% (5.5-16.4%), respectively. The correlation between total and free antibiotic concentrations was moderate for both the midpoint (ρ = 0.79, P = 0.0021) and trough (ρ = 0.63, P = 0.027). Only 42% and 58% of patients were in the lower and higher therapeutic ranges, respectively. In conclusion, use of standard dosing for teicoplanin leads to inappropriate concentrations in a high proportion of critically ill patients. Variability in teicoplanin protein binding is very high, placing significant doubt on the validity of total concentrations for therapeutic drug monitoring in critically ill patients. © 2014 Elsevier B.V. and the International Society of Chemotherapy.


Abdul-Aziz M.H.,University of Queensland | McDonald C.,Royal Brisbane and Womens Hospital | McWhinney B.,Queensland Pathology | Ungerer J.P.J.,Queensland Pathology | And 4 more authors.
Annals of Pharmacotherapy | Year: 2014

Objective: To report the difficulty in achieving and maintaining target antibiotic exposure in critically ill patients with deep-seeded infections. Case Summary: We present a case of a 36-year-old man who was admitted to the intensive care unit with diffuse central nervous system and peripheral methicillin-sensitive Staphylococcus aureus infection (minimum inhibitory concentration; MIC, 1 μg/mL). Owing to the complicated nature of the infection, sequential concentrations of free flucloxacillin were measured in plasma and cerebrospinal fluid (CSF) and used to direct antibiotic dosing. Unsurprisingly, the trough plasma concentrations of flucloxacillin were below the MIC (0.2-0.4 μg/mL), and the corresponding CSF concentrations were undetectable (<0.1 μg/mL) with standard intermittent bolus dosing of 2 g every 4 hours. By administering flucloxacillin by continuous infusion (CI) and increasing the dose to 20 g daily, the plasma (2.2-5.7 μg/mL) and CSF (0.1 μg/mL) levels were increased, albeit lower than the predefined targets (plasma, 40 μg/mL; CSF, 4 μg/mL). Discussion: The presence of physiological changes associated with critical illness-namely, hypoalbuminemia and augmented renal clearance-may significantly alter antibiotic pharmacokinetics, and this phenomenon may lead to suboptimal antibiotic exposure if they are not accounted for. This case also highlights the value of applying CI in such patient groups and demonstrates the significance of monitoring plasma and CSF drug concentrations in optimizing antibiotic delivery. Conclusions: Future research should aim to evaluate the utility of such drug monitoring with regard to patient outcomes and cost-effectiveness. © The Author(s) 2014.


Yaxley J.W.,Royal Brisbane & Womens Hospital | Coughlin G.D.,Royal Brisbane & Womens Hospital | Chambers S.K.,Griffith University | Chambers S.K.,University of Queensland | And 15 more authors.
The Lancet | Year: 2016

Background The absence of trial data comparing robot-assisted laparoscopic prostatectomy and open radical retropubic prostatectomy is a crucial knowledge gap in uro-oncology. We aimed to compare these two approaches in terms of functional and oncological outcomes and report the early postoperative outcomes at 12 weeks. Method In this randomised controlled phase 3 study, men who had newly diagnosed clinically localised prostate cancer and who had chosen surgery as their treatment approach, were able to read and speak English, had no previous history of head injury, dementia, or psychiatric illness or no other concurrent cancer, had an estimated life expectancy of 10 years or more, and were aged between 35 years and 70 years were eligible and recruited from the Royal Brisbane and Women's Hospital (Brisbane, QLD). Participants were randomly assigned (1:1) to receive either robot-assisted laparoscopic prostatectomy or radical retropubic prostatectomy. Randomisation was computer generated and occurred in blocks of ten. This was an open trial; however, study investigators involved in data analysis were masked to each patient's condition. Further, a masked central pathologist reviewed the biopsy and radical prostatectomy specimens. Primary outcomes were urinary function (urinary domain of EPIC) and sexual function (sexual domain of EPIC and IIEF) at 6 weeks, 12 weeks, and 24 months and oncological outcome (positive surgical margin status and biochemical and imaging evidence of progression at 24 months). The trial was powered to assess health-related and domain-specific quality of life outcomes over 24 months. We report here the early outcomes at 6 weeks and 12 weeks. The per-protocol populations were included in the primary and safety analyses. This trial was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number ACTRN12611000661976. Findings Between Aug 23, 2010, and Nov 25, 2014, 326 men were enrolled, of whom 163 were randomly assigned to radical retropubic prostatectomy and 163 to robot-assisted laparoscopic prostatectomy. 18 withdrew (12 assigned to radical retropubic prostatectomy and six assigned to robot-assisted laparoscopic prostatectomy); thus, 151 in the radical retropubic prostatectomy group proceeded to surgery and 157 in the robot-assisted laparoscopic prostatectomy group. 121 assigned to radical retropubic prostatectomy completed the 12 week questionnaire versus 131 assigned to robot-assisted laparoscopic prostatectomy. Urinary function scores did not differ significantly between the radical retropubic prostatectomy group and robot-assisted laparoscopic prostatectomy group at 6 weeks post-surgery (74·50 vs 71·10; p=0·09) or 12 weeks post-surgery (83·80 vs 82·50; p=0·48). Sexual function scores did not differ significantly between the radical retropubic prostatectomy group and robot-assisted laparoscopic prostatectomy group at 6 weeks post-surgery (30·70 vs 32·70; p=0·45) or 12 weeks post-surgery (35·00 vs 38·90; p=0·18). Equivalence testing on the difference between the proportion of positive surgical margins between the two groups (15 [10%] in the radical retropubic prostatectomy group vs 23 [15%] in the robot-assisted laparoscopic prostatectomy group) showed that equality between the two techniques could not be established based on a 90% CI with a Δ of 10%. However, a superiority test showed that the two proportions were not significantly different (p=0·21). 14 patients (9%) in the radical retropubic prostatectomy group versus six (4%) in the robot-assisted laparoscopic prostatectomy group had postoperative complications (p=0·052). 12 (8%) men receiving radical retropubic prostatectomy and three (2%) men receiving robot-assisted laparoscopic prostatectomy experienced intraoperative adverse events. Interpretation These two techniques yield similar functional outcomes at 12 weeks. Longer term follow-up is needed. In the interim, we encourage patients to choose an experienced surgeon they trust and with whom they have rapport, rather than a specific surgical approach. Funding Cancer Council Queensland. © 2016 Elsevier Ltd


Hayashi Y.,University of Queensland | Hayashi Y.,Royal Brisbane and Womens Hospital | Lipman J.,Royal Brisbane and Womens Hospital | Lipman J.,University of Queensland | And 9 more authors.
International Journal of Antimicrobial Agents | Year: 2013

β-Lactams are routinely prescribed in the treatment of serious infections. Empirical dosing schedules are typically derived from studies in healthy volunteers and largely fail to consider the significant changes in antibacterial pharmacokinetics often encountered in the critically ill. These changes are primarily driven by the underlying pathophysiology and the interventions provided, leading to altered protein binding, poor tissue penetration, and fluctuations in the volume of distribution and drug clearance. Each separately, and in combination, is likely to complicate successful β-lactam administration in this setting. Although antibacterial therapeutic drug monitoring (TDM) has traditionally been employed to minimise drug toxicity, the challenges to achieving 'optimal' drug concentrations in the critically ill suggest β-lactam TDM as an attractive means to optimise drug exposure. Whilst there is currently little evidence to support routine widespread application of such a service, β-lactam TDM may still have a role in select patients where difficulty in establishing therapeutic concentrations can be illustrated. This series utilises three representative cases from a β-lactam TDM service that highlight the utility of this intervention in optimising antibacterial dosing. These preliminary data support an expanding role for β-lactam TDM in select critically ill patients and provide insight into the subpopulations most at risk of suboptimal drug exposure. Future studies investigating the clinical outcome benefits of β-lactam TDM in these patient groups are now warranted. © 2012 Elsevier B.V. and the International Society of Chemotherapy.


Tan T.,Princess Alexandra Hospital | Chang L.,Princess Alexandra Hospital | Woodward A.,Princess Alexandra Hospital | McWhinney B.,Queensland Pathology | And 6 more authors.
Journal of Hepatology | Year: 2010

Background & Aims: Adrenal insufficiency (AI) has been reported in patients with advanced liver disease. Diagnosing AI is problematic owing to controversies in using total serum cortisol as a measure of adrenal function. No published data exist on directly measured plasma free cortisol (PFC) in patients with liver disease. Methods: This prospective study compared serum total and measured plasma free cortisol to evaluate adrenal function in clinically stable cirrhotic patients and healthy controls. Cortisol levels were measured at baseline and following 250 μg corticotrophin. AI was defined by total cortisol increments (delta cortisol) of less than 250 nmol/L, or a peak total cortisol under 500 nmol/L after cosyntropin. We used a peak plasma free cortisol concentration of 33 nmol/L as the threshold for AI. Results: Forty-three consecutive patients and 10 healthy controls were studied. Cirrhotic patients had significantly lower peak (526 vs. 649 nmol/L, p = 0.004) and delta total cortisol (264 vs. 397 nmol/L, p = 0.002) responses compared to healthy controls. However, basal plasma free cortisol was higher in patients (10.9 vs. 6.4 nmol/L, p = 0.03), and there were no differences in peak plasma free cortisol (p = 0.69) between the two groups. The prevalence of AI using total cortisol criteria was 58% compared to 12% using free cortisol (p <0.001). Conclusion: In patients with stable severe liver disease, a significant discrepancy exists between the rates of diagnosis of AI using the total and free cortisol criteria. We would advise caution in the interpretation of adrenal function testing using total cortisol measurements in this group. © 2010 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.


Magor G.W.,University of Queensland | Tallack M.R.,University of Queensland | Gillinder K.R.,University of Queensland | Bell C.C.,University of Queensland | And 4 more authors.
Blood | Year: 2015

We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis. © 2015 by The American Society of Hematology.


PubMed | Royal Brisbane and Womens Hospital, University of Queensland and Queensland Pathology
Type: Case Reports | Journal: The Annals of pharmacotherapy | Year: 2014

To report the difficulty in achieving and maintaining target antibiotic exposure in critically ill patients with deep-seeded infections.We present a case of a 36-year-old man who was admitted to the intensive care unit with diffuse central nervous system and peripheral methicillin-sensitive Staphylococcus aureus infection (minimum inhibitory concentration; MIC, 1 g/mL). Owing to the complicated nature of the infection, sequential concentrations of free flucloxacillin were measured in plasma and cerebrospinal fluid (CSF) and used to direct antibiotic dosing. Unsurprisingly, the trough plasma concentrations of flucloxacillin were below the MIC (0.2-0.4 g/mL), and the corresponding CSF concentrations were undetectable (<0.1 g/mL) with standard intermittent bolus dosing of 2 g every 4 hours. By administering flucloxacillin by continuous infusion (CI) and increasing the dose to 20 g daily, the plasma (2.2-5.7 g/mL) and CSF (0.1 g/mL) levels were increased, albeit lower than the predefined targets (plasma, 40 g/mL; CSF, 4 g/mL).The presence of physiological changes associated with critical illness-namely, hypoalbuminemia and augmented renal clearance-may significantly alter antibiotic pharmacokinetics, and this phenomenon may lead to suboptimal antibiotic exposure if they are not accounted for. This case also highlights the value of applying CI in such patient groups and demonstrates the significance of monitoring plasma and CSF drug concentrations in optimizing antibiotic delivery.Future research should aim to evaluate the utility of such drug monitoring with regard to patient outcomes and cost-effectiveness.


PubMed | Royal Brisbane and Womens Hospital, University of Queensland and Queensland Pathology
Type: Case Reports | Journal: Blood | Year: 2015

We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis.

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