In vivo microdialysis to determine subcutaneous interstitial fluid penetration and pharmacokinetics of fluconazole in intensive care unit patients with sepsis

The objective of the study was to describe the subcutaneous interstitial fluid (ISF) pharmacokinetics of fluconazole in critically ill patients with sepsis. This prospective observational study was conducted at two tertiary intensive care units in Australia. Serial fluconazole concentrations were measured over 24 h in plasma and subcutaneous ISF using microdialysis. The concentrations in plasma and microdialysate were measured using a validated high-performance liquid chromatography system with electrospray mass spectrometer detector method. Noncompartmental pharmacokinetic analysis was performed. Twelve critically ill patients with sepsis were enrolled. The mean in vivo fluconazole recovery rates +/- standard deviation (SD) for microdialysis were 51.4% +/- 16.1% with a mean (+/- SD) fluconazole ISF penetration ratio of 0.52 +/- 0.30 (coefficient of variation, 58%). The median free plasma area under the concentration-time curve from 0 to 24 h (AUC(0-24)) was significantly higher than the median ISF AUC(0-24) (340.4 versus 141.1 mg . h/liter; P = 0.004). There was no statistical difference in median fluconazole ISF penetration between patients receiving and not receiving vasopressors (median, 0.28 versus 0.78; P = 0.106). Both minimum and the maximum concentrations of drug in serum (C-max and C-min) showed a significant correlation with the fluconazole plasma exposure (Cmax, R-2 = 0.86, P < 0.0001; Cmin, R-2 = 0.75, P < 0.001). Our data suggest that fluconazole was distributed variably, but incompletely, from plasma into subcutaneous interstitial fluid in this cohort of critically ill patients with sepsis. Given the variability of fluconazole interstitial fluid exposures and lack of clinically identifiable factors by which to recognize patients with reduced distribution/exposure, we suggest higher than standard doses to ensure that drug exposure is adequate at the site of infection

Effect of obesity on the population pharmacokinetics of meropenem in critically ill patients

Severe pathophysiological changes in critical illness can lead to dramatically altered antimicrobial pharmacokinetics (PK). The additional effect of obesity on PK potentially increases the challenge for effective dosing. The aim of this prospective study was to describe the population PK of meropenem for a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients prescribed meropenem were recruited into the following three body mass index (BMI) groups: nonobese (18.5 to 29.9 kg/m(2)), obese (30.0 to 39.9 kg/m(2)), and morbidly obese (>= 40 kg/m(2)). Serial plasma samples were taken, and meropenem concentrations were determined using a validated chromatographic method. Population PK analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Nineteen critically ill patients with different BMI categories were enrolled. The patients' mean +/- standard deviation (SD) age, weight, and BMI were 49 +/- 15.9 years, 95 +/- 22.0 kg, and 33 +/- 7.0 kg/m(2), respectively. A two-compartment model described the data adequately. The mean +/- SD parameter estimates for the final covariate model were as follows: clearance (CL), 15.5 +/- 6.0 liters/h; volume of distribution in the central compartment (V-1), 11.7 +/- 5.8 liters; intercompartmental clearance from the central compartment to the peripheral compartment, 25.6 +/- 35.1 liters h(-1); and intercompartmental clearance from the peripheral compartment to the central compartment, 8.32 +/- 12.24 liters h(-1). Higher creatinine clearance (CLCR) was associated with a lower probability of target attainment, with BMI having little effect. Although obesity was found to be associated with an increased V-1, dose adjustment based on CLCR appears to be more important than patient BMI

Determining the mechanisms underlying augmented renal drug clearance in the critically ill: use of exogenous marker compounds

Introduction: The aim of this study was to explore changes in glomerular filtration (GFR) and renal tubular function in critically ill patients at risk of augmented renal clearance (ARC), using exogenous marker compounds

Population pharmacokinetics of piperacillin in nonobese, obese, and morbidly obese critically ill patients

The treatment of infections in critically ill obese and morbidly obese patients is challenging because of the combined physiological changes that result from obesity and critical illness. The aim of this study was to describe the population pharmacokinetics of piperacillin in a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients who received piperacillin-tazobactam were classified according to their body mass index (BMI) as nonobese, obese, and morbidly obese. Plasma samples were collected, and piperacillin concentrations were determined by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Pmetrics software. Thirty-seven critically ill patients (including 12 obese patients and 12 morbidly obese patients) were enrolled. The patients' mean ± standard deviation age, weight, and BMI were 50 ± 15 years, 104 ± 35 kg, and 38.0 ± 15.0 kg/m(2), respectively. The concentration-time data were best described by a two-compartment linear model. The mean ± SD parameter estimates for the final covariate model were a clearance of 14.0 ± 7.1 liters/h, a volume of distribution of the central compartment of 49.0 ± 19.0 liters, an intercompartmental clearance from the central compartment to the peripheral compartment of 0.9 ± 0.6 liters · h(-1), and an intercompartmental clearance from the peripheral compartment to the central compartment of 2.3 ± 2.8 liters · h(-1) A higher measured creatinine clearance and shorter-duration infusions were associated with a lower likelihood of achieving therapeutic piperacillin exposures in patients in all BMI categories. Piperacillin pharmacokinetics are altered in the presence of obesity and critical illness. As with nonobese patients, prolonged infusions increase the likelihood of achieving therapeutic concentrations

Effect of obesity on the population pharmacokinetics of fluconazole in critically Ill patients

Our objective was to describe the population pharmacokinetics of fluconazole in a cohort of critically ill nonobese, obese, and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, nonobese (18.5 to 29.9 kg/m(2)), obese (30.0 to 39.9 kg/m(2)), and morbidly obese (>= 40 kg/m(2)). Serial fluconazole concentrations were determined using a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Twenty-one critically ill patients (11 male) were enrolled, including obese (n = 6) and morbidly obese (n = 4) patients. The patients mean +/- standard deviation (SD) age, weight, and BMI were 54 +/- 15 years, 90 +/- 24 kg, and 31 +/- 9 kg/m(2), respectively. A two-compartment linear model described the data adequately. The mean +/- SD population pharmacokinetic parameter estimates were clearance (CL) of 0.95 +/- 0.48 liter/h, volume of distribution of the central compartment (V-c) of 15.10 +/- 11.78 liter, intercompartmental clearance from the central to peripheral compartment of 5.41 +/- 2.28 liter/h, and intercompartmental clearance from the peripheral to central compartment of 2.92 +/- 4.95 liter/h. A fluconazole dose of 200 mg daily was insufficient to achieve an area under the concentration-time curve for the free, unbound drug fraction/MIC ratio of 100 for pathogens with MICs of >= 2 mg/liter in patients with BMI of >30 kg/m(2). A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter

Effect of Exogenous Melatonin Administration in Critically Ill Patients on Delirium and Sleep: A Randomized Controlled Trial

Introduction. Sleep deprivation is a contributor for delirium in intensive care. Melatonin has been proposed as a pharmacological strategy to improve sleep, but studies have shown that the increase in plasma levels of melatonin do not correlate to a beneficial clinical effect; in addition, melatonin’s short half-life may be a major limitation to achieving therapeutic levels. This study applies a previously published novel regimen of melatonin with proven sustained levels of melatonin during a 12 h period. In this study, the aim is to determine if such melatonin dosing positively influences on the sleep architecture and the incidence of delirium in intensive care. Methods. Single center, randomized control trial with consecutive recruitment over 5 years. Medical and surgical patients were in a recovery phase, all weaning from mechanical ventilation. Randomized allocation to placebo or enteral melatonin, using a previously described regimen (loading dose of 3 mg at 21 h, followed by 0.5 mg hourly maintenance dose until 03am through a nasogastric tube). Sleep recordings were performed using polysomnogram at baseline (prior to intervention) and the third night on melatonin (postintervention recording). Delirium was assessed using the Richmond Agitation and the Confusion Assessment Method Scales. Environmental light and noise levels were recorded using a luxmeter and sound meter. Results. 80 patients were screened, but 33 were recruited. Sleep studies showed no statistical differences on arousal index or length of sleep. Baseline delirium scores showed no difference between groups when compared to postintervention scores. RASS scores were 1 in both groups at baseline, compared to zero (drug group) and 0.5 (placebo group) posttreatment. CAM scores were zero (drug group) and 1 (placebo group) at baseline, compared to zero (in both groups) postintervention. Conclusion. High levels of plasma melatonin during the overnight period of intensive care cohort patients did not improve sleep nor decreased the prevalence of delirium. This trial is registered with Anzctr.org.au/ACTRN12620000661976.aspx

Cortisol responses at baseline and after corticotropin in acute aneurysmal subarachnoid haemorrhage: A prospective study

Free to read on publisher's website Background: Measurements of total plasma cortisol (TPC) in the acute phase of aneurysmal subarachnoid haemorrhage (aSAH) have suggested a high incidence of adrenal insufficiency (AI). Objective: To compare TPC and free plasma cortisol (FPC) measurements in acute aSAH and to assess whether rates of diagnosis of AI based on TPC and FPC criteria were discordant. Methods: A prospective, observational study of 20 patients admitted within 7 days of aSAH to a tertiary intensive care unit. Cortisol binding globulin (CBG), TPC and FPC levels were measured at baseline, and cortisol profiles at 30 and 60 minutes after administration of 250 g corticotropin. Results: Compared with controls, the mean baseline FPC (46nmol/L [SD, 48 nmol/L] v 9nmol/L [SD, 6nmol/L], P <0.0001), and TPC (566 nmol/L [SD, 288 nmol/L] v 352 nmol/L [SD, 146nmol/L], P=0.01) were significantly elevated with a greater proportional increase of FPC over TPC (6 v 1.2 times, P <0.0001). The relative increment of FPC compared with TPC in the patient group was 505% v 114% (P <0.0001) and in the control group was 662% v 145% (P <0.0001). The prevalence of AI, measured using TPC compared with FPC, was 30% v 0% (P=0.04). Conclusion: In the acute phase after aSAH, the FPC increase is fivefold greater than that of TPC. There is discordance between TPC and FPC responses to corticotropin. The prevalence of AI, as assessed by FPC measurements, is negligible. We advocate caution in the assessment of adrenal cortical function using measurements of TPC in this population

Cerebrospinal fluid penetration of ceftolozane/tazobactam in critically ill patients with an indwelling external ventricular drain

The aim of this study was to describe the pharmacokinetics of ceftolozane/tazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥ 18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0g ceftolozane/tazobactam. Serial plasma and CSF samples were collected for measurement of unbound ceftolozane and tazobactam concentration by liquid chromatography. Unbound concentration-time data were modelled in R using Pmetrics. Dosing simulations were performed using the final model. A three-compartment model adequately described the data from 10 patients. For ceftolozane, the median (Inter quartile range, IQR) area under the unbound concentration-time curve from time zero to infinity (fAUC0-inf) in the CSF and plasma were 30 (19-128) h*mg/L, and 323 (183-414) h*mg/L respectively. For tazobactam, these values were 5.6 (2-24) h*mg/L and 52 (36-80) h*mg/L, respectively. Mean ± standard deviation (SD) CSF penetration ratios were 0.2 ± 0.2 and 0.2±0.26 for ceftolozane and tazobactam respectively. With the 3.0 g 8-houly regimen, ≥ 0.9 probability of target attainment (PTA) for 40%\ua0fT>MIC\ua0in the CSF was possible only when MICs were ≤ 0.25 mg/L. The CSF cumulative fractional response for\ua0P. aeruginosa\ua0susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20%\ua0fT>1mg/L\ua0was 12%. The current maximal dose of ceftolozane/tazobactam (3.0 g 8-hourly) does not provide adequate CSF exposure for treatment of Gram-negative meningitis or ventriculitis unless the MIC for the causative pathogen is very low (≤0.25 mg/L)

Population pharmacokinetics of unbound ceftolozane and tazobactam in critically ill patients without renal dysfunction

Evaluation of dosing regimens for critically ill patients requires pharmacokinetic data in this population. This prospective observational study aimed to describe the population pharmacokinetics of unbound ceftolozane and tazobactam in critically ill patients without renal impairment and assess adequacy of recommended dosing regimens for treatment of systemic infections. Patients received 1.5 or 3.0 g ceftolozane/tazobactam according to clinician recommendation. Unbound ceftolozane and tazobactam plasma concentrations were assayed and data were analysed with Pmetrics® with subsequent Monte Carlo simulations. A two-compartment model adequately described the data from twelve patients. Urinary creatinine clearance and body weight described between-patient variability in clearance (CL) and central volume of distribution (V) respectively. Mean (± SD) parameter estimates for unbound ceftolozane and tazobactam were CL of 7.2±3.2 and 25.4±9.4 L/h; V of 20.4±3.7 and 32.4±10 L; rate constants Kcp of 0.46±0.74 and 2.96±8.6 h, Kpc of 0.39±0.37 and 26.5±8.4 h, respectively. With 1.5 g and 3.0 g 8-hourly dosing, fractional target attainment (FTA) against was ≥85% for directed therapy (MIC ≤ 4mg/L). However, for empiric coverage (MIC up to 64 mg/L), the FTA was 84 % with 1.5 g 8-hourly regimen when creatinine clearance is 180 mL/min/1.73m Whereas the 3.0 g 8-hourly regimen consistently achieved FTA of ≥85 %. For 40% T target, 3g q8h by intermittent infusion is suggested unless a highly susceptible pathogen are present whereby 1.5g dosing could be used. If a higher target of 100% T is required, a 1.5 g loading dose plus 4.5 g continuous infusion maybe adequate