Suboptimal exposure to fluconazole in critically ill patients: Pharmacokinetic analysis and determinants.

OBJECTIVES: This study aims at evaluating fluconazole exposure in critically ill patients and identifying variables associated with the latter. PATIENTS AND METHODS: This was a 2-year (2018-2019) retrospective multicenter cohort study. Adult patients > 18 years-old with at least one fluconazole concentration measurement during their ICU stay were included. RESULTS: Twenty patients were included. Only 11 patients had a fluconazole trough concentration (Cmin) within the target range (≥15 mg/L). According to bivariable analysis, SOFA score, GGT, fluconazole clearance, Ke, and Vd, were independently associated with a decrease in fluconazole Cmin. The median loading dose required to achieve the Cmin target appeared to be greater in patients with higher SOFA or GGT level and in patients undergoing renal replacement therapy. CONCLUSIONS: This study supports recommendation for routine fluconazole therapeutic drug monitoring in ICU patients so as to avoid underexposure, especially if SOFA score is ≥ 7 and/or GGT is ≥ 100 U/L.

[Pharmacokinetic modifications and pharmacokinetic/pharmacodynamic optimization of beta-lactams in ICU]. / Modifications pharmacocinétiques et optimisation pharmacocinétique/pharmacodynamique des bêta-lactamines en réanimation.

Pharmacokinetic modifications in critically ill patients and those induced by ICU therapeutics raise a lot of issues about antibiotic dose adaptation. Beta-lactams are anti-infectious widely used in ICU. Frequent beta-lactam underdoses induce a risk of therapeutic failure potentially lethal and of emergence of bacterial resistance. Overdoses expose to a neurotoxic and nephrotoxic risk. Therefore, an understanding of pharmacokinetics modifications appears to be essential. A global pharmacokinetic/pharmacodynamic approach is required, including use of prolonged or continued beta-lactam infusions to optimise probability of pharmacokinetic/pharmacodynamic target attainment. Beta-lactam therapeutic drug monitoring should also be considered. Experts agree to target a free plasma betalactam concentration above four times the MIC of the causative bacteria for 100 % of the dosing interval. Bayesian methods could permit individualized doses adaptations.

The role of the critical care pharmacist during the COVID-19 pandemic.

On January 4 2020, the World Health Organization (WHO) reported the emergence of a cluster of pneumonia cases in Wuhan, China due to a new coronavirus, the SARS-CoV-2. A few weeks later, hospitals had to put in place a series of drastic measures to deal with the massive influx of suspected COVID-19 (COronaroVIrus Disease) patients while securing regular patient care, in particular in the intensive care units (ICU). Since March 12th, 77 of the 685 COVID-19 patients admitted to our hospital required hospitalization in the ICU. What are the roles and the added-value of the critical care pharmacist during this period? His missions have evolved although they have remained focused on providing health services for the patients. Indeed, integrated into a steering committee created to organize the crisis in the intensive care units, the role of the clinical pharmacist was focused on the organization and coordination between ICU and the pharmacy, the implementation of actions to secure practices, to train new professionals and the adaptation of therapeutic strategies. He participated to literature monitoring and increased his involvement in the clinical research team. He provided a link between the ICU and the pharmacy thanks to his knowledges of practices and needs.

Effects of low fat diets varying in P/S ratio on nutrient intakes, fecal excretion, blood chemistry profiles, and fatty acids of adult men.

Twenty-three apparently healthy volunteers aged 35 to 60 years consumed closely monitored self-selected (SS) diets for five weeks followed by two low fat controlled diets (25% energy) for two six-week periods followed by another five-week SS diet. The two low fat diets, fed in a crossover design to one-half of the subjects per controlled diet period, had a polyunsaturated/saturated (P/S) fat ratio of either 0.3 or 1.0. Results are reported for bi-weekly measurements of energy and nutrients; blood profiles and plasma fatty acids; and for end-of-period values for stool characteristics. Blood chemistry profiles differed in the two groups. The low P/S diet produced significant increases not only in cholesterol, but in 16:0, 16:1, and percent saturated fatty acids and decreases in 18:2 and omega 6 fatty acids. The reverse was seen with the high P/S diet. The essential fatty acid (EFA) linoleic acid returned in the poststudy period to prestudy levels (all subjects), but arachidonic acid did not. The explanation for negative correlation between magnesium intake or excretion and percent plasma linoleic acid must await further research.

Moderate changes in linoleate intake do not influence the systemic production of E prostaglandins.

A pilot study was undertaken to determine if moderate changes in linoleate (18:2 omega 6) intake would modulate the prostaglandin E turnover concurrently with, or independently of, changes in the plasma prostaglandin (PG) precursor levels. Four adult male volunteers in good health were fed two controlled diets containing 35% of energy from fat, with either 10 (diet L) or 30 g (diet H) linoleate/day, 30 to 50 g saturated fatty acids/day, and the balance mainly monounsaturated fatty acids. All four subjects were consuming sufficient amounts of polyunsaturates before the study. Protein (13-14%) and carbohydrate (51-53%) contribution to total caloric intake was kept constant. The menu cycle was 7 days, and all diets were calculated to provide adequate amounts of nutrients known to be required by man when data were available. Plasma fatty acids were determined by gas-liquid chromatography, and the turnover of E prostaglandins was assessed by measuring the urinary output of the major metabolite of PGE1 + PGE2 (PGE-M). Whereas we found a clear correlation between 18:2 omega 6 intake and 18:2 omega 6 concentrations in the neutral lipid (P = 0.007) and phosphoglyceride (P = 0.012) fractions of plasma, arachidonate (20:4 omega 6) concentrations in those same plasma fractions did not respond significantly to changes in linoleate intake. Moreover, we could not detect an influence of moderate changes in dietary levels of 18:2 omega 6 on the systemic production of PGE as measured by the daily urinary output of PGE-M.

Variations in plasma fatty acid concentrations during a one-year self-selected dietary intake study.

A group of healthy volunteers, maintaining their usual lifestyle, was monitored as to their nutrient intake for a period of 1 yr. Diet records were kept daily and blood samples were collected at even intervals five times during the year. Plasma fatty acid levels were analyzed to determine any sex, age, or seasonal variations or if the plasma fatty acid levels could be correlated to dietary fat intake. In the population studied, there was a significant (p less than 0.0001) sex by age interaction, but no seasonal effect was observed. No major differences in plasma fatty acids related to diet were found. However, the younger men had the highest linoleic acid intake and the lowest plasma linoleic acid. Plasma linoleic acid levels for males older than 35 yr of age (87.0 +/- 3.1 mg/dl) were significantly greater than for males younger than 36 yr of age (67.9 +/- 1.8 mg/dl). The plasma linoleic acid levels of all the women were intermediate in value to the men but not different from each other (73.8 +/- 1.7 mg/dl for the younger women and 78.7 +/- 1.9 mg/dl for the older women). There was a significant (p less than 0.01) sex effect in the relative percentage of plasma linoleic acid (34.4 +/- 0.4% for the women and 32.4 +/- 0.6% for the men), but no age or seasonal effect was observed.

Effect of dietary fat on the fluidity of platelet membranes.

Dietary fat type was reflected in the phospholipid fatty acid composition of the plasma membrane of rabbit platelets and apparently controlled the fluidity of these membranes. Rabbits were maintained for 6 months on diets that varied in stearic and polyunsaturated fatty acids and thus had different potentials for thrombosis. Microviscosities at 37 C, calculated from the arisotropy of fluorescence from the probe 1,6-diphenyl-1,3,5-hexatriene, were 3.5, 3.4, 2.8 and 2.2 poise for platelet membranes isolated from rabbits whose only source of dietary fat was cocoa butter, milkfat, coconut oil, or corn oil, respectively. The relative findings of the membrane isolates were correlated with the polyunsaturated fatty acid contents of the membrane phospholipids.

Kinetics of procainamide and N-acetylprocainamide in renal failure.

Four normal subjects and four functionally anephric patients were given 6.5 mg/kg of body wt of procainamide hydrochloride i.v., and plasma concentrations of procainamide (PA) and its major active metabolite N-acetylprocainamide (NAPA) were measured. Two individuals in each group were fast isonicotinic acid hydrazide (INH) and PA acetylators. The pharmacokinetics of PA and NAPA were analyzed with a computer program (SAAM 23). Volume of distribution (Vdss) and renal clearance of PA were similar in normal subjects regardless of acetylator phenotype. Nonrenal clearance was faster (383 vs. 244 ml/min), and PA elimination half-life (t 1/2) was shorter (2.6 vs. 3.5 hr) in fast acetylators. In the functionally anephric patients, Vdss was similar to that of normal subjects. Nonrenal clearence was faster (117.5 vs. 93.5 ml/min) and PA t 1/2 shorter (10.8 vs. 17.0 hr) in fast than in slow acetylators. In these patients, acetylation accounted for 56% of PA elimination, and NAPA concentrations reached 0.8 microgram/ml or more. The t 1/2 of NAPA in renal failure was 41.5 hr, in accord with predictions from studies in normal subjects, assuming no impairment in nonrenal NAPA elimination. PA metabolism, however, is severely impaired by renal failure, so PA t 1/2 was prolonged to an unpredictably greater extent than would be expected from studies in normal subjects.

Artificial kidneys and clearance calculations.

Clearance of solutes by artificial kidneys can be calculated using plasma flow and solute concentration, whole blood flow and plasma solute concentration, and midpoint of dialysis blood or plasma solute concentration and total amount of solute removed. Using these methods, the clearance of procainamide (PA) and N-acetylprocainamide (NAPA) was determined in 4 patients. In all but one case clearances using total amount recovered were greater than clearances using whole blood flow and plasma concentration. Without exception, clearance determined using amount recovered was substantially greater than clearance using plasma flow and plasma levels, suggesting that both PA and NAPA are removed not only from plasma but also from red blood cells. In vitro clearance of PA, NAPA, quinidine, and phenobarbital by 11 clinically available artificial kidneys and an XAD-4 hemoperfusion column was determined and differences were found.

N-Acetylprocainamide levels in patients with end-stage renal failure.

Serum concentrations of procainamide (PA) and N-acetylprocainamide (NAPA) were measured by fluorometry in subjects with normal renal function (n = 4) and in patients with end-stage renal failure (n = 3) after administration of 6.5 mg/kg of PA-HCl orally. Two subjects with normal renal function were rapid isonicotinic acid hydrazide (INH) acetylators and two were slow acetylators. The rapid acetylators had higher peak serum levels of NAPA (1.80 mug/ml) than the slow acetylators (0.40 mug/ml). Peak serum levels of PA were essentially identical in both. The half-life (T1/2) of PA was shorter, 2.5 hr, in the rapid acetylators than in the slow, 4.1 hr. The slope of the terminal portion of the blood time curve for NAPA was steeper (-0.087) for slow acetylators than for rapid (-0.078). These apparent differences between rapid and slow acetylators are not conclusive in themselves but tend to support the differences in acetylation previously reported. In the absence of renal function, the serum levels of PA were higher and the T1/2 prolonged. The serum levels of NAPA rose slowly and reached peak levels of 2 to 3 mug/ml and declined only with hemodialysis. In 3 patients measurable levels of NAPA were still present 78 hr (0.62 mug/ml), 94 hr (0.36 mug/ml), and 124 hr (0.70 mug/ml) after the single oral dose of PA. Clearance of NAPA during clinical hemodialysis was 48 +/- 10 cc/min compared to 75 +/- 12 ml/min for PA.

Fluorometric assay for N-acetylprocainamide.

We describe a simple, rapid fluorometric assay for separate quantitative analysis of procainamide and N-acetylprocainamide in mixtures. The effective lenear range (fluorescence vs. concentration) in serum is 0.1 to 10.0 mg/liter, regardless of the ratio (by weight) of the two drugs from 1:10 to 10:1. Analytical recoveries by the extraction method used were 100.0 +/- 3.0% and 98.0 +/- 4.0%, respectively. For determination of either compound, the maximum coefficient of variation was 10%.

Acetylation of procainamide in man and its relationship to isonicotinic acid hydrazide acetylation phenotype.

To assess the extent of the acetylation of procainamide (PA) to N-acetylprocainamide (NAPA) in man, and its relation to isonicotinic acid hydrazide (INH) acetylation phenotype, the following study was done. Fourteen subjects received 500 mg of PA - HCL orally. INH acetylation phenotype was determined by the serum half-life of INH after 4 mg/kg of INH orally. Each urine voided for 96 hr after procainamide was saved and levels of procainamide and NAPA measured by gas-liquid chromatography. The 14 subjects eliminated 52 plus or minus 4 percent of the dose as procainamide and 16 plus or minus 2 percent of the dose as NAPA. Four fast INH acetylators eliminated 23 plus or minus 3 percent of the dose as NAPA compared to 12 plus or minus 1 percent by the slow acetylators (p smaller than 0.05). The amount of unaltered procainamide excreted by the fast and slow INH acetylators was not significantly different, 50 plus or minus 4 percent and 53 plus or minus 4 percent, respectively. Of the total amount of drug recovered in the urine of the fast and slow INH acetylators, NAPA accounted for 32 percent and 19 percent, respectively (p smaller than 0.01). There appears to be a positive correlation between the ability to acetylate INH and the ability to acetylate procainamide.