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* Letter * Open Access The kinetic glomerular filtration rate is not interchangeable with measured creatinine clearance for prediction of piperacillin underexposure in critically ill patients with augmented renal clearance * Cédric Carrié1, 6Email author, * Sébastien Rubin2, * Pierre Sioniac1, * Dominique Breilh3, 4 and * Matthieu Biais1, 5 Critical Care2018 22:177 https://doi.org/10.1186/s13054-018-2117-7 © The Author(s). [...]the area under the ROC curve generated for KeGFR was significantly lower than the one generated for measured CrCL for prediction of piperacillin underdosing (0.76 [0.68–0.83] vs 0.85 [0.79–0.91], p = 0.03; Fig. 2). The importance of empiric antibiotic dosing in critically ill trauma patients: are we under-dosing based on augmented renal clearance and inaccurate renal clearance estimates? J Trauma Acute Care Surg. 2016;81(6):1115–21.View ArticlePubMedGoogle Scholar Carrié C, Petit L, d'Houdain N, Sauvage N, Cottenceau V, Lafitte M, Foumenteze C, Hisz Q, Menu D, Legeron R, Breilh D, Sztark F. Association between augmented renal clearance, antibiotic exposure and clinical outcome in critically ill septic patients receiving high doses of β-lactams administered by continuous infusion: a prospective observational study.

Background: Open abdomen with vacuum-assisted wound closure therapy (OA/VAC) is frequently used in critically ill patients although the impact of OA/VAC on antibiotics pharmacokinetics (PK) remains unknown. We thus aimed to characterize the PK of piperacillin–tazobactam (PTZ) in critically ill patients with OA/VAC and assess the optimal dosing regimens based on pharmacodynamics (PD) target attainment. Methods: Over a 15-month study period, 45 patients with OA/VAC treated with PTZ administered continuously and adapted to 24 h creatinine clearance (CLCR) underwent measurements of free concentrations in their plasma, urine, VAC exudate, and peritoneal fluid. Population PK modeling was performed considering the effect of covariates, and Monte Carlo simulations were employed to determine the probability of target attainment (PTA) for the PK/PD targets (100% fT > 16 mg/L) in the plasma and at the peritoneal site at steady state. Results: Piperacillin concentrations were described using a two-compartment model, with age and total body weight as significant covariates for central volume of distribution (V1) and estimated renal function for clearance (CL). Tazobactam concentrations were described using a two-compartment model with estimated renal function as a significant covariate. The central volume of distributions V1 of piperacillin and tazobactam were 21.2 and 23.2 L, respectively. The VAC-induced peritoneal clearance was negligible compared to renal clearance. Most patients achieved the desirable PK/PD target when using a CLCR-pondered PTZ dosing regimen from 12 g/1.5 g/day to 20 g/2.5 g/day. Conclusions: Despite a wide inter-individual variability, the influence of OA/VAC on piperacillin and tazobactam PK parameters is not straightforward. The use of a CLCR-pondered PTZ dosing regimen from 12 g/1.5 g/day to 20 g/2.5 g/day is needed to reach a PTA > 85%.

To determine whether augmented renal clearance (ARC) impacts negatively on piperacillin-tazobactam unbound concentrations in critically ill patients receiving 16 g/2 g/day administered continuously. Fifty nine critically ill patients without renal impairment underwent 24-h creatinine clearance (CrCL) measurement and therapeutic drug monitoring during the first three days of antimicrobial therapy by piperacillin-tazobactam. The main outcome was the rate of piperacillin underexposure, defined by at least one of three samples under 16 mg/L. Monte Carlo simulation was performed to predict the distribution of piperacillin concentrations for various CrCL and minimal inhibitory concentration (MIC) values. The rate of piperacillin underexposure was 19%, significantly higher in ARC patients (0 vs. 31%, p = .003). A threshold of CrCL ≥ 170 mL/min had a sensitivity and specificity of 1 (95%CI: 0.79–1) and 0.69 (95%CI: 0.61–0.76) to predict piperacillin underexposure. In ARC patients, a 20 g/2.5 g/24 h PTZ dosing regimen was associated with the highest probability to reach the 16 mg/L empirical target, without risk of excessive dosing. When targeting a theoretical MIC at the upper limit of the susceptibility range, the desirable target (100%fT>16) may not be achieved in patients with CrCL ≥ 170 mL/min receiving PTZ 16 g/2 g/day administered continuously. •Continuous infusion of piperacillin 16 g/day is inadequate in patients with augmented renal clearance•A 20 g/2.5 g/24 h dosing regimen is best suitable when targeting for empirical antibiotic therapy This increased regimen is not associated with excessive dosing in patients with ARC

Objective: To assess the relative strengths and weaknesses of carbapenems by considering their microbiological, clinical, pharmacokinetics and pharmacokinetic/pharmacodynamic (PK/PD) properties and defining optimal conditions of uses of the new generation of carbapenems.Methods: Literature review.Results: Except for ertapenem, the spectrum of activity is similar for all carbapenems, with little differences in activities of individual agents. The absence or reduced expression of two major porins in combination with various beta-lactamases and alteration of some penicillin binding proteins have been implicated in carbapenem resistance. All carbapenems are not alike, although they have very similar pharmacokinetic properties. The most important PK/PD parameter predicting bacteriological and clinical efficacy is T>MIC. There is some circumstantial evidence, such as clinical data in severe critically ill septic patients, impaired renal function patients and neutropenic patients that imipenem has to exceed 66% of T>MIC to result in good clinical outcome. Continuous or extend infusion of carbapenems should result in at least equal efficacy to that of intermittent infusion in the treatment of infections with susceptible bacteria and appear highly appropriate for use in critically ill patients.Conclusions: Maximizing clinical outcomes and minimizing antibiotic resistance using individualized doses may be best achieved with therapeutic drug monitoring of carbapenems. [PUBLICATION ABSTRACT]

To determine the steady-state trough serum and epithelial lining fluid (ELF) concentrations of teicoplanin 12 mg/kg per day in critically ill patients with ventilator associated pneumonia. Prospective, pharmacokinetic study in the surgical intensive care unit in a university hospital. Thirteen adult patients with nosocomial bacterial pneumonia on mechanical ventilation were enrolled. All subjects received a 30-min intravenous infusion of 12 mg/kg teicoplanin every 12 h for 2 consecutive days followed by 12 mg/kg once daily. Teicoplanin concentrations in serum and ELF were determined simultaneously 4-6 days after antibiotic administration started. The median total and free concentrations of teicoplanin in serum at trough were 15.9 microg/ml (range 8.8-29.9) and 3.7 (2.0-5.4), respectively. The concentration in ELF was 4.9 (2.0-11.8). In critically ill patients with ventilator-associated pneumonia the administration of high teicoplanin doses is required to reach sufficient trough antibiotic concentrations in lung tissues at steady state. At that time trough-free concentrations of teicoplanin in serum and ELF are comparable.

We conducted a prospective, open-label study to determine the steady-state serum and epithelial lining fluid (ELF) concentrations of unbound ertapenem administered once daily to critically ill patients with early-onset ventilator-associated pneumonia (VAP). Prospective, open-label study in an intensive care unit and research ward in a university hospital. Fifteen patients with VAP received 1-h intravenous infusions of 1 g ertapenem once daily. After 2 days of therapy the steady-state serum and ELF concentrations of free ertapenem were determined by high-performance liquid chromatography. The median (interquartile range) free ertapenem peak (C(max)), intermediate (C(12)), and trough (C(min)) concentrations (mg/l) 1, 12, and 24 h after the end of infusion were 30.3 (27.1-37.8), 4.8 (3.9-6.4), and 0.8 (0.5-1.2) in serum and 9.4 (8.0-10.7), 2.0 (1.1-2.5), and 0.3 (0.2-0.4) in ELF, respectively, showing a median free ertapenem percentage penetration in ELF of approx. 30%. The median (interquartile range) serum area under concentration-time curve of free ertapenem during the observational period was 226.7 mg h(-1) l(-1) (202.2-263.9). Our study shows satisfactory results, with unbound ertapenem concentrations both in serum and ELF exceeding the MIC(90) values of most of the causative pathogens encountered in early-onset VAP during 50-100% time. This suggests that 1 g intravenous ertapenem administered once daily should be effective during the treatment of early-onset VAP in critically ill patients with no known risk factors for multidrug-resistant pathogens.

P < 0.005). All agents were easily filtered. Mean sieving coefficient ranged from 38.7% to 96.7%. Mean elimination half-life of all agents was significantly shorter during HV-CVVH (from 1.29 to 28.54 h) than during SV-CVVH (from 1.51 to 33.85 h) (P < 0.05).Conclusions This study confirms that CVVH influences the PK/PD behavior of most antimicrobial agents. Antimicrobial elimination was directly correlated with convection rate. Current antimicrobial dose recommendations will expose patients to underdosing and increase the risk for treatment failure and development of resistance. Dose recommendations are proposed for some major antibiotic and antifungal treatments in patients receiving at least 25 mL/kg/h CVVH.

To evaluate the reliability of mini-bronchoalveolar lavage (mini-BAL) for the measurement of tobramycin concentrations in epithelial lining fluid (ELF) in comparison with conventional bronchoscopic bronchoalveolar lavage (BAL). Prospective, open-label study. An intensive care unit and research ward in a university hospital. Twelve critically ill adult patients with ventilator-associated pneumonia (VAP). All subjects received intravenous infusions of tobramycin 7-10 mg/kg once daily. After 2 days of therapy, the steady-state serum and ELF concentrations (obtained from BAL and mini-BAL) of tobramycin were determined by means of high-performance liquid chromatography. We observed poor penetration of tobramycin in ELF of approximately approximately 12% with ELF peak concentrations of approximately approximately 3 mg/l with both methods. Good agreement in Bland-Altman analysis (mean +/- SD bias = 0.04 +/- 0.38 mg/l) was observed between the two methods of sampling. Our results suggest that tobramycin 7-10 mg/kg once daily in critically ill patients with VAP might provide insufficient lung concentrations in the case of difficult-to-treat pathogens. Besides, mini-BAL, which is simple, non-invasive and easily repeatable at the bedside, appears to be a reliable method for the measurement of antibiotic concentrations in ELF in comparison with bronchoscopic BAL in critically ill patients with VAP.

To determine the steady-state plasma and epithelial lining fluid (ELF) concentrations of piperacillin/tazobactam (P/T) administered to critically ill patients with severe bacterial pneumonia. Prospective, open-label study. An intensive care unit and research ward in a university hospital. Ten adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation. All subjects received a 30-min intravenous infusion of P/T 4 g/0.5 g every 8 h. The steady-state plasma and ELF concentrations of P/T were determined by high-performance liquid chromatography. The mean+/-SD steady-state plasma trough, peak, and intermediate concentrations were 8.5+/-4.6 microg/ml, 55.9+/-21.6 microg/ml, and 24.0+/-13.8 microg/ml for piperacillin, and 2.1+/-1.0 microg/ml, 4.8+/-2.1 microg/ml, and 2.4+/-1.2 microg/ml for tazobactam, respectively. The mean+/-SD steady-state intermediate ELF concentrations were 13.6+/-9.4 microg/ml for piperacillin and 2.1+/-1.1 microg/ml for tazobactam, respectively, showing a mean percentage penetration of piperacillin and tazobactam into ELF of 56.8% and 91.3 %, respectively, with a P/T ratio of 6.5:1. Our results show that during the treatment of severe nosocomial pneumonia, a regimen of P/T 4 g/0.5 g every 8 h might provide insufficient concentrations into lung tissue to exceed the MIC of many causative pathogens. This suggests that higher doses of P/T should be administered in order to maximize the antibiotic concentration at the site of infection, or that a second antimicrobial agent should be used in association.

To determine the steady-state plasma and epithelial lining fluid (ELF) concentrations of ceftazidime administered in continuous infusion to critically ill patients with severe nosocomial pneumonia. Prospective, open-label study. An intensive care unit and research ward in a university hospital. A total of 15 adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation were enrolled. All subjects received a 30 min intravenous infusion of 2 g ceftazidime followed by a continuous infusion of 4 g over 24 h. The concentrations of ceftazidime in plasma and ELF were determined at steady-state after 2 days of therapy by high performance liquid chromatography. The mean +/-SD steady-state plasma and ELF concentrations of 4 g ceftazidime in continuous infusion were 39.6+/-15.2 microg/mL and 8.2+/-4.8 microg/mL, respectively, showing a mean +/-SD percentage penetration of ceftazidime into ELF of 20.6+/-8.9%. The administration of 4 g ceftazidime in continuous infusion in critically ill patients with severe nosocomial pneumonia provides concentrations in excess of the minimal inhibitory concentration of many susceptible organisms over the course of therapy both in serum and ELF. However, for some pathogens such as P. aeruginosa, higher doses of ceftazidime should be administered, or another agent should be used in combination.