Impaired target site penetration of β -lactams may account for therapeutic failure in patients with septic shock

Joukhadar, Christian; Frossard, Martin; Mayer, Bernd; Brunner, Martin; Klein, Nikolas; Siostrzonek, Peter; Eichler, Hans Georg; Müller, Markus

doi:10.1097/00003246-200102000-00030

Cited by 256 publications

(186 citation statements)

References 28 publications

Supporting

Mentioning

168

Contrasting

Unclassified

Order By: Relevance

“…Our PD data resembled the data of others, suggesting that the probability of target attainment (probability of reaching fT.MIC564 mg/ml>50%) was not 100% (10,19,20).…”

Section: Discussionsupporting

confidence: 85%

Pharmacokinetics and Pharmacodynamics of Piperacillin-Tazobactam in 42 Patients Treated with Concomitant CRRT

Bauer¹,

Salem

Connor

et al. 2012

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

SummaryBackground and objectives Current recommendations for piperacillin-tazobactam dosing in patients receiving continuous renal replacement therapy originate from studies with relatively few patients and lower continuous renal replacement therapy doses than commonly used today. This study measured the pharmacokinetic and pharmacodynamic characteristics of piperacillin-tazobactam in patients treated with continuous renal replacement therapy using contemporary equipment and prescriptions.Design, setting, participants, & measurements A multicenter prospective observational study in the intensive care units of two academic medical centers was performed, enrolling patients with AKI or ESRD receiving piperacillin-tazobactam while being treated with continuous renal replacement therapy. Pregnant women, children, and patients with end stage liver disease were excluded from enrollment. Plasma and continuous renal replacement therapy effluent samples were analyzed for piperacillin and tazobactam levels using HPLC. Pharmacokinetic and pharmacodynamic parameters were calculated using standard equations. Multivariate analyses were used to examine the association of patient and continuous renal replacement therapy characteristics with piperacillin pharmacokinetic parameters.Results Forty-two of fifty-five subjects enrolled had complete sampling. Volume of distribution (median=0.38 L/kg, intraquartile range=0.20 L/kg) and elimination rate constants (median=0.104 h 21 , intraquartile range=0.052 h 21 ) were highly variable, and clinical parameters could explain only a small fraction of the large variability in pharmacokinetic parameters. Probability of target attainment for piperacillin was 83% for total drug but only 77% when the unbound fraction was considered.Conclusions There is significant patient to patient variability in pharmacokinetic/pharmacodynamic parameters in patients receiving continuous renal replacement therapy. Many patients did not achieve pharmacodynamic targets, suggesting that therapeutic drug monitoring might optimize therapy.

show abstract

“…Our PD data resembled the data of others, suggesting that the probability of target attainment (probability of reaching fT.MIC564 mg/ml>50%) was not 100% (10,19,20).…”

Section: Discussionsupporting

confidence: 85%

Pharmacokinetics and Pharmacodynamics of Piperacillin-Tazobactam in 42 Patients Treated with Concomitant CRRT

Bauer¹,

Salem

Connor

et al. 2012

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…In this study, however, the proportionality factor was necessary to allow the prediction of free tissue concentrations based on plasma PK parameters, indicating that infection caused physiological changes in muscle such as increase in vascular permeability leading to increase in protein concentration at the infection site, increase in tissue temperature and pH alterations that would ultimately lead to an around 30% decrease in free interstitial levels of PIP. Joukhadar et al 10 studied the tissue penetration of piperacillin in skeletal muscle and s.c. adipose tissue in patients with septic shock, using microdialysis, and observed that the free levels of piperacillin in these situations were 5-10 times lower than the corresponding free plasma concentrations, indicating the infectious process changed the penetration of this antimicrobial, reducing its clinical effectiveness. The difference between this study and that reported by Joukhadar et al is that in the present one the animals had a localized infection instead of a septic shock that definitively alters body homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…However, some studies have demonstrated that infection changes the physiological characteristics of the infected tissue due to the inflammatory process developed by host aiming to eliminate the invasive organism, as observed in soft tissue infections, septic shock, pneumonia or vascular alterations associated to diabetes. [9][10][11][12] In this context, it is not always possible to predict the antimicrobial-free fraction at the site of infection, based on the microdialysis data obtained in healthy tissue or unbound plasma levels.…”

Section: Introductionmentioning

confidence: 99%

PK-PD modeling of β-lactam antibiotics: In vitro or in vivo models?

et al. 2011

View full text Add to dashboard Cite

A modified E max -pharmacokinetic-pharmacodynamic (PK-PD) model was previously proposed in literature for describing the antimicrobial activity of b-lactam antibiotics based on in vitro experiments. However, bacteria behave differently in vitro and in vivo. Thus, the aims of this study were to model the killing effect of piperacillin (PIP) against Escherichia coli on immunocompromised infected rats using this model and to compare the parameters obtained in vitro and in vivo for the same bacteria/drug combination. The PK-PD parameters determined in vitro and in vivo were as follows: generation rate constant of 1.30 ± 0.10 and 0.76 ± 0.20 h À1 , maximum killing effect of 3.11 ± 0.27 and 1.38 ± 0.20 h À1 and concentration to produce 50% of the maximum effect of 5.44 ± 0.03 and 1.31 ± 0.27 lg ml À1 , respectively. The comparison between the in vitro and in vivo parameters was not straightforward and had to take into consideration the intrinsic differences of the models involved. So far, the main application of the PK-PD model evaluated is for the comparison of different antimicrobial agent's potency and efficacy, under equivalent conditions.

show abstract

“…Despite tremendous investments in new treatments, arresting poor clinical outcomes has been a global challenge [2]. For -lactam antibiotics, which are the mainstay of therapy in severely ill patents, emerging evidence suggest that poor antibiotic exposure is a potential cause of poor clinical outcomes [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Simultaneous determination of seven β-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies

Sime

Roberts

et al. 2014

Journal of Chromatography B

View full text Add to dashboard Cite

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThere is strong evidence in literature supporting the benefit of monitoring plasma concentrations of -lactam antibiotics in the critically ill to ensure appropriateness of dosing.The objective of this work was to develop a method for the simultaneous determination of total concentrations piperacillin, benzylpenicillin, flucloxacillin, meropenem, ertapenem, cephazolin and ceftazidime in human plasma. Sample preparation involved protein precipitation with acetonitrile containing 0.1% formic acid and subsequent dilution of supernatant with 0.1% formic acid in water. Chromatographic separation was achieved on a reversed phase column (C18, 2.6µm, 2.1* 50 mm) via gradient elution using water and acetonitrile, each containing 0.1% formic acid, as mobile phase. Tandem mass spectrometry (MSMS) analysis was performed, after electrospray ionization in the positive mode, with multiple reaction monitoring (MRM). The method is accurate with the inter-day and intra-day accuracies of quality control samples (QCs) ranging from 95%-107% and 95%-108%, respectively. It is also precise with intra-day and inter-day coefficient of variations ranging from 4 to 12 % and 5-14% respectively. The lower limit of quantification was 0.1g/mL for each antibiotic except flucloxacillin (0.25g/mL). Recovery was greater than 96% for all analytes except for ertapenem (78%). Coefficients of variation for the matrix effect were less than 10% over the six batches of plasma. Analytes were stable over three freeze-thaw cycles, and for reasonable hours on the bench top as well as post-preparation. This novel liquid chromatography tandem mass spectrometry method proved accurate, precise and applicable for therapeutic drug monitoring and pharmacokinetic studies of the selected -lactam antibiotics.Page 5 Highlights  We present a method for simultaneous determination of seven beta-lactams in plasma  The selected antibiotics are those commonly used in critically ill patients  The method is accurate, precise and meets validation requirements by guidelines  It proved applicable for therapeutic drug monitoring and pharmacokinetic studies

show abstract

Impaired target site penetration of β -lactams may account for therapeutic failure in patients with septic shock

Cited by 256 publications

References 28 publications

Pharmacokinetics and Pharmacodynamics of Piperacillin-Tazobactam in 42 Patients Treated with Concomitant CRRT

Pharmacokinetics and Pharmacodynamics of Piperacillin-Tazobactam in 42 Patients Treated with Concomitant CRRT

PK-PD modeling of β-lactam antibiotics: In vitro or in vivo models?

Simultaneous determination of seven β-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies

Contact Info

Product

Resources

About