Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T&gt;MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections

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

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“…This is further supported by studies that correlate optimised antibiotic exposure with improved patient outcome [6][7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 72%

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

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“…Dr. Roberts and colleagues suggested the use of trough concentrations as another PK-PD target at 4-5 × the concentration of the MIC for the pathogen and reported that the clinical success rate was 87.3% during beta-lactam TDM [25]. As observed by Dr. Roberts and colleagues, contrasting target values of %T > MIC were recently reported by some authors [26,27]. The very limited pertinent literature for beta-lactam TDM does not allow a direct comparison between our evaluation and those of previous trials; however, the results from the available reports and the present study are equivalent and suggest that beta-lactam TDM is useful to successfully personalize treatment.…”

Section: Dose Individualizationmentioning

confidence: 94%

Application of Beta-lactam Therapeutic Drug Monitoring in Clinical Practice Using HPLC

Aoki¹

2013

JBABM

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In beta-lactam therapy, investigation of the pharmacokinetic-pharmacodynamic (PK-PD) relationship has provided surrogate makers to predict clinical outcome. This study was designed to verify the therapeutic efficacy and clinical utility of beta-lactam therapeutic drug monitoring (TDM) in critically ill patients using high-performance liquid chromatography (HPLC). This cohort study included 13 patients who were intravenously administered ceftazidime (n = 6), cefepime (n = 1), imipenem (n = 1), meropenem (n = 1), or piperacillin (n = 4). Blood samples were collected at 3 time points fitted to a 1-compartment model, and concentrations were determined using HPLC. The PK-PD target was the percentage of the dosing interval during which the antibiotic concentration exceeded the minimum inhibitory concentration for the pathogens (%T > MIC), which is 50% for penicillins (piperacillin), 60% for cephalosporins (ceftazidime and cefepime), and 40% for carbapenems (imipenem and meropenem). Our process using HPLC enables the analytical results of TDM to be available within half a day. The results revealed significant inter-patient pharmacokinetic variability. During the initial regimen, beta-lactam concentrations reached the target %T > MIC in all patients, and dosage reduction was required for 5 patients (38%). Of the 13 evaluable patients, clinical improvement was observed in 11 (85%), and microbiological success was observed in 10 (77%). In summary, beta-lactam TDM achieved the treatment goals and might also allow for the personalization to prevent overdosing for variable pharmacokinetic changes in critically ill patients. These findings indicate that beta-lactam TDM using HPLC can be used in the standard pharmacy clinical practice for critically ill patients.

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“…The fT>MIC is lower for carbapenems because a more pronounced post-antibiotic effect is assumed for this substance class than for other substances [198]. These recommendations are derived from animal experiments; clinical investigations underscore the fact that in sepsis patients, an fT>MIC of 100% elicits a more effective anti-infective effect, and is thus relevant for outcome [190,[201][202][203]. Especially on the basis of striving to achieve adequate tissue concentrations even in deep-lying compartments (pneumonia; bone infections; infections of the central nervous system, CNS)-frequently in the context of disturbed microcirculation in sepsis patients [204][205][206] and also wishing to avoid development of resistance [207,208]-many experts recommend aiming for a concentration of β-lactam antibiotics in the primary compartment (serum/plasma) that exceeds the MIC by 4-times (up to 6-times) for 60-100% of the dosing interval [209].…”

Section: Pharmacokinetic Conceptsmentioning

confidence: 99%

Bacterial sepsis

et al. 2018

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Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections

Cited by 420 publications

References 30 publications

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

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

Application of Beta-lactam Therapeutic Drug Monitoring in Clinical Practice Using HPLC

Bacterial sepsis

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