Pharmacokinetics and Pharmacodynamics of Meropenem in Febrile Neutropenic Patients with Bacteremia

Ariano, Robert E.; Nyhlén, Anna; Donnelly, J. Peter; Sitar, Daniel S.; Harding, G. K. M.; Zelenitsky, Sheryl

doi:10.1345/aph.1e271

Cited by 170 publications

(143 citation statements)

References 26 publications

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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%

“…A c c e p t e d M a n u s c r i p t 8 Confirmation of dosing appropriateness through monitoring of plasma concentrations is therefore essential for -lactam antibiotics in the critically ill patient population. Routine therapeutic drug monitoring (TDM), enables a rational, patient specific dose adjustment thereby maximizing treatment efficacy while minimizing drug toxicity [35].…”

Section: Page 8 Of 48mentioning

confidence: 99%

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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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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%

Section: Page 8 Of 48mentioning

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

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“…However, as also observed in the studies described above (11,13), treatment failure with rapid resistance emergence nonetheless occurred even in some situations where fT ϾMIC was at or close to 100%. Such in vitro findings plus data from recent retrospective clinical studies supporting a longer fT ϾMIC in critically ill patients (42)(43)(44)(45) challenge the traditional PK/PD targets. With maximal bactericidal activity of the ␤-lactams occurring at 4ϫ to 5ϫ MIC (46,47) and regrowth often observed as soon as concentrations fall below the MIC (48-50), other targets, e.g., 100% fT Ͼ4 -5ϫMIC (14, 51, 52) and fC min /MIC, have been investigated.…”

Section: Effect Of Meropenem Clearance On Antibacterial Effectsmentioning

confidence: 98%

Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model

Bergen

Bulitta

Kirkpatrick

et al. 2017

Antimicrob Agents Chemother

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Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MIC meropenem 0.25 mg/ liter) was studied in the hollow-fiber infection model (inoculum ϳ10 7.5 CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ϳ10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (Յϳ2.5 log 10 ). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h; regrowth then occurred with 0.5-and 1-g regimens with normal renal function (fT Ͼ5ϫMIC ϭ 56 and 69%, fC min /MIC Ͻ 2); the emergence of less-susceptible populations (Ն32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function (fT Ͼ5ϫMIC Ն 82%, fC min /MIC Ն 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.

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“…Therefore population pharmacokinetic parameters are essential for Monte Carlo simulation. Population pharmacokinetic analyses have been generally determined in healthy volunteers, since several studies have indicated that there is no difference between healthy volunteers and patients in terms of pharmacokinetic profiles [17,19]. Nevertheless, true between-patient variability was observed in our patients.…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 88%

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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Pharmacokinetics and Pharmacodynamics of Meropenem in Febrile Neutropenic Patients with Bacteremia

Cited by 170 publications

References 26 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

Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model

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

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