Clinical Pharmacodynamics of Meropenem in Patients with Lower Respiratory Tract Infections

Li, Chonghua; Du, Xin; Kuti, Joseph L.; Nicolau, David P.

doi:10.1128/aac.00294-06

Cited by 272 publications

(198 citation statements)

References 18 publications

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“…For LZD, the determined value of 56 for f AUC/MIC in the present work is fairly close to the breakpoints in animals (AUC/MIC of 83)37 and humans (AUC/MIC of 51–85)38 for bloodstream infections if protein binding is considered. For MER, the determined value of 52% f %T >MIC was also in good agreement with the clinical breakpoint for microbiological response of 54% determined in patients with lower respiratory tract infections, in which S. aureus was the second‐most abundant pathogen 39. For VAN, the f AUC/MIC breakpoints from the clinical studies40, 41 tended to be fairly higher (125–400) than the calculated values (59–94) of the present work, which could originate from the partly impaired tissue distribution of VAN,42 whereas for MER and LZD, unbound plasma concentrations might be a fair predictor of tissue concentrations,43, 44, 45 if determined under appropriate analytic conditions 24, 46, 47.…”

Section: Discussionsupporting

confidence: 79%

Translational Pharmacometric Evaluation of Typical Antibiotic Broad-Spectrum Combination Therapies AgainstStaphylococcus AureusExploitingIn VitroInformation

Wicha

Huisinga

Kloft

2017

CPT Pharmacometrics Syst. Pharmacol.

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Broad‐spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad‐spectrum combination therapies consisting of either linezolid (LZD) or vancomycin (VAN) combined with meropenem (MER) against Staphylococcus aureus (S. aureus) as the most frequent causative pathogen of severe infections. A semimechanistic pharmacokinetic‐pharmacodynamic (PK‐PD) model mimicking a simplified bacterial life‐cycle of S. aureus was developed upon time‐kill curve data to describe the effects of LZD, VAN, and MER alone and in dual combinations. The PK‐PD model was successfully (i) evaluated with external data from two clinical S. aureus isolates and further drug combinations and (ii) challenged to predict common clinical PK‐PD indices and breakpoints. Finally, clinical trial simulations were performed that revealed that the combination of VAN‐MER might be favorable over LZD‐MER due to an unfavorable antagonistic interaction between LZD and MER.

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Section: Discussionsupporting

confidence: 79%

Translational Pharmacometric Evaluation of Typical Antibiotic Broad-Spectrum Combination Therapies AgainstStaphylococcus AureusExploitingIn VitroInformation

Wicha

Huisinga

Kloft

2017

CPT Pharmacometrics Syst. Pharmacol.

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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: Introductionsupporting

confidence: 52%

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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“…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: 76%

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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Clinical Pharmacodynamics of Meropenem in Patients with Lower Respiratory Tract Infections

Cited by 272 publications

References 18 publications

Translational Pharmacometric Evaluation of Typical Antibiotic Broad-Spectrum Combination Therapies AgainstStaphylococcus AureusExploitingIn VitroInformation

Translational Pharmacometric Evaluation of Typical Antibiotic Broad-Spectrum Combination Therapies AgainstStaphylococcus AureusExploitingIn VitroInformation

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

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