Recommendations for enterovirus diagnostics and characterisation within and beyond Europe.

Enteroviruses (EV) can cause severe neurological and respiratory infections, and occasionally lead to devastating outbreaks as previously demonstrated with EV-A71 and EV-D68 in Europe. However, these infections are still often underdiagnosed and EV typing data is not currently collected at European level. In order to improve EV diagnostics, collate data on severe EV infections and monitor the circulation of EV types, we have established European non-polio enterovirus network (ENPEN).

Population pharmacokinetics of continuous infusion of piperacillin in critically ill patients.

Dosing recommendations for continuous infusion of piperacillin, a broad-spectrum beta-lactam antibiotic, are mainly guided by outputs from population pharmacokinetic models constructed with intermittent infusion data. However, the probability of target attainment in patients receiving piperacillin by continuous infusion may be overestimated when drug clearance estimates from population pharmacokinetic models based on intermittent infusion data are used, especially when higher doses (e.g.

Development and validation of an LC tandem MS assay for the quantification of β-lactam antibiotics in the sputum of cystic fibrosis patients.

Objectives: Antibiotic therapy is of vital importance for the control of infectious exacerbations in cystic fibrosis (CF) patients. However, very little is known regarding the fraction of systemically administered antibiotics reaching the lower respiratory tract secretions. We developed and validated a method to measure the concentrations of piperacillin, ceftazidime, meropenem and aztreonam in CF sputum, and present the validation data.

Dose optimization of piperacillin/tazobactam in critically ill children.

Objectives: To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen.

Patients And Methods: This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC-MS/MS method.

Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children.

There is little data available to guide amoxicillin-clavulanic acid dosing in critically ill children. The primary objective of this study was to investigate the pharmacokinetics of both compounds in this pediatric subpopulation. Patients admitted to the pediatric intensive care unit (ICU) in whom intravenous amoxicillin-clavulanic acid was indicated (25 to 35 mg/kg of body weight every 6 h) were enrolled.

Assays for therapeutic drug monitoring of β-lactam antibiotics: A structured review.

In some patient groups, including critically ill patients, the pharmacokinetics of β-lactam antibiotics may be profoundly disturbed due to pathophysiological changes in distribution and elimination. Therapeutic drug monitoring (TDM) is a strategy that may help to optimise dosing. The aim of this review was to identify and analyse the published literature on the methods used for β-lactam quantification in TDM programmes.

Population pharmacokinetics and dosing simulations of cefepime in septic shock patients receiving continuous renal replacement therapy.

The aim of this study was to describe the population pharmacokinetics of cefepime in septic shock patients requiring continuous renal replacement therapy and to determine whether current or alternative dosing regimens can achieve PK/PD targets. In this observational PK study, 62 samples from 13 patients were analysed using non-linear mixed-effects modelling. Different dosing regimens were evaluated using Monte Carlo simulations with ultrafiltration flow rates (UFRs) of 1000, 1500 and 2000 mL/h.

A Simulation Study Reveals Lack of Pharmacokinetic/Pharmacodynamic Target Attainment in De-escalated Antibiotic Therapy in Critically Ill Patients.

De-escalation of empirical antibiotic therapy is often included in antimicrobial stewardship programs in critically ill patients, but differences in target attainment when antibiotics are switched are rarely considered. The primary objective of this study was to compare the fractional target attainments of contemporary dosing of empirical broad-spectrum β-lactam antibiotics and narrower-spectrum antibiotics for a number pathogens for which de-escalation may be considered. The secondary objective was to determine whether alternative dosing strategies improve target attainment.

Subtleties in practical application of prolonged infusion of β-lactam antibiotics.

Prolonged infusion (PI) of β-lactam antibiotics is increasingly used in order to optimise antibiotic exposure in critically ill patients. Physicians are often not aware of a number of subtleties that may jeopardise the treatment. In this clinically based paper, we stress pragmatic issues, such as the importance of a loading dose before PI, and discuss a number of important practicalities that are mandatory to benefit from the pharmacokinetic advantages of prolonged β-lactam antibiotic administration.

Comparison of different equations to assess glomerular filtration in critically ill patients.

Purpose: To evaluate equations for estimation of glomerular filtration rate (GFR) and measured urinary creatinine clearance, compared to measured GFR in critically ill patients.

Methods: GFR was measured using inulin clearance. Multiple blood samples were collected per patient for determination of serum creatinine, cystatin C and inulin.

Ultrafast quantification of β-lactam antibiotics in human plasma using UPLC-MS/MS.

There is an increasing interest in monitoring plasma concentrations of β-lactam antibiotics. The objective of this work was to develop and validate a fast ultra-performance liquid chromatographic method with tandem mass spectrometric detection (UPLC-MS/MS) for simultaneous quantification of amoxicillin, cefuroxime, ceftazidime, meropenem and piperacillin with minimal turn around time. Sample clean-up included protein precipitation with acetonitrile containing 5 deuterated internal standards, and subsequent dilution of the supernatant with water after centrifugation.

Measuring unbound versus total vancomycin concentrations in serum and plasma: methodological issues and relevance.

Background: Studies on the unbound fraction (fu) of vancomycin report highly variable results. Great controversy also exists about the correlation between unbound and total vancomycin concentrations. As differences in (pre-)analytic techniques may explain these findings, we investigated the impact of the procedure used to isolate unbound vancomycin in serum/plasma on fu and the correlation between total and unbound concentrations.

Beta-lactam antibiotic dosing during continuous renal replacement therapy: how can we optimize therapy?

Correct antibiotic treatment is of utmost importance to treat infections in critically ill patients, not only in terms of spectrum and timing but also in terms of dosing. However, this is a real challenge for the clinician because the pathophysiology (such as shock, augmented renal clearance, and multiple organ dysfunction) has a major impact on the pharmacokinetics of hydrophilic antibiotics. The presence of extra-corporal circuits, such as continuous renal replacement therapy, may further complicate this difficult exercise.

Population pharmacokinetics and dosing simulations of cefuroxime in critically ill patients: non-standard dosing approaches are required to achieve therapeutic exposures.

Objectives: To investigate the population pharmacokinetics of cefuroxime in critically ill patients.

Methods: In this observational pharmacokinetic study, multiple blood samples were taken over one dosing interval of intravenous cefuroxime. Blood samples were analysed using a validated ultra HPLC tandem mass spectrometry technique.

Does consistent piperacillin dosing result in consistent therapeutic concentrations in critically ill patients? A longitudinal study over an entire antibiotic course.

Piperacillin plasma concentrations are known to vary between critically ill patients. However, there are no comprehensive data on the variability of antibiotic concentrations within the same patient. The purpose of this study was to investigate the adequacy of dosing during an entire 7-day antibiotic course and to investigate the variability in antibiotic trough concentrations both between patients and within the same patient.

An international, multicentre survey of β-lactam antibiotic therapeutic drug monitoring practice in intensive care units.

Objectives: Emerging evidence supports the use of therapeutic drug monitoring (TDM) of β-lactams for intensive care unit (ICU) patients to optimize drug exposure, although limited detail is available on how sites run this service in practice. This multicentre survey study was performed to describe the various approaches used for β-lactam TDM in ICUs.

Methods: A questionnaire survey was developed to describe various aspects relating to the conduct of β-lactam TDM in an ICU setting.

Population pharmacokinetics and dosing simulations of amoxicillin/clavulanic acid in critically ill patients.

Objectives: The objective of this study was to investigate the population pharmacokinetics and pharmacodynamics of amoxicillin and clavulanic acid in critically ill patients.

Methods: In this observational pharmacokinetic study, multiple blood samples were taken over one dosing interval of intravenous amoxicillin/clavulanic acid (1000/200 mg). Blood samples were analysed using a validated ultra HPLC-tandem mass spectrometry technique.

Identifying patients at risk for augmented renal clearance in the ICU - limitations and challenges.

Augmented renal clearance (ARC) is an important determinant of antibiotic exposure in critically ill patients, and identifying patients at risk is therefore an important goal. There is a growing body of evidence that a younger patient with a low to moderate degree of organ dysfunction typically is at risk of ARC and therefore decreased exposure to renally eliminated antibiotics. Mechanisms potentially involved, such as increased cardiac output, have, however, not been identified as appropriate surrogate markers, and the search for suitable alternatives to readily identify patients with ARC continues.

Meropenem and piperacillin/tazobactam prescribing in critically ill patients: does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used?

Background: Correct antibiotic dosing remains a challenge for the clinician. The aim of this study was to assess the influence of augmented renal clearance on pharmacokinetic/pharmacodynamic target attainment in critically ill patients receiving meropenem or piperacillin/tazobactam, administered as an extended infusion.

Methods: This was a prospective, observational, pharmacokinetic study executed at the medical and surgical intensive care unit at a large academic medical center.

Quantification of seven β-lactam antibiotics and two β-lactamase inhibitors in human plasma using a validated UPLC-MS/MS method.

There is an increasing interest in monitoring plasma concentrations of β-lactam antibiotics. The objective of this work was to develop and validate a rapid ultra-performance liquid chromatographic method with tandem mass spectrometric detection (UPLC-MS/MS) for simultaneous quantification of amoxicillin, ampicillin, cefuroxime, cefazolin, ceftazidime, meropenem, piperacillin, clavulanic acid and tazobactam. Sample clean-up included protein precipitation with acetonitrile and back-extraction of acetonitrile with dichloromethane.