What is the optimal loading dose of broad-spectrum β-lactam antibiotics in septic patients? Results from pharmacokinetic simulation modelling.

Optimal loading doses of β-lactams to rapidly achieve adequate drug concentrations in critically ill patients are unknown. This was a post-hoc analysis of a prospective study that evaluated broad-spectrum β-lactams [piperacillin (PIP), ceftazidime (CAZ), cefepime (FEP) and meropenem (MEM)] pharmacokinetics (PKs) in patients with sepsis or septic shock (n = 88). Monte Carlo simulation was performed for 1000 virtual patients using specific sets of covariates for various dosing regimens and different durations of administration.

Single-dose pharmacokinetics of temocillin in plasma and soft tissues of healthy volunteers after intravenous and subcutaneous administration: a randomized crossover microdialysis trial.

Background: The antibiotic temocillin has recently been rediscovered as a promising therapeutic option against MDR Gram-negative bacteria. However, some aspects of the pharmacokinetic (PK) profile of the drug are still to be elucidated: subcutaneous administration of temocillin might be of interest as an alternative to the intravenous route in selected patients. Similarly, information on the penetration of temocillin into human soft tissues is lacking.

Optimizing β-lactams treatment in critically-ill patients using pharmacokinetics/pharmacodynamics targets: are first conventional doses effective?

The pharmacokinetic/pharmacodynamic index determining β-lactam activity is the percentage of the dosing interval (%T) during which their free serum concentration remains above a critical threshold over the minimum inhibitory concentration (MIC). Regrettably, neither the value of %T nor that of the threshold are clearly defined for critically-ill patients. Areas covered: We review and assess the targets proposed for β-lactams in critical illness by screening the literature since 1997.

Population pharmacokinetic modeling and optimal sampling strategy for Bayesian estimation of amikacin exposure in critically ill septic patients.

Because the sepsis-induced pharmacokinetic (PK) modifications need to be considered in aminoglycoside dosing, the present study aimed to develop a population PK model for amikacin (AMK) in severe sepsis and to subsequently propose an optimal sampling strategy suitable for Bayesian estimation of the drug PK parameters. Concentration-time profiles for AMK were obtained from 88 critically ill septic patients during the first 24 hours of antibiotic treatment. The population PK model was developed using a nonlinear mixed effects modeling approach.

Empirical models for dosage optimization of four beta-lactams in critically ill septic patients based on therapeutic drug monitoring of amikacin.

Objectives: The study aims to develop empirical models able to predict the pharmacokinetics (PK) of four beta-lactams using the amikacin (AMK) therapeutic drug monitoring (TDM), in order to optimize their dosage regimens.

Design And Methods: 69 critically ill septic patients were included. All received a first dose of AMK combined with piperacillin/tazobactam, ceftazidime, cefepime or meropenem.

Validation of a liquid chromatography-mass spectrometric assay for tacrolimus in peripheral blood mononuclear cells.

As a potential alternative to whole-blood tacrolimus (TAC) monitoring, a sensitive and selective method was developed for quantifying this immunosuppressant in human peripheral blood mononuclear cell population (PBMCs). These cells, expected to be a more specific biological matrix than whole blood to reflect pharmacological efficacy, could be promising for TAC therapeutic drug monitoring (TDM). The assay was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Validation of a liquid chromatography-mass spectrometric assay for tacrolimus in liver biopsies after hepatic transplantation: correlation with histopathologic staging of rejection.

The aims of this work were both to validate a sensitive and specific method to quantify tacrolimus (TAC) in liver biopsies after hepatic transplantation and to evaluate the predictive value of either tissue or blood TAC concentrations for rejection in 146 adult patients under a TAC-based immunosuppression. Trough blood levels were monitored daily during the hospital stay by immunoassay. Liver biopsies were routinely performed at day 7 posttransplantation.

Permeability of 13 different gloves to 13 cytotoxic agents under controlled dynamic conditions.

Purpose: The permeability of 13 different gloves to 13 cytotoxic agents under controlled dynamic conditions is described.

Methods: Thirteen cytotoxic agents were prepared at the highest concentrations normally encountered by pharmacy personnel. Four glove types--neoprene, natural rubber latex, nitrile, and vinyl--were exposed to the cytotoxic agents for 15, 30, and 60 minutes.

Therapeutic monitoring of immunosuppressant drugs. Where are we?

The emergence of specific immunosuppressive drugs (cyclosporine, tacrolimus, mycophenolate mofetil and sirolimus) during the last two decades has contributed dramatically to the success of organ transplantation. However, optimum balance between therapeutic efficacy and the occurrence of side effects has been a real challenge for physicians, mainly due to inter- and intra-patient variability arising from pharmacokinetic, pharmacogenetic and pharmacodynamic individual properties. Therapeutic drug monitoring, defined as the measurement and interpretation of concentrations of these drugs in biological fluids, with as a final objective the prediction of organ responses, became an integral part of transplant protocols.

Information-dependent acquisition-mediated LC-MS/MS screening procedure with semiquantitative potential.

The development of a LC-MS/MS general unknown screening procedure for toxicologically relevant substances in blood samples by means of information-dependent acquisition on a Q-TOF is reported. IDA is an artificial intelligence-based product ion scan mode providing automatic "on-the-fly" MS to MS/MS switching. By performing information-dependent scanning at two different fragmentation energies, two collision-induced dissociation product ion spectra for each of the detected compounds are generated.

Plasma and tissue determination of 4-methylpyrazole for pharmacokinetic analysis in acute adult and pediatric methanol/ethylene glycol poisoning.

Methanol and ethylene glycol poisoning may result in severe intoxication. The inhibition of alcohol dehydrogenase by ethanol or 4-methylpyrazole (4-MP, fomepizole) is fundamental to their treatment. 4-MP presents several advantages over ethanol therapy and has been recently approved as a specific antidote for both intoxications.

High-throughput liquid chromatography-tandem mass spectrometric analysis of sirolimus in whole blood.

Sirolimus appears as a new potent immunosuppressive agent taking advantage of therapeutic drug monitoring to optimize its use in organ transplantation. In the absence of any available commercial immunoassay it was mandatory to develop chromatographic assays. Some methods have already been proposed to quantify sirolimus in whole blood, based either on HPLC-UV, liquid chromatography-mass spectrometry (LC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS).