Is continuous infusion of beta-lactam antibiotics worthwhile?--efficacy and pharmacokinetic considerations

The most important pharmacodynamic parameter for beta-lactam antibiotics has been shown to be the time above the MIC, which is used as an argument to administer beta-lactam antibiotics by continuous infusion. Studies in vitro and in laboratory animals comparing efficacy of continuous an

Pharmacokinetic-pharmacodynamic modeling of activity of ceftazidime during continuous and intermittent infusion

We developed and applied pharmacokinetic-pharmacodynamic (PK-PD) models to characterize in vitro bacterial rate of killing as a function of ceftazidime concentrations over time. For PK-PD modeling, data obtained during continuous and intermittent infusion of ceftazidime in Pseudomonas aeruginosa killing experiments with an in vitro pharmacokinetic model were used. The basic PK-PD model was a maximum-effect model which described the number of viable bacteria (N) as a function of the growth rate (lambda) and killing rate (epsilon) according to the equation dN/dt = [lambda - epsilon x [Cgamma(EC50gamma + Cgamma)]] N, where gamma is the Hill factor, C is the concentration of antibiotic, and EC50 is the concentration of antibiotic at which 50% of the maximum effect is obtained. Next, four different models with increasing complexity were analyzed by using the EDSIM program (MediWare, Groningen, The Netherlands). These models incorporated either an adaptation rate factor and a maximum number of bacteria (Nmax) factor or combinations of the two parameters. In addition, a two-population model was evaluated. Model discrimination was by Akaike's information criterion. The experimental data were best described by the model which included an Nmax term and a rate term for adaptation for a period up to 36 h. The absolute values for maximal growth rate and killing rate in this model were different from those in the original experiment, but net growth rates were comparable. It is concluded that the derived models can describe bacterial growth and killing in the presence of antibiotic concentrations mimicking human pharmacokinetics. Application of these models will eventually provide us with parameters which can be used for further dosage optimization

Novel therapeutic modalities: the future is now

Pharmacolog

Personalized therapy for mycophenolate: consensus report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.Personalised Therapeutic

Verantwoording en kosteneffectiviet van therapeutic drug monitoring (1): Betere behandeling voor minder geld

There are a number of effective but highly toxic drugs that exhibit a narrow therapeutic index and marked intersubject pharmacokinetic variability. Optimal therapy with such drugs requires therapeutic drug monitoring (TDM) in order to safely obtain the desired clinical effects. A systematic review was carried out to document the cost-effectiveness of TDM. The Cochrane database and Medline were searched. Reference lists of articles found were searched manually for relevant articles. Very few studies are performed that document the cost-effectiveness of TDM. Only for aminoglycosides it has been demonstrated that TDM is cost-effective. For the other classes of TDM drugs, its rationale has been made plausible, but cost-effectiveness has not been investigated. Since the use of many of these drugs would contain risks of underdosing or overdosing without TDM, emphasis should not be placed on its cost-effectiveness, but rather on how to use it in the most cost-effective and clinically effective manner possible

Verantwoording en kosteneffectiviteit von therapeutic drug monitoring (2): Betere behandeling voor minder geld

There are a number of effective but highly toxic drugs that exhibit a narrow therapheutic index and marked intersubject pharmacokinetic variability. Optimal therapy with such drugs requires therapeutic drug monitoring (TDM) in order to safely obtain the desired clinical effects. A systematic review was carried out to document the cost-effectiveness of TDM. The Cochrane database and Medline were searched. Reference lists of articles found were searched manually for relevant articles. Very few studies are performed that document the cost-effectiveness of TDM. Only for aminoglycosides it has been demonstrated that TDM is cost-effective. For the other classes of TDM drugs, its rationale has been made plausible, but cost-effectiveness has not been investigated. Since the use of many of these drugs would contain risks of underdosing or overdosing without TDM, emphasis should not be placed on its cost-effectiveness, but rather on how to use it in the most cost-effective and clinically effective manner possible

Better treatment for less money. Rationale and cost-effectiveness of therapeutic drug monitoring (2)

There are a number of effective but highly toxic drugs that exhibit a narrow therapeutic index and marked intersubject pharmacokinetic variability. Optimal therapy with such drugs requires therapeutic drug monitoring (TDM) in order to safely obtain the desired clinical effects. A systematic review was carried out to document the cost-effectiveness of TDM. The Cochrane database and Medline were searched. Reference lists of articles found were searched manually for relevant articles. Very few studies are performed that document the cost-effectiveness of TDM. Only for aminoglycosides it has been demonstrated that TDM is cost-effective. For the other classes of TDM drugs, its rationale has been made plausible, but cost-effectiveness has not been investigated. Since the use of many of these drugs would contain risks of underdosing or overdosing without TDM, emphasis should not be placed on its cost-effectiveness, but rather on how to use it in the most cost-effective and clinically effective manner possible