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Nijmegen, Netherlands

Mouton J.W.,Radboud University Nijmegen | Mouton J.W.,Nijmegen Institute for Infection | Ambrose P.G.,Institute for Clinical Pharmacodynamics Inc. | Canton R.,CIBER ISCIII | And 5 more authors.
Drug Resistance Updates

There is a growing need to optimize the use of old and new antibiotics to treat serious as well as less serious infections. The topic of how to use pharmacokinetic and pharmacodynamic (PK/PD) knowledge to conserve antibiotics for the future was elaborated on in a workshop of the conference (The conference "The Global Need for Effective Antibiotics - moving towards concerted action", ReAct, Uppsala, Sweden, 2010). The optimization of dosing regimens is accomplished by choosing the dose and schedule that results in the antimicrobial exposure that will achieve the microbiological and clinical outcome desired while simultaneously suppressing emergence of resistance. PK/PD of antimicrobial agents describe how the therapeutic drug effect is dependent on the potency of a drug against a microorganism and the exposure (the concentration of antimicrobial available for effect over time). The description and modeling of these relationships quantitatively then allow for a rational approach to dose optimization and several strategies to that purpose are described. These strategies include not only the dosing regimen itself but also the duration of therapy, preventing collateral damage through inappropriate use and the application of PK/PD in drug development. Furthermore, PK/PD relationships of older antibiotics need to be urgently established. The need for global harmonization of breakpoints is also suggested and would add efficacy to antibiotic therapy. For each of the strategies, a number of priority actions are provided. © 2011 Elsevier Ltd. All Rights Reserved. Source

Van Poppel P.C.M.,Radboud University Nijmegen | Netea M.G.,Radboud University Nijmegen | Netea M.G.,Nijmegen Institute for Infection | Smits P.,Radboud University Nijmegen | Tack C.J.,Radboud University Nijmegen
Diabetes Care

OBJECTIVE - To investigate whether the dipeptidyl peptidase-4 inhibitor vildagliptin improves endothelium-dependent vasodilatation in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS - Sixteen subjects with type 2 diabetes (age 59.8 ± 6.8 years, BMI 29.1 ± 4.8 kg/m 2, HbA 1c 6.97 ± 0.61) on oral blood glucose-lowering treatment were included. Participants received vildagliptin 50 mg b.i.d. or acarbose 100 mg t.i.d. for four consecutive weeks in a randomized, double-blind, cross-over design. At the end of each treatment period, we measured forearm vasodilator responses to intra-arterially administered acetylcholine (endothelium-dependent vasodilator) and sodium nitroprusside (endotheliumin-dependent vasodilator). RESULTS - Infusion of acetylcholine induced a dose-dependent increase in forearm blood flow in the experimental arm, which was higher during vildagliptin (3.1 ± 0.7, 7.9 ± 1.1, and 12.6 ± 1.4 mL · dL -1 · min -1 in response to three increasing dosages of acetylcholine) than during acarbose (2.0 ± 0.7, 5.0 ± 1.2, and 11.7 ± 1.6 mL · dL -1 · min -1, respectively; P = 0.01 by two-way ANOVA). Treatment with vildagliptin did not significantly change the vascular responses to sodium nitroprusside. CONCLUSIONS - Four weeks' treatment with vildagliptin improves endothelium-dependent vasodilatation in subjects with type 2 diabetes. This observationmight have favorable cardiovascular implications. © 2011 by the American Diabetes Association. Source

Levy O.,Boston Childrens Hospital | Levy O.,Harvard University | Netea M.G.,Radboud University Nijmegen | Netea M.G.,Nijmegen Institute for Infection
Pediatric Research

Unique features of immunity early in life include a distinct immune system particularly reliant on innate immunity, with weak T helper (Th)1-polarizing immune responses, and impaired responses to certain vaccines leading to a heightened susceptibility to infection. To these important aspects, we now add an increasingly appreciated concept that the innate immune system displays epigenetic memory of an earlier infection or vaccination, a phenomenon that has been named "trained immunity." Exposure of neonatal leukocytes in vitro or neonatal animals or humans in vivo to specific innate immune stimuli results in an altered innate immune set point. Given the particular importance of innate immunity early in life, trained immunity to early life infection and/or immunization may play an important role in modulating both acute and chronic diseases. © 2014 International Pediatric Research Foundation, Inc. Source

Kox M.,Radboud University Nijmegen | Kox M.,Nijmegen Institute for Infection | Pickkers P.,Radboud University Nijmegen
JAMA Internal Medicine

The current view in intensive care medicine is that very sick patients need very intensive treatment. However, in this group of highly vulnerable patients, more intensive reatment may promote the chances of unwanted adverse effects and hence, iatrogenic damage. Therefore, we state that critically ill patients probably benefit from a more cautious approach. Using data from large clinical trials of previous years, we exemplify that less intensive treatment is associated with a better outcome in intensive care patients and suggest that we reappraise patient management as well as trial design in intensive care medicine while bearing in mind the "less is more" paradigm.We illustrate our case by describing the intensity of the most relevant treatment options for patients with septic shock, including mechanical ventilation, fluid management, blood pressure-targeted therapy, corticosteroids, patient monitoring, sedation, and nutrition.We conclude that treatment of critically ill patients while keeping in mind the "le s is more" paradigm might not only benefit the patient but could also have a notable impact on the ever-increasing intensive care-related health care costs. Source

Colbers A.,Radboud University Nijmegen | Colbers A.,Nijmegen Institute for Infection | Greupink R.,Radboud University Nijmegen | Burger D.,Radboud University Nijmegen
Current Opinion in Infectious Diseases

PURPOSE OF REVIEW: Treatment with combination antiretroviral therapy during pregnancy reduces the chance of mother to child transmission of HIV. Physiological changes during pregnancy can lead to lower exposure to antiretrovirals, possibly resulting in virological failure. For most antiretrovirals, data on exposure during pregnancy and transplacental passage are limited. This review summarizes the most recent information on pharmacokinetics (including transplacental passage), efficacy, as well as the safety of antiretrovirals during pregnancy. RECENT FINDINGS: Intensive-sampling pharmacokinetic studies as well as observational studies using sparse sampling were performed to explore the exposure to antiretrovirals during pregnancy. Transplacental passage, efficacy (viral load at delivery and infection status of the newborn) and safety information were evaluated for several antiretrovirals. SUMMARY: For most nucleoside/nucleotide reverse transcriptase inhibitors and protease inhibitors, recent research shows a decreased exposure during pregnancy. However, the advantage of a general dose increase during pregnancy still remains unclear. For newer compounds and efavirenz, limited or no data on pharmacokinetics during pregnancy or transplacentally are available, while the mechanisms of transplacental passage also remain unknown. For safety reasons, it will be important to monitor pregnancy outcomes in resource-limited settings during the implementation of the WHO guidelines (including the use of efavirenz during pregnancy). © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

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