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Background: The MeroRisk-calculator, an easy-to-use tool to determine the risk of meropenem target non-attainment after standard dosing (1000 mg, q8h), uses a patient’s creatinine clearance and the minimum inhibitory concentration (MIC) of the pathogen. In clinical practice, however, the MIC is rarely available. The objectives were to evaluate the MeroRisk-calculator and to extend risk assessment by including general pathogen sensitivity data. Methods: Using a clinical routine dataset (155 patients, 891 samples), a direct data-based evaluation was not feasible. Thus, in step 1, the performance of a pharmacokinetic model was determined for predicting the measured concentrations. In step 2, the PK model was used for a model-based evaluation of the MeroRisk-calculator: risk of target non-attainment was calculated using the PK model and agreement with the MeroRisk-calculator was determined by a visual and statistical (Lin’s concordance correlation coefficient (CCC)) analysis for MIC values 0.125–16 mg/L. The MeroRisk-calculator was extended to include risk assessment based on EUCAST-MIC distributions and cumulative-fraction-of-response analysis. Results: Step 1 showed a negligible bias of the PK model to underpredict concentrations (−0.84 mg/L). Step 2 revealed a high level of agreement between risk of target non-attainment predictions for creatinine clearances &gt, 50 mL/min (CCC = 0.990), but considerable deviations for patients &lt, 50 mL/min. For 27% of EUCAST-listed pathogens the median cumulative-fraction-of-response for the observed patients receiving standard dosing was &lt, 90%. Conclusions: The MeroRisk-calculator was successfully evaluated: For patients with maintained renal function it allows a reliable and user-friendly risk assessment. The integration of pathogen-based risk assessment substantially increases the applicability of the tool.

Background: Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application. Methods: A prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCRCG). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100% T->MIC, 50% T->4xMIC) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCRCG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment. Results: Large inter-and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100% T->MIC was merely 48.4% and 20.6%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50% T->4xMIC. A hyperbolic relationship between CLCRCG (25-255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C-8h) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment). Conclusions: The investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy-and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed.

PK/PD target attainment.pdf. (PDF 65 kb)

Study design.pdf. (PDF 170 kb)

Regression model for risk calculation.pdf. (PDF 475 kb)

Synaptische Vesikel (SV) besitzen abhängig vom Neurontyp unterschiedliche Neurotransmittertransporter. In glutamatergen Neuronen kommen die vesikulären Glutamattransporter (VGLUT)1, VGLUT2 und VGLUT3 vor. GABAerge Neurone besitzen den vesikulären GABA-Transporter (VGAT). Die getrennte Glutamat- und GABA-Speicherung in unterschiedlichen Neuronen dient dem exakten Funktionieren neuronaler Netze. Mitunter setzen glutamaterge Neurone auch GABA frei. Einige entscheidende Proteine GABAerger Nervenendigungen wurden auf dem Protein- und mRNA-Niveau nachgewiesen. GABAerge Transmission glutamaterger Neurone wurde elektrophysiologisch gezeigt. Diese Studie untersucht eine mögliche VGLUT/VGAT-Kolokalisation mittels Immunisolierungen (II) von SV (SP), Neurotransmitteraufnahmeversuchen mit aufgereinigten SV, SP und der elektronenmikroskopischen Postembeddingmethode. II aus dem Rattengehirn zeigen, dass die VGLUT1-SP VGLUT2 und die VGLUT2-SP auch VGLUT1 enthält. Beide VGLUT kommen auf dem selben SV vor. Die VGLUT2-SP beinhaltet VGAT- und die VGAT-SP VGLUT2-tragende SV. SP aus frühen Entwicklungsstadien zeigen bereits eine ausgeprägte vesikuläre VGLUT2/VGAT- Kolokalisation. SV der VGAT-SP akkumulieren GABA und Glutamat. Die Hemmung der VGLUT zeigt ihren unterstützenden Einfluss auf die vesikuläre GABA- und Monoaminaufnahme. Damit moduliert die VGLUT-Aktivität die Neurotransmitterspeicherung in nicht glutamatergen Neuronen. Doppelmarkierung im Postembeddingverfahren zeigen die synaptische VGLUT/VGAT- Kolokalisation in glutamatergen hippokampalen und cerebellären Moosfaserendigungen. Dagegen ist VGAT weder in den nur VGLUT1-positiven cerebellären Parallelfaser- noch in den nur VGLUT2-positiven Kletterfaserendigungen detektierbar. Die cerebellären GABAergen Korbzellenendigungen beinhalten auch VGLUT2. Diese Befunde liefern den morphologischen Beweis für die synaptische GABA/Glutamat-Koausschüttung aus speziellen großen glutamatergen und GABAergen präsynaptischen Endigungen. Synaptic vesicles (SV) are equipped with a common set of proteins. Dependent on the type of nerve cell SV differ in their neurotransmitter transporters, i.e. the vesicular glutamate transporters (VGLUT) 1 and VGLUT2 in types of glutamatergic neurons and the vesicular GABA transporter (VGAT) in types of GABAergic neurons. The strict separation of glutamate and GABA storage generally guarantees the precise function of neuronal networks. However, GABA may be released by glutamatergic neurons under certain conditions as shown by electrophysiological studies. The project aims to analyse a putative vesicular and synaptic co-localisation of VGLUT and VGAT using immunoisolations, neurotransmitter uptake assays, and post-embedding electron microscopy. Immunoisolations from whole brain of adult rats revealed that VGLUT1 immunoisolates (ii) contain VGLUT2 and VGLUT2-ii also have VGLUT1 indicating the vesicular co-localisation of both VGLUT. VGLUT2-ii harbour in addition VGAT and VGAT-ii also contain VGLUT2. Transporter-specific ii from rat brain at different postnatal levels (P5/15/30) show a pronounced vesicular co-localisation of VGLUT2 and VGAT during these early developmental stages. Transmitter uptake studies show GABA and also glutamate concentrating VGAT-ii. Using the specific inhibitor trypan blue we found that VGLUT activity improves GABA as well as monoamine uptake into SV. Thus VGLUT activity modulates transmitter storage in non-glutamatergic neurons. Post-embedding immunogold double labelling indicates a synaptic co-localisation of VGLUT and VGAT in glutamatergic hippocampal and cerebellar mossy fibre terminals while VGAT was not seen in cerebellar parallel fibre (VGLUT1-positive only) and climbing fibre (VGLUT2-positive only) terminals. Remarkably, cerebellar GABAergic basket cell terminals also contain VGLUT2. These findings provide the morphological evidence for a synaptic co-release of GABA and glutamate from some large glutamatergic and GABAergic terminals.