Arbeitsgedächtnisleistung und genotypische Varianz bei remittierter Depression : eine fMRT-Studie

Hintergrund: Kognitive Defizite in der akuten Phase einer Depression sind hinreichend belegt, sowohl empirisch als auch durch Bildgebungsstudien (Nair et al. 1999, Harvey et al. 2004). Kaum erforscht ist, ob neuronale Auffälligkeiten nachweisbar sind, wenn die depressive Symptomatik zurückgegangen ist. Die vorliegende fMRT-Studie ist eine der wenigen, die remittierte Patienten untersucht. Besonderes Augenmerk liegt auf Gehirn-arealen, die in der akuten Phase während Arbeitsgedächtnisaufgaben hyperaktiviert sind: Der präfrontale Kortex und das anteriore Cingulum (Fossati et al. 2002). Heutzutage geht man von einer multifaktoriellen Genese depressiver Symptomatik aus. Es gibt Hinweise darauf, dass verschiedene genetische Polymorphismen Vulnerabili-tätsmarker darstellen. Kandidatengene sind folgende: Der funktionelle Polymorphismus in der Promotorregion des 5HTTLPR-Gens (Hariri et al. 2002), der funktionelle Poly-morphismus des Serotoninrezeptors 5HT1A (Domschke et al. 2006), Allelvarianten in der Promotorregion des MAO-A-Gens (Brummett et al. 2007) und der funktionelle Einzel-nukleotidpolymorphismus Val/Met im COMT-Gen (O’Hara et al. 1998). Fragestellung: Es gilt zu überprüfen, ob neuronale Auffälligkeiten auch in Remission belegbar sind und ob ein Zusammenhang der hypothetischen „Depressionsmarker“ 5HTTLPR, 5HT1A, MAO-A und COMT mit der Erkrankung aufgezeigt werden kann. Material und Methoden: 28 remittierte Patienten mit depressivem Syndrom und 28 sorgfältig gematchte Kontrollprobanden wurden rekrutiert. Es wurde eine fMRT-Messung mit geblocktem n-zurück-Paradigma (0-, 1- und 2-zurück) durchgeführt. Anschließend wurde Blut abgenommen und die Genetikanalyse ausgeführt. Die funkti-onellen Daten wurden mittels SPM 5 Software ausgewertet. Die statistische Datenerhe-bung erfolgte mit der SPSS 18.0 Software. Ergebnisse: Alle Probanden aktivierten während der n-zurück-Aufgabe ein für das verbale Arbeitsgedächtnis typisches fronto-parietales Netzwerk. Patienten wiesen verglichen mit den Kontrollprobanden bei vergleichbarer Leistung signifikant vermehrte Aktivierung im Cingulum auf. Träger der Risikoallele des HTTLPR-Polymorphismus zeigten gegenüber Nichtrisikoallelträgern ebenso eine Hyperaktivierung im cingulären Kortex. Auch bei gesonderter Betrachtung der Kontrollprobandengruppe spiegelte sich der Effekt Risikoallelträger als gesteigerte cinguläre Aktivierung wider. Der funktionelle Polymorphismus 5HT1A hatte keine signifikante Auswirkung auf die neuronale Aktivie-rung. Aufgrund ungleicher Allelverteilungen innerhalb der Stichprobe wurden die Analysen zu den Polymorphismen COMT Val/Met und MAO-A VNRT nicht weiterge-führt. Fazit: Im Vergleich zu Patienten in der akuten Phase der Erkrankung weisen remittierte Patienten im Cingulum ebenfalls eine Hyperaktivierung auf, während der PFC nicht vermehrt aktiviert ist. Diese Resultate sprechen entweder für eine langsamere Normali-sierung in den limbischen Strukturen oder für eine bleibende oder für eine vorbestehen-de neuronale Auffälligkeit. Gesunde Kontrollprobanden mit den HTTLPR-Risikoallelen weisen ähnliche Hyperaktivierungen auf. Diese Ergebnisse legen nahe, dass der HTTLPR-Polymorphismus einen Vulnerabilitätsmarker für die Entstehung depressiver Symptomatik darstellt

Impact of Key Components of Intensified Ceftaroline Dosing on Pharmacokinetic/Pharmacodynamic Target Attainment

Background and Objective Ceftaroline fosamil is a β-lactam antibiotic approved as a 600 mg twice daily dose (≤1 h infusion, ‘standard dosing’) or a 600 mg thrice daily dose (2 h infusion) to treat complicated skin and soft tissue infections caused by Staphylococcus aureus (minimum inhibitory concentration [MIC] 2–4 mg/L). We sought to systematically evaluate the relative impact of the three key components of the intensified dosing regimen (i.e. shortened dosing interval, prolonged infusion duration and increased total daily dose [TDD]) on the pharmacokinetic/pharmacodynamic (PK/PD) target attainment given different grades of bacterial susceptibility. Methods A population PK model was developed using data from 12 healthy volunteers (EudraCT-2012-005134-11) receiving standard or intensified dosing. PK/PD target attainment (ƒT>MIC = 35% and 100%) after 24 h was compared following systematically varied combinations of the (1) dosing interval (every 12 h [q12h]→ every 8 h [q8h]); (2) infusion duration (1 h→2 h); and (3) individual and total daily dose (400→900 mg, i.e. TDD 1200→1800 mg), as well as for varying susceptibility of S. aureus (MIC 0.032–8 mg/L). Results A two-compartment model with linear elimination adequately described ceftaroline concentrations (n = 274). The relevance of the dosing components dosing interval/infusion duration/TDD for ƒT>MIC systematically changed with pathogen susceptibility. For susceptible pathogens with MIC ≤1 mg/L, shortened dosing intervals appeared as the main driver of the improved target attainment associated with the intensified dosing regimen, followed by increased TDD and infusion duration. For less susceptible pathogens, the advantage of q8h dosing and 2 h infusions declined, and increased TDD improved ƒT>MIC the most. Conclusion The analysis calls to mind consideration of dose increases when prolonging the infusion duration in the case of low bacterial susceptibility

From Therapeutic Drug Monitoring to Model-Informed Precision Dosing for Antibiotic

Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have evolved as important tools to inform rational dosing of antibiotics in individual patients with infections. In particular, critically ill patients display altered, highly variable pharmacokinetics and often suffer from infections caused by less susceptible bacteria. Consequently, TDM has been used to individualize dosing in this patient group for many years. More recently, there has been increasing research on the use of MIPD software to streamline the TDM process, which can increase the flexibility and precision of dose individualization but also requires adequate model validation and re-evaluation of existing workflows. In parallel, new minimally invasive and noninvasive technologies such as microneedle-based sensors are being developed, which-together with MIPD software-have the potential to revolutionize how patients are dosed with antibiotics. Nonetheless, carefully designed clinical trials to evaluate the benefit of TDM and MIPD approaches are still sparse, but are critically needed to justify the implementation of TDM and MIPD in clinical practice. The present review summarizes the clinical pharmacology of antibiotics, conventional TDM and MIPD approaches, and evidence of the value of TDM/MIPD for aminoglycosides, beta-lactams, glycopeptides, and linezolid, for which precision dosing approaches have been recommended

Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients: a prospective observational study

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 >4×MIC) 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 >4×MIC. A hyperbolic relationship between CLCRCG (25–255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C8h) 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. Trial registration Clinicaltrials.gov, NCT01793012 . Registered on 24 January 2013

A prospective observational study

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>4×MIC) 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>4×MIC. A hyperbolic relationship between CLCRCG (25–255 ml/ minute) and meropenem serum concentrations at the end of the dosing interval (C8h) 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

Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting

Purpose: Inadequate piperacillin (PIP) exposure in intensive care unit (ICU) patients threatens therapeutic success. Model-informed precision dosing (MIPD) might be promising to individualize dosing; however, the transferability of published models to external populations is uncertain. This study aimed to externally evaluate the available PIP population pharmacokinetic (PopPK) models. Methods: A multicenter dataset of 561 ICU patients (11 centers/3654 concentrations) was used for the evaluation of 24 identified models. Model performance was investigated for a priori (A) predictions, i.e., considering dosing records and patient characteristics only, and for Bayesian forecasting, i.e., additionally including the first (B1) or first and second (B2) therapeutic drug monitoring (TDM) samples per patient. Median relative prediction error (MPE) [%] and median absolute relative prediction error (MAPE) [%] were calculated to quantify accuracy and precision. Results: The evaluation revealed a large inter-model variability (A: MPE - 135.6-78.3% and MAPE 35.7-135.6%). Integration of TDM data improved all model predictions (B1/B2 relative improvement vs. A: |MPE|median_all_models 45.1/67.5%; MAPEmedian_all_models 29/39%). The model by Kim et al. was identified to be most appropriate for the total dataset (A/B1/B2: MPE - 9.8/- 5.9/- 0.9%; MAPE 37/27.3/23.7%), Udy et al. performed best in patients receiving intermittent infusion, and Klastrup et al. best predicted patients receiving continuous infusion. Additional evaluations stratified by sex and renal replacement therapy revealed further promising models. Conclusion: The predictive performance of published PIP models in ICU patients varied considerably, highlighting the relevance of appropriate model selection for MIPD. Our differentiated external evaluation identified specific models suitable for clinical use, especially in combination with TDM. Keywords: Intensive care medicine; Model-informed precision dosing; Pharmacokinetics/pharmacodynamics; Piperacillin; Therapeutic drug monitoring