Entwicklung und Erprobung von HPLC-basierten Methoden für das Therapeutische Drug-Monitoring von Betalaktam-Antibiotika, Linezolid und Tigecyclin – Bestimmung von freien und totalen Konzentrationen im Plasma von Intensivpatienten

In klinischen Studien konnte gezeigt werden, dass eine zu niedrig dosierte antibiotische Therapie das Behandlungsergebnis insbesondere bei Intensivpatienten verschlechtert sowie der Entwicklung von resistenten Erregern Vorschub leistet. Die nach wie vor hohe Mortalität bei schwerer Sepsis von bis zu 80 % verdeutlicht eindringlich die klinische Relevanz dieser Tatsache. Zu hoch dosierte Therapien gefährden hingegen durch Toxizität den Patienten, ohne zusätzlichen antiinfektiven Nutzen zu erzielen. Kritisch kranke Patienten weisen in Folge ihrer schweren Erkrankung eine stark veränderte und variable Pharmakokinetik auf. Da die Standarddosierungen für Antibiotika aus pharmakokinetischen Studien an gesunden Probanden abgeleitet wurden, ist zu hinterfragen, ob mit diesen Dosierungen auch bei Intensivpatienten optimale Wirkspiegel erreicht werden. Die Betalaktam-Antibiotika stellen die in der klinischen Routine am Universitätsklinikum Regensburg am häufigsten eingesetzten Antibiotika dar. Linezolid und Tigecyclin sind wichtige Reserveantibiotika zur Behandlung von Infektionen durch multiresistente grampositive Erreger. Trotz der großen Relevanz dieser Antibiotika für die klinische Praxis ist es bisher am Universitätsklinikum Regensburg nicht möglich, in der klinischen Routine die Plasmakonzentrationen dieser Substanzen im Rahmen eines Therapeutischen-Drug-Monitoring (TDM) zu bestimmen. Zur Bestimmung der o.g. Antibiotika in Plasma wurden isokratische HPLC-Methoden mit UV-photometrischer Detektion entwickelt und validiert. Das chromatographische System bestand aus C18-Kieselgel-Säulen und Mischungen aus Phosphatpuffer und Acetonitril als mobile Phase. Da für die pharmakologische Wirkung eines Arzneistoffs aber nur die freie, nicht an Plasmaproteine gebundene Fraktion zu Verfügung steht, erfolgte auch die Messung freier Konzentrationen. Hierzu wurde eine schnelle und einfache Ultrafiltrationsmethode entwickelt und validiert. Da dass das Ausmaß der Proteinbindung von den experimentellen Bedingungen wie Temperatur, pH-Wert und Zentrifugalkraft beeinflusst werden kann, wurde die Bedeutung dieser Parameter für die gemessene freie Konzentration der untersuchten Substanzen evaluiert. Es konnte gezeigt werden, dass die freie Konzentration substanzspezifisch stark von den experimentellen Bedingungen abhängt. Daher wurde für die Routinemethode zur Bestimmung der freien Konzentration durch Ultrafiltration die Aufrechterhaltung physiologischer Temperatur- und pH-Werte etabliert, d.h. ein pH von 7,4 und 37°C. Das Verfahren war zur zuverlässigen Messung der freien Wirkstoffkonzentrationen gut geeignet. So konnte gezeigt werden, dass die Ultrafiltration eine schnelle, einfache und elegante Methode zur Vorbereitung von Plasma für die HPLC-Analyse darstellt. Die entwickelten Methoden erwiesen sich als hinreichend präzise, sensitiv und selektiv zur Bestimmung der Konzentrationen der Arzneistoffe im Plasma von Intensivpatienten. Die Ergebnisse der klinischen Untersuchung für Meropenem und Piperacillin konnten zeigen, dass bei ca. 50 % der Patienten der PK/PD-Zielparameter einer Plasmakonzentration oberhalb der MHK des Leitkeims Pseudomonas aeruginosa über das gesamte Dosisintervall nicht erreicht wurde. Die gemessenen Spiegel zeigten eine breite Streuung. Beide Faktoren sprechen für die Anwendung modifizierter Dosierungsstrategien, sowie eines TDM zur Optimierung der Dosierung von Antibiotika in der klinischen Routine

Tigecycline Soft Tissue Penetration in Obese and Non-obese Surgical Patients Determined by Using In Vivo Microdialysis

Background and Objective Tigecycline, a broad-spectrum glycylcycline antibiotic, is approved for use at a fixed dose irrespective of body weight. However, its pharmacokinetics may be altered in obesity, which would impact on the antibiotic’s effectiveness. The objective of this study was to investigate the plasma and subcutaneous tissue concentrations of tigecycline in obese patients compared with those in a non-obese control group. Methods Fifteen obese patients (one class II and 14 class III) undergoing bariatric surgery and 15 non-obese patients undergoing intra-abdominal surgery (mainly tumour resection) received a single dose of 50 or 100 mg tigecycline as an intravenous short infusion. Tigecycline concentrations were measured up to 8 h after dosing in plasma (total concentration), in ultrafiltrate of plasma (free concentration), and in microdialysate from subcutaneous tissue, respectively. Results In obese patients, total peak plasma concentration (1.31 ± 0.50 vs 2.27 ± 1.40 mg/L) and the area under the concentration–time curve from 0 to 8 h (AUC8h,plasma: 2.15 ± 0.42 vs 2.74 ± 0.73 h⋅mg/L), as normalized to a 100 mg dose, were significantly lower compared with those of non-obese patients. No significant differences were observed regarding the free plasma concentration, as determined by ultrafiltration, or the corresponding AUC8h (fAUC8h,plasma). Concentrations in interstitial fluid (ISF) of subcutaneous tissue were lower than the free plasma concentrations in both groups, and they were lower in obese compared to non-obese patients: the AUC8h in ISF (AUC8h,ISF) was 0.51 ± 0.22 h⋅mg/L in obese and 0.79 ± 0.23 h⋅mg/L in non-obese patients, resulting in a relative tissue drug exposure (AUC8h,ISF/fAUC8h,plasma) of 0.38 ± 0.19 and 0.63 ± 0.24, respectively. Conclusion Following a single dose of tigecycline, concentrations in the ISF of subcutaneous adipose tissue are decreased in heavily obese subjects, calling for an increased loading dose

Counteridenticals

A counteridentical is a counterfactual with an identity statement in the antecedent. While counteridenticals generally seem non-trivial, most semantic theories for counterfactuals, when combined with the necessity of identity and distinctness, attribute vacuous truth conditions to such counterfactuals. In light of this, one could try to save the orthodox theories either by appealing to pragmatics or by denying that the antecedents of alleged counteridenticals really contain identity claims. Or one could reject the orthodox theory of counterfactuals in favor of a hyperintensional semantics that accommodates non-trivial counterpossibles. In this paper, I argue that none of these approaches can account for all the peculiar features of counteridenticals. Instead, I propose a modified version of Lewis’s counterpart theory, which rejects the necessity of identity, and show that it can explain all the peculiar features of counteridenticals in a satisfactory way. I conclude by defending the plausibility of contingent identity from objections

Counting homomorphisms onto finite solvable groups

We present a method for computing the number of epimorphisms from a finitely-presented group G to a finite solvable group \Gamma, which generalizes a formula of G\"aschutz. Key to this approach are the degree 1 and 2 cohomology groups of G, with certain twisted coefficients. As an application, we count low-index subgroups of G. We also investigate the finite solvable quotients of the Baumslag-Solitar groups, the Baumslag parafree groups, and the Artin braid groups.Comment: 30 pages; accepted for publication in the Journal of Algebr

What makes inpatient treatment for PTSD effective? Investigating daily therapy process factors

ObjectiveTherapeutic process factors including alliance and motivation are considered to play a key role in the treatment of post-traumatic stress disorder (PTSD). Yet, our understanding of change processes in therapy is mostly based on theoretical considerations with limited empirical evidence. In order to identify process characteristics of successful inpatient treatments of PTSD, we investigated the intraindividual, interindividual, and temporal associations of daily assessments of therapy process factors like motivation, alliance, and insight.MethodTherapy process questionnaire (TPQ) assessments were collected from 101 inpatients with PTSD over 50 days, resulting in 5050 assessments. Multilevel vector autoregressive (mlVAR) modelling was applied to investigate the networks of the TPQ factors in a subgroup with good outcome regarding PTSD symptomatology and a subgroup with less favourable outcome.ResultsThe two subgroups differed markedly in their network models, suggesting that therapy processes might be different for those with good and those with poor treatment outcomes.ConclusionsOur results suggest that good treatment outcome is linked to a specific therapy process dynamic where mindfulness and insight lead to the kind of temporary well-being required to effectively engage with problems and negative emotions, while motivation to change ensures the continuity of confronting negative emotions and problems

STRoe deer: a validated forensic STR profiling system for the European roe deer (Capreolus capreolus)

European roe deer (Capreolus capreolus L.) are the most common game species in Europe, hunted for meat and trophies. Forensic investigations involving roe deer poaching may often benefit from an individual identification method to link a suspect to a specific incident. The current paper presents a forensically validated DNA profiling system for European roe deer called “STRoe deer”. This DNA profiling system consists of 12 novel unlinked tetra-nucleotide short tandem repeat (STR) loci and two sexing markers, with an allelic ladder to facilitate accurate genotyping. Validation results using 513 European roe deer samples collected from a single population from the Swiss Plateau demonstrated successful amplification of all 14 loci with as little as 0.05 ng of European roe deer DNA. Species-specificity tests showed that other members of the Cervidae family exhibited partial profiles and non-specific peaks, whereas most members of the Bovidae family showed just non-specific cross-species amplification products. Three different methods to calculate match probabilities for randomly sampled European roe deer genotypes resulted in median match probabilities ranging from 1.4 × 10−13 to 2.5 × 10−5. These methods accounted for possible population structure, occurrence of null alleles and individual relatedness. Based on these results, we conclude that STRoe deer is a robust genotyping system that should prove a valuable tool for individual identification and sexing of European roe deer to support criminal investigations

Interprofessional Collaboration between ICU Physicians, Staff Nurses, and Hospital Pharmacists Optimizes Antimicrobial Treatment and Improves Quality of Care and Economic Outcome

(1) Background: Antibiotic resistance is a worldwide health threat. The WHO published a global strategic plan in 2001 to contain antimicrobial resistance. In the following year, a workshop identified crucial barriers to the implementation of the strategy, e.g., underdeveloped health infrastructures and the scarcity of valid data as well as a lack of implementation of antibiotic stewardship (ABS) programs in medical curricula. Here, we show that interprofessional learning and education can contribute to the optimization of antibiotic use and preserving antibiotic effectiveness. We have initiated interprofessional rounds on a medical intensive care unit (MICU) with a focus on gastroenterology, hepatology, infectious diseases, endocrinology, and liver transplantation. We integrated ICU physicians, hospital pharmacists, nursing staff, and medical students as well as students of pharmacy to broaden the rather technical concept of ABS with an interprofessional approach to conceptualize awareness and behavioral change in antibiotic prescription and use. Methods: Clinical performance data and consumption figures for antibiotics were analyzed over a 10-year period from 2012 to 2021. The control period covered the years 2012–2014. The intervention period comprised the years 2015–2021, following the implementation of an interprofessional approach to ABS at a MICU of a German university hospital. Data from the hospital pharmacy, hospital administration, and hospital information system were included in the analyses. A specific electronic platform was developed for the optimization of documentation, interprofessional learning, education, and sustainability. The years 2020 and 2021 were analyzed independently due to the SARS-CoV-2 pandemic and the care of numerous COVID-19 patients at the MICU. Results: Implementation of an interprofessional ABS program resulted in the optimization of antibiotic management at the MICU. The suggestions of the hospital pharmacist for optimization can be divided into the following categories (i) indication for and selection of therapy (43.6%), (ii) optimization of dosing (27.6%), (iii) drug interactions (9.4%), (iv) side effects (4.1%), and (v) other pharmacokinetic, pharmacodynamic, and pharmacoeconomic topics (15.3%). These suggestions were discussed among the interprofessional team at the MICU; 86.1% were consequently implemented and the prescription of antibiotics was changed. In addition, further analysis of the intensive care German Diagnosis Related Groups (G-DRGs) showed that the case mix points increased significantly by 31.6% during the period under review. Accordingly, the severity of illness of the patients treated at the ICU as measured by the Simplified Acute Physiology Score (SAPS) II increased by 21.4% and the proportion of mechanically ventilated patients exceeded 50%. Antibiotic spending per case mix point was calculated. While spending was EUR 60.22 per case mix point in 2015, this was reduced by 42.9% to EUR 34.37 per case mix point by 2019, following the implementation of the interprofessional ABS program on the MICU. Through close interprofessional collaboration between physicians, hospital pharmacists, and staff nurses, the consumption of broad-spectrum antibiotics, e.g., carbapenems, was significantly reduced, thus improving patient care. In parallel, the case mix and case mix index increased. Thus, the responsible use of resources and high-performance medicine are not contradictory. In our view, close interprofessional and interdisciplinary collaboration between physicians, pharmacists, and nursing staff will be of outstanding importance in the future to prepare health care professionals for global health care to ensure that the effectiveness of our antibiotics is preserved

Co-occurrence of severe PTSD, Somatic Symptoms and Dissociation in a large sample of childhood trauma inpatients: A Network Analysis

Co-occurrence of mental disorders including severe PTSD, somatic symptoms, and dissociation in the aftermath of trauma is common and sometimes associated with poor treatment outcomes. However, the interrelationships between these conditions at symptom-level are not well understood. In the present study, we aimed to explore direct connections between PTSD, somatic symptoms, and dissociation to gain a deeper insight into the pathological processes underlying their comorbidity that can inform future treatment plans. In a sample of 655 adult inpatients with a diagnosis of severe PTSD following childhood abuse (85.6% female; mean age = 47.57), we assessed symptoms of PTSD, somatization, and dissociation. We analyzed the comorbidity structure using a partial correlation network with regularization. Mostly positive associations between symptoms characterized the network structure. Muscle or joint pain was among the most central symptoms. Physiological reactivation was central in the full network and together with concentrations problems acted as bridge between symptoms of PTSD and somatic symptoms. Headaches connected somatic symptoms with others and derealization connected dissociative symptoms with others in the network. Exposure to traumatic events has a severe and detrimental effect on mental and physical health and these consequences worsen each other trans-diagnostically on a symptom-level. Strong connections between physiological reactivation and pain with other symptoms could inform treatment target prioritization. We recommend a dynamic, modular approach to treatment that should combine evidence-based interventions for PTSD and comorbid conditions which is informed by symptom prominence, readiness to address these symptoms and preference

Similar Piperacillin/Tazobactam Target Attainment in Obese versus Nonobese Patients despite Differences in Interstitial Tissue Fluid Pharmacokinetics

Precision dosing of piperacillin/tazobactam in obese patients is compromised by sparse information on target-site exposure. We aimed to evaluate the appropriateness of current and alternative piperacillin/tazobactam dosages in obese and nonobese patients. Based on a prospective, controlled clinical trial in 30 surgery patients (15 obese/15 nonobese; 0.5-h infusion of 4 g/0.5 g piperacillin/tazobactam), piperacillin pharmacokinetics were characterized in plasma and at target-site (interstitial fluid of subcutaneous adipose tissue) via population analysis. Thereafter, multiple 3–4-times daily piperacillin/tazobactam short-term/prolonged (recommended by EUCAST) and continuous infusions were evaluated by simulation. Adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target-attainment (PTA ≥ 90%) based on time unbound piperacillin concentrations exceed the minimum inhibitory concentration (MIC) during 24 h (%fT>MIC). Lower piperacillin target-site maximum concentrations in obese versus nonobese patients were explained by the impact of lean (approximately two thirds) and fat body mass (approximately one third) on volume of distribution. Simulated steady-state concentrations were 1.43-times, 95%CI = (1.27; 1.61), higher in plasma versus target-site, supporting targets of %fT>2×MIC instead of %fT>4×MIC during continuous infusion to avoid target-site concentrations constantly below MIC. In all obesity and renally impairment/hyperfiltration stages, at MIC = 16 mg/L, adequate PTA required prolonged (thrice-daily 4 g/0.5 g over 3.0 h at %fT>MIC = 50) or continuous infusions (24 g/3 g over 24 h following loading dose at %fT>MIC = 98) of piperacillin/tazobactam