361 results on '"Markus Zeitlinger"'
Search Results
2. A national evaluation analysis and expert interview study of real-world data sources for research and healthcare decision-making
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Veronika Mikl, Dejan Baltic, Thomas Czypionka, Alexander Degelsegger-Márquez, Nikolaus Forgó, Ghazaleh Gouya-Lechner, Arnold Herzog, Peter Klimek, David Benjamin Lumenta, Bernhard Mraz, Herwig Ostermann, Robert Scharinger, Tanja Stamm, Michael Strassnig, Markus Zeitlinger, and Johannes Pleiner-Duxneuner
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Real-world data ,Real-world evidence ,Data quality ,Data quality criteria ,Health data use ,Secondary use of health data ,Medicine ,Science - Abstract
Abstract Real-world data (RWD) can provide intel (real-world evidence, RWE) for research and development, as well as policy and regulatory decision-making along the full spectrum of health care. Despite calls from global regulators for international collaborations to integrate RWE into regulatory decision-making and to bridge knowledge gaps, some challenges remain. In this work, we performed an evaluation of Austrian RWD sources using a multilateral query approach, crosschecked against previously published RWD criteria and conducted direct interviews with representative RWD source samples. This article provides an overview of 73 out of 104 RWD sources in a national legislative setting where major attempts are made to enable secondary use of RWD (e.g. law on the organisation of research, "Forschungsorganisationsgesetz"). We were able to detect omnipresent challenges associated with data silos, variable standardisation efforts and governance issues. Our findings suggest a strong need for a national health data strategy and data governance framework, which should inform researchers, as well as policy- and decision-makers, to improve RWD-based research in the healthcare sector to ultimately support actual regulatory decision-making and provide strategic information for governmental health data policies.
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- 2024
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3. Advancing 6-bromo-7-[11C]methylpurine to clinical use: improved regioselective radiosynthesis, non-clinical toxicity data and human dosimetry estimates
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Severin Mairinger, Matthias Jackwerth, Ondřej Soukup, Matthias Blaickner, Clemens Decristoforo, Lukas Nics, Jens Pahnke, Marcus Hacker, Markus Zeitlinger, and Oliver Langer
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6-Bromo-7-[11C]methylpurine ,Investigational medicinal product dossier ,Multidrug resistance-associated protein 1 ,PET ,Regioselective N‑alkylation ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract Background 6-Bromo-7-[11C]methylpurine ([11C]BMP) is a radiotracer for positron emission tomography (PET) to measure multidrug resistance-associated protein 1 (MRP1) transport activity in different tissues. Previously reported radiosyntheses of [11C]BMP afforded a mixture of 7- and 9-[11C]methyl regioisomers. To prepare for clinical use, we here report an improved regioselective radiosynthesis of [11C]BMP, the results of a non-clinical toxicity study as well as human dosimetry estimates based on mouse PET data. Results [11C]BMP was synthesised by regioselective N 7 -methylation of 6-bromo-7H-purine (prepared under good manufacturing practice) with [11C]methyl triflate in presence of 2,2,6,6-tetramethylpiperidine magnesium chloride in a TRACERlab™ FX2 C synthesis module. [11C]BMP was obtained within a total synthesis time of approximately 43 min in a decay-corrected radiochemical yield of 20.5 ± 5.2%, based on starting [11C]methyl iodide, with a radiochemical purity > 99% and a molar activity at end of synthesis of 197 ± 130 GBq/μmol (n = 28). An extended single-dose toxicity study conducted in male and female Wistar rats under good laboratory practice after single intravenous (i.v.) administration of unlabelled BMP (2 mg/kg body weight) revealed no test item related adverse effects. Human dosimetry estimates, based on dynamic whole-body PET data in female C57BL/6J mice, suggested that an i.v. injected activity amount of 400 MBq of [11C]BMP will deliver an effective dose in the typical range of 11C-labelled radiotracers. Conclusions [11C]BMP can be produced in sufficient amounts and acceptable quality for clinical use. Data from the non-clinical safety evaluation showed no adverse effects and suggested that the administration of [11C]BMP will be safe and well tolerated in humans.
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- 2024
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4. St. John's wort extract with a high hyperforin content does not induce P‐glycoprotein activity at the human blood–brain barrier
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Myriam El Biali, Michael Wölfl‐Duchek, Matthias Jackwerth, Severin Mairinger, Maria Weber, Karsten Bamminger, Stefan Poschner, Ivo Rausch, Natalie Schindler, Irene Hernández Lozano, Walter Jäger, Lukas Nics, Nicolas Tournier, Marcus Hacker, Markus Zeitlinger, Martin Bauer, and Oliver Langer
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Therapeutics. Pharmacology ,RM1-950 ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P‐glycoprotein (P‐gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P‐gp activity at the human blood–brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)‐targeted P‐gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P‐gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3–6%) for 12–19 days (1800 mg/day), the activity of P‐gp at the BBB was assessed by means of PET imaging with the P‐gp substrate [11C]metoclopramide and the activity of peripheral P‐gp and CYPs was assessed by administering a low‐dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P‐gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P‐gp‐mediated efflux of [11C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P‐gp induction at the human BBB despite its ability to induce peripheral P‐gp and CYPs. Simultaneous intake of SJW with CNS‐targeted P‐gp substrate drugs is not expected to lead to P‐gp‐mediated drug interactions at the BBB.
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- 2024
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5. Phase I dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an inhaled recombinant human ACE2
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Martin Bauer, Anselm Jorda, Valentin al-Jalali, Michael Wölfl-Duchek, Felix Bergmann, Alina Nussbaumer-Pröll, Ariane Steindl, Romana Gugenberger, Sarah Bischof, Doris Wimmer, Marco Idzko, and Markus Zeitlinger
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Medicine - Abstract
Background APN01 is a soluble recombinant human angiotensin-converting enzyme 2 (rhACE2), a key player in the renin–aldosterone–angiotensin system (RAAS). In clinical studies, APN01 was administered intravenously only, so far. The aim of this study (ClinicalTrials.gov: NCT05065645) was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of inhaled APN01. Methods This was a phase I, double-blind, placebo-controlled, dose-escalation study. Inhalation was conducted via a nebuliser over 15 min in three single ascending dose (SAD) cohorts (n=24) and two multiple ascending dose (MAD) cohorts (n=16: every 12 h for 7 days). Doses in the SAD cohort were 1.25, 2.5 and 5 mg·mL−1; doses in the MAD cohort were 2.5 and 5 mg·mL−1. Safety (including adverse events (AEs), laboratory findings and lung function results), PK and PD data were assessed. Results In the SAD and MAD cohorts, treatment-related AEs were slightly more frequent in the active treatment group than in the placebo group. AEs were mild to moderate, with no dose-limiting toxicities. No clinically relevant changes in lung function and laboratory results were observed. The mean maximum observed plasma concentration (Cmax) values after single and multiple doses of 5 mg·mL−1 APN01 were 1.88 and 6.61 ng·mL−1, respectively. Among the PD variables, significance was found for ACE2 and angiotensin 1–5. Conclusions The application of aerosolised APN01 is safe and well tolerated after single and multiple doses. By achieving a high local concentration in the lungs and low systemic bioavailability, inhaled rhACE2 may present a therapeutic option in ACE2-related diseases.
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- 2024
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6. The impact of biological sex in peripheral nerve blockade: A prospective pharmacodynamic, pharmacokinetic and morphometric study in volunteers
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Markus Zadrazil, Peter Marhofer, Malachy Columb, Philipp Opfermann, Werner Schmid, Daniela Marhofer, Thomas Stimpfl, Sabine Reichel, Valentin Al Jalali, and Markus Zeitlinger
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Medicine ,Science - Published
- 2024
7. Predicting the next pandemic: VACCELERATE ranking of the World Health Organization's Blueprint for Action to Prevent Epidemics
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Jon Salmanton-García, Pauline Wipfler, Janina Leckler, Pontus Nauclér, Patrick W. Mallon, Patricia C.J.L. Bruijning-Verhagen, Heinz-Joseph Schmitt, Ullrich Bethe, Ole F. Olesen, Fiona A. Stewart, Kerstin Albus, Oliver A. Cornely, Martin Busch, Ulrike Seifert, Andreas Widmer, Miki Nagao, Jordi Rello, Tatina Todorova, Sabina Cviljević, Christopher H. Heath, Ligita Jančorienė, Thea Koelsen Fischer, Hans Martin Orth, Isik Somuncu Johansen, Mehmet Doymaz, Athanasios Tragiannidis, Thomas Löscher, Jin-Fu Xu, Petr Husa, José Antonio Oteo, Mohammad I. Issack, Markus Zeitlinger, Roger Le Grand, Przemysław Zdziarski, Fatih Demirkan, Paloma Merino Amador, Tomás García-Lozano, Qing Cao, Lourdes Vázquez, Juan Pablo Caeiro, Peter Hermans, Shahroch Nahrwar, Korkut Avsar, Deepak Kumar, Norma Fernández, Masoud Mardani, Esther Segal, Angelo Pan, Despoina Gkentzi, Georgia Gioula, Jorge Alberto Cortés, Joaquim Oliveira, Pierre van Damme, Mohd Zaki Bin Mohd Zaili, Spinello Antinori, Birutė Zablockienė, Georgios Papazisis, Chioma Inyang Aneke, Maricela Valerio, Samuel McConkey, Avinash Aujayeb, Anna Maria Azzini, Jelena Roganović, Kristin Greve-Isdahl Mohn, Peter Kremsner, Effrossyni Gkrania-Klotsas, Dora Corzo, Nina Khanna, Tomasz Smiatacz, Simone Scheithauer, Maria Merelli, Boris Klempa, Radovan Vrḫovac, Antonio Ruggiero, Pankaj Chaudhary, Julio Maquera-Afaray, Miquel Ekkelenkamp, Pavel Jindra, Nikola Pantić, Gemma Jiménez Guerra, Guenter Weiss, Behrad Roohi, Christos D. Argyropoulos, Sven Aprne Silfverdal, Jens van Praet, Zumrut Sahbudak Bal, Souha Kanj, Barnaby Young, Zoi Dorothea Pana, Emmanuel Roilides, Stephen C. Stearns, Joost Wauters, Jesús Rodríguez Baño, Mathias W. Pletz, Maja Travar, Steven Kühn, Fernando Riera, Daniel Cornely, Vlad Jeni Laura, Philipp Koehler, Brian Eley, Pravin K. Nair, Sandra Ciesek, Ioana Diana Olaru, Laura Marques, Emanuele Pontali, Alexandra Naunheim, Adrian Lieb, Markus Gerhard, Joveria Qais Farooqi, Lance Turtle, Gustavo Adolfo Méndez, Rebecca Jane Cox, Nigel Goodman, Billie Caceca, Javier Pemán, Halima Dawood, Helena Hervius Askling, Anders Fomsgaard, Alejandra Calderón Hernández, Cornelia Staehelin, Chia-Ying Liu, Giancarlo Icardi, Elio Castagnola, Helmut J.F. Salzer, Jens Lundgren, Samir Javadli, and Fabio Forghieri
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WHO R&D Blueprint for action to prevent epidemics ,Pandemic ,Influenza viruses ,Disease X ,SARS-CoV-2 ,SARS-CoV ,Arctic medicine. Tropical medicine ,RC955-962 ,Infectious and parasitic diseases ,RC109-216 - Abstract
Introduction: The World Health Organization (WHO)'s Research and Development (R&D) Blueprint for Action to Prevent Epidemics, a plan of action, highlighted several infectious diseases as crucial targets for prevention. These infections were selected based on a thorough assessment of factors such as transmissibility, infectivity, severity, and evolutionary potential. In line with this blueprint, the VACCELERATE Site Network approached infectious disease experts to rank the diseases listed in the WHO R&D Blueprint according to their perceived risk of triggering a pandemic. VACCELERATE is an EU-funded collaborative European network of clinical trial sites, established to respond to emerging pandemics and enhance vaccine development capabilities. Methods: Between February and June 2023, a survey was conducted using an online form to collect data from members of the VACCELERATE Site Network and infectious disease experts worldwide. Participants were asked to rank various pathogens based on their perceived risk of causing a pandemic, including those listed in the WHO R&D Blueprint and additional pathogens. Results: A total of 187 responses were obtained from infectious disease experts representing 57 countries, with Germany, Spain, and Italy providing the highest number of replies. Influenza viruses received the highest rankings among the pathogens, with 79 % of participants including them in their top rankings. Disease X, SARS-CoV-2, SARS-CoV, and Ebola virus were also ranked highly. Hantavirus, Lassa virus, Nipah virus, and henipavirus were among the bottom-ranked pathogens in terms of pandemic potential. Conclusion: Influenza, SARS-CoV, SARS-CoV-2, and Ebola virus were found to be the most concerning pathogens with pandemic potential, characterised by transmissibility through respiratory droplets and a reported history of epidemic or pandemic outbreaks.
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- 2024
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8. Antimicrobial activity and pathogen mutation prevention of originator and generics of cefepime, linezolid and piperacillin/tazobactam against clinical isolates of Staphylococcus aureus
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Felix Bergmann, Alina Nussbaumer-Pröll, Beatrix Wulkersdorfer, Sabine Eberl, Werner Ruppitsch, Sarah Lepuschitz, and Markus Zeitlinger
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Antibiotics ,MIC ,MPC ,Bioequivalence ,S. aureus ,Genome ,Microbiology ,QR1-502 - Abstract
ABSTRACT: Objectives: Although generic medicinal products are required to have the same qualitative and quantitative composition of the active substance as their reference originator product, patients and health care professionals express concerns about their interchangeability and safety. Therefore, the present study investigated the antimicrobial activity and pathogen mutation prevention of original and generic cefepime, linezolid and piperacillin/tazobactam against Staphylococcus aureus. Methods: Two generic formulations of cefepime, linezolid and piperacillin/tazobactam were tested against their respective originator products. Susceptibility testing was performed with twenty-one clinical isolates of S. aureus and ATCC-29213 using broth microdilution. Time kill curves (TKC) were performed with ATCC-29213 at drug concentrations above and below the respective minimum inhibitory concentrations (MIC). Mutation prevention concentration was determined for each drug formulation against ATCC-29213. All experiments were performed in triplicate. Mutant colonies from mutation prevention concentration (MPC) experiments were genotypically tested by sequence analysis. Results: MIC ratios between contiguous originator and generic drugs were similar for each isolate. No visual differences were observed in TKCs between originator and generic substances. The MPC did not differ between different formulations of the same substance. Although sequence analysis of mutant colonies revealed genomic differences compared with the original ATCC-29213, no differences in mutation frequencies were observed between clinical isolates and ATCC-29213 treated with originator or generic substances. Conclusions: Similar antimicrobial activity and pathogen mutation prevention was observed between contiguous substances. These results support the interchangeability of generic and originator drug formulations with the same active ingredient.
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- 2023
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9. Renin-angiotensin system inhibitor discontinuation in COVID-19 did not modify systemic ACE2 in a randomized controlled trial
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Vincent Rathkolb, Marianna T. Traugott, Andreas Heinzel, Marko Poglitsch, Judith Aberle, Farsad Eskandary, Agnes Abrahamowicz, Martin Mueller, Petra Knollmueller, Tarik Shoumariyeh, Jasmin Stuflesser, Ivan Seeber, Georg Gibas, Hannah Mayfurth, Viktoria Tinhof, Lukas Schmoelz, Markus Zeitlinger, Christian Schoergenhofer, Bernd Jilma, Bernd Genser, Wolfgang Hoepler, Sara Omid, Mario Karolyi, Christoph Wenisch, Rainer Oberbauer, Alexander Zoufaly, Manfred Hecking, and Roman Reindl-Schwaighofer
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Virology ,Human metabolism ,Science - Abstract
Summary: Despite the similar clinical outcomes after renin-angiotensin system (RAS) inhibitor (RASi) continuation or withdrawal in COVID-19, the effects on angiotensin-converting enzyme 2 (ACE2) and RAS metabolites remain unclear. In a substudy of the randomized controlled Austrian Corona Virus Adaptive Clinical Trial (ACOVACT), patients with hypertension and COVID-19 were randomized 1:1 to either RASi continuation (n = 30) or switch to a non-RASi medication (n = 29). RAS metabolites were analyzed using a mixed linear regression model (n = 30). Time to a sustained clinical improvement was equal and ACE2 did not differ between the groups but increased over time in both. Overall ACE2 was higher with severe COVID-19. ACE-S and Ang II levels increased as expected with ACE inhibitor discontinuation. These data support the safety of RASi continuation in COVID-19, although RASi were frequently discontinued in our post hoc analysis. The study was not powered to draw definite conclusions on clinical outcomes using small sample sizes.
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- 2023
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10. Prophylactic treatment with oral azithromycin in cancer patients during the COVID-19 pandemic (OnCoVID): a randomized, single-blinded, placebo-controlled phase 2 trial
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Maximilian J. Mair, Agnieszka Maj-Hes, Alina Nussbaumer-Pröll, Rainer Puhr, Agnieszka Christenheit, Marlene Troch, Hannah C. Puhr, Angelika M. Starzer, Ariane Steindl, Sabine Eberl, Helmuth Haslacher, Thomas Perkmann, Christoph Minichsdorfer, Gerald W. Prager, Wolfgang W. Lamm, Anna S. Berghoff, Barbara Kiesewetter, Markus Zeitlinger, Matthias Preusser, and Markus Raderer
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COVID-19 ,SARS-CoV-2 ,Azithromycin ,Prophylactic treatment ,Oncology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Patients with cancer are at high risk for severe courses of COVID-19. Based on (pre-)clinical data suggesting a potential protective effect due to the immunomodulating properties of azithromycin, we have initiated a prospective randomized trial. Methods This randomized, single-center, single-blinded, placebo-controlled phase 2 trial included adult patients with cancer undergoing systemic treatment. Patients were 1:1 randomized to oral azithromycin (1500 mg once weekly for 8 weeks) or placebo. The primary endpoint was the cumulative number of SARS-CoV-2 infections 12 weeks after treatment initiation. Results In total, 523 patients were screened, 68 patients were randomized, and 63 patients received at least one dose of the study drug. Due to low acceptance and a lack of SARS-CoV-2 infections in the study cohort, the study was prematurely closed. With no reported grade III–IV possibly treatment-related adverse events, azithromycin was generally well tolerated. Overall survival (OS) rates after 12 months were 83.5% and 70.3% in the azithromycin and placebo group, respectively (p = 0.37). Non-SARS-CoV-2 infections occurred in 4/32 (12.5%) in the azithromycin and 3/31 (9.7%) in the placebo group (p = 1). No emergence of azithromycin-resistant S. aureus strains could be observed. According to treatment group, longitudinal alterations in systemic inflammatory parameters were detected for neutrophil/lymphocyte and leukocyte/lymphocyte ratios. Conclusion Although efficacy could not be assessed due to premature closure and low incidence of SARS-CoV-2 infections, azithromycin was associated with a favorable side effect profile in patients with cancer. As other prophylactic treatments are limited, SARS-CoV-2 vaccination remains a high priority in oncological patients. ClinicalTrials.gov registration number and date (dd/mm/yyyy): NCT04369365, 30/04/2020.
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- 2023
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11. Direct endothelial ENaC activation mitigates vasculopathy induced by SARS-CoV2 spike protein
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Maritza J. Romero, Qian Yue, Bhupesh Singla, Jürg Hamacher, Supriya Sridhar, Auriel S. Moseley, Chang Song, Mobarak A. Mraheil, Bernhard Fischer, Markus Zeitlinger, Trinad Chakraborty, David Fulton, Lin Gan, Brian H. Annex, Gabor Csanyi, Douglas C. Eaton, and Rudolf Lucas
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Epithelial sodium channel (ENaC) ,SARS-CoV2 spike protein ,receptor binding domain (RBD) ,human ACE-2 ,endothelial dysfunction ,NADPH oxidase 2 (NOX2) ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionAlthough both COVID-19 and non-COVID-19 ARDS can be accompanied by significantly increased levels of circulating cytokines, the former significantly differs from the latter by its higher vasculopathy, characterized by increased oxidative stress and coagulopathy in lung capillaries. This points towards the existence of SARS-CoV2-specific factors and mechanisms that can sensitize the endothelium towards becoming dysfunctional. Although the virus is rarely detected within endothelial cells or in the circulation, the S1 subunit of its spike protein, which contains the receptor binding domain (RBD) for human ACE2 (hACE2), can be detected in plasma from COVID-19 patients and its levels correlate with disease severity. It remains obscure how the SARS-CoV2 RBD exerts its deleterious actions in lung endothelium and whether there are mechanisms to mitigate this.MethodsIn this study, we use a combination of in vitro studies in RBD-treated human lung microvascular endothelial cells (HL-MVEC), including electrophysiology, barrier function, oxidative stress and human ACE2 (hACE2) surface protein expression measurements with in vivo studies in transgenic mice globally expressing human ACE2 and injected with RBD.ResultsWe show that SARS-CoV2 RBD impairs endothelial ENaC activity, reduces surface hACE2 expression and increases reactive oxygen species (ROS) and tissue factor (TF) generation in monolayers of HL-MVEC, as such promoting barrier dysfunction and coagulopathy. The TNF-derived TIP peptide (a.k.a. solnatide, AP301) -which directly activates ENaC upon binding to its a subunit- can override RBD-induced impairment of ENaC function and hACE2 expression, mitigates ROS and TF generation and restores barrier function in HL-MVEC monolayers. In correlation with the increased mortality observed in COVID-19 patients co-infected with S. pneumoniae, compared to subjects solely infected with SARS-CoV2, we observe that prior intraperitoneal RBD treatment in transgenic mice globally expressing hACE2 significantly increases fibrin deposition and capillary leak upon intratracheal instillation of S. pneumoniae and that this is mitigated by TIP peptide treatment.
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- 2023
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12. Heterologous vector versus homologous mRNA COVID-19 booster vaccination in non-seroconverted immunosuppressed patients: a randomized controlled trial
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Daniel Mrak, Daniela Sieghart, Elisabeth Simader, Selma Tobudic, Helga Radner, Peter Mandl, Lisa Göschl, Maximilian Koblischke, Nikolaus Hommer, Angelika Wagner, Margareta Mayer, Lorenz Schubert, Lukas Hartl, Karin Kozbial, Philipp Hofer, Felix Kartnig, Thomas Hummel, Andreas Kerschbaumer, Thomas Deimel, Antonia Puchner, Venugopal Gudipati, Renate Thalhammer, Petra Munda, Keziban Uyanik-Ünal, Andreas Zuckermann, Gottfried Novacek, Thomas Reiberger, Erika Garner-Spitzer, Roman Reindl-Schwaighofer, Renate Kain, Stefan Winkler, Josef S. Smolen, Karin Stiasny, Gottfried F. Fischer, Thomas Perkmann, Helmuth Haslacher, Markus Zeitlinger, Ursula Wiedermann, Judith H. Aberle, Daniel Aletaha, Leonhard X. Heinz, and Michael Bonelli
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Science - Abstract
Optimizing COVID-19 vaccination strategies for patients under immunosuppressive medication is of high importance. In this clinical trial including non-seroconverted immunosuppressed patients, a homologous mRNA booster vaccination resulted in higher seroconversion rate than a switch to a vector-based vaccine.
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- 2022
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13. Enhancing Public Health Communication Regarding Vaccine Trials: Design and Development of the Pan-European VACCELERATE Toolkit
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Christos D Argyropoulos, Janina Leckler, Jon Salmanton-García, Marinos Constantinou, Alexandra Alexandrou, Sophia Themistocleous, Evgenia Noula, George Shiamakkides, Andria Nearchou, Fiona A Stewart, Kerstin Albus, Markela Koniordou, Ioannis Kopsidas, Orly Spivak, Margot Hellemans, Greet Hendrickx, Ruth Joanna Davis, Anna Maria Azzini, Paula Valle Simon, Antonio Javier Carcas-Sansuan, Helena Hervius Askling, Sirkka Vene, Jana Baranda Prellezo, Elena Álvarez-Barco, Alan J Macken, Romina Di Marzo, Catarina Luís, Ole F Olesen, Jesus A Frias Iniesta, Imre Barta, Krisztina Tóth, Murat Akova, Marc M J Bonten, Miriam Cohen-Kandli, Rebecca Jane Cox, Lenka Součková, Petr Husa, Ligita Jancoriene, Odile Launay, Jens Lundgren, Patrick Mallon, Charis Armeftis, Laura Marques, Pontus Naucler, Jordi Ochando, Evelina Tacconelli, Pierre van Damme, Theoklis Zaoutis, Sanne Hofstraat, Patricia Bruijning-Verhagen, Markus Zeitlinger, Oliver A Cornely, and Zoi Dorothea Pana
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Public aspects of medicine ,RA1-1270 - Abstract
BackgroundThe pan-European VACCELERATE network aims to implement the first transnational harmonized and sustainable vaccine trial Volunteer Registry, being a single entry point for potential volunteers of large-scale vaccine trials across Europe. This work exhibits a set of harmonized vaccine trial–related educational and promotional tools for the general public, designed and disseminated by the pan-European VACCELERATE network. ObjectiveThis study primarily aimed to design and develop a standard toolkit to increase positive attitudes and access to trustworthy information for better access and increased recruitment to vaccine trials for the public. More specifically, the produced tools are focused on inclusiveness and equity, and are targeting different population groups, including underserved ones, as potential volunteers for the VACCELERATE Volunteer Registry (older individuals, migrants, children, and adolescents). The promotional and educational material is aligned with the main objectives of the Volunteer Registry to increase public literacy and awareness regarding vaccine-related clinical research or trials and trial participation, including informed consent and legal issues, side effects, and frequently asked questions regarding vaccine trial design. MethodsTools were developed per the aims and principles of the VACCELERATE project, focusing on trial inclusiveness and equity, and are adjusted to local country-wise requirements to improve public health communication. The produced tools are selected based on the cognitive theory, inclusiveness, and equity of differently aged and underrepresented groups, and standardized material from several official trustworthy sources (eg, COVID-19 Vaccines Global Access; the European Centre for Disease Prevention and Control; the European Patients’ Academy on Therapeutic Innovation; Gavi, the Vaccine Alliance; and the World Health Organization). A team of multidisciplinary specialists (infectious diseases, vaccine research, medicine, and education) edited and reviewed the subtitles and scripts of the educational videos, extended brochures, interactive cards, and puzzles. Graphic designers selected the color palette, audio settings, and dubbing for the video story-tales and implemented QR codes. ResultsThis study presents the first set of harmonized promotional and educational materials and tools (ie, educational cards, educational and promotional videos, extended brochures, flyers, posters, and puzzles) for vaccine clinical research (eg, COVID-19 vaccines). These tools inform the public about possible benefits and disadvantages of trial participation and build confidence among participants about the safety and efficacy of COVID-19 vaccines and the health care system. This material has been translated into several languages and is intended to be freely and easily accessible to facilitate dissemination among VACCELERATE network participant countries and the European and global scientific, industrial, and public community. ConclusionsThe produced material could help fill knowledge gaps of health care personnel, providing the appropriate future patient education for vaccine trials, and tackling vaccine hesitancy and parents’ concerns for potential participation of children in vaccine trials.
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- 2023
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14. Early Bacterial Coinfections in Patients Admitted to the ICU With COVID-19 or Influenza: A Retrospective Cohort Study
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Felix Bergmann, MD, Cornelia Gabler, MSc, Alina Nussbaumer-Pröll, PhD, Michael Wölfl-Duchek, MD, Amelie Blaschke, MD, Christine Radtke, MD, Markus Zeitlinger, MD, and Anselm Jorda, MD
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Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
IMPORTANCE:. Previous findings suggest that bacterial coinfections are less common in ICU patients with COVID-19 than with influenza, but evidence is limited. OBJECTIVES:. This study aimed to compare the rate of early bacterial coinfections in ICU patients with COVID-19 or influenza. DESIGN, SETTING AND PARTICIPANTS:. Retrospective propensity score matched cohort study. We included patients admitted to ICUs of a single academic center with COVID-19 or influenza (January 2015 to April 2022). MAIN OUTCOMES AND MEASURES:. The primary outcome was early bacterial coinfection (i.e., positive blood or respiratory culture within 2 d of ICU admission) in the propensity score matched cohort. Key secondary outcomes included frequency of early microbiological testing, antibiotic use, and 30-day all-cause mortality. RESULTS:. Out of 289 patients with COVID-19 and 39 patients with influenza, 117 (n = 78 vs 39) were included in the matched analysis. In the matched cohort, the rate of early bacterial coinfections was similar between COVID-19 and influenza (18/78 [23%] vs 8/39 [21%]; odds ratio, 1.16; 95% CI, 0.42–3.45; p = 0.82). The frequency of early microbiological testing and antibiotic use was similar between the two groups. Within the overall COVID-19 group, early bacterial coinfections were associated with a statistically significant increase in 30-day all-cause mortality (21/68 [30.9%] vs 40/221 [18.1%]; hazard ratio, 1.84; 95% CI, 1.01–3.32). CONCLUSIONS AND RELEVANCE:. Our data suggest similar rates of early bacterial coinfections in ICU patients with COVID-19 and influenza. In addition, early bacterial coinfections were significantly associated with an increased 30-day mortality in patients with COVID-19.
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- 2023
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15. The Challenges of Vaccine Trial Participation among Underserved and Hard-to-Reach Communities: An Internal Expert Consultation of the VACCELERATE Consortium
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Dimitrios Poulimeneas, Markela Koniordou, Dimitra Kousi, Christina Merakou, Ioannis Kopsidas, Grammatiki Christina Tsopela, Christos D. Argyropoulos, Sophia C. Themistocleous, George Shiamakkides, Marinos Constantinou, Alexandra Alexandrou, Evgenia Noula, Andria Nearchou, Jon Salmanton-García, Fiona A. Stewart, Sarah Heringer, Kerstin Albus, Elena Álvarez-Barco, Alan Macken, Romina Di Marzo, Catarina Luis, Paula Valle-Simón, Helena H. Askling, Margot Hellemans, Orly Spivak, Ruth Joanna Davis, Anna Maria Azzini, Imre Barta, Lenka Součková, Ligita Jancoriene, Murat Akova, Patrick W. G. Mallon, Ole F. Olesen, Jesus Frias-Iniesta, Pierre van Damme, Krisztina Tóth, Miriam Cohen-Kandli, Rebecca Jane Cox, Petr Husa, Pontus Nauclér, Laura Marques, Jordi Ochando, Evelina Tacconelli, Markus Zeitlinger, Oliver A. Cornely, Zoi Dorothea Pana, and Theoklis E. Zaoutis
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barriers ,COVID-19 ,Europe ,pandemic preparedness ,SARS-CoV-2 ,vaccinations ,Medicine - Abstract
Underserved and hard-to-reach population groups are under-represented in vaccine trials. Thus, we aimed to identify the challenges of vaccine trial participation of these groups in member countries of the VACCELERATE network. Seventeen National Coordinators (NC), each representing their respective country (15 European countries, Israel, and Turkey), completed an online survey. From 15 eligible groups, those that were more frequently declared underserved/hard-to-reach in vaccine research were ethnic minorities (76.5%), persons experiencing homelessness (70.6%), illegal workers and refugees (64.7%, each). When prioritization for education on vaccine trials was considered, ethnic groups, migrants, and immigrants (5/17, 29.4%) were the groups most frequently identified by the NC as top targets. The most prominent barriers in vaccine trial participation affecting all groups were low levels of health literacy, reluctance to participate in trials due to engagement level, and low levels of trust in vaccines/vaccinations. This study highlighted population groups considered underserved/hard-to-reach in countries contained within the European region, and the respective barriers these groups face when participating in clinical studies. Our findings aid with the design of tailored interventions (within—and across—countries of the European region) and with the development of strategies to overcome major barriers in phase 2 and phase 3 vaccine trial participation.
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- 2023
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16. Bacterial growth and ceftriaxone activity in individual ascitic fluids in an in vitro model of spontaneous bacterial peritonitis
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Wisse van Os, Beatrix Wulkersdorfer, Sabine Eberl, Zoe Oesterreicher, Philipp Schwabl, Thomas Reiberger, Rafael Paternostro, Maria Weber, Birgit Willinger, and Markus Zeitlinger
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ascites ,ascitic fluid ,bacterial growth ,ceftriaxone ,spontaneous bacterial peritonitis ,time-kill ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Introduction: The environment of the infection site affects bacterial growth and antibiotic activity. When bacterial growth and antibiotic activity are studied in body fluids, samples of multiple subjects are usually pooled, averaging out potentially relevant differences in composition. The ascitic fluid (AF) environment is frequently associated with spontaneous bacterial peritonitis (SBP) in cirrhotic patients. In this study, bacterial growth and ceftriaxone activity were evaluated in individual AF using an in vitro model of SBP, reflecting the environment and pharmacokinetics at the infection site.Methods: AF was obtained from nine cirrhotic patients with non-infected ascites. Growth of nine bacterial strains (three Escherichia coli, four Staphylococcus aureus, one Enterococcus faecalis, and one Klebsiella pneumoniae) in individual AF was assessed and correlated with biomarkers including potential risk factors for SBP. Ceftriaxone time-kill experiments, in which the pharmacokinetic profile observed in AF following a 1 g intravenous infusion was replicated, were performed with two E. coli and two S. aureus isolates with minimum inhibitory concentrations around the ceftriaxone resistance breakpoint.Results: Significant correlations were found between bacterial growth and AF levels of protein (Spearman’s rank correlation coefficient ρ = −0.35), albumin (ρ = −0.31), and complement C3c (ρ = −0.28), and serum levels of bilirubin (ρ = 0.39) and aspartate aminotransferase (ρ = 0.25). Ceftriaxone was active in AF, even against resistant isolates, generally resulting in ≥2 log reductions in bacterial count within 24 h.Conclusion: Ascites patients may be predisposed to or protected against SBP based on the antimicrobial capacity of their AF. Ceftriaxone at clinical AF concentrations is active in the AF environment.
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- 2023
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17. Editorial: Pharmacokinetics, pharmacodynamics (PK/PD) of antibiotics: A reality check
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Markus Zeitlinger, Glenn Tillotson, and Roger Echols
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PK/PD ,antibiotic ,drug develoment process ,betalactam ,gram negative ,Therapeutics. Pharmacology ,RM1-950 - Published
- 2023
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18. Orphan drugs’ clinical uncertainty and prices: Addressing allocative and technical inefficiencies in orphan drug reimbursement
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Hans-Georg Eichler, Michael Kossmeier, Markus Zeitlinger, and Brigitte Schwarzer-Daum
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orphan drugs ,real world data ,clinical uncertainty ,drug prices ,managed entry agreement ,budget impact ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Legislations incentivising orphan drug development and scientific advances have made orphan drugs pharma’s high-end favourite for the past two decades. Currently, around 50% of new marketing authorizations are for orphan drugs. For third-party healthcare payers (“payers”) the rise of orphan drugs presents new challenges, including a high degree of uncertainty around clinical benefits and harms, a moderate effect size (for many orphan drugs), and a high price tag. The association of high clinical uncertainty and moderate effect sizes is not surprising in small target populations but in combination with high prices creates the risk of allocative and technical inefficiencies for payers. We here discuss and illustrate these risks. A combination of policies is needed for mitigation of allocative inefficiency: while there may be a rationale for higher prices for orphan than non-orphan drugs, a focus of pricing and reimbursement negotiations should include considerations of product profitability and of the consequences of orphan drug costs on the distribution inequality of medication costs for individual insured persons, coupled to knowledge generation from reimbursement contracts covering high-price orphan drugs that would benefit the wider patient community. Performance-based managed entry agreements could help to de-risk the economic consequences of clinical uncertainty and to mitigate technical inefficiency.
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- 2023
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19. Identification of tumor tissue-derived DNA methylation biomarkers for the detection and therapy response evaluation of metastatic castration resistant prostate cancer in liquid biopsies
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Thomas Dillinger, Raheleh Sheibani-Tezerji, Walter Pulverer, Ines Stelzer, Melanie R. Hassler, Janine Scheibelreiter, Carlos Uziel Pérez Malla, Madeleine Kuroll, Sandra Domazet, Elisa Redl, Sarah Ely, Stefanie Brezina, Andreas Tiefenbacher, Katharina Rebhan, Nicolai Hübner, Bernhard Grubmüller, Markus Mitterhauser, Marcus Hacker, Andreas Weinhaeusel, Judit Simon, Markus Zeitlinger, Andrea Gsur, Gero Kramer, Shahrokh F. Shariat, Lukas Kenner, and Gerda Egger
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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20. Topical niclosamide (ATx201) reduces Staphylococcus aureus colonization and increases Shannon diversity of the skin microbiome in atopic dermatitis patients in a randomized, double‐blind, placebo‐controlled Phase 2 trial
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Anne Weiss, Emilie Delavenne, Carina Matias, Heimo Lagler, Daniel Simon, Ping Li, Jon U. Hansen, Teresa Pires dosSantos, Bimal Jana, Petra Priemel, Christine Bangert, Martin Bauer, Sabine Eberl, Alina Nussbaumer‐Pröll, Zoe Anne Österreicher, Peter Matzneller, Tamara Quint, Maria Weber, Hanne Mørck Nielsen, Thomas Rades, Helle Krogh Johansen, Henrik Westh, Wooseong Kim, Eleftherios Mylonakis, Christian Friis, Luca Guardabassi, John Pace, Carina Vingsbo Lundberg, Fatima M'Zali, Pascal Butty, Nikolaj Sørensen, Henrik Bjørn Nielsen, Rasmus Toft‐Kehler, Emma Guttman‐Yassky, Georg Stingl, Markus Zeitlinger, and Morten Sommer
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bench‐to‐bedside ,dermatology ,microbiome ,small molecule ,Medicine (General) ,R5-920 - Abstract
Abstract Background In patients with atopic dermatitis (AD), Staphylococcus aureus frequently colonizes lesions and is hypothesized to be linked to disease severity and progression. Treatments that reduce S. aureus colonization without significantly affecting the skin commensal microbiota are needed. Methods and findings In this study, we tested ATx201 (niclosamide), a small molecule, on its efficacy to reduce S. aureus and propensity to evolve resistance in vitro. Various cutaneous formulations were then tested in a superficial skin infection model. Finally, a Phase 2 randomized, double‐blind and placebo‐controlled trial was performed to investigate the impact of ATx201 OINTMENT 2% on S. aureus colonization and skin microbiome composition in patients with mild‐to‐severe AD (EudraCT:2016‐003501‐33). ATx201 has a narrow minimal inhibitory concentration distribution (.125–.5 μg/ml) consistent with its mode of action – targeting the proton motive force effectively stopping cell growth. In murine models, ATx201 can effectively treat superficial skin infections of methicillin‐resistant S. aureus. In a Phase 2 trial in patients with mild‐to‐severe AD (N = 36), twice‐daily treatment with ATx201 OINTMENT 2% effectively reduces S. aureus colonization in quantitative colony forming unit (CFU) analysis (primary endpoint: 94.4% active vs. 38.9% vehicle success rate, p = .0016) and increases the Shannon diversity of the skin microbiome at day 7 significantly compared to vehicle. Conclusion These results suggest that ATx201 could become a new treatment modality as a decolonizing agent.
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- 2022
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21. Pulmonary Aspergillosis in Critically Ill COVID-19 Patients Admitted to the Intensive Care Unit: A Retrospective Cohort Study
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Felix Bergmann, Anselm Jorda, Amelie Blaschke, Cornelia Gabler, Serhii Bohdan, Alina Nussbaumer-Pröll, Christine Radtke, and Markus Zeitlinger
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ICU ,CAPA ,IPA ,SARS-CoV-2 ,co-infection ,fungal ,Biology (General) ,QH301-705.5 - Abstract
COVID-19-associated pulmonary aspergillosis (CAPA) is a life-threatening fungal infection that mainly affects critically ill patients. The aim of this study was to assess the incidence and clinical outcomes of putative CAPA in critically ill COVID-19 patients. This retrospective observational cohort study included 181 cases from 5 ICUs at Vienna General Hospital between January 2020 and April 2022. Patients were diagnosed with putative CAPA according to the AspICU classification, which included a positive Aspergillus culture in a bronchoalveolar lavage sample, compatible signs and symptoms, and abnormal medical imaging. The primary outcome was adjusted 60-day all-cause mortality from ICU admission in patients with vs. without putative CAPA. Secondary outcomes included time from ICU admission to CAPA diagnosis and pathogen prevalence and distribution. Putative CAPA was identified in 35 (19.3%) of 181 COVID-19 patients. The mean time to diagnosis was 9 days. Death at 60 days occurred in 18 of 35 (51.4%) patients with CAPA and in 43 of 146 (29.5%) patients without CAPA (adjusted HR (95%CI) = 2.15 (1.20–3.86, p = 0.002). The most frequently isolated Aspergillus species was Aspergillus fumigatus. The prevalence of putative pulmonary aspergillosis in critically ill COVID-19 patients was high and was associated with significantly higher mortality.
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- 2023
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22. Effect of Antibiotic Eye Drops on the Nasal Microbiome in Healthy Subjects—A Pilot Study
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Clemens Nadvornik, Martin Kallab, Nikolaus Hommer, Andreas Schlatter, Theresa Stengel, Gerhard Garhöfer, Markus Zeitlinger, Sabine Eberl, Ingeborg Klymiuk, Slave Trajanoski, Marion Nehr, Athanasios Makristathis, Doreen Schmidl, and Alina Nussbaumer-Proell
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antibiotic eye drops ,gentamicin ,ciprofloxacin ,nasal microbiome ,next-generation sequencing ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Background: Antibiotic eye drops are frequently used in clinical practice. Due to the anatomical connection via the nasolacrimal duct, it seems possible that they have an influence on the nasal/pharyngeal microbiome. This was investigated by using two different commonly used antibiotic eye drops. Methods: 20 subjects were randomized to four groups of five subjects receiving eye drops containing gentamicin, ciprofloxacin, or, as controls, unpreserved povidone or benzalkonium chloride-preserved povidone. Nasal and pharyngeal swabs were performed before and after the instillation period. Swabs were analyzed by Illumina next-generation sequencing (NGS)-based 16S rRNA analysis. Bacterial culture was performed on solid media, and bacterial isolates were identified to the species level by MALDI-TOF MS. Species-dependent antimicrobial susceptibility testing was performed using single isolates and pools of isolates. Results: Bacterial richness in the nose increased numerically from 163 ± 30 to 243 ± 100 OTUs (gentamicin) and from 114 ± 17 to 144 ± 45 OTUs (ciprofloxacin). Phylogenetic diversity index (pd) of different bacterial strains in the nasal microbiome increased from 12.4 ± 1.0 to 16.9 ± 5.6 pd (gentamicin) and from 10.2 ± 1.4 to 11.8 ± 3.1 pd (ciprofloxacin). Unpreserved povidone eye drops resulted in minimal changes in bacterial counts. Preservative-containing povidone eye drops resulted in no change. A minor increase (1–2-fold) in the minimal inhibitory concentration (MIC) was observed in single streptococcal isolates. Conclusions: Antibiotic eye drops could affect the nasal microbiome. After an instillation period of seven days, an increase in the diversity and richness of bacterial strains in the nasal microbiome was observed.
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- 2023
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23. Editorial for the Special Issue 'A Themed Issue in Honor of Professor Hartmut Derendorf—Outstanding Contributions in the Fields of Quantitative Clinical Pharmacology'
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Françoise Van Bambeke, Sebastian Wicha, Paul M. Tulkens, and Markus Zeitlinger
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n/a ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Pharmacokinetics (PK) is the discipline investigating the absorption, distribution, metabolization and elimination of a drug in the body [...]
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- 2023
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24. Convalescent Plasma Treatment in Patients with Covid-19: A Systematic Review and Meta-Analysis
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Anselm Jorda, Manuel Kussmann, Nebu Kolenchery, Jolanta M. Siller-Matula, Markus Zeitlinger, Bernd Jilma, and Georg Gelbenegger
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antibodies ,passive immunization ,SARS-CoV-2 ,convalescent plasma (CP) therapy ,coronavirus – COVID-19 ,serotherapy ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Convalescent plasma is a suggested treatment for Coronavirus disease 2019 (Covid-19), but its efficacy is uncertain. We aimed to evaluate whether the use of convalescent plasma is associated with improved clinical outcomes in patients with Covid-19.In this systematic review and meta-analysis, we searched randomized controlled trials investigating the use of convalescent plasma in patients with Covid-19 in Medline, Embase, Web of Science, Cochrane Library, and medRxiv from inception to October 17th, 2021. Two reviewers independently extracted the data. The primary efficacy outcome was all-cause mortality. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used. This study was registered with PROSPERO, CRD42021284861. Of the 8874 studies identified in the initial search, sixteen trials comprising 16 317 patients with Covid-19 were included. In the overall population, the all-cause mortality was 23.8% (2025 of 8524) with convalescent plasma and 24.4% (1903 of 7769) with standard of care (risk ratio (RR) 0.97, 95% CI 0.90-1.04) (high-certainty evidence). All-cause mortality did not differ in the subgroups of noncritically ill (21.7% [1288 of 5929] vs. 22.4% [1320 of 5882]) and critically ill (36.9% [518 of 1404] vs. 36.4% [455 of 1247]) patients with Covid-19. The use of convalescent plasma in patients who tested negative for anti-SARS-CoV-2 antibodies at baseline was not associated with significantly improved survival (RR 0.94, 95% CI 0.87-1.02). In the overall study population, initiation of mechanical ventilation (RR 0.97, 95% CI 0.88-1.07), time to clinical improvement (HR 1.09, 95% CI 0.91-1.30), and time to discharge (HR 0.95, 95% CI 0.89-1.02) were similar between the two groups. In patients with Covid-19, treatment with convalescent plasma, as compared with control, was not associated with lower all-cause mortality or improved disease progression, irrespective of disease severity and baseline antibody status.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier PROSPERO (CRD42021284861).
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- 2022
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25. Sensitivity and Specificity of SARS-CoV-2 Rapid Antigen Detection Tests Using Oral, Anterior Nasal, and Nasopharyngeal Swabs: a Diagnostic Accuracy Study
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Michael Wölfl-Duchek, Felix Bergmann, Anselm Jorda, Maria Weber, Matthias Müller, Tamara Seitz, Alexander Zoufaly, Robert Strassl, Markus Zeitlinger, Harald Herkner, Harald Schnidar, Karolina Anderle, and Ulla Derhaschnig
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PCR ,SARS-CoV-2 ,infectious disease ,rapid antigen detection ,sensitivity ,specificity ,Microbiology ,QR1-502 - Abstract
ABSTRACT The objective of our study was to evaluate the sensitivity and specificity of rapid antigen detection tests versus those of reverse transcriptase PCR (RT-PCR) using oral, anterior nasal, and nasopharyngeal swabs. The underlying prospective, diagnostic case-control-type accuracy study included 87 hospitalized and nonhospitalized participants in a positive and a negative sample cohort between 16 March and 14 May 2021 in two hospitals in Vienna. SARS-CoV-2 infection status was confirmed by RT-PCR. Participants self-performed one oral and one anterior nasal swab for the rapid antigen test, immediately followed by two nasopharyngeal swabs for the rapid antigen test and RT-PCR by the investigator. Test results were read after 15 min, and participants completed a questionnaire in the meantime. Test parameters were calculated based on the evaluation of 87 participants. The overall sensitivity of rapid antigen detection tests versus that of RT-PCR with oral, anterior nasal, and nasopharyngeal samples was 18.18% (95% confidence interval [CI] 8.19% to 32.71%), 63.04% (95% CI 47.55% to 76.79%), and 73.33% (95% CI 58.06% to 85.4%), respectively. All sampling methods had a test specificity of 100% regardless of the cycle threshold (CT) value. Rapid antigen detection tests using self-collected anterior nasal swabs proved to be as sensitive as and more tolerable than professionally collected nasopharyngeal swabs for CT values up to 30 determined by RT-PCR. This finding illustrates the reliability of tests obtained by adequate self-collected anterior nasal specimen. Sensitivity was dependent upon the CT value for each sampling method. While the main advantage of rapid antigen detection tests is the immediate availability of results, PCR should be preferred in crucial settings wherever possible. IMPORTANCE Rapid antigen detection devices for SARS-CoV-2 represent a valuable tool for monitoring the spread of infection. However, the reliability of the tests depends largely on the test performance and the respective sampling method. Nasopharyngeal swabs mark the gold standard for sample collection in suspected respiratory tract infections but are unsuitable for widespread application, as they must be performed by medically trained personnel. With the underlying study, the head-to-head test performance and the usability of self-collected samples for SARS-CoV-2 detection using rapid antigen detection devices were evaluated. The results confirm similar sensitivity of self-collected anterior nasal swabs to that of professionally collected nasopharyngeal swabs for patients with a CT of < 30 determined by RT-PCR.
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- 2022
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26. Incidence of ARDS and outcomes in hospitalized patients with COVID-19: a global literature survey
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Susan J. Tzotzos, Bernhard Fischer, Hendrik Fischer, and Markus Zeitlinger
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ARDS ,COVID-19 ,Hospital ,ICU ,Incidence ,Mortality ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Published
- 2020
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27. Assessment of brain delivery of a model ABCB1/ABCG2 substrate in patients with non-contrast-enhancing brain tumors with positron emission tomography
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Beatrix Wulkersdorfer, Martin Bauer, Rudolf Karch, Harald Stefanits, Cécile Philippe, Maria Weber, Thomas Czech, Marie-Claude Menet, Xavier Declèves, Johannes A. Hainfellner, Matthias Preusser, Marcus Hacker, Markus Zeitlinger, Markus Müller, and Oliver Langer
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Non-contrast-enhancing brain tumor ,Blood–brain tumor barrier ,PET ,[11C]Tariquidar ,P-glycoprotein ,Breast cancer resistance protein ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Abstract Background P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two efflux transporters expressed at the blood–brain barrier which effectively restrict the brain distribution of the majority of currently known anticancer drugs. High-grade brain tumors often possess a disrupted blood–brain tumor barrier (BBTB) leading to enhanced accumulation of magnetic resonance imaging contrast agents, and possibly anticancer drugs, as compared to normal brain. In contrast to high-grade brain tumors, considerably less information is available with respect to BBTB integrity in lower grade brain tumors. Materials and methods We performed positron emission tomography imaging with the radiolabeled ABCB1 inhibitor [11C]tariquidar, a prototypical ABCB1/ABCG2 substrate, in seven patients with non-contrast -enhancing brain tumors (WHO grades I–III). In addition, ABCB1 and ABCG2 levels were determined in surgically resected tumor tissue of four patients using quantitative targeted absolute proteomics. Results Brain distribution of [11C]tariquidar was found to be very low across the whole brain and not significantly different between tumor and tumor-free brain tissue. Only one patient showed a small area of enhanced [11C]tariquidar uptake within the brain tumor. ABCG2/ABCB1 ratios in surgically resected tumor tissue (1.4 ± 0.2) were comparable to previously reported ABCG2/ABCB1 ratios in isolated human micro-vessels (1.3), which suggested that no overexpression of ABCB1 or ABCG2 occurred in the investigated tumors. Conclusions Our data suggest that the investigated brain tumors had an intact BBTB, which is impermeable to anticancer drugs, which are dual ABCB1/ABCG2 substrates. Therefore, effective drugs for antitumor treatment should have high passive permeability and lack ABCB1/ABCG2 substrate affinity. Trial registration European Union Drug Regulating Authorities Clinical Trials Database (EUDRACT), 2011-004189-13. Registered on 23 February 2012, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2011-004189-13.
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- 2019
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28. Phase I Study to Assess Safety of Laser-Assisted Topical Administration of an Anti-TNF Biologic in Patients With Chronic Plaque-Type Psoriasis
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Martin Bauer, Edith Lackner, Peter Matzneller, Valentin Al Jalali, Sahra Pajenda, Vincent Ling, Christof Böhler, Werner Braun, Reinhard Braun, Maximilian Boesch, Patrick M. Brunner, and Markus Zeitlinger
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plaque-type psoriasis ,topical ,etanercept (enbrel) ,biologic active molecule ,laser ,phase 1 clinical studies ,Medicine (General) ,R5-920 - Abstract
Ablative fractional laser treatment facilitates epidermal drug delivery, which might be an interesting option to increase the topical efficacy of biological drugs in a variety of dermatological diseases. This work aims at investigating safety and tolerability of this new treatment approach in patients with plaque-type psoriasis. Eight patients with plaque-type psoriasis were enrolled in this study. All patients received (i) ablative fractional laser microporation (AFL) of a psoriatic lesion with an Er:YAG laser + etanercept (ETA; Enbrel® solution for injection) (AFL-ETA), (ii) ETA alone on another lesion, and, if feasible, (iii) AFL alone on an additional lesion. Overall, all treatment arms showed a favorable safety profile. AFL-ETA improved the lesion-specific TPSS score by 1.75 vs. baseline, whereas ETA or AFL alone showed a TPSS score improvement of 0.75 points, a difference that was not statistically significant and might be attributable to differences in baseline scores. Topical administration of ETA to psoriatic plaques via AFL-generated micropores was generally well-tolerated. No special precautions seem necessary in future studies. Clinical benefit will need assessment in sufficiently powered follow-up studies.
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- 2021
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29. Protein Binding in Translational Antimicrobial Development-Focus on Interspecies Differences
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Hifza Ahmed, Felix Bergmann, and Markus Zeitlinger
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plasma protein binding ,fraction unbound ,pharmacokinetics ,antibiotics ,interspecies differences ,equilibrium dialysis ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Background/Introduction: Plasma protein binding (PPB) continues to be a key aspect of antibiotic development and clinical use. PPB is essential to understand several properties of drug candidates, including antimicrobial activity, drug-drug interaction, drug clearance, volume of distribution, and therapeutic index. Focus areas of the review: In this review, we discuss the basics of PPB, including the main drug binding proteins i.e., Albumin and α-1-acid glycoprotein (AAG). Furthermore, we present the effects of PPB on the antimicrobial activity of antibiotics and the current role of PPB in in vitro pharmacodynamic (PD) models of antibiotics. Moreover, the effect of PPB on the PK/PD of antibiotics has been discussed in this review. A key aspect of this paper is a concise evaluation of PPB between animal species (dog, rat, mouse, rabbit and monkey) and humans. Our statistical analysis of the data available in the literature suggests a significant difference between antibiotic binding in humans and that of dogs or mice, with the majority of measurements from the pre-clinical species falling within five-fold of the human plasma value. Conversely, no significant difference in binding was found between humans and rats, rabbits, or monkeys. This information may be helpful for drug researchers to select the most relevant animal species in which the metabolism of a compound can be studied for extrapolating the results to humans. Furthermore, state-of-the-art methods for determining PPB such as equilibrium dialysis, ultracentrifugation, microdialysis, gel filtration, chromatographic methods and fluorescence spectroscopy are highlighted with their advantages and disadvantages.
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- 2022
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30. ABCB1 and ABCG2 Together Limit the Distribution of ABCB1/ABCG2 Substrates to the Human Retina and the ABCG2 Single Nucleotide Polymorphism Q141K (c.421C> A) May Lead to Increased Drug Exposure
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Myriam El Biali, Rudolf Karch, Cécile Philippe, Helmuth Haslacher, Nicolas Tournier, Marcus Hacker, Markus Zeitlinger, Doreen Schmidl, Oliver Langer, and Martin Bauer
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ABCG2 ,ABCB1 ,blood-retinal barrier ,A%22">c421C>A ,single-nucleotide polymorphism ,PET ,Therapeutics. Pharmacology ,RM1-950 - Abstract
The widely expressed and poly-specific ABC transporters breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1) are co-localized at the blood-brain barrier (BBB) and have shown to limit the brain distribution of several clinically used ABCB1/ABCG2 substrate drugs. It is currently not known to which extent these transporters, which are also expressed at the blood-retinal barrier (BRB), may limit drug distribution to the human eye and whether the ABCG2 reduced-function single-nucleotide polymorphism (SNP) Q141K (c.421C > A) has an impact on retinal drug distribution. Ten healthy male volunteers (five subjects with the c.421CC and c.421CA genotype, respectively) underwent two consecutive positron emission tomography (PET) scans after intravenous injection of the model ABCB1/ABCG2 substrate [11C]tariquidar. The second PET scan was performed with concurrent intravenous infusion of unlabelled tariquidar to inhibit ABCB1 in order to specifically reveal ABCG2 function.In response to ABCB1 inhibition with unlabelled tariquidar, ABCG2 c.421C > A genotype carriers showed significant increases (as compared to the baseline scan) in retinal radiotracer influx K1 (+62 ± 57%, p = 0.043) and volume of distribution VT (+86 ± 131%, p = 0.043), but no significant changes were observed in subjects with the c.421C > C genotype. Our results provide the first evidence that ABCB1 and ABCG2 may together limit the distribution of systemically administered ABCB1/ABCG2 substrate drugs to the human retina. Functional redundancy between ABCB1 and ABCG2 appears to be compromised in carriers of the c.421C > A SNP who may therefore be more susceptible to transporter-mediated drug-drug interactions at the BRB than non-carriers.
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- 2021
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31. Macrolide Treatment Failure due to Drug–Drug Interactions: Real-World Evidence to Evaluate a Pharmacological Hypothesis
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Brian Cicali, Stephan Schmidt, Markus Zeitlinger, and Joshua D. Brown
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macrolide antibiotics ,treatment failure ,drug–drug interactions ,pharmacoepidemiology ,Pharmacy and materia medica ,RS1-441 - Abstract
Macrolide antibiotics have received criticism concerning their use and risk of treatment failure. Nevertheless, they are an important class of antibiotics and are frequently used in clinical practice for treating a variety of infections. This study sought to utilize pharmacoepidemiology methods and pharmacology principles to estimate the risk of macrolide treatment failure and quantify the influence of their pharmacokinetics on the risk of treatment failure, using clinically reported drug–drug interaction data. Using a large, commercial claims database (2006–2015), inclusion and exclusion criteria were applied to create a cohort of patients who received a macrolide for three common acute infections. Furthermore, an additional analysis examining only bacterial pneumonia events treated with macrolides was conducted. These criteria were formulated specifically to ensure treatment failure would not be expected nor influenced by intrinsic or extrinsic factors. Treatment failure rates were 6% within the common acute infections and 8% in the bacterial pneumonia populations. Regression results indicated that macrolide AUC changes greater than 50% had a significant effect on treatment failure risk, particularly for azithromycin. In fact, our results show that decreased or increased exposure change can influence failure risk, by 35% or 12%, respectively, for the acute infection scenarios. The bacterial pneumonia results were less significant with respect to the regression analyses. This integration of pharmacoepidemiology and clinical pharmacology provides a framework for utilizing real-world data to provide insight into pharmacokinetic mechanisms and support future study development related to antibiotic treatments.
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- 2022
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32. Comparison of Antimycotic Activity of Originator and Generics of Voriconazole and Anidulafungin against Clinical Isolates of Candida albicans and Candida glabrata
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Alina Karoline Nussbaumer-Pröll, Sabine Eberl, René Welte, Tiziana Gasperetti, Jana Marx, Romuald Bellmann, and Markus Zeitlinger
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antifungals ,generic ,innovator ,MIC ,TKC ,C. albicans ,Biology (General) ,QH301-705.5 - Abstract
Background: Concerns have been expressed about the interchangeability of innovator and generic antifungals in their activity and chemical stability. Materials/methods: The activity of two different antimycotics was tested, each with one originator and two generics. For voriconazole, the originator VFEND® (Pfizer) and the generics (Ratiopharm and Stada) were used for susceptibility testing (21 clinical isolates of Candida albicans (C. albicans); ATCC-90028 C. albicans) in RPMI growth media in compliance with the EUCAST criteria. Likewise, for anidulafungin, the originator ECALTA® (Pfizer) and the generics (Stada and Pharmore) were used for testing (20 clinical isolates of Candida glabrata (C. glabrata); ATCC-22019 Candida parapsilosis (C. parapsilosis)). Time Kill Curves (TKC) with concentrations above and below the respective MIC were performed for one strain for each antifungal. Stability testing of the antimycotics stored at 4 °C and at room temperature over 24 h was done, and samples were subsequently analyzed with HPLC. Results: MIC results showed no significant difference in activity of generic and innovator antimycotic in all settings, which was also confirmed by TKC. Stability testing revealed no differences between originator and generic drugs. Conclusions: The present study demonstrates the interchangeability of generic and originator antimycotic in-vitro, potentially leading to broader public acceptance for generic antimycotics.
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- 2022
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33. Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches
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Wisse van Os and Markus Zeitlinger
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pharmacokinetics ,pharmacodynamics ,target site ,probability of target attainment ,time–kill curves ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Antibiotic dosing strategies are generally based on systemic drug concentrations. However, drug concentrations at the infection site drive antimicrobial effect, and efficacy predictions and dosing strategies should be based on these concentrations. We set out to review different translational pharmacokinetic-pharmacodynamic (PK/PD) approaches from a target site perspective. The most common approach involves calculating the probability of attaining animal-derived PK/PD index targets, which link PK parameters to antimicrobial susceptibility measures. This approach is time efficient but ignores some aspects of the shape of the PK profile and inter-species differences in drug clearance and distribution, and provides no information on the PD time-course. Time–kill curves, in contrast, depict bacterial response over time. In vitro dynamic time–kill setups allow for the evaluation of bacterial response to clinical PK profiles, but are not representative of the infection site environment. The translational value of in vivo time–kill experiments, conversely, is limited from a PK perspective. Computational PK/PD models, especially when developed using both in vitro and in vivo data and coupled to target site PK models, can bridge translational gaps in both PK and PD. Ultimately, clinical PK and experimental and computational tools should be combined to tailor antibiotic treatment strategies to the site of infection.
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- 2021
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34. Similar Piperacillin/Tazobactam Target Attainment in Obese versus Nonobese Patients despite Differences in Interstitial Tissue Fluid Pharmacokinetics
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David Busse, Philipp Simon, David Petroff, Christoph Dorn, Lisa Schmitt, Davide Bindellini, Alexander Kratzer, Arne Dietrich, Markus Zeitlinger, Wilhelm Huisinga, Robin Michelet, Hermann Wrigge, and Charlotte Kloft
- Subjects
piperacillin/tazobactam ,target-site ,obesity ,Pharmacy and materia medica ,RS1-441 - Abstract
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.
- Published
- 2021
- Full Text
- View/download PDF
35. Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits
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Martin Kallab, Kornelia Schuetzenberger, Nikolaus Hommer, Bhavapriya Jasmin Schäfer, Doreen Schmidl, Helga Bergmeister, Markus Zeitlinger, Aimin Tan, Phatsawee Jansook, Thorsteinn Loftsson, Einar Stefansson, and Gerhard Garhöfer
- Subjects
γ-cyclodextrin ,irbesartan ,candesartan ,multiple instillation ,single instillation ,nanoparticles ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study, a total number of 59 New Zealand White albino rabbits were consecutively assigned to two study groups. Group 1 (n = 31) received irbesartan 1.5% and group 2 (n = 28) candesartan 0.15% eye drops. In both groups, single dose and multiple administration pharmacokinetic studies were performed. Rabbits were euthanized at five predefined time points after single-dose administration, whereas multiple-dose animals were dosed for 5 days twice-daily and then euthanized 1 h after the last dose administration. Drug concentration was measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the retinal tissue, vitreous humor, aqueous humor, corneal tissue and in venous blood samples. Pharmacokinetic parameters including maximal drug concentration (Cmax), time of maximal drug concentration (Tmax), half-life and AUC were calculated. To assess local tolerability, six additional rabbits received 1.5% irbesartan eye drops twice daily in one eye for 28 days. Tolerability was assessed using a modified Draize test and corneal sensibility by Cochet Bonnet esthesiometry. Both γCD based eye drops were rapidly absorbed and distributed in the anterior and posterior ocular tissues. Within 0.5 h after single administration, the Cmax of irbesartan and candesartan in retinal tissue was 251 ± 142 ng/g and 63 ± 39 ng/g, respectively. In the vitreous humor, a Cmax of 14 ± 16 ng/g for irbesartan was reached 0.5 h after instillation while Cmax was below 2 ng/g for candesartan. For multiple dosing, the observed Cmean in retinal tissue was 338 ± 124 ng/g for irbesartan and 36 ± 10 ng/g for candesartan, whereas mean vitreous humor concentrations were 13 ± 5 ng/g and max 5.64 ± 4.08 ng/mL) and candesartan (Cmax 4.32 ± 1.04 ng/mL) were reached 0.5 h (Tmax) after single administration. Local tolerability was favorable with no remarkable differences between the treated and the control eyes. These results indicate that irbesartan and candesartan in γCD based nanoparticle eye drops can be delivered to the retinal tissue of the rabbit’s eye in pharmacologically relevant concentrations. Moreover, safety and tolerability profiles appear to be favorable in the rabbit animal model.
- Published
- 2021
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36. Meropenem Plasma and Interstitial Soft Tissue Concentrations in Obese and Nonobese Patients—A Controlled Clinical Trial
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Philipp Simon, David Petroff, David Busse, Jana Heyne, Felix Girrbach, Arne Dietrich, Alexander Kratzer, Markus Zeitlinger, Charlotte Kloft, Frieder Kees, Hermann Wrigge, and Christoph Dorn
- Subjects
antibiotic dosing ,concentrations ,meropenem ,microdialysis ,obesity ,pharmacokinetics ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Background: This controlled clinical study aimed to investigate the impact of obesity on plasma and tissue pharmacokinetics of meropenem. Methods: Obese (body mass index (BMI) ≥ 35 kg/m2) and age-/sex-matched nonobese (18.5 kg/m2 ≥ BMI ≤ 30 kg/m2) surgical patients received a short-term infusion of 1000-mg meropenem. Concentrations were determined via high performance liquid chromatography-ultraviolet (HPLC-UV) in the plasma and microdialysate from the interstitial fluid (ISF) of subcutaneous tissue up to eight h after dosing. An analysis was performed in the plasma and ISF by noncompartmental methods. Results: The maximum plasma concentrations in 15 obese (BMI 49 ± 11 kg/m2) and 15 nonobese (BMI 24 ± 2 kg/m2) patients were 54.0 vs. 63.9 mg/L (95% CI for difference: −18.3 to −3.5). The volume of distribution was 22.4 vs. 17.6 L, (2.6–9.1), but the clearance was comparable (12.5 vs. 11.1 L/h, −1.4 to 3.1), leading to a longer half-life (1.52 vs. 1.31 h, 0.05–0.37) and fairly similar area under the curve (AUC)8h (78.7 vs. 89.2 mg*h/L, −21.4 to 8.6). In the ISF, the maximum concentrations differed significantly (12.6 vs. 18.6 L, −16.8 to −0.8) but not the AUC8h (28.5 vs. 42.0 mg*h/L, −33.9 to 5.4). Time above the MIC (T > MIC) in the plasma and ISF did not differ significantly for MICs of 0.25–8 mg/L. Conclusions: In morbidly obese patients, meropenem has lower maximum concentrations and higher volumes of distribution. However, due to the slightly longer half-life, obesity has no influence on the T > MIC, so dose adjustments for obesity seem unnecessary.
- Published
- 2020
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37. Use of Supplemented or Human Material to Simulate PD Behavior of Antibiotics at the Target Site In Vitro
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Alina Nussbaumer-Pröll and Markus Zeitlinger
- Subjects
adapted growth media ,body fluids ,in vitro ,PD ,MIC ,TKC ,Pharmacy and materia medica ,RS1-441 - Abstract
In antimicrobial drug development, in vitro antibiotic susceptibility testing is conducted in standard growth media, such as Mueller–Hinton broth (MHB). These growth media provide optimal bacterial growth, but do not consider certain host factors that would be necessary to mimic the in vivo bacterial environment in the human body. The present review aimed to include relevant data published between 1986 and 2019. A database search (PubMed) was done with text keywords, such as “MIC” (minimal inhibitory concentration), “TKC” (time kill curve), “blood”, “body fluid”, “PD” (pharmacodynamic), and “in vitro”, and 53 papers were ultimately selected. Additionally, a literature search for physiologic characteristics of body fluids was conducted. This review gives an excerpt of the complexity of human compartments with their physiologic composition. Furthermore, we present an update of currently available in vitro models operated either with adapted growth media or body fluids themselves. Moreover, the feasibility of testing the activity of antimicrobials in such settings is discussed, and pro and cons for standard practice methods are given. The impact on bacterial killing varies between individual adapted microbiological media, as well as direct pharmacodynamic simulations in body fluids, between bacterial strains, antimicrobial agents, and the compositions of the adjuvants or the biological fluid itself.
- Published
- 2020
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38. Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study
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Philipp Simon, David Busse, David Petroff, Christoph Dorn, Lisa Ehmann, Sophie Hochstädt, Felix Girrbach, Arne Dietrich, Markus Zeitlinger, Frieder Kees, Charlotte Kloft, and Hermann Wrigge
- Subjects
antibiotic dosing ,concentrations ,linezolid ,microdialysis ,obesity ,pharmacokinetics ,Medicine - Abstract
Background: Linezolid is used for the treatment of soft tissue infections in critically ill patients. However, data for characterizing the pharmacokinetics (PK) and assessing whether effective concentrations are reached at the target site are lacking. We hypothesized that current dosing regimens do not lead to effective concentrations in the plasma and interstitial fluid (ISF) of subcutaneous tissue in obese patients. Methods: As a controlled clinical model, critically ill obese and non-obese patients undergoing intra-abdominal surgery received 600 mg linezolid as a single infusion. Concentrations in the plasma and microdialysate from the ISF of subcutaneous tissue were determined up to 8 h after dosing. Pharmacokinetic analysis was performed by non-compartmental methods. As a therapeutic target, we used fAUC/MIC > 80. Results: Fifteen obese (BMI: 48.7 ± 11.2 kg/m2) and 15 non-obese (23.9 ± 2.1 kg/m2) patients were analyzed. AUC0–8 in ISF decreased by −1.69 mg*h/L (95% CI: −2.59 to −0.79, p < 0.001) for every 10 kg increase in weight. PK in obese patients were characterized by lower maximal plasma concentrations (median 3.8 vs. 8.3 mg/L, p < 0.001) and a higher volume of distribution (41.0 vs. 30.8 L, p < 0.001), and the therapeutic target was not reached for MIC ≥ 1 mg/L in ISF and ≥ 2 mg/L in plasma. Conclusions: Increasing the weight led to a decrease of linezolid concentrations in the plasma and subcutaneous tissue. The current dosing regimen does not seem to produce sufficient concentrations to kill bacteria with MIC ≥ 2 mg/L, especially as empirical antimicrobial therapy in critically ill obese patients.
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- 2020
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39. Microdialysis Assessment of Cerebral Perfusion during Cardiac Arrest, Extracorporeal Life Support and Cardiopulmonary Resuscitation in Rats - A Pilot Trial.
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Andreas Schober, Alexandra M Warenits, Christoph Testori, Wolfgang Weihs, Arthur Hosmann, Sandra Högler, Fritz Sterz, Andreas Janata, Thomas Scherer, Ingrid A M Magnet, Florian Ettl, Anton N Laggner, Harald Herkner, and Markus Zeitlinger
- Subjects
Medicine ,Science - Abstract
Cerebral metabolic alterations during cardiac arrest, cardiopulmonary resuscitation (CPR) and extracorporeal cardiopulmonary life support (ECLS) are poorly explored. Markers are needed for a more personalized resuscitation and post-resuscitation care. Aim of this study was to investigate early metabolic changes in the hippocampal CA1 region during ventricular fibrillation cardiac arrest (VF-CA) and ECLS versus conventional CPR. Male Sprague-Dawley rats (350g) underwent 8min untreated VF-CA followed by ECLS (n = 8; bloodflow 100ml/kg), mechanical CPR (n = 18; 200/min) until return of spontaneous circulation (ROSC). Shams (n = 2) were included. Glucose, glutamate and lactate/pyruvate ratio were compared between treatment groups and animals with and without ROSC. Ten animals (39%) achieved ROSC (ECLS 5/8 vs. CPR 5/18; OR 4,3;CI:0.7-25;p = 0.189). During VF-CA central nervous glucose decreased (0.32±0.1mmol/l to 0.04±0.01mmol/l; p
- Published
- 2016
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40. Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response
- Author
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Ulrich Jäger, Michael Fridrik, Markus Zeitlinger, Daniel Heintel, Georg Hopfinger, Sonja Burgstaller, Christine Mannhalter, Wilhelm Oberaigner, Edit Porpaczy, Cathrin Skrabs, Christine Einberger, Johannes Drach, Markus Raderer, Alexander Gaiger, Monique Putman, and Richard Greil
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Treatment of follicular lymphoma with rituximab is currently recommended at a dose of 375 mg/m2. We aimed to provide a rationale for optimal dosing and scheduling of this anti-CD20 antibody based on pharmacokinetics.Design and Methods Clinical efficacy of immunochemotherapy with rituximab, fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial (AGMT-NHL9). Pharmacokinetic analysis was assessed in 17 patients.Results Induction treatment resulted in high clinical response rates (complete remission 66%; ORR 100%). Significantly higher complete remission rates were observed in female patients (86 vs. 47%; Odds Ratio 6.8, 95% CI: 1.12; 41.82; P=0.05). Rituximab pharmacokinetic analysis showed a high variability ranging over almost 1 order of magnitude at maintenance cycle 1 (area under the curve 1,540–12,025 g/L*days). Median area under the curve was lower in men (81%) and in patients with initial bone marrow infiltration (76%). Higher rituximab serum concentrations before next therapy (Ctrough) were associated with female sex (P=0.04) as well as with absence of initial bone marrow infiltration (P=0.001). Ctrough correlated with remission quality (complete vs. partial remission; P=0.005) and progression-free survival (P=0.03). A decline in rituximab Ctrough below 25,000 ng/mL was observed 9.5 to 62 months before clinical relapse (P=0.008).Conclusions The results of this pilot trial suggest that more differentiated dosing schedules based on gender and bone marrow infiltration should be explored for rituximab therapy for lymphoma. This study was registered in ClinicalTrials.gov (Identifier: NCT01560117).
- Published
- 2012
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41. Population plasma and urine pharmacokinetics and the probability of target attainment of fosfomycin in healthy male volunteers
- Author
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Angela Elma Edwina, Birgit C. P. Koch, Anouk E. Muller, Valentin al Jalali, Peter Matzneller, Markus Zeitlinger, Sebastiaan D. T. Sassen, Pharmacy, and Medical Microbiology & Infectious Diseases
- Subjects
Pharmacology ,Pharmacology (medical) ,General Medicine - Abstract
Purpose A population pharmacokinetic model of fosfomycin was developed in healthy volunteers after intravenous administration, and different dosing regimens were evaluated in terms of the probability of target attainment for Escherichia coli using both plasma and urinary pharmacokinetic/pharmacodynamic targets. Methods Eight healthy men received fosfomycin as both intermittent 8 g q8h and continuous infusion 1 g/h with a loading dose of 8 g in a crossover study design. Dense sampling was conducted during both regimens. Population pharmacokinetic modelling was performed using NONMEM. Monte Carlo simulations were conducted to evaluate the Probability of Target Attainment (PTA) of different dosing regimens using bactericidal (AUC24h/MIC of 83 and 75%T>MIC) and bacteriostatic (AUC24h/MIC of 25) plasma targets and bacteriostatic (AUC24h/MIC of 3994) urine target. Results A total of 176 plasma and 86 urine samples were available for PK analysis. A two-compartment model with a urine compartment best described the data. Glomerular filtration rate (GFR) showed a significant correlation with renal clearance and was implemented in the final model. Simulation results show that the dose of 4 g q8h reached 100% of PTA using bactericidal and bacteriostatic targets for MIC up to 16 mg/L. Conclusion For the clinical breakpoint of 32 mg/L, the standard dosing regimen (4 g q8h) might not be sufficient to reach the bactericidal target. Higher dosing of 8 g q8h as an intermittent infusion or 0.75 g/h as a continuous infusion might be required. Continuous infusion resulted in better attainment of the %T>MIC target than intermittent infusion.
- Published
- 2023
42. A protocol for an international, multicentre pharmacokinetic study for Screening Antifungal Exposure in Intensive Care Units: The SAFE-ICU study
- Author
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Jason A. Roberts, Fekade Sime, Jeffrey Lipman, Maria Patricia Hernández-Mitre, João Pedro Baptista, Roger J. Brüggemann, Jai Darvall, Jan J. De Waele, George Dimopoulos, Jean-Yves Lefrant, Mohd Basri Mat Nor, Jordi Rello, Leonardo Seoane, Monica A. Slavin, Miia Valkonen, Mario Venditti, Wai Tat Wong, Markus Zeitlinger, and Claire Roger
- Subjects
Anesthesiology and Pain Medicine ,Emergency Medicine ,Critical Care and Intensive Care Medicine - Published
- 2023
43. Impact of surfactants and other body fluids on in vitro activity of a novel β-lactamase inhibitor enmetazobactam in combination with cefepime against clinical isolates of Klebsiella pneumoniae
- Author
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Alina Nussbaumer-Pröll, Sabine Eberl, Adam Belley, Philipp Knechtle, Michael D. Huband, Holly K. Huynh, and Markus Zeitlinger
- Subjects
Pharmacology ,Drug Discovery - Published
- 2023
44. A narrative review of the intermediate category of the antimicrobial susceptibility test: relation with dosing and possible impact on antimicrobial stewardship
- Author
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Erlangga, Yusuf, Markus, Zeitlinger, and Sylvain, Meylan
- Subjects
Pharmacology ,Microbiology (medical) ,Infectious Diseases ,SDG 3 - Good Health and Well-being ,Pharmacology (medical) - Abstract
The interpretation of ‘susceptible (S)’ or ‘resistant (R)’ results of antimicrobial susceptibility testing is easily understood, but the interpretation of the ‘intermediate (I)’ category can be confusing. This review critically discusses how this categorization (clinical breakpoints) comes into being with the emphasis on the use of pharmacokinetics and pharmacodynamic data. It discusses the differences between the ‘I’ according to the CLSI and the EUCAST. This review also discusses the recent EUCAST change of the ‘I’ definition, and the impact of this change from laboratory and clinical points of view.
- Published
- 2022
45. Comparison of ultrafiltration and microdialysis for ceftriaxone protein-binding determination
- Author
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Maria Sanz-Codina, Sebastian G Wicha, Beatrix Wulkersdorfer, Valentin Al Jalali, Wisse Van Os, Matthias G Vossen, Martin Bauer, Edith Lackner, Christoph Dorn, and Markus Zeitlinger
- Subjects
Pharmacology ,Microbiology (medical) ,Infectious Diseases ,Pharmacology (medical) - Abstract
Background High protein binding (PB) of antibiotics has an impact on their antimicrobial activity. It has been questioned whether in vitro PB determination can capture the dynamic and concentration-dependent PB of highly bound antibiotics. Objectives This clinical study compared in vitro ultrafiltration (UF) and in vivo IV microdialysis (MD) methods to determine ceftriaxone PB. Methods Six healthy male volunteers received a single IV 2 g dose of ceftriaxone. Unbound ceftriaxone plasma concentrations were measured with MD and venous plasma sampling with subsequent UF. Pharmacokinetic parameters were determined using non-compartmental pharmacokinetic analysis. Non-linear mixed-effects modelling was used to quantify the PB. The PTA was estimated. Results The Cmax of ceftriaxone total plasma concentration (297.42 ± 21.0 mg/L) was approximately 5.5-fold higher than for free concentrations obtained with UF (52.83 ± 5.07 mg/L), and only 3.5-fold higher than for free concentrations obtained with MD (81.37 ± 26.93 mg/L). Non-linear, saturable PB binding was confirmed for both UF and MD. Significantly different dissociation constants (Kd) for the albumin/ceftriaxone complex were quantified: in UF it was 23.7 mg/L (95% CI 21.3–26.2) versus 15.9 mg/L (95% CI 13.6–18.6) in MD. Moreover, the estimated number of binding sites (95% CI) per albumin molecule was 0.916 (0.86–0.97) in UF versus 0.548 in MD (0.51–0.59). The PTA obtained with MD was at most 27% higher than with UF. Conclusions In vitro UF versus in vivo intravasal MD revealed significantly different PB, especially during the distribution phase. The method of PB determination could have an impact on the breakpoint determination and dose optimisation of antibiotics.
- Published
- 2022
46. Treatment of Infants and Children With SARS-CoV-2 Monoclonal Antibodies: A European Case Series
- Author
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Cornelius Rau, Lorenz Auer-Hackenberg, Hedwig E. Deubzer, Elisabeth Schwabel, Maria Jaros, Antonia Diederichs, Thomas Lehrnbecher, Mette Holm, Marie-Louise von Linstow, Luise Martin, Sarah Svenja Dinges, Maria Rothensteiner, Meinolf Siepermann, Volker Strenger, Ulrich von Both, Norbert Teig, Folke Brinkmann, Franziska Leeb, Markus Zeitlinger, Robin Kobbe, and Florian Götzinger
- Subjects
Microbiology (medical) ,Infectious Diseases ,Pediatrics, Perinatology and Child Health - Published
- 2022
47. Multiparametric Prediction Models for Coronavirus Disease 2019 Vaccine Selection: Results of a Comparative Population-Based Cohort Study
- Author
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Daniela Sieghart, Claudia A Hana, Helmuth Haslacher, Thomas Perkmann, Leonhard X Heinz, Clemens Fedrizzi, Karolina Anderle, Ursula Wiedermann, Irina Condur, Susanne Drapalik, Helmut Steinbrecher, Daniel Mrak, Patrick Mucher, Timothy Hasenoehrl, Andrej Zrdavkovic, Barbara Wagner, Stefano Palma, Galateja Jordakieva, Anselm Jorda, Christa Firbas, Angelika Wagner, Nadja Haiden, Felix Bergmann, Richard Crevenna, Markus Zeitlinger, Michael Bonelli, Daniel Aletaha, and Helga Radner
- Subjects
Microbiology (medical) ,Infectious Diseases - Abstract
BackgroundAn understanding vaccine-dependent effects on protective and sustained humoral immune response is crucial to planning future vaccination strategies against coronavirus disease 2019 (COVID-19).MethodsIn this multicenter, population-based, cohort study including 4601 individuals after primary vaccination against COVID-19 ≥ 4 months earlier we compared factors associated with residual antibody levels against severe acute respiratory syndrome coronavirus-2 receptor-binding domain (RBD) across different vaccination strategies (BNT162b2, mRNA-1273, or ChAdOx1).ResultsOur main model including 3787 individuals (2 × BNT162b2, n = 2271; 2 × mRNA-1273, n = 251; 2 × ChAdOx1, n = 1265), predicted significantly lower levels of anti-RBD antibodies after 6 months in individuals vaccinated with ChAdOx1 (392.7 binding antibody units per milliliter [BAU/mL]) compared with those vaccinated with BNT162b2 (1179.5 BAU/mL) or mRNA-1273 (2098.2 BAU/mL). Vaccine-dependent association of antibody levels was found for age with a significant predicted difference in BAU/ml per year for BNT162b2 (−21.5; 95% confidence interval [CI], −24.7 to −18.3) and no significant association for mRNA-1273 (−4.0; 95% CI, −20.0 to 12.1) or ChAdOx1 (1.7; 95% CI, .2 to 3.1). The predicted decrease over time since full immunization was highest in mRNA-1273 (−23.4; 95% CI, −31.4 to −15.4) compared with BNT162b2 (−5.9; 95% CI, −7 to −4.8).ConclusionsOur study revealed population-based evidence of vaccine-dependent effects of age and time since full immunization on humoral immune response. Findings underline the importance of individualized vaccine selection, especially in elderly individuals.
- Published
- 2022
48. Effect of the human endotoxin challenge on tedizolid tissue penetration
- Author
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Anselm Jorda, Beatrix Wulkersdorfer, Christian Schoergenhofer, Peter Matzneller, Valentin al Jalali, Martin Bauer, Michael Wölfl‐Duchek, Edith Lackner, Christoph Dorn, Bernd Jilma, and Markus Zeitlinger
- Subjects
Pharmacology ,Pharmacology (medical) - Abstract
The effects of the human endotoxin challenge on tissue pharmacokinetics are unknown. In the present study, we aimed to assess the effect of the endotoxin challenge on interstitial fluid pharmacokinetics of tedizolid in healthy volunteers using intramuscular microdialysis. Eight healthy male subjects were treated with 200 mg of tedizolid phosphate for 6 days. On Day 6, an intravenous bolus of lipopolysaccharide (LPS) (2 ng/kg body weight) was administered. LPS infusion did not affect plasma pharmacokinetics of tedizolid. In contrast, following LPS infusion, median muscle tissue fAUC (0.83 [0.75-1.15] vs. 1.14 [1.11-1.43] mg × h/L, P = .0078) and muscle tissue fC
- Published
- 2022
49. Accelerator mass spectrometry for quantification of micro- and therapeutic-dose diclofenac in microdialysis samples
- Author
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Oliver Langer, Jinho Song, Min Sun Choi, Edith Lackner, Felix Bergmann, Chang Su Yeo, Miwha Kwon, Mihye Kwon, Jae Hoon Shim, Stephen R Dueker, Markus Zeitlinger, and Martin Bauer
- Subjects
Medical Laboratory Technology ,Diclofenac ,Pharmaceutical Preparations ,Albumins ,Dialysis Solutions ,Microdialysis ,Clinical Biochemistry ,Carbon Radioisotopes ,General Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Mass Spectrometry ,Analytical Chemistry - Abstract
Background: Microdialysis sampling after drug microdosing may provide tissue pharmacokinetic data early in clinical drug development. However, low administered doses and small sample volumes pose an analytical challenge, particularly for highly protein-bound drugs. Materials & methods: Carbon-14 [14C]diclofenac was used as a model drug to assess the technical and analytical feasibility of in vivo microdialysis after microdose administration in an in vitro setup. Results: [14C]diclofenac dialysate concentrations were accurately quantified with accelerator MS. [14C]diclofenac dialysate recoveries were similar in the presence and absence of therapeutic diclofenac concentrations but were considerably decreased when albumin was added to the immersion solution, suggesting high protein binding. Conclusion: These results demonstrate the feasibility of combining microdosing and microdialysis to assess tissue pharmacokinetics.
- Published
- 2022
50. Perception of clinical research among patients and healthy volunteers of clinical trials
- Author
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Felix Bergmann, Peter Matzneller, Maria Weber, Lusine Yeghiazaryan, Thorsten Fuereder, Thomas Weber, and Markus Zeitlinger
- Subjects
Pharmacology ,Motivation ,Pharmaceutical Preparations ,Surveys and Questionnaires ,Humans ,Perception ,Pharmacology (medical) ,General Medicine ,Healthy Volunteers - Abstract
Purpose Clinical research relies on data from patients and volunteers, yet the target sample size is often not achieved. Here, we assessed the perception of clinical research among clinical trial participants to improve the recruitment process for future studies. Methods We conducted a single-center descriptive and exploratory study of 300 current or former participants in various phase I–III clinical trials. Questionnaires were either distributed to current clinical trial participants or emailed to former subjects. Results Subjects strongly agreed or agreed that contributing to improving medical care (> 81%), contributing to scientific research (> 79%), and trusting their treating physicians (> 77%) were motives for study participation. Among healthy volunteers, financial motives positively correlated with the number of clinical trials they had participated in (p p Conclusion Altruistic motives and trust in treating physicians were predominant motives for clinical trial participation. Older patients expected to receive the best available treatment during participation. Healthy volunteers who reported financial motives had participated in more clinical trials. Consistent with great trust in medical staff and government research institutions, little concern was expressed about the misuse of personal data during the trial.
- Published
- 2022
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