Markus Zeitlinger

Medical University of Vienna | MedUni Vienna · Section of Pharmacokinetics / Pharmacogenetics and Imaging

Background There is conflicting evidence whether prediabetes is associated with adverse clinical outcomes in patients with chronic coronary syndrome. We aimed to assess the effect of prediabetes in patients with chronic coronary syndrome on clinical outcomes. Methods This is a secondary analysis of data from the ISCHEMIA and ISCHEMIA-CKD trials, i...

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 re...

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...

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), whi...

To date, evidence has been lacking regarding bevacizumab pharmacokinetics in the cerebrospinal fluid (CSF). This study assessed the penetration of bevacizumab, as part of a metronomic antiangiogenic treatment regimen, into the CSF of children, adolescents, and young adults with recurrent brain tumors. Serum and CSF concentrations, malignant cells,...

Background Little is known about the pharmacodynamic characteristics of liposomal bupivacaine. Hypothesizing that we would not identify pharmacodynamic differences from plain bupivacaine during the initial period after administration, but would find better long-term pharmacodynamic characteristics, we designed a randomized, controlled, triple-blind...

Background Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remai...

Purpose This study investigates how surfactants affect the in-vitro anti-infective efficacy of micafungin, caspofungin, anidulafungin, and amphotericin B in treating pulmonary mycoses. Methods MIC values for antifungal agents were determined against Candida krusei (now Pichia kudriavzevii) ATCC 6258, Candida albicans ATCC 90028, and 18 clinical is...

For antimicrobial agents in particular, plasma protein binding (PPB) plays a pivotal role in deciphering key properties of drug candidates. Animal models are generally used in the preclinical development of new drugs to predict their effects in humans using translational pharmacokinetics/pharmacodynamics (PK/PD). Thus, we compared the protein bindi...

Background Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure. Linezolid exhibits good penetration into the CSF, but its penetration into cerebral interstitial fluid (ISF) is unknown. Objectives To determine linezolid penetration into CSF a...

Study objective The impact of biological sex in peripheral regional anaesthesia is largely unknown. We therefore designed a prospective study in volunteers to investigate the impact of biological sex on pharmacodynamic, pharmacokinetic and morphometric characteristics for peripheral nerve blockade. Methods The initial study plan was powered to inc...

P-glycoprotein (P-gp, encoded in humans by the ABCB1 gene and in rodents by the Abcb1a/b genes) is a membrane transporter that can restrict the intestinal absorption and tissue distribution of many drugs and may also contribute to renal and hepatobiliary drug excretion. The aim of this study was to compare the performance and sensitivity of current...

Objectives Lefamulin is a pleuromutilin antibiotic approved for the treatment of community-acquired bacterial pneumonia (CABP). Its spectrum of activity, good penetration into soft tissues and low rates of cross-resistance also make lefamulin a potentially valuable option for treatment of acute bacterial skin and skin structure infections (ABSSSIs)...

ToTheEditor—We thank Li et al and Zhu et al for their interest in this topic and the meticulous review of our meta-analysis, which found a survival benefit of corticosteroids in patients with community-acquired pneumonia (CAP). First, concerning the omission of the Mikami et al study [1], while we were aware of its existence and its inclusion in ot...

Purpose Due to constantly rising therapy costs, biosimilars and generic drugs have gained tremendous importance through recent decades. Nevertheless, the acceptance among healthcare workers regarding biosimilars and generic drugs in previously published international studies is considerably lower than the scientific data on equivalent safety and ef...

Rationale: Pneumonia is a frequent and feared complication in intubated critically ill patients. Tissue concentrations of antimicrobial drugs need to be sufficiently high to treat the infection and also prevent development of bacterial resistance. It is uncertain whether pulmonary inflammation and injury affect antimicrobial drug penetration into...

Background Pathophysiological changes in severely burned patients alter the pharmacokinetics (PK) of anti-infective agents, potentially leading to subtherapeutic concentrations at the target site. Albumin supplementation, to support fluid resuscitation, may affect pharmacokinetic properties by binding drugs. This study aimed to investigate the PK o...

Ceftaroline fosamil is a β-lactam antibiotic approved as a 600 mg twice daily dose (≤1 h infusion, ‘standard dosing’) or a 600 mg thrice daily dose (2 h infusion) to treat complicated skin and soft tissue infections caused by Staphylococcus aureus (minimum inhibitory concentration [MIC] 2–4 mg/L). We sought to systematically evaluate the relative i...

Background Antimicrobial activity of antibiotics can be impacted by pH, enhancing or reducing their bactericidal properties. Cefiderocol, a novel cephalosporin antibiotic that is among others indicated for the treatment of complicated urinary tract infections (cUTIs), lacks data on activity in urine. Methods Pooled human urine (iron levels ∼0.05 m...

Antifungal drug development is essential as invasive fungal disease is still associated with a very high mortality rate and the emergence of resistant species in the last decade. In Europe, the European Medical Agency (EMA) approves antifungals and publishes the European Public Assessment Report (EPAR) including the information leading up to the au...

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two ATP-binding cassette efflux transporters that are coexpressed at the human blood–brain barrier (BBB) and blood–retina barrier (BRB). While pharmacological inhibition of P-gp and/or BCRP results in increased brain distribution of dual P-gp/BCRP substrate drugs, such as the tyr...

Background Community-acquired pneumonia (CAP) is associated with high morbidity and mortality. In the present study, we aimed to assess the effect of corticosteroids on all-cause mortality in patients hospitalized with CAP. Methods For this meta-analysis and meta-regression, we conducted a systematic search of trials that evaluated the effect of c...

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 a...

The efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier limits the cerebral uptake of various xenobiotics. To assess the sensitivity of [ ¹¹ C]metoclopramide to measure decreased cerebral P-gp function, we performed [ ¹¹ C]metoclopramide PET scans without (baseline) and with partial P-gp inhibition by tariquidar in wild-type, hetero...

Background and objectives: Model-informed precision dosing (MIPD) frequently uses nonlinear mixed-effects (NLME) models to predict and optimize therapy outcomes based on patient characteristics and therapeutic drug monitoring data. MIPD is indicated for compounds with narrow therapeutic range and complex pharmacokinetics (PK), such as voriconazole...

Introduction: Nimodipine is routinely administered to aneurysmal subarachnoid hemorrhage patients to improve functional outcomes. Nimodipine can induce marked systemic hypotension, which might impair cerebral perfusion and brain metabolism. Methods: Twenty-seven aneurysmal subarachnoid hemorrhage patients having multimodality neuromonitoring and...

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...

Background Bacterial co-infections are believed to be less frequent in patients with Covid-19 than influenza, but frequencies varied between studies. Methods This single-center retrospective, propensity score-matched analysis included adult patients with Covid-19 or influenza admitted to normal-care wards between 02/2014 and 12/2021. Covid-19 case...

Objectives: Peritonitis is a serious complication in patients undergoing automated peritoneal dialysis (APD) that increases morbidity and frequently disqualifies patients from the peritoneal dialysis program. Ceftazidime/Avibactam (CAZ/AVI) is a potential treatment option for APD patients with peritonitis caused by resistant Gram-negative bacteria...

Objective To describe whether contemporary dosing of antifungal drugs achieves therapeutic exposures in critically ill patients that are associated with optimal outcomes. Adequate antifungal therapy is a key determinant of survival of critically ill patients with fungal infections. Critical illness can alter an antifungal agents’ pharmacokinetics,...

Objectives: A weak correlation between symptom severity and antibody levels after primary immunization against COVID-19 has already been shown. This study aimed to describe the association between reactogenicity and immunogenicity after booster vaccination. Methods: This secondary analysis of a prospective cohort study included 484 healthcare wo...

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 f...

Unlabelled: 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 scor...

Background: It is unclear whether thrombectomy alone is non-inferior to thrombectomy with intravenous thrombolysis in patients with acute ischemic stroke due to large-vessel occlusion. Purpose: To perform a comprehensive, trial-level data, non-inferiority meta-analysis of randomised controlled trials comparing endovascular thrombectomy with and...

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 wi...

Rabbits are frequently used for the examination of the pharmacokinetics and effectiveness of antibiotic substances. However, antibiotics vary substantially in protein binding affecting the concentration of the antimicrobially effective unbound drug. We hypothesized that the binding properties of vancomycin, meropenem and ceftriaxone might vary betw...

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 grou...

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 Ge...

Background: Therapeutic drug management (TDM) and model-informed precision dosing (MIPD) allow dose individualisation to increase drug effectivity and reduce toxicity. Objectives: Evaluate the available evidence on the clinical efficacy of individualised antimicrobial dosing optimisation. Methods: Data sources: Pubmed, Embase, Web of Science,...

Transporter-mediated drug-drug interactions (DDIs) are of concern in antimicrobial drug development, as they can have serious safety consequences. We used positron emission tomography (PET) imaging-based pharmacokinetic (PK) analysis to assess the effect of different drugs, which may cause transporter-mediated DDIs, on the tissue distribution and e...

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 inc...

Pharmacokinetics (PK) is the discipline investigating the absorption, distribution, metabolization and elimination of a drug in the body. This term was first introduced in 1953 by Prof Hartmut Dost, a pediatrician and active member of the German Pharmacological Society, who was concerned with the possibility of adapting dose regimens in children ba...

In the lungs, the membrane transporter P-glycoprotein (P-gp) is expressed in the apical (i.e. lumen-facing) membrane of airway epithelial cells and in the luminal (blood-facing) membrane of pulmonary capillary endothelial cells. To better understand the influence of P-gp on the pulmonary disposition of inhaled P-gp substrate drugs, we measured the...

Multidrug resistance-associated protein 1 (MRP1/ABCC1) is a highly abundant efflux transporter in the lungs, which protects cells from toxins and oxidative stress and has been implicated in the pathophysiology of chronic obstructive pulmonary disease and cystic fibrosis. There is evidence from in vitro studies that the inhaled glucocorticoid budeso...

Rationale: The present study set out to investigate if PET imaging can be used as a potential substitute for immunohistochemical analysis of tumor samples in prostate cancer (PC) patients. Correlation between imaging signals of two PET tracers and the corresponding target structures was assessed. The first tracer was [68Ga]Ga-PSMAHBED-CC([68Ga]PSMA...

Background and objective: Exhaustive pharmacokinetic (PK) studies in paediatric patients are unavailable for most antibiotics and feasibility of PK studies is limited by challenges, such as low blood volume and venipuncture-related pain. Microdialysis (MD) represents a promising method to overcome these obstacles. The aim of this proof-of-concept...

OBJECTIVE To investigate immunogenicity and safety of BNT162b2 booster vaccination with and without a tetravalent influenza vaccine. METHODS A prospective, open-label cohort study on immunogenicity and safety of COVID-19 booster vaccination with or without a tetravalent influenza vaccine was performed. 838 health care workers were included in the...

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) metho...

Background Understanding vaccine-dependent effects on protective and sustained humoral immune response are crucial to plan further vaccination strategies against COVID-19. Population-based data comparing different vaccination strategies are lacking. Methods This multicenter, population-based cohort study included 4,601 individuals ≥18 years of age...

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 f...

Purpose Voriconazole is an essential antifungal drug whose complex pharmacokinetics with high interindividual variability impedes effective and safe therapy. By application of the minimally-invasive sampling technique microdialysis, interstitial space fluid (ISF) concentrations of VRC and its potentially toxic N-oxide metabolite (NO) were assessed...

Introduction: : Drugs for the treatment of respiratory diseases are commonly administered by oral inhalation. Yet surprisingly little is known about the pulmonary pharmacokinetics of inhaled molecules. Nuclear medicine imaging techniques (i.e. planar gamma scintigraphy, single-photon emission computed tomography [SPECT] and positron emission tomog...

Purpose Voriconazole is a therapeutically challenging antifungal drug associated with high interindividual pharmacokinetic variability. As a prerequisite to performing clinical trials using the minimally-invasive sampling technique microdialysis, a comprehensive in vitro microdialysis characterization of voriconazole (VRC) and its potentially toxic...

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 [ ¹⁴ C]diclofenac was used as a model drug to assess...

Impaired response to COVID-19 vaccination is of particular concern in immunosuppressed patients. To determine the best vaccination strategy for this vulnerable group we performed a single center, 1:1 randomized blinded clinical trial. Patients who failed to seroconvert upon two mRNA vaccinations (BNT162b2 or mRNA-1273) are randomized to receive eit...

Objectives The efficacy and quality of generic antibacterial drug formulations are often questioned by both healthcare specialists and patients. Therefore, the present study investigated the interchangeability of generic drugs with their originators by comparing bioequivalence parameters and stability data of generic cefepime, linezolid and piperac...

Background Temocillin plasma protein binding (PPB) in healthy individuals is reported to be ∼85% but had not been studied in patients. Objectives To obtain normative data on temocillin PPB in patients in relation to infection and impact of co-medications widely used in ICU. Methods Plasma was obtained from healthy individuals (Group #1), non-ICU...

Ceftaroline, approved to treat skin infections and pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA), has been considered for the treatment of central nervous system (CNS) infections. A population pharmacokinetic (popPK) model was developed to describe ceftaroline soft tissue and cerebrospinal fluid (CSF) distributions and investi...

Background and objective: Tigecycline, a broad-spectrum glycylcycline antibiotic, is approved for use at a fixed dose irrespective of body weight. However, its pharmacokinetics may be altered in obesity, which would impact on the antibiotic's effectiveness. The objective of this study was to investigate the plasma and subcutaneous tissue concentra...

Spider silk has fascinated mankind for millennia, but it is only in recent decades that scientific research has begun to unravel all its characteristics and applications. The uniqueness of spider silk resides in its versatility, in which a combination of high strength and extensibility results in extraordinary toughness, superior to almost all natu...

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...

Meropenem is a broad spectrum carbapenem used for the treatment of cerebral infections. There is a need for data describing meropenem pharmacokinetics (PK) in the brain tissue to optimize therapy in these infections. Here, we present a meropenem PK model in the central nervous system and simulate dosing regimens. This was a population PK analysis o...

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 th...

Background: To date, no oral antiviral drug has proven to be beneficial in hospitalized patients with COVID-19. Methods: In this randomized, controlled, open-label, platform trial, we randomly assigned patients ≥18 years hospitalized with COVID-19 pneumonia to receive either camostat mesylate (CM) (considered standard-of-care) or lopinavir/ritonavi...

Background Tedizolid is a novel oxazolidinone antibiotic. Considering the higher antibacterial effect in immunocompetent compared with immunosuppressed animals, it is not recommended in immunocompromised patients. Objectives In this study, we assessed the ‘pure’ pharmacokinetic-pharmacodynamic (PKPD) relationship for tedizolid against Enterococcus...

Antibiotic resistance presents an incessant threat to our drug armamentarium that necessitates novel approaches to therapy. Over the past several decades, investigation of pharmacokinetic and pharmacodynamic (PKPD) principles has substantially improved our understanding of the relationships between the antibiotic, pathogen, and infected patient. Ho...

The objectives of this study were the identification in (morbidly) obese and nonobese patients of (i) the most appropriate body size descriptor for fosfomycin dose adjustments and (ii) adequacy of the currently employed dosing regimens. Plasma and target site (interstitial fluid of subcutaneous adipose tissue) concentrations after fosfomycin admini...

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...

Objective: For meropenem 40%T > MIC is associated with optimal killing of P. aeruginosa and E. coli . However, it is unknown how the distribution of %T > MIC through a treatment day impacts the antimicrobial effect in vitro . Therefore, we investigated the in vitro antibiotic activity of meropenem, precisely if 40%T > MIC is achieved in one single...

The pathophysiology of sepsis alters drug pharmacokinetics, resulting in inadequate drug exposure and target-site concentration. Suboptimal exposure leads to treatment failure and the development of antimicrobial resistance. Therefore, we seek to optimize antimicrobial therapy in sepsis by selecting the right drug and the correct dosage. A prerequi...

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...

Background: Preclinical data suggested anti-inflammatory properties of tedizolid. Objectives: To investigate the influence of tedizolid on the cytokine response to the human endotoxin challenge and the effect of endotoxaemia on the pharmacokinetics and protein binding of tedizolid. Methods: In this cross-over trial, 14 male healthy volunteers...

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 t...

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.

There is evidence that Staphylococcus aureus colonisation is linked to severity of atopic dermatitis. As no gold standard for S. aureus sampling on atopic dermatitis skin lesions exists, this study compared three commonly used methods. In addition, effectiveness of standard skin disinfection to remove S. aureus colonisation from these inflamed skin...

Several studies investigated diclofenac tissue concentrations using microdialysis (MD). However, thorough evaluations of the optimal MD setup for diclofenac are unavailable. Thus, this in vitro MD study aimed to compare different setups to improve quantitative recovery of diclofenac. In forward and reverse in vitro MD experiments with diclofenac at...

Objectives SARS‐CoV‐2-induced COVID-19 has led to exponentially rising mortality, particularly in immunosuppressed patients, who inadequately respond to conventional COVID-19 vaccination. Methods In this blinded randomised clinical trial, we compare the efficacy and safety of an additional booster vaccination with a vector versus mRNA vaccine in n...

Background and Objective In microdose studies, drug pharmacokinetics is measured in humans after administration of subtherapeutic doses. While previous microdose studies focused primarily on plasma pharmacokinetics, we set out to evaluate the feasibility of microdosing for a pharmacokinetic assessment in subcutaneous tissue and epithelial lining fl...

Introduction Pathogen-focused, randomized, controlled trials (PF-RCT) are important in the fight against carbapenem-resistant (CR) Gram-negative infections. Some recently approved antibiotics and older generic antibiotics with activity against CR Gram-negative bacteria were investigated in PF-RCTs in a variety of infections. Areas covered We searc...

Background and ObjectivesA quantitative evaluation of the PK of meropenem, a broad-spectrum β-lactam antibiotic, in plasma and interstitial space fluid (ISF) of subcutaneous adipose tissue of obese patients is lacking as of date. The objective of this study was the characterisation of meropenem population pharmacokinetics in plasma and ISF in obese...