Antibiosis; Bacterial Infections; Clinical Trial, Phase I; Dose-Response Relationship, Drug; Drug Approval; Drug Interactions; Drug Monitoring; Microdialysis; Pharmacokinetics
Beside clinical trial design in general, my scientific interests cover antimicrobial agents with focus on pharmacokinetics, PK/PD and protein binding as well as cellular transporters and pharmacogenetics. By performing clinical studies in healthy volunteers and patients I aim at elucidating the impact of genetic variants and various pathophysiological states on pharmacokinetics and pharmacodynamics.
Another focus is drug-drug interactions as well as therapeutic drug monitoring (TDM).
Techniques, methods & infrastructure
Microdialysis is a minimal invasive tool for measuring pharmacokinetics continuously in the extracellular space of human and animal tissues. By inserting a small microdialysis catheter and sampling of analyses exogenous (drugs) and endogenous compounds (e.g. lactate, pyruvate, glucose, cytokines) can be determined in virtually all tissues including brain, muscle tissue, skin and adipose tissue. Microdialysis has thereby become an indispensable technique in commercial drug development and academic research.
In order to support clinical breakpoints and to optimize therapy with a specific antimicrobial agent the pharmacokinetic profile (which at our department can be determined by techniques like e.g. intensive pharmacokinetic blood sampling, isolation of leucocytes, microdialysis and bronchoalveolar lavage) and its pharmacodynamic activity have to be set into context. To achieve this goal we use standard techniques like the minimal inhibitory concentration (MIC) and time kill curves (TCC) but employ also dynamic TCK. A specific focus is the evaluation of the impact of protein binding on antimicrobial activity and the estimation of bacterial killing simulating physiologic conditions, e.g. by performing pharmacodynamic experiments in the presence of surfactant, bile or at different pH values.
For TDM purposes we use modern LCMS techniques.
- Zeitlinger M, Dehghanyar P, Mayer BX, Schenk BS, Neckel U, Heinz G, Georgopoulos A, Muller M, Joukhadar C. Relevance of soft-tissue penetration by levofloxacin for target site bacterial killing in patients with sepsis. Antimicrob Agents Chemother. 2003 Nov;47(11):3548-53.
- Zeitlinger MA, Derendorf H, Mouton JW, Cars O, Craig WA, Andes D, Theuretzbacher U. Protein binding - do we ever learn? Antimicrob Agents Chemother. 2011 Jul;55(7):3067-74.
- Wressnigg N, Pöllabauer EM, Aichinger G, Portsmouth D, Löw-Baselli A, Fritsch S, Livey I, Crowe BA, Schwendinger M, Brühl P, Pilz A, Dvorak T, Singer J, Firth C, Luft B, Schmitt B, Zeitlinger M, Müller M, Kollaritsch H, Paulke-Korinek M, Esen M, Kremsner PG, Ehrlich HJ, Barrett PN. Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomised, dose-escalation phase 1/2 trial. Lancet Infect Dis. 2013 Aug;13(8):680-9.
- Bauer M, Karch R, Zeitlinger M, Liu J, Koepp MJ, Asselin MC, Sisodiya SM, Hainfellner JA, Wadsak W, Mitterhauser M, Müller M, Pataraia E, Langer O. In vivo P-glycoprotein function before and after epilepsy surgery. Neurology. 2014 Oct 7;83(15):1326-31.
- Zeitlinger M, Schwameis R, Burian A, Burian B, Matzneller P, Müller M, Wicha WW, Strickmann DB, Prince W. Simultaneous assessment of the pharmacokinetics of a pleuromutilin, lefamulin, in plasma, soft tissues and pulmonary epithelial lining fluid. J Antimicrob Chemother. 2016 Jan 7. pii: dkv442.