ISBN 978-3-8439-2784-0

978-3-8439-2784-0, Reihe Pharmazeutische Technologie

Marika Kutscher
Novel Approaches to Antimicrobial Therapy of Pneumonia using Antibiotics and Therapeutic Antibodies

188 Seiten, Dissertation Bayerische Julius-Maximilians-Universität Würzburg (2016), Softcover, B5

Zusammenfassung / Abstract

Nosocomial pneumonia is mostly caused by methicillin-resistant Staphylococcus aureus (MRSA). However, the standard antibiotic therapy is affected by increasing emergence of bacterial resistance. Therefore, novel therapeutic options are in high demand. New antimicrobial agents alone cannot handle the problem of increasing bacterial resistance but innovative drug delivery strategies and fast identification of infection causing pathogens are required to diminish bacterial resistance development. A very promising approach to improve the therapy of pneumonia is presented by local drug delivery to the lung. This application method enables high local drug concentrations in the lung leading to shorter application of antibiotics and hence reduces the risk of resistance development. Furthermore, the systemic concentration is lowered reducing the emergence of adverse effects.

Therefore, in this thesis several approaches to improve the therapy of MRSA pneumonia are studied.

One approach to achieve an efficient local delivery of antibiotics are nano-sized drug delivery systems which enable the nebulization of poorly-soluble antibiotics and can lead to even higher local drug concentrations due to their small size since nanoparticles improve mucus penetration and decrease phagocytosis by alveolar macrophages. Here, an analytical setup was developed that facilitates the identification of optimal preparation conditions for drug polyelectrolyte nanoplexes.

Another promising approach to support antimicrobial therapy of pneumonia is presented by antibody-based immunotherapy. Since the stability of the antibody and hence its therapeutic activity are endangered during production, transport, storage, and application, a stabilizing formulation was developed for hUK-66, an antibody targeting surface antigens of S. aureus. Furthermore, nebulization of this formulated monoclonal antibody was studied to enable local application. Finally, the immunotherapeutic efficacy of the nebulized hUK-66 formulation was investigated in an animal in vivo study.

Furthermore, rapid identification of the infection triggering pathogen is very important. The selective detection of S. aureus was achieved using optical planar Bragg grating sensors functionalized with hUK-66. In addition, the reusability of this system was studied applying a surface functionalization based on the cross-linker SPDP which enables a reversible fixation of the antibody.