Work Package 3: Optimisation of antibiotic therapy – University of Copenhagen

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WP3 Optimisation of antibiotic therapy

Main partners:

  • Niels Høiby, SUND, Department of International Health, Immunology and Microbiology (ISIM) (WP leader)
  • Oana Ciofu, SUND, Department of International Health, Immunology and Microbiology (ISIM)
  • Michael Givskov, SUND, Department of International Health, Immunology and Microbiology (ISIM)
  • Thomas Bjarnsholt, SUND, Department of International Health, Immunology and Microbiology (ISIM)
  • Luca Guardabassi, SUND, Department of Veterinary Disease Biology (IVS)
  • Christian Friis, SUND, Department of Veterinary Disease Biology (IVS)
  • Hanne Mørck Nielsen, SUND, Department of Pharmacy (IF)

External collaborators:

  • Peter Østrup Jensen (Rigshospitalet)
  • Niels Frimodt-Møller (Hvidovre Hospital)

Main objectives:

  1. To improve the dosage and formulation of treatment of chronic biofilm infections
  2. To improve antibiotic delivery to the infection site
  3. To identify positive and negative interactions with non-antibiotic drugs.

Task 3.1 .To improve the dosage and formulation of treatment of chronic biofilm infections

Task 3.1.1 Antibiotic pharmacokinetic/pharmakodynamic (PK/PD) in Pseudomonas aeruginosa biofilms
Scientists in charge: postdoc Wang Hengzhuang (ISIM) ( 1/12-2013-1/12-2015)

Biofilm infections are resistant to conventional antibiotics and to the body’s defence mechanisms. In this task ISIM will study in vitro and in vivo the pharmacodynamic/pharmacokinetic (PK/PD) properties of various antibiotics and their combinations on planktonic and biofilm P. aeruginosa. The synergistic effects of antibiotic combination with antioxidants (e.g. n-acetylcystein), quorum sensing inhibitors (e.g. Ajoene from garlic, Ginseng), agents which can dissolve the biofilm matrix (e.g. DNase and OligoG), and conventional drugs without antibacterial effect on P. aeruginosa (e.g. macrolides, neuroleptica, salicylic acid) will be assessed using this approach.

Task 3.1.2 Mechanism of action of antibiotics on P. aeruginosa biofilms in aerobic and anaerobic conditions
Scientist in charge: postdoc Mette Kolpen (ISIM) (1/1-2014-1/1_2016)

Research at ISIM has shown that killing of bacteria in biofilms depends ultimately on increased concentrations of reactive oxygen species (e.g. hydroxyl radicals) produced during the metabolism of bacteria induced by antibiotics. The effect of antibiotics on biofilms grown in anaerobic conditions is highly clinical relevant and has not been studied. Bacterial killing by various classes of antibiotics will be visualized and quantified through measurement of reactive radical species in biofilms in aerobic and anaerobic conditions and will be correlated with biofilm killing.

Task 3.2. New drug delivery systems
Scientist in charge: Hanne Mørck Nielsen (IF)

More efficient delivery of novel and known drugs will not only result in improved targeting, but also in less off target delivery, decreasing the risk of resistance development. Peptides conferring eukaryote membrane penetration and antimicrobial drugs formulated in stable (nano) particles surface modified for improved cellular uptake will be investigated to target intracellular or biofilm-growing pathogens. IF will design drug delivery systems (DDS) for improved delivery to and controlled release of drug at the infection. Formulation approaches to increase mucus binding and diffusivity will be taken. Specific design and advanced processing technologies will be used for targeted and efficient deposition of DDS to specific sites in the airways and in biofilms. In vitro epithelial infection and in vivo animal respiratory infection models will be used to assess the effects of DDS for treatment of airway infections caused by S. aureus and P. aeruginosa in humans, and A. pleuropneumoniae in pigs.

Task 3.3. Interactions between antibiotic and non-antibiotic drugs
Scientist in charge: new PhD employed by Luca Guardabassi (IVS).

Recent studies have accidentally discovered that non-antibiotic drugs such antipsychotic (phenothiazine) and anticholesterol (statins) drugs enhance antibiotic effects and/or possess antibacterial activity. IVS will use a systematic approach to identify synergistic and antagonistic interactions of antibiotics with non-antibiotic drugs widely used in the community (e.g. anti-cholesterol drugs, NSAIDs, pain killers, decongestants, expectorants, cough suppressants, etc.) and additives included in antibiotic-medicated feed for animal use by microdilution checkboard and disc diffusion assays. The interactions of selected drug combinations will be elucidated at the molecular level using the transcriptomic/proteomic approach described in WP1.The PK of some of these candidates will be examined in animal models, and the outputs of this research will be translated to WP4 for improving current therapeutic protocols.