Improved therapy

It is generally recognized that any use of antimicrobials selects for antimicrobial resistance but the relative contribution of different drugs, dosages and durations of treatment to antimicrobial resistance is poorly understood. We pursue the objective of improving therapy by understanding and reducing the contribution of each of these variables to development of antimicrobial resistance. This research line includes development of new tools for discovery of innovative antimicrobials, combination therapies based on reversal of antimicrobial resistance, pathogen-targeted therapies with minimal impact on the commensal microbiota, and alternatives to conventional antimicrobials.

These are the current projects in this area:

Alternatives to Veterinary ANTimicrobials (AVANT)

Objective: to develop and test the efficacy and sustainability of alternatives to antimicrobials for the management of post-weaning diarrhoea in pigs. The alternatives under study include gut microbiome modulators based on synbiotic products or faecal microbiota transplantation, innovative medicines targeting the pathogen or stimulating the pig immune response, as well as feeding strategies for prevention of the disease. Based on the results of pre-clinical studies, including regulatory and implementation considerations, the efficacy of the three most promising interventions will be assessed by farm trials. Mathematical modelling will be used to quantify the benefits on reduction of antimicrobial use at the farm and EU level if these interventions were implemented in pig farming.
PI: Luca Guardabassi (coordinator)
Scientist is charge: Carmen Espinosa Gongora
Key collaborators: The AVANT consortium involves 14 international partners, including 5 Universities, 4 industries, 4 SMEs and the Federation of Veterinarians in Europe (FVE), as well as 4 research groups at the Department of Veterinary and Animal Sciences.
Funding: EU Commission Duration: 2020 – 2024
Budget: 6 mio EUR

European Network for Optimization of Veterinary Antimicrobial Treatment (ENOVAT)

Objective: to optimize veterinary antimicrobial use with special emphasis on the development of animal- and disease-specific antimicrobial treatment guidelines and refinement of microbiological diagnostic procedures. This will be fulfilled through the contribution of five working groups, namely WG1 (Mapping microbiological diagnostics and treatment guidelines), WG2 (European strain database), WG3 (clinical breakpoints), WG4 (antimicrobial treatment guidelines) and WG5 (Dissemination).
PI and Scientist in charge:: Peter Damborg
Key collaborators: ENOVAT has more than 180 participants (microbiologists, pharmacologists, and epidemiologists, political stakeholders, etc) from almost 40 countries in- and outside Europe
Funding: COST Association via the EU Commission
Duration: 2019 – 2023
Budget: 500,000 €

Re-sensitizing multidrug-resistant Escherichia coli to fosfomycin and macrolides

Objective: To identify a set of non-resistance genes/proteins that are essential for expression of macrolide and fosfomycin resistance in E. coli, and ultimately use them as drug targets to re-sensitize pathogenic E. coli to these antimicrobials.
PI: Luca Guardabassi
Scientist in charge: Lawrence Cohen (Yibing Ma)
Key collaborators: Henrik Franzyk, Bimal Jana, Stefano Donadio and Mark Poolman
Funding: 2020 MSCA-ITN-ETN - European Training Network (ETN) INNOTARGETS
Duration: 2021-2024
Budget: €180,000

Identification of novel antibiotics by hypomorphic expression of essential genes

Objective: to enhance discovery of truly novel antimicrobial classes that interfere with untapped bacterial proteins using a screening strategy based on CRISPRi (clustered regularly interspaced short palindromic repeats interference).
PI: Luca Guardabassi
Scientist in charge: Frida Svanberg Frisinger
Key collaborators: John Elmerdahl Olsen, Bimal Jana and Stefano Donadio
Funding: 2020 MSCA-ITN-ETN - European Training Network (ETN)  CARTNET
Duration: 2018-2022
Budget:  €180,000.

Optimizing antimicrobial treatment length for cystitis and pyoderma in dogs

Objective: to compare the clinical efficacy of two amoxicillin treatment regimens in dogs with cystitis, and two cephalexin treatment length in dogs with superficial pyoderma
PI: Peter Damborg
Scientists in charge: Peter Damborg
Key collaborators: Lisbeth Rem Jessen, Tina Møller Sørensen, Mette Schjærff, Jo Fjeldsted-Holm Lundsgaard & Lene Boysen
Funding: Agria och SKKs Forskningsfond and the Danish Veterinary Dermatology Network (DVEN)
Duration: 2017-2022
Budget: 600,000 DKK

Assessment of cephalexin and amoxicillin clavulanate efficacy for canine MRSP

Objective: to provide a safe and effective systemic option for MRSP infections that require systemic therapy by i) evaluating the clinical efficacy of cefalexin and amoxicillin clavulanate and ii) identifying MRSP isolates that display in vitro susceptibility to these β-lactam antibiotics.
PI: Luca Guardabassi
Scientist is charge: Mattia Pirolo
Key collaborators: Mette Schjærff, Lisbeth Rem Jessen, Peter Damborg, Anette Loeffler (Royal Veterinary College, UK), Els Broens (Utrecht University, NL)
Funding: Agria och SKKs Forskningsfond
Duration: 2020-2022
Budget: 550,000 DKK

Potential novel antimicrobials

Objective: to investigate the potential of a collection of novel, synthetic compounds as antimicrobials. The investigations include both in vitro and in vivo experiments. Read more  https://innovationsfonden.dk/da/investeringer/investeringshistorier (in Danish)
PI: Rikke Heidemann Olsen
Scientist is charge: Rikke H. Olsen
Key collaborators: Jørn B. Christensen
Funding: Innovation Fund Denmark and Novo Nordisk foundation
Duration: 2019-2022
Budget: 2,500,000 DK

Key references (last 5 years):

  1. Svanberg Frisinger F, Jana B, Donadio S, Guardabassi L. 2021. In silico prediction and prioritization of novel selective antimicrobial drug targets in Escherichia coli. Antibiotics. 10(6):632.
  1. Ronaghinia AA, Nikolaisen NK, Hansen SG, Poulsen HH, Frandsen HL, Struve T, Toutain PL, Damborg P. 2021. Validating an empiric sulfadiazine-trimethoprim dosage regimen for treatment of Escherichia coli and Staphylococcus delphini infections in mink (Neovison vison). J Vet Pharmacol Ther. 2021 Jan;44(1):93-106. doi: 10.1111/jvp.12894. Epub 2020 Sep 13.
  2. Ronaghinia AA, Birch JM, Frandsen HL, Toutain PL, Damborg P, Struve T. 2021. Evaluating a tylosin dosage regimen for treatment of Staphylococcus delphini infection in mink (Neovison vison): a pharmacokinetic-pharmacodynamic approach. Vet Res. 52(1):34.
  3. Wegener A, Damborg P, Guardabassi L, Moodley A, Mughini-Gras L, Duim B, Wagenaar JA, Broens EM. 2020. Specific staphylococcal cassette chromosome mec (SCCmec) types and clonal complexes are associated with low-level amoxicillin/clavulanic acid and cefalotin resistance in methicillin-resistant Staphylococcus pseudintermedius. J Antimicrob Chemother 75(3):508-511.
  1. Espinosa-Gongora C, Rem Jessen L, Nordang Kieler I, Damborg P, Reinhard Bjørnvad C, Dadi Gudeta D, Pires Dos Santos T, Sablier-Gallis F, Sayah-Jeanne S, Corbel T, Nevière A, Hugon P, Saint-Lu N, de Gunzburg J, Guardabassi L. 2020. Impact of oral amoxicillin and amoxicillin/clavulanic acid treatment on bacterial diversity and β-lactam resistance in the canine faecal microbiota. J Antimicrob Chemother75:351-361.
  2. Baker KR, Jana B, Hansen AM, Nielsen HM, Franzyk H, Guardabassi L. 2019. Repurposing azithromycin and rifampicin against Gram-negative pathogens by combination with peptidomimetics. Front Cell Infect Microbiol
  3. Baker KR, Jana B, Hansen AM, Vissing KJ, Nielsen HM, Franzyk H, Guardabassi L. 2019. Repurposing azithromycin and rifampicin against Gram-negative pathogens by combination with peptide potentiators.Int J Antimicrob Agents [Epub ahead of print].
  4. Greco I, Plahn Emborg A, Jana B, Molchanova N, Oddo A, Damborg P, Guardabassi L, Hansen PR. 2019. Characterization, mechanism of action and optimization of activity of a novel peptide-peptoid hybrid against bacterial pathogens involved in canine skin infections. Sci Rep9: 3679.
  5. Magnowska Z, Jana B, Brochmann RP, Hesketh A, Lametsch R, De Gobba C, Guardabassi L. 2019. Carprofen-induced depletion of proton motive force reverses TetK-mediated doxycycline resistance in methicillin-resistant Staphylococcus pseudintermedius. Sci Rep9:17834.
  6. Sadaka C, Damborg P, Watts JL. 2018. High-throughput screen identifying the Thiosemicarbazone NSC319726 Compound as a potent antimicrobial lead against resistant strains of Escherichia coli. Biomolecules 8:4.
  7. Adler DMT, Damborg P, Verwilghen DR. 2017. The antimicrobial activity of bupivacaine, lidocaine and mepivacaine against equine pathogens: An investigation of 40 bacterial isolates. Vet J 223: 27-31.