Poster Presentation Australian Society for Microbiology Annual Scientific Meeting 2016

Repurposing Polyether Ionophores for Veterinary Applications (#219)

Elizabeth Hickey 1 , Manouchehr Khazandi 1 , Hui San Wong 1 , Abiodun D Ogunniyi 1 , Wen Wang 2 , Yunmei Song 2 , Patricia Eats 3 , Jeanette Perry 3 , Sam Abraham 4 , Geoff Coombs 4 , Kiro R Petrovski 3 , Sanjay Garg 2 , Stephen W Page 5 , Ryan O'Handley 3 , Darren J Trott 1
  1. Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide, Adelaide, SA, Australia
  2. School of Pharmacy and Medical Science, The University of South Australia, Adelaide, SA, Australia
  3. University of Adelaide, Roseworthy, SA, Australia
  4. School of Veterinary and Life Sciences, Murdoch University, Murdoch, WA, Australia
  5. Luoda Pharma Pty Ltd, Caringbah, NSW, Australia

Objectives: The potential of four polyether ionophores (lasalocid, monensin, narasin, salinomycin) as agents against antimicrobial resistant Gram-positive veterinary pathogens was investigated. This included an assessment of their in vitro efficacy and pharmacodynamic profiles and potential cytotoxic effects against a variety of mammalian cell lines.

Methods: Antimicrobial susceptibility testing against 301 isolates of Gram-positive veterinary pathogens was performed using the broth microdilution method according to CLSI guidelines. Spot-plating of microdilution plates and time-kill kinetics assays were performed to assess pharmacodynamic profiles. Erythrocyte haemolysis and WST-1 cell proliferation assays were used to assess cell cytotoxicity for mammalian cells. Formulations of lasalocid were prepared to assess in vivo efficacy using a murine model of staphylococcal skin and soft tissue infection and a Streptococcus uberis challenge model of bovine mastitis.

Results: Salinomycin, lasalocid and narasin exhibited bacteriostatic activity against all pathogens tested at ≤8 mg/L, including methicillin-resistant staphylococci. Monensin also exhibited bacteriostatic activity, but MIC values were elevated against phenotypically methicillin-resistant coagulase negative staphylococci. Time-kill kinetics assays also indicated that activity in vitro was retained over 24 hours. Narasin and monensin displayed the least mammalian cell toxicity. In vivo trials of bovine mastitis, demonstrated a 66.7% microbiological cure rate for cows treated with an intramammary preparation of lasalocid over a 3 day period, compared with the positive control with a microbial cure rate of 62.5%. Topical application of a pilot formulation of lasalocid in a staphylococcal skin and soft tissue infection model resulted in a 3log10 reduction in bacterial viable counts (CFU/g) over 7 days.

Conclusions: Polyether ionophores offer potentially novel treatments for veterinary applications. They have demonstrated safety against a variety of mammalian cells and efficacy in vivo against Gram-positive pathogens as well as efficacy in vitro against antimicrobial resistant isolates.