title: Development of intramammary delivery systems containing lasalocid for the treatment of bovine mastitis: impact of solubility improvement on safety, efficacy, and milk distribution in dairy cattle.
abstract: BACKGROUND
  Mastitis is a major disease of dairy cattle. Given the recent emergence of methicillin-resistant Staphylococcus aureus as a cause of bovine mastitis, new intramammary (IMA) treatments are urgently required. Lasalocid, a member of the polyether ionophore class of antimicrobial agents, has not been previously administered to cows by the IMA route and has favorable characteristics for development as a mastitis treatment. This study aimed to develop an IMA drug delivery system (IMDS) of lasalocid for the treatment of bovine mastitis.
  
  
  METHODS
  Minimum inhibitory concentrations (MICs) were determined applying the procedures recommended by the Clinical and Laboratory Standards Institute. Solid dispersions (SDs) of lasalocid were prepared and characterized using differential scanning calorimetry and Fourier transform infrared spectroscopy. IMDSs containing lasalocid of micronized, nano-sized, or as SD form were tested for their IMA safety in cows. Therapeutic efficacy of lasalocid IMDSs was tested in a bovine model involving experimental IMA challenge with the mastitis pathogen Streptococcus uberis.
  
  
  RESULTS
  Lasalocid demonstrated antimicrobial activity against the major Gram-positive mastitis pathogens including S. aureus (MIC range 0.5-8 μg/mL). The solubility test confirmed limited, ion-strength-dependent water solubility of lasalocid. A kinetic solubility study showed that SDs effectively enhanced water solubility of lasalocid (21-35-fold). Polyvinylpyrrolidone (PVP)-lasalocid SD caused minimum mammary irritation in treated cows and exhibited faster distribution in milk than either nano or microsized lasalocid. IMDSs with PVP-lasalocid SD provided effective treatment with a higher mastitis clinical and microbiological cure rate (66.7%) compared to cloxacillin (62.5%).
  
  
  CONCLUSIONS
  Lasalocid SD IMDS provided high cure rates and effectiveness in treating bovine mastitis with acceptable safety in treated cows.
authors: School of Pharmacy and Medical Science, University of South Australia Adelaide, SA, Australia.
authors: Wen
authors: W
authors: Wang
authors: School of Pharmacy and Medical Science, University of South Australia Adelaide, SA, Australia.
authors: Yunmei
authors: Y
authors: Song
authors: School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, SA, Australia.
authors: Kiro
authors: K
authors: Petrovski
authors: School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, SA, Australia.
authors: Patricia
authors: P
authors: Eats
authors: School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, SA, Australia.
authors: Darren J
authors: DJ
authors: Trott
authors: School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, SA, Australia.
authors: Hui San
authors: HS
authors: Wong
authors: Luoda Pharma Pty Ltd, Caringbah, NSW, Australia.
authors: Stephen W
authors: SW
authors: Page
authors: School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, SA, Australia.
authors: Jeanette
authors: J
authors: Perry
authors: School of Pharmacy and Medical Science, University of South Australia Adelaide, SA, Australia.
authors: Sanjay
authors: S
authors: Garg
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D002152:Calorimetry, Differential Scanning; D002417:Cattle; D002626:Chemistry, Pharmaceutical; D003612:Dairying; D004333:Drug Administration Routes; D005260:Female; D007700:Kinetics; D007832:Lasalocid / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000382:microbiology / Q000503:physiopathology; D008414:Mastitis, Bovine / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology / Q000503:physiopathology; D008826:Microbial Sensitivity Tests; D008892:Milk / Q000378:metabolism; D053758:Nanoparticles; D011205:Povidone / Q000737:chemistry; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013290:Streptococcal Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology / Q000503:physiopathology
chemical_list: D000900:Anti-Bacterial Agents; D011205:Povidone; D007832:Lasalocid
keywords: intramammary drug delivery system; ionophore; methicillin-resistant Staphylococcus aureus; solid dispersion; superbugs
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