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Efficacy evaluation of iclaprim in a neutropenic rat lung infection model with methicillin-resistant Staphylococcus aureus entrapped in alginate microspheres

  • David B. Huang
  • Ian Morrissey
  • Timothy Murphy
  • Stephen Hawser
  • Mark H. Wilcox
Original Article

Abstract

The objective of this study was to demonstrate the efficacy of iclaprim in a neutropenic rat lung infection model with methicillin-resistant Staphylococcus aureus (MRSA) entrapped in alginate beads. An inoculum of 5.25 × 105 colony-forming units (CFU)/mL of S. aureus strain AH1252 was administered intratracheally to rats with prepared alginate bacteria suspensions. Beginning 2 h post-infection, rats received: (1) iclaprim 80 mg/kg (n = 16); (2) iclaprim 60 mg/kg (n = 16), or (3) vancomycin 50 mg/kg (n = 24), for 3 days via subcutaneous (SC) injection every 12 h. Twelve hours after the last treatment, rats were euthanized and lungs collected for CFU determination. Iclaprim administered at 80 mg/kg or 60 mg/kg or vancomycin 50 mg/kg SC twice a day for 3 days resulted in a 6.05 log10 CFU reduction (iclaprim 80 mg/kg compared with control, p < 0.0001), 5.11 log10 CFU reduction (iclaprim 60 mg/kg compared with control, p < 0.0001), and 3.42 log10 CFU reduction, respectively, from the controls (p < 0.0001). Iclaprim 80 mg/kg and 60 mg/kg resulted in 2.59 and 1.69 log10 CFU reductions, respectively, from vancomycin-treated animals (80 mg/kg iclaprim vs. vancomycin, p = 0.0005; 60 mg/kg iclaprim vs. vancomycin, p = 0.07). Animals receiving iclaprim, vancomycin, and controls demonstrated 100%, 91.7%, and 48.3% survival, respectively. In this neutropenic rat S. aureus lung infection model, rats receiving iclaprim demonstrated a greater CFU reduction than the controls or those receiving vancomycin.

Notes

Funding

This study was funded by Motif BioSciences Inc., New York, NY, USA.

Compliance with ethical standards

Conflict of interest

DBH is an employee of Motif BioSciences. IM and SH are employees of IHMA. TM is an employee of NeoSome Life Sciences. MHW has received consulting fees from Abbott Laboratories, Actelion, Astellas, AstraZeneca, Bayer, biomérieux, Cerexa, Cubist, Durata, The European Tissue Symposium, The Medicines Company, MedImmune, Merck, Motif BioSciences, Nabriva, Optimer, Paratek, Pfizer, Qiagen, Roche, Sanofi-Pasteur, Seres, Summit, and Synthetic Biologics; lecture fees from Abbott, Alere, Astellas, AstraZeneca, Merck, Pfizer, and Roche; and grant support from Abbott, Actelion, Astellas, bioMérieux, Cubist, Da Volterra, Micro-Pharm, Morphochem AG, Sanofi-Pasteur, Seres, Summit, The European Tissue Symposium, and Merck.

Ethical approval

This research involved animals. All procedures in this research were in compliance with the Animal Welfare Act, the Guide for the Care and Use of Laboratory Animals, and the Office of Laboratory Animal Welfare.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • David B. Huang
    • 1
  • Ian Morrissey
    • 2
  • Timothy Murphy
    • 3
  • Stephen Hawser
    • 2
  • Mark H. Wilcox
    • 4
  1. 1.Motif BioSciencesNew YorkUSA
  2. 2.IHMA Europe SàrlMontheySwitzerland
  3. 3.NeoSome Life Sciences, LLCLexingtonUSA
  4. 4.Leeds Teaching Hospitals & University of LeedsLeedsUK

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