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


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.



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.


  1. 1.
    Kollef MH, Shorr A, Tabak YP, Gupta V, Liu LZ, Johannes RS (2005) Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culture-positive pneumonia. Chest 128:3854–3862CrossRefPubMedGoogle Scholar
  2. 2.
    Rubinstein E, Kollef MH, Nathwani D (2008) Pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis 46:S378–S385CrossRefPubMedGoogle Scholar
  3. 3.
    Lewis SS, Walker VJ, Lee MS, Chen L, Moehring RW, Cox CE, Sexton DJ, Anderson DJ (2014) Epidemiology of methicillin-resistant Staphylococcus aureus pneumonia in community hospitals. Infect Control Hosp Epidemiol 35:1452–1457CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Menéndez R, Montull B, Reyes S, Amara-Elori I, Zalacain R, Capelastegui A, Aspa J, Borderías L, Martín-Villasclaras JJ, Bello S, Alfageme I, Rodríguez de Castro F, Rello J, Molinos L, Ruiz-Manzano J, Torres A (2016) Pneumonia presenting with organ dysfunctions: causative microorganisms, host factors and outcome. J Infect 73:419–426CrossRefPubMedGoogle Scholar
  5. 5.
    Shorr AF, Haque N, Taneja C, Zervos M, Lamerato L, Kothari S, Zilber S, Donabedian S, Perri MB, Spalding J, Oster G (2010) Clinical and economic outcomes for patients with health care-associated Staphylococcus aureus pneumonia. J Clin Microbiol 48:3258–3262CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Sader HS, Fritsche TR, Jones RN (2009) Potency and bactericidal activity of iclaprim against recent clinical gram-positive isolates. Antimicrob Agents Chemother 53:2171–2175CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Schneider P, Hawser S, Islam K (2003) Iclaprim, a novel diaminopyrimidine with potent activity on trimethoprim sensitive and resistant bacteria. Bioorg Med Chem Lett 13:4217–4221CrossRefPubMedGoogle Scholar
  8. 8.
    Huang DB, Hawser S, Gemmell CG, Sahm DF (2017) In vitro activity of iclaprim against methicillin-resistant Staphylococcus aureus nonsusceptible to daptomycin, linezolid or vancomycin. Can J Infect Dis Med Microbiol (in press)Google Scholar
  9. 9.
    Laue H, Valensise T, Seguin A, Lociuro S, Islam K, Hawser S (2009) In vitro bactericidal activity of iclaprim in human plasma. Antimicrob Agents Chemother 53:4542–4544CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Pedersen SS, Shand GH, Hansen BL, Hansen GN (1990) Induction of experimental chronic Pseudomonas aeruginosa lung infection with P. aeruginosa entrapped in alginate microspheres. APMIS 98:203–211CrossRefPubMedGoogle Scholar
  11. 11.
    Entenza JM, Haldimann A, Giddey M, Lociuro S, Hawser S, Moreillon P (2009) Efficacy of iclaprim against wild-type and thymidine kinase-deficient methicillin-resistant Staphylococcus aureus isolates in an in vitro fibrin clot model. Antimicrob Agents Chemother 53:3635–3641CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Clinical and Laboratory Standards Institute (CLSI) (2015) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved standard—Tenth edition. CLSI document M07-A10. CLSI, Wayne, PA 19087-1898, USAGoogle Scholar
  13. 13.
    Clinical and Laboratory Standards Institute (CLSI) (2017) Performance standards for antimicrobial susceptibility testing; Informational supplement—Twenty-seventh edition. CLSI document M100-S27. CLSI, Wayne, PA 19087-1898, USAGoogle Scholar
  14. 14.
    Roosendaal R, Bakker-Woudenberg IA, van den Berghe-van Raffe M, Michel MF (1986) Continuous versus intermittent administration of ceftazidime in experimental Klebsiella pneumoniae pneumonia in normal and Leukopenic rats. Antimicrob Agents Chemother 30:403–408CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zak O, Sande MA (eds) (1999) Handbook of animal models of infection. Academic Press, New York, p 727CrossRefGoogle Scholar
  16. 16.
    Murphy TM, Deitz JM, Petersen PJ, Mikels SM, Weiss WJ (2000) Therapeutic efficacy of GAR-936, a novel glycylcycline, in a rat model of experimental endocarditis. Antimicrob Agents Chemother 44:3022–3027CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    de Górgolas M, Avilés P, Verdejo C, Fernández Guerrero ML (1995) Treatment of experimental endocarditis due to methicillin-susceptible or methicillin-resistant Staphylococcus aureus with trimethoprim–sulfamethoxazole and antibiotics that inhibit cell wall synthesis. Antimicrob Agents Chemother 39:953–957CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Andrews J, Honeybourne D, Ashby J, Jevons G, Fraise A, Fry P, Warrington S, Hawser S, Wise R (2007) Concentrations in plasma, epithelial lining fluid, alveolar macrophages and bronchial mucosa after a single intravenous dose of 1.6 mg/kg of iclaprim (AR-100) in healthy men. J Antimicrob Chemother 60:677–680CrossRefPubMedGoogle Scholar
  19. 19.
    Jones C, Stevens DL, Ojo O (1987) Effect of minimal amounts of thymidine on activity of trimethoprim–sulfamethoxazole against Staphylococcus epidermidis. Antimicrob Agents Chemother 31:144–147CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Huang DB, File TM Jr, Torres A, Shorr AF, Wilcox MH, Hadvary P, Dryden M, Corey GR (2017) A phase II randomized, double-blind, multicenter study to evaluate efficacy and safety of intravenous iclaprim versus vancomycin for the treatment of nosocomial pneumonia suspected or confirmed to be due to Gram-positive pathogens. Clin Ther 39:1706–1718CrossRefPubMedGoogle Scholar

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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