title: Prophylactic efficacy of single dose pulmonary administration of amphotericin B inhalation powder in a guinea pig model of invasive pulmonary aspergillosis.
abstract: OBJECTIVE
  Amphotericin B inhalation powder (ABIP) is a novel dry-powder amphotericin B formulation that is directly delivered to the lung, resulting in elevated lung tissue drug concentrations of this polyene. We evaluated the prophylactic efficacy of single dose administration of ABIP in a guinea pig model of invasive pulmonary aspergillosis.
  
  
  METHODS
  Guinea pigs were immunosuppressed with cyclophosphamide and cortisone acetate and challenged with Aspergillus fumigatus conidia in an aerosol chamber. Guinea pigs received prophylaxis with a single inhaled dose of ABIP at 0.05, 0.5, 4 or 10 mg/kg administered 24 h prior to infection. Treatment with oral voriconazole at doses of 5 or 10 mg/kg twice daily beginning 24 h post-challenge served as the positive control.
  
  
  RESULTS
  Improvements in survival were observed with ABIP prophylaxis. A single inhaled dose of 4 mg/kg ABIP and treatment with 5 mg/kg voriconazole both improved median and percentage survival compared with untreated controls. In addition, pulmonary fungal burden, as assessed by cfu, quantitative PCR and galactomannan, was also reduced in a dose-dependent fashion with ABIP prophylaxis as well as with both doses of voriconazole treatment.
  
  
  CONCLUSIONS
  Single-dose prophylaxis with inhaled ABIP as prophylaxis demonstrated a significant survival advantage and reductions in pulmonary fungal burden in this model of invasive pulmonary aspergillosis. Optimization of the dose and dosing frequency of ABIP dose may help to further enhance the anti-Aspergillus activity of this novel amphotericin B formulation.
authors.affiliation: The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA. kirkpatrick@uthscsa.edu
authors.forename: William R
authors.initials: WR
authors.lastname: Kirkpatrick
authors.forename: Laura K
authors.initials: LK
authors.lastname: Najvar
authors.forename: Ana C
authors.initials: AC
authors.lastname: Vallor
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Wiederhold
authors.forename: Rosie
authors.initials: R
authors.lastname: Bocanegra
authors.forename: Juergen
authors.initials: J
authors.lastname: Pfeiffer
authors.forename: Kimberly
authors.initials: K
authors.lastname: Perkins
authors.forename: Alan R
authors.initials: AR
authors.lastname: Kugler
authors.forename: Theresa D
authors.initials: TD
authors.lastname: Sweeney
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Patterson
mesh_terms: D000280:Administration, Inhalation; D000666:Amphotericin B / Q000008:administration & dosage*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000472:pathogenicity*; D018890:Chemoprevention / Q000379:methods*; D015169:Colony Count, Microbial; D003348:Cortisone / Q000008:administration & dosage / Q000031:analogs & derivatives; D003520:Cyclophosphamide / Q000008:administration & dosage; D004195:Disease Models, Animal; D006168:Guinea Pigs; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D055744:Invasive Pulmonary Aspergillosis / Q000517:prevention & control*; D008168:Lung / Q000382:microbiology; D008297:Male; D011743:Pyrimidines / Q000008:administration & dosage; D016019:Survival Analysis; D014230:Triazoles / Q000008:administration & dosage; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D011743:Pyrimidines; D014230:Triazoles; D000666:Amphotericin B; D003520:Cyclophosphamide; D065819:Voriconazole; D003348:Cortisone