Prophylactic efficacy of single dose pulmonary administration of amphotericin B inhalation powder in a guinea pig model of invasive pulmonary aspergillosis.

Abstract

OBJECTIVES:

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: William R Kirkpatrick, Laura K Najvar, Ana C Vallor, Nathan P Wiederhold, Rosie Bocanegra, Juergen Pfeiffer, Kimberly Perkins, Alan R Kugler, Theresa D Sweeney, Thomas F Patterson
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 67 Issue 4 Pg. 970-6 (Apr 2012) ISSN: 1460-2091 [Electronic] England
• PMID: 22240402 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antifungal Agents
• Immunosuppressive Agents
• Pyrimidines
• Triazoles
• Amphotericin B
• Cyclophosphamide
• Voriconazole
• Cortisone

Topics

• Administration, Inhalation
• Amphotericin B (administration & dosage)
• Animals
• Antifungal Agents (administration & dosage)
• Aspergillus fumigatus (drug effects, pathogenicity)
• Chemoprevention (methods)
• Colony Count, Microbial
• Cortisone (administration & dosage, analogs & derivatives)
• Cyclophosphamide (administration & dosage)
• Disease Models, Animal
• Guinea Pigs
• Immunosuppressive Agents (administration & dosage)
• Invasive Pulmonary Aspergillosis (prevention & control)
• Lung (microbiology)
• Male
• Pyrimidines (administration & dosage)
• Survival Analysis
• Triazoles (administration & dosage)
• Voriconazole