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The initial 96 hours of invasive pulmonary aspergillosis: histopathology, comparative kinetics of galactomannan and (1->3) β-d-glucan and consequences of delayed antifungal therapy.

Abstract
Acute invasive pulmonary aspergillosis is a rapidly progressive and frequently lethal infection. Relatively little is known about early events in the pathogenesis and relationship between the cell wall biomarkers galactomannan and (1→3)-β-d-glucan. The consequences of delayed antifungal therapy are also poorly defined. A persistently neutropenic rabbit model of invasive pulmonary aspergillosis was used to describe the histopathology of early invasive pulmonary aspergillosis and the kinetics of galactomannan and (1→3)-β-d-glucan. The time course of both molecules was mathematically modeled by using a population methodology, and Monte Carlo simulations were performed. The effect of progressive delay in the administration of amphotericin B deoxycholate 1 mg/kg at 24, 48, 72, and 96 h postinoculation on fungal burden, lung weight, pulmonary infarct score, and survival was determined. Histopathology showed phagocytosis of conidia by pulmonary alveolar macrophages at 4 h postinoculation. At 12 to 24 h, there was a progressive focal inflammatory response with conidial germination and hyphal extension. Subsequently, hyphae invaded into the contiguous lung. Galactomannan and (1→3)-β-d-glucan had similar trajectories, and both exhibited considerable interindividual variability, which was reflected in Monte Carlo simulations. Concentrations of both molecules began to rise <24 h postinoculation before pulmonary hemorrhagic infarction was present. Delays of 72 and 96 h in the administration of amphotericin B resulted in fungal burdens and lung weights that were indistinguishable from those of controls, respectively. Galactomannan and (1→3)-β-d-glucan have similar kinetics and are comparable biomarkers of early invasive pulmonary aspergillosis. Antifungal treatment at ≥48 h postinoculation is associated with suboptimal therapeutic outcomes.
AuthorsWilliam W Hope, Vidmantas Petraitis, Ruta Petraitiene, Tamarra Aghamolla, John Bacher, Thomas J Walsh
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 54 Issue 11 Pg. 4879-86 (Nov 2010) ISSN: 1098-6596 [Electronic] United States
PMID20713673 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
Chemical References
  • Antifungal Agents
  • Drug Combinations
  • Mannans
  • Proteoglycans
  • beta-Glucans
  • Deoxycholic Acid
  • galactomannan
  • polysaccharide-K
  • Amphotericin B
  • amphotericin B, deoxycholate drug combination
  • Galactose
Topics
  • Amphotericin B (therapeutic use)
  • Animals
  • Antifungal Agents (therapeutic use)
  • Aspergillus fumigatus (drug effects, metabolism, pathogenicity)
  • Deoxycholic Acid (therapeutic use)
  • Drug Combinations
  • Galactose (analogs & derivatives)
  • Invasive Pulmonary Aspergillosis (drug therapy, metabolism)
  • Mannans (metabolism)
  • Proteoglycans
  • Rabbits
  • beta-Glucans (metabolism)

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