title: Delay of antifungal therapy influences the outcome of invasive aspergillosis in experimental models of infection.
abstract: The aim of the present study was to evaluate the effects of delayed antifungal therapy on the outcome of invasive aspergillosis due to Aspergillus fumigatus in experimental models of infection.
  
  
  
  A clinical isolate of A. fumigatus susceptible to amphotericin B (MIC 0.5 mg/L) and micafungin [minimum effective concentration (MEC) 0.03 mg/L] was used in all experiments. Two models of infection were investigated in immunosuppressed mice: disseminated infection and pulmonary infection. Twenty-four hours (early therapy) and 48 h (delayed therapy) post-infection, the mice were given vehicle, liposomal amphotericin B, micafungin or liposomal amphotericin B plus micafungin (combination). Drug efficacy was assessed by either survival or tissue burden experiments.
  
  
  
  In disseminated infection, any drug regimen given early significantly prolonged survival. When therapy was delayed, only micafungin and the combination were effective. In pulmonary infection, although there was a trend towards a prolongation of survival of mice treated early with liposomal amphotericin B, only the combination was effective. Similarly, when therapy was delayed, only the combination was effective. In disseminated infection, any drug regimen given early was effective at reducing the cfu in kidney tissue. In pulmonary infection, only liposomal amphotericin B and the combination given early were effective at reducing the cfu in lung tissue. Conversely, when therapy was delayed, no regimen was effective at reducing the tissue burden, regardless of the type of infection.
  
  
  
  Our data indicate that delayed initiation of antifungal therapy is deleterious in experimental models of invasive aspergillosis. A combination regimen seems to have some advantages over a single-drug approach when the therapy is started late.
authors.affiliation: Infectious Diseases Clinic, Polytechnic University of Marche, Ancona, Italy f.barchiesi@univpm.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Barchiesi
authors.affiliation: Pathological Anatomy and Histopathology, Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Santinelli
authors.affiliation: Pathological Anatomy and Histopathology, Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Tommasina
authors.initials: T
authors.lastname: Biscotti
authors.affiliation: Infectious Diseases Clinic, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Greganti
authors.affiliation: Management Centre of Medicine and Surgery, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Giannini
authors.affiliation: Laboratory of Microbiology, Azienda Ospedaliero-Universitaria, Ospedali Riuniti, Umberto I-Lancisi-Salesi, Ancona, Italy.
authors.forename: Esther
authors.initials: E
authors.lastname: Manso
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000187:drug effects; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D054714:Echinocandins / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy*; D055666:Lipopeptides / Q000008:administration & dosage / Q000494:pharmacology; D008168:Lung / Q000382:microbiology; D000077551:Micafungin; D051379:Mice; D008826:Microbial Sensitivity Tests; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; C068538:liposomal amphotericin B; D000666:Amphotericin B; D000077551:Micafungin