title: Efficacy of posaconazole as treatment and prophylaxis against Fusarium solani.
abstract: Invasive fusariosis is a highly aggressive fungal infection associated with high mortality in heavily immunocompromised patients. Although posaconazole is efficacious as salvage therapy against infections caused by Fusarium species, concerns remain regarding this agent in the setting of reduced potency. To evaluate the efficacy of posaconazole as treatment or prophylaxis against invasive fusariosis caused by Fusarium solani, we utilized a neutropenic murine model of disseminated disease. ICR mice were administered escalating doses of posaconazole (6.25, 12.5, 25, or 50 mg/kg of body weight twice daily [BID]) by oral gavage beginning 2 days prior to inoculation in the prophylaxis studies or beginning 12 h after inoculation as treatment. Therapy was continued until day 9 postinoculation, and animals were monitored off therapy until day 15 for survival. Fungal burden was assessed as CFU in the kidneys. A clear dose-response relationship was observed, as the highest dose of posaconazole (50 mg/kg) was the most effective in prolonging survival and reducing tissue fungal burden both as prophylaxis and as treatment. This dose response was associated with high posaconazole serum concentrations as measured by bioassay. However, the extent of efficacy was also dependent on the infecting inoculum, as greater increases in survival and reductions in fungal burden were observed with the lower inocula tested. In this model high dosages of posaconazole were effective as treatment and prophylaxis against disseminated fusariosis caused by F. solani.
authors.affiliation: University of Texas at Austin College of Pharmacy, Austin, Texas, USA. wiederholdn@uthscsa.edu
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Wiederhold
authors.forename: Laura K
authors.initials: LK
authors.lastname: Najvar
authors.forename: Rosie
authors.initials: R
authors.lastname: Bocanegra
authors.forename: John R
authors.initials: JR
authors.lastname: Graybill
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Patterson
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018890:Chemoprevention; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal; D005670:Fusarium / Q000145:classification / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000382:microbiology; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009181:Mycoses / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D009503:Neutropenia / Q000150:complications; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole