title: Comparative antifungal activities and plasma pharmacokinetics of micafungin (FK463) against disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits.
abstract: Micafungin (FK463) is an echinocandin that demonstrates potent in vitro antifungal activities against Candida and Aspergillus species. However, little is known about its comparative antifungal activities in persistently neutropenic hosts. We therefore investigated the plasma micafungin pharmacokinetics and antifungal activities of micafungin against experimental disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. The groups with disseminated candidiasis studied consisted of untreated controls (UCs); rabbits treated with desoxycholate amphotericin B (DAMB) at 1 mg/kg of body weight/day; or rabbits treated with micafungin at 0.25, 0.5, 1, and 2 mg/kg/day intravenously. Compared with the UCs, rabbits treated with micafungin or DAMB showed significant dosage-dependent clearance of Candida albicans from the liver, spleen, kidney, brain, eye, lung, and vena cava. These in vivo findings correlated with the results of in vitro time-kill assays that demonstrated that micafungin has concentration-dependent fungicidal activity. The groups with invasive pulmonary aspergillosis studied consisted of UCs; rabbits treated with DAMB; rabbits treated with liposomal amphotericin B (LAMB) at 5 mg/kg/day; and rabbits treated with micafungin at 0.5, 1, and 2 mg/kg/day. In comparison to the significant micafungin dosage-dependent reduction of the residual burden (in log CFU per gram) of C. albicans in tissue, micafungin-treated rabbits with invasive pulmonary aspergillosis had no reduction in the concentration of Aspergillus fumigatus in tissue. DAMB and LAMB significantly reduced the burdens of C. albicans and A. fumigatus in tissues (P < 0.01). Persistent galactomannan antigenemia in micafungin-treated rabbits correlated with the presence of an elevated burden of A. fumigatus in pulmonary tissue. By comparison, DAMB- and LAMB-treated animals had significantly reduced circulating galactomannan antigen levels. Despite a lack of clearance of A. fumigatus from the lungs, there was a significant improvement in the rate of survival (P < 0.001) and a reduction in the level of pulmonary infarction (P < 0.05) in micafungin-treated rabbits. In summary, micafungin demonstrated concentration-dependent and dosage-dependent clearance of C. albicans from persistently neutropenic rabbits with disseminated candidiasis but not of A. fumigatus from persistently neutropenic rabbits with invasive pulmonary aspergillosis.
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Vidmantas
authors.initials: V
authors.lastname: Petraitis
authors.forename: Ruta
authors.initials: R
authors.lastname: Petraitiene
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Groll
authors.forename: Kristin
authors.initials: K
authors.lastname: Roussillon
authors.forename: Melissa
authors.initials: M
authors.lastname: Hemmings
authors.forename: Caron A
authors.initials: CA
authors.lastname: Lyman
authors.forename: Tin
authors.initials: T
authors.lastname: Sein
authors.forename: John
authors.initials: J
authors.lastname: Bacher
authors.forename: Ihor
authors.initials: I
authors.lastname: Bekersky
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D054714:Echinocandins; D005690:Galactose / Q000031:analogs & derivatives; D055666:Lipopeptides; D008074:Lipoproteins / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D008168:Lung / Q000382:microbiology; D008351:Mannans / Q000097:blood; D000077551:Micafungin; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications*; D009929:Organ Size / Q000187:drug effects; D010456:Peptides, Cyclic / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D011817:Rabbits
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D008074:Lipoproteins; D008351:Mannans; D010456:Peptides, Cyclic; C012990:galactomannan; D000077551:Micafungin; D005690:Galactose