title: Intermittent Dosing of Micafungin Is Effective for Treatment of Experimental Disseminated Candidiasis in Persistently Neutropenic Rabbits.
abstract: BACKGROUND
  The current standard of treatment of invasive candidiasis with echinocandins requires once-daily therapy. To improve quality of life, reduce costs, and improve outcome, we studied the pharmacokinetics (PK), efficacy, and safety of alternate dosing regimens of micafungin (MFG) for the treatment of experimental subacute disseminated candidiasis.
  
  
  METHODS
  MFG was administered for 12 days starting 24 hours after intravenous inoculation of 1 × 10(3) Candida albicans blastoconidia. Study groups consisted of MFG at 1 mg/kg every 24 hours (MFG1), 2 mg/kg every 48 hours (MFG2), and 3 mg/kg every 72 hours (MFG3), and untreated controls. PK of MFG were determined on day 7 by high-performance liquid chromatography and modeled using nonparametric adaptive grid program. A 2-compartment PK model with volume of the central compartment (Vc), clearance (SCL), and the intercompartmental rate constants Kcp and Kpc was used. The fungal burden in 7 tissues was determined 312 hours after the initiation of therapy.
  
  
  RESULTS
  PK of MFG were linear and the parameter means ± SD were Vc = 0.41 ± 0.18 L, Kcp = 2.80 ± 1.55/hour, Kpc = 1.71 ± 0.93/hour, and SCL = 0.16 ± 0.003 L/hour (r(2) = 0.99). The area under the plasma drug concentration - time curve for MFG1, MFG2, and MFG3 was 198.7 ± 19.8, 166.3 ± 36.7, and 192.8 ± 46.2 mg × hour/L, respectively (P = .24). All treatment groups showed significant and comparable resolution of (1→3)-β-D-glucan levels and clearance of C. albicans from liver, spleen, kidney, brain, lung, vitreous humor, and vena cava in comparison to untreated controls (P ≤ .05). There were no differences in hepatic or renal function among study groups.
  
  
  CONCLUSIONS
  Less fractionated MFG regimens of every 48 and 72 hours are safe and as effective in experimental disseminated candidiasis as once-daily therapy in neutropenic hosts.
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical Center of Cornell University, New York, New York.
authors.forename: Ruta
authors.initials: R
authors.lastname: Petraitiene
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical Center of Cornell University, New York, New York.
authors.forename: Vidmantas
authors.initials: V
authors.lastname: Petraitis
authors.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical Center of Cornell University, New York, New York Department of Pediatrics and Department of Microbiology and Immunology, Weill Cornell Medical Center of Cornell University, New York, New York.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002176:Candida albicans / Q000187:drug effects*; D002177:Candidiasis / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D058365:Candidiasis, Invasive / Q000188:drug therapy* / Q000382:microbiology; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D054714:Echinocandins / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D055666:Lipopeptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000077551:Micafungin; D009503:Neutropenia / Q000150:complications*; D011509:Proteoglycans; D011817:Rabbits; D047071:beta-Glucans / Q000097:blood
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D011509:Proteoglycans; D047071:beta-Glucans; C010770:polysaccharide-K; D000077551:Micafungin
keywords: Candida albicans; disseminated candidiasis; micafungin; neutropenia; serum (1→3)-β-D-glucan