title: Pharmacodynamics of liposomal amphotericin B and flucytosine for cryptococcal meningoencephalitis: safe and effective regimens for immunocompromised patients.
abstract: BACKGROUND
  Cryptococcal meningoencephalitis is a lethal infection with relatively few therapeutic options. The optimal dosage of liposomal amphotericin B (LAmB) alone or in combination with flucytosine is not known.
  
  
  METHODS
  A murine model of cryptococcal meningoencephalitis was used. The fungal density in the brain was determined using quantitative cultures. Pharmacokinetic-pharmacodynamic relationships were determined for LAmB and flucytosine administered alone. The effect of the combination was described using the Greco model and a mathematical model. The results were bridged to humans.
  
  
  RESULTS
  Inoculation resulted in hematogenous dissemination and logarithmic growth within the central nervous system. There was histological evidence of multifocal infection throughout the brain. Both LAmB and flucytosine produced a dose-dependent reduction in fungal burden. The effect of the combination of agents in the brain was additive. Bridging studies suggested that a human dosage of LAmB 3 mg/kg/d resulted in a submaximal antifungal effect. Regimens of LAmB 6 mg/kg/d alone, LAmB 3 mg/kg/d plus flucytosine 50 mg/kg/d, and LAmB 3 mg/kg/d plus flucytosine 100 mg/kg/d all resulted in near-maximal antifungal activity.
  
  
  CONCLUSIONS
  Potential regimens for further study in clinical trials include LAmB 6 mg/kg/d alone, LAmB 3 mg/kg/d plus flucytosine 50 mg/kg/d, and LAmB 3 mg/kg/d plus flucytosine 100 mg/kg/d.
authors.affiliation: School of Translational Medicine, The University of Manchester, Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust, United Kingdom.
authors.forename: Lucy
authors.initials: L
authors.lastname: O'Connor
authors.forename: Joanne
authors.initials: J
authors.lastname: Livermore
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Sharp
authors.forename: Joanne
authors.initials: J
authors.lastname: Goodwin
authors.forename: Lea
authors.initials: L
authors.lastname: Gregson
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Howard
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Felton
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schwartz
authors.forename: Michael N
authors.initials: MN
authors.lastname: Neely
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Harrison
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
mesh_terms: D000666:Amphotericin B / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000302:isolation & purification; D004359:Drug Therapy, Combination; D005437:Flucytosine / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D016919:Meningitis, Cryptococcal / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008590:Meningoencephalitis / Q000188:drug therapy* / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008954:Models, Biological
chemical_list: D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B; D005437:Flucytosine
keywords: Cryptococcus; flucytosine; liposomal amphotericin B; meningitis; meningoencephalitis