title: Anidulafungin for neonatal hematogenous Candida meningoencephalitis: identification of candidate regimens for humans using a translational pharmacological approach.
abstract: Hematogenous Candida meningoencephalitis (HCME) is a serious infection in premature neonates. Anidulafungin is an echinocandin antifungal agent with potent activity against Candida spp., but its efficacy and optimal regimens for human neonates with HCME are not known. A well-validated rabbit model of HCME was used to define pharmacokinetic-pharmacodynamic (PK-PD) relationships of anidulafungin. A mathematical model was fitted to the entire data set. The experimental data were bridged to humans. A population PK model was fitted to the data from human neonates receiving anidulafungin receiving a loading dose of 3 mg/kg, followed by 1.5 mg/kg/day. Monte Carlo simulations were performed to identify candidate anidulafungin regimens for humans. All untreated rabbits succumbed by ≤96 h postinoculation. The PK of anidulafungin was linear with dose-dependent penetration into the cerebrum. Anidulafungin exerted a rapid antifungal effect that was apparent in the first dosing interval. Near-maximal antifungal activity was observed with dosages of 10 to 20 mg/kg/day. The bridging studies suggested that the current regimen of first 3 mg/kg, followed by 1.5 mg/kg/day, is suboptimal. Higher dosages were associated with progressively greater antifungal effect. Anidulafungin is effective for the treatment of experimental HCME. Higher dosages than those currently used for clinical care are required for maximal antifungal effect.
authors: The University of Manchester, Manchester Academic Health Science Centre, NIHR Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
authors: Peter A
authors: PA
authors: Warn
authors: Joanne
authors: J
authors: Livermore
authors: Susan
authors: S
authors: Howard
authors: Timothy W
authors: TW
authors: Felton
authors: Andrew
authors: A
authors: Sharp
authors: Lea
authors: L
authors: Gregson
authors: Joanne
authors: J
authors: Goodwin
authors: Ruta
authors: R
authors: Petraitiene
authors: Vidmantas
authors: V
authors: Petraitis
authors: Michael
authors: M
authors: Cohen-Wolkowiez
authors: Thomas J
authors: TJ
authors: Walsh
authors: Daniel K
authors: DK
authors: Benjamin
authors: William W
authors: WW
authors: Hope
mesh_terms: D000077612:Anidulafungin; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D002176:Candida albicans / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D004195:Disease Models, Animal; D054714:Echinocandins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000188:drug therapy* / Q000382:microbiology; D008297:Male; D016921:Meningitis, Fungal / Q000188:drug therapy / Q000382:microbiology; D008590:Meningoencephalitis / Q000188:drug therapy* / Q000382:microbiology; D009010:Monte Carlo Method; D011817:Rabbits; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D000077612:Anidulafungin