title: High-Dose Micafungin for Preterm Neonates and Infants with Invasive and Central Nervous System Candidiasis.
abstract: High doses of micafungin are advocated in neonates with systemic candidiasis, but limited pharmacokinetic (PK) and safety data are available to support their use. Eighteen preterm neonates and infants with systemic candidiasis, three of whom had meningitis, were treated for at least 14 days with 8 to 15 mg/kg of body weight/day of intravenous micafungin. Plasma micafungin concentrations (four measurements for each patient) were determined after the third dose, and the cerebrospinal fluid (CSF) micafungin concentrations in three patients were also obtained. Population PK analyses were used to identify the optimal model, and the model was further validated using external data (n = 5). The safety of micafungin was assessed by measurement of the levels of liver and kidney function biomarkers. The mean age and weight at the initiation of treatment were 2.33 months (standard deviation [SD], 1.98 months) and 3.24 kg (SD, 1.61 kg), respectively. The optimal PK model was one that scaled plasma clearance to weight and the transaminase concentration ratio. The CSF of three patients was sampled, and the observed concentrations were between 0.80 and 1.80 mg/liter. The model-predicted mean micafungin area under the concentration-time curve over 24 h was 336 mg · h/liter (SD, 165 mg · h/liter) with the 10-mg/kg/day dosage. Eighteen of the 23 subjects (78.2%) had clinical resolution of their infection, but 5 had neurologic impairments. Among the transaminases, alkaline phosphatase measurements were significantly higher posttreatment, with a geometric mean ratio of 1.17 (90% confidence interval, 1.01, 1.37). Furthermore, marked elevations in the gamma-glutamyltransferase (GGT) level were observed in three patients treated with 10- to 15-mg/kg/day doses, and improvement of the GGT level was noted after a dose reduction. Higher weight-based doses of micafungin were generally well tolerated in neonates and infants and achieved pharmacokinetic profiles predictive of an effect.
authors.affiliation: Neonatal Intensive Care Unit, Department of Neonatology, Bambino Gesù Children's Hospital, Rome, Italy cinzia.auriti@opbg.net.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Auriti
authors.affiliation: Infectious Diseases Section, Department of Public Health and Infectious Diseases, La Sapienza University, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Falcone
authors.affiliation: Neonatal Intensive Care Unit, Department of Neonatology, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Ronchetti
authors.affiliation: Biochemistry Laboratory, Department of Specialist Pediatrics, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Bianca Maria
authors.initials: BM
authors.lastname: Goffredo
authors.affiliation: Neonatal Intensive Care Unit, Department of Neonatology, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cairoli
authors.affiliation: Neonatal Intensive Care Unit, Department of Neonatology, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Crisafulli
authors.affiliation: Neonatal Intensive Care Unit, Department of Neonatology, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Fiammetta
authors.initials: F
authors.lastname: Piersigilli
authors.affiliation: Unit of Clinical Pharmacy, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Corsetti
authors.affiliation: Neonatal Intensive Care Unit, Department of Neonatology, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Dotta
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Manjunath P
authors.initials: MP
authors.lastname: Pai
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002177:Candidiasis / Q000188:drug therapy*; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000382:microbiology; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007668:Kidney / Q000502:physiology; D055666:Lipopeptides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008099:Liver / Q000502:physiology; D008297:Male; D016921:Meningitis, Fungal / Q000188:drug therapy / Q000382:microbiology; D000077551:Micafungin; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D005723:gamma-Glutamyltransferase; D000077551:Micafungin