title: Comparative Population Plasma and Tissue Pharmacokinetics of Micafungin in Critically Ill Patients with Severe Burn Injuries and Patients with Complicated Intra-Abdominal Infection.
abstract: Severely burned patients have altered drug pharmacokinetics (PKs), but it is unclear how different they are from those in other critically ill patient groups. The aim of the present study was to compare the population pharmacokinetics of micafungin in the plasma and burn eschar of severely burned patients with those of micafungin in the plasma and peritoneal fluid of postsurgical critically ill patients with intra-abdominal infection. Fifteen burn patients were compared with 10 patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of micafungin. Micafungin concentrations in serial blood, peritoneal fluid, and burn tissue samples were determined and were subjected to a population pharmacokinetic analysis. The probability of target attainment was calculated using area under the concentration-time curve from 0 to 24 h/MIC cutoffs of 285 for Candida parapsilosis and 3,000 for non-parapsilosis Candida spp. by Monte Carlo simulations. Twenty-five patients (18 males; median age, 50 years; age range, 38 to 67 years; median total body surface area burned, 50%; range of total body surface area burned, 35 to 65%) were included. A three-compartment model described the data, and only the rate constant for the drug distribution from the tissue fluid to the central compartment was statistically significantly different between the burn and intra-abdominal infection patients (0.47 ± 0.47 versus 0.15 ± 0.06 h(-1), respectively; P < 0.05). Most patients would achieve plasma PK/pharmacodynamic (PD) targets of 90% for non-parapsilosis Candida spp. and C. parapsilosis with MICs of 0.008 and 0.064 mg/liter, respectively, for doses of 100 mg daily and 150 mg daily. The PKs of micafungin were not significantly different between burn patients and intra-abdominal infection patients. After the first dose, micafungin at 100 mg/day achieved the PK/PD targets in plasma for MIC values of ≤0.008 mg/liter and ≤0.064 mg/liter for non-parapsilosis Candida spp. and Candida parapsilosis species, respectively.
authors.affiliation: Burn Unit/Intensive Care Medicine Service, La Paz University Hospital/IdiPAZ Institute for Health Research, Orthopaedics Surgery Hospital, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: García-de-Lorenzo
authors.affiliation: Pharmacy Department, Hospital del Mar, Barcelona, Spain Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain sluque@parcdesalutmar.cat.
authors.forename: S
authors.initials: S
authors.lastname: Luque
authors.affiliation: Pharmacy Department, Hospital del Mar, Barcelona, Spain Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Grau
authors.affiliation: Burn Unit/Intensive Care Medicine Service, La Paz University Hospital/IdiPAZ Institute for Health Research, Orthopaedics Surgery Hospital, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Agrifoglio
authors.affiliation: Burn Unit/Intensive Care Medicine Service, La Paz University Hospital/IdiPAZ Institute for Health Research, Orthopaedics Surgery Hospital, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Cachafeiro
authors.affiliation: Burn Unit/Intensive Care Medicine Service, La Paz University Hospital/IdiPAZ Institute for Health Research, Orthopaedics Surgery Hospital, Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Herrero
authors.affiliation: Burn Unit/Intensive Care Medicine Service, La Paz University Hospital/IdiPAZ Institute for Health Research, Orthopaedics Surgery Hospital, Madrid, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Asensio
authors.affiliation: Burn Unit/Intensive Care Medicine Service, La Paz University Hospital/IdiPAZ Institute for Health Research, Orthopaedics Surgery Hospital, Madrid, Spain.
authors.forename: S M
authors.initials: SM
authors.lastname: Sánchez
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Roberts
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics*; D001202:Ascitic Fluid / Q000187:drug effects; D002056:Burns / Q000150:complications / Q000382:microbiology; D016638:Critical Illness; D054714:Echinocandins / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D059413:Intraabdominal Infections / Q000188:drug therapy*; D055666:Lipopeptides / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D000077551:Micafungin; D008875:Middle Aged; D009010:Monte Carlo Method; D011446:Prospective Studies; D014018:Tissue Distribution
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077551:Micafungin