title: Monitoring and impact of fluconazole serum and cerebrospinal fluid concentration in HIV-associated cryptococcal meningitis-infected patients.
abstract: OBJECTIVE
  The aim of the present study was to assess fluconazole pharmacokinetic measures in serum and cerebrospinal fluid (CSF); and the correlation of these measures with clinical outcomes of invasive fungal infections.
  
  
  METHODS
  A randomized trial was conducted in HIV-infected patients receiving three different regimens of fluconazole plus amphotericin B (AmB) for the treatment of cryptococcal meningitis. Regimens included fluconazole 400 mg/day+AmB (AmB+Fluc400) or fluconazole 800 mg/day+AmB (AmB+Fluc800) (14 days followed by fluconazole alone at the randomized dose for 56 days); or AmB alone for 14 days followed by fluconazole 400 mg/day for 56 days. Serum (at 24 h after dosing) and CSF samples were taken at baseline and days 14 and 70 (serum only) for fluconazole measurement, using gas-liquid chromatography.
  
  
  RESULTS
  Sixty-four treated patients had fluconazole measurements: 11 in the AmB group, 12 in the AmB+Fluc400 group and 41 in the AmB+Fluc800 group. Day 14 serum concentration geometric means were 24.7 mg/L for AmB+Fluc400 and 37.0 mg/L for AmB+Fluc800. Correspondingly, CSF concentration geometric means were 25.1 mg/L and 32.7 mg/L. Day 14 Serum and CSF concentrations were highly correlated with AmB+Fluc800 (P<0.001, r=0.873) and AmB+Fluc400 (P=0.005, r=0.943). Increased serum area under the curve (AUC) appears to be associated with decreased mortality at day 70 (P=0.061, odds ratio=2.19) as well as with increased study composite endpoint success at days 42 and 70 (P=0.081, odds ratio=2.25 and 0.058, 2.89, respectively).
  
  
  CONCLUSIONS
  High fluconazole dosage (800 mg/day) for the treatment of HIV-associated cryptococcal meningitis was associated with high serum and CSF fluconazole concentration. Overall, high serum and CSF concentration appear to be associated with increased survival and primary composite endpoint success.
authors.affiliation: Department of Medicine, Bamrasnaradura Infectious Diseases Institute, Nonthaburi, Thailand. drweerawat@hotmail.com
authors.forename: W
authors.initials: W
authors.lastname: Manosuthi
authors.forename: P
authors.initials: P
authors.lastname: Chetchotisakd
authors.forename: T L
authors.initials: TL
authors.lastname: Nolen
authors.forename: D
authors.initials: D
authors.lastname: Wallace
authors.forename: S
authors.initials: S
authors.lastname: Sungkanuparph
authors.forename: T
authors.initials: T
authors.lastname: Anekthananon
authors.forename: K
authors.initials: K
authors.lastname: Supparatpinyo
authors.forename: P G
authors.initials: PG
authors.lastname: Pappas
authors.forename: R A
authors.initials: RA
authors.lastname: Larsen
authors.forename: S G
authors.initials: SG
authors.lastname: Filler
authors.forename: D
authors.initials: D
authors.lastname: Andes
mesh_terms: D000666:Amphotericin B / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000935:Antifungal Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active; D001682:Biological Availability; D002849:Chromatography, Gas; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D015725:Fluconazole / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D016919:Meningitis, Cryptococcal / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D008954:Models, Biological; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D000935:Antifungal Agents; D000666:Amphotericin B; D015725:Fluconazole