title: Cerebrospinal fluid and plasma (1-->3)-beta-D-glucan as surrogate markers for detection and monitoring of therapeutic response in experimental hematogenous Candida meningoencephalitis.
abstract: The treatment, diagnosis and therapeutic monitoring of hematogenous Candida meningoencephalitis (HCME) are not well understood. We therefore studied the expression of (1-->3)-beta-D-glucan (beta-glucan) in cerebrospinal fluid (CSF) and plasma in a nonneutropenic rabbit model of experimental HCME treated with micafungin and amphotericin B. Groups studied consisted of micafungin (0.5 to 32 mg/kg) and amphotericin B (1 mg/kg) treatment groups and the untreated controls (UC). Despite well-established infection in the cerebrum, cerebellum, choroid, vitreous humor (10(2) to 10(3) CFU/ml), spinal cord, and meninges (10 to 10(2) CFU/g), only 8.1% of UC CSF cultures were positive. By comparison, all 25 UC CSF samples tested for beta-glucan were positive (755 to 7,750 pg/ml) (P < 0.001). The therapeutic response in CNS tissue was site dependent, with significant decreases of the fungal burden in the cerebrum and cerebellum starting at 8 mg/kg, in the meninges at 2 mg/kg, and in the vitreous humor at 4 mg/kg. A dosage of 24 mg/kg was required to achieve a significant effect in the spinal cord and choroid. Clearance of Candida albicans from blood cultures was not predictive of eradication of organisms from the CNS; conversely, beta-glucan levels in CSF were predictive of the therapeutic response. A significant decrease of beta-glucan concentrations in CSF, in comparison to that for UC, started at 0.5 mg/kg (P < 0.001). Levels of plasma beta-glucan were lower than levels in simultaneously obtained CSF (P < 0.05). CSF beta-glucan levels correlated in a dose-dependent pattern with therapeutic responses and with Candida infection in cerebral tissue (r = 0.842). Micafungin demonstrated dose-dependent and site-dependent activity against HCME. CSF beta-glucan may be a useful biomarker for detection and monitoring of therapeutic response in HCME.
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892-1100, USA.
authors.forename: Ruta
authors.initials: R
authors.lastname: Petraitiene
authors.forename: Vidmantas
authors.initials: V
authors.lastname: Petraitis
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
authors.forename: Diana
authors.initials: D
authors.lastname: Mickiene
authors.forename: Amy M
authors.initials: AM
authors.lastname: Kelaher
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Murray
authors.forename: Christine
authors.initials: C
authors.lastname: Mya-San
authors.forename: Johanna E
authors.initials: JE
authors.lastname: Hughes
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Cotton
authors.forename: John
authors.initials: J
authors.lastname: Bacher
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D002177:Candidiasis / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D054714:Echinocandins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D055666:Lipopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D016921:Meningitis, Fungal / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000473:pathology; D008590:Meningoencephalitis / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000473:pathology; D000077551:Micafungin; D011817:Rabbits; D047071:beta-Glucans / Q000097:blood* / Q000134:cerebrospinal fluid*
chemical_list: D000935:Antifungal Agents; D015415:Biomarkers; D054714:Echinocandins; D055666:Lipopeptides; D047071:beta-Glucans; D000666:Amphotericin B; D000077551:Micafungin
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