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Antimicrobial Agents and Chemotherapy, November 2008, p. 4121-4129, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00674-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Cerebrospinal Fluid and Plasma (1->3)-β-D-Glucan as Surrogate Markers for Detection and Monitoring of Therapeutic Response in Experimental Hematogenous Candida Meningoencephalitis{triangledown}

Ruta Petraitiene,1,2 Vidmantas Petraitis,1,2 William W. Hope,1 Diana Mickiene,1,2 Amy M. Kelaher,1 Heidi A. Murray,1 Christine Mya-San,1 Johanna E. Hughes,1 Margaret P. Cotton,1 John Bacher,3 and Thomas J. Walsh1*

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda,1 Laboratory Animal Sciences Program, SAIC-Frederick, Inc., Frederick,2 Surgery Service, Division of Veterinary Resources, Office of Research Services, Bethesda, Maryland3

Received 22 May 2008/ Returned for modification 25 June 2008/ Accepted 28 August 2008

The treatment, diagnosis and therapeutic monitoring of hematogenous Candida meningoencephalitis (HCME) are not well understood. We therefore studied the expression of (1->3)-β-D-glucan (β-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 (102 to 103 CFU/ml), spinal cord, and meninges (10 to 102 CFU/g), only 8.1% of UC CSF cultures were positive. By comparison, all 25 UC CSF samples tested for β-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, β-glucan levels in CSF were predictive of the therapeutic response. A significant decrease of β-glucan concentrations in CSF, in comparison to that for UC, started at 0.5 mg/kg (P < 0.001). Levels of plasma β-glucan were lower than levels in simultaneously obtained CSF (P < 0.05). CSF β-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 β-glucan may be a useful biomarker for detection and monitoring of therapeutic response in HCME.

* Corresponding author. Mailing address: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Building 10, CRC, Rm. 1W—5740, 10 Center Drive, Bethesda, MD 20892-1100. Phone: (301) 402-0023. Fax: (301) 480-2308. E-mail: walsht{at}mail.nih.gov

{triangledown} Published ahead of print on 8 September 2008.

Antimicrobial Agents and Chemotherapy, November 2008, p. 4121-4129, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00674-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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