Cerebrospinal fluid and plasma (1-->3)-beta-D-glucan as surrogate markers for detection and monitoring of therapeutic response in experimental hematogenous Candida meningoencephalitis.
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.
Petraitiene
Ruta
R
Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892-1100, USA.
Petraitis
Vidmantas
V
Hope
William W
WW
Mickiene
Diana
D
Kelaher
Amy M
AM
Murray
Heidi A
HA
Mya-San
Christine
C
Hughes
Johanna E
JE
Cotton
Margaret P
MP
Bacher
John
J
Walsh
Thomas J
TJ
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*
D000935:Antifungal Agents; D015415:Biomarkers; D054714:Echinocandins; D055666:Lipopeptides; D047071:beta-Glucans; D000666:Amphotericin B; D000077551:Micafungin
Clin Infect Dis. 2005 Sep 1;41(5):654-9
16080087
J Clin Pharmacol. 2007 Aug;47(8):1049-54
17525169
Antimicrob Agents Chemother. 2007 Oct;51(10):3714-9
17638696
Pediatr Infect Dis J. 2004 Dec;23(12):1093-7
15626944
N Engl J Med. 2002 Dec 19;347(25):2020-9
12490683
Pediatrics. 2006 Jan;117(1):84-92
16396864
Clin Vaccine Immunol. 2007 Jul;14(7):924-5
17538119
Lancet. 2003 Oct 4;362(9390):1142-51
14550704
J Paediatr Child Health. 2000 Oct;36(5):509-10
11036812
Antimicrob Agents Chemother. 1997 Jun;41(6):1392-5
9174207
J Infect Dis. 2008 Jan 1;197(1):163-71
18171300
J Clin Microbiol. 1987 May;25(5):931-2
3294892
J Clin Microbiol. 2004 Jan;42(1):236-8
14715758
J Med Vet Mycol. 1997 Mar-Apr;35(2):79-86
9147267
Clin Infect Dis. 2004 Jul 15;39(2):199-205
15307029
Eur J Clin Microbiol Infect Dis. 2005 Oct;24(10):662-4
16247615
Pediatrics. 2003 Sep;112(3 Pt 1):634-40
12949295
N Engl J Med. 2007 Jun 14;356(24):2472-82
17568028
Lab Anim Sci. 1988 Aug;38(4):467-71
3184859
Expert Rev Anti Infect Ther. 2006 Apr;4(2):325-42
16597212
Pediatr Infect Dis J. 2000 Jun;19(6):499-504
10877162
J Antimicrob Chemother. 2002 Jun;49(6):889-91
12039879
Pediatrics. 2006 Apr;117(4):1094-100
16585303
J Infect Dis. 2000 Jul;182(1):274-82
10882607
Expert Opin Investig Drugs. 2003 Aug;12(8):1313-33
12882619
Pediatrics. 2000 Oct;106(4):712-8
11015513
Antimicrob Agents Chemother. 2001 Dec;45(12):3322-7
11709303
Med Mycol. 2005 Sep;43(6):559-64
16320498
Clin Infect Dis. 2000 Aug;31(2):458-63
10987705
J Perinatol. 2007 Feb;27(2):97-100
17080094
Antimicrob Agents Chemother. 2002 Jun;46(6):1857-69
12019101
Paediatr Drugs. 2007;9(3):139-42
17523693