zerebrale aspergillose
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U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Zerebrale Aspergillose
PEG-FrühjahrstagungSektion Antimykotische
Chemotherapie7.-8.5.2010, Bonn
First reports on pulmonary aspergillosis
John Hughes Bennett(1812-1875)1842 Aspergillus in sputum of a patient with pneumonia
Rudolf Virchow(1821-1902)1856 report on ‚Broncho- und Pneumo-mycosis aspergillina‘ in 4 patients
First report on CNS aspergillosis
Oppe, Zbl allg Path path Anat. 1897; 8/9:301.
hematogenous
CNS invasion by Aspergillus
continuous
Forms of CNS aspergillosis
abscess +/- hemorrhage
meningitis
mycotic aneurysm
ischemic infarction
granuloma
Kleinschmidt-DeMasters BK. Hum Pathol. 2002;33:116-124. Ho CL, Deruytter MJ. Acta Neurochir 2004;146:851. Petrick M, Honegger J, Daschner F, Feuerhake F, Zentner J. Neurosurgery. 2003;52:955-958.
myelitis
Frequency of fungal CNS involvement
CNS-aspergillosis3.3%
Yamazaki T, et al. J Clin Microbiol. 1999;37:1732-1738.
1964-1994
594,263 autopsies
7,960 invasive mycoses
107
28
15 14
0
20
40
60
80
100
120
140
Lung CNS Kidney Heart
Frequency of CNS aspergillosis
Bodey G, et al. Eur J Clin Microbiol Infect Dis. 1992;11:99-109.
no. o
f pts
.
4,096 autopsies (1980-1988) patients with malignant diseases12 centers from Europe, Canada, and Japan
CNS-aspergillosis20%
137 patients with invasive aspergillosis
Brain Abscess After Bone Marrow Transplant
33
19
5 41
0
10
20
30
40
aspergillus candida other filamentousfungi
bacteria T. gondii
Num
ber o
f Org
anis
ms
Results from stereotactic biopsies/autopsies (1984-1992) Frequency of brain abscesses in BMT patients: 2%!
Hagensee ME, et al. Clin Infect Dis. 1994;19:402-408.
Mixed infections: 3x aspergillus + candida; 1x candida + enterobacter
Mortality 97%
58 patients after BMT (allo 56, auto 2)
Invasive aspergillosis: response rates
Patterson T et al., Medicine 2000, 79: 250
0
20
40
60
80
100
pulmonary disseminated cerebral other
Com
plet
e or
par
tial r
espo
nse
(%)
595 patients since 1990, 92 centers72% amphotericin B
9%
response rate: 37% (221/595 patients)
28 skin27 sinusitis9 tracheobronchitis53 other
Mortality According to Site
Denning D. Clin Infect Dis. 1996;23:608-615.
0
20
40
60
80
100
Pulmonary Sinusitis Cerebral
Mor
talit
y (%
)
99% (140/141 patients)
Review of studies with ≥4 patients since 1971Definite/probable aspergillosis
Overall mortality: 80% (981/1223 patients)
0
20
40
60
80
100
CNS ordisseminated
multisite diffusepulmonary
tracheobronchitis localisedpulmonary
sinusitis cutaneous/other
Case fatality rate according to site
Cas
e fa
talit
y ra
te (%
)Review of studies with ≥10 patients since 1995
1941 patients with invasive aspergillosis
88% (74/84 patients)
Disseminated → >1 organMultisite → >1 lesion in a single organ
overall case fatality rate: 58%
Lin SJ, Schranz J, Teutsch SM. Clin Infect Dis. 2001;32:358-366.
Survival CNS aspergillosis
aConventional amphotericin B, bLiposomal amphotericin B, cFlucytosine, dItraconazole
0 20 40 600
25
50
75
100
Time (Days)
Surv
ival
func
tion
17 patients with proven/probable CNS-aspergillosisconvAMBa (13), L-AmBb (5), 5-FCc (3), ITRAd (2), none (2)
1993-1999
10
Schwartz S, et al. Mycoses. 2007;50:196-200.
Blood-brain Barrier
Basal membrane
Tight junctions
Astrocyte
Endothelial cell
Approximate total vessel length: 600 km ≈ 373 milesApproximate area of blood-brain barrier (BBB): 20m2
Blood-cerebrospinal-fluid Barrier- Choroid plexi and arachnoid (fenestred) epithelium- Faces the cerebrospinal fluid- Approximate area of blood-cerebrospinal fluid barrier ≈ BBB: 20m2
Blood-brain Barrier Transport Systems
de Boer AG, Gaillard PJ. Annu Rev Pharmacol Toxicol. 2007;47:323-355.
Endothelialcell layer
polycationicpeptidesglucose insulin
octanol/water-gradient
cAMB
ITRA POS
FLC VRC
Log P
0.95
6.99 / 6.1
-0.89
2.17 / 2.56
-3.8, -2.8, +0.21
CASPOMICA ANIDULA5-FC
L-AMB
Kethireddy S & Andes D, Expert Opin Drug Metab Toxicol. 2007; 3:573.
lipop
hilic
hydr
ophi
lic
Molecular size of antifungal agents
cAMB
ITRA POS
FLC VRC
molecularweight(Da)
924
705/708
129
306/349
~1200CASPO MICA ANIDULA
5-FC
L-AMB
400 - 600diffusion
across the intact BBB
Amphotericin B in Human Brain Tissue
Tissue specimens from necropsymethanolic extraction -> HPLC
Brain tissue (µg/g)median (range)
Recovery (% total dose)median (range)
Amphotericin Bdeoxycholate (n=9)
0.5 (0.2-5.8) 0.3 (0-1.4)
LiposomalAmphotericin B (n=8) 0.7 (<0.1-1.6) 0.2 (<0.1-0.2)
Collette N, et al. Antimicrob Agents Chemother 1989;33:362.Collette N, et al. J Antimicrob Chemother 1991;27:535.
Tissue level measurements of D-AmB
Collette N, et al. Antimicrob Agents Chemother. 1989;33:362.
Methanolic extraktion -> HPLCMethanolic extraktion -> bioassay (Paecilomyces var.)Homogenisate -> bioassay (Paecilomyces var.)
Methanol/Bioassay
Homogenisat/Bioassay
Methanol/HPLC
Leber Milz Lunge Niere
Brain Tissue Penetration Caspofungin
Hajdu R, et al. Antimicrob Agents Chemother 1997;41:2339.
Concentrations of caspofungin over timeSingle i.p. injection of 1mg/kg
3 mice per time point
The Future: Higher Doses of Echinocandins?
0
1
2
3
4
brai
n tis
sue
conc
entr
atio
n (µ
g/g)
0,1 0,25 0,5 1 2 5 10dose (mg/kg)
Anidulafungin Micafungin
Groll AH, et al. Antimicrob Agents Chemother 2001;45:2845.Groll AH, et al. Antimicrob Agents Chemother 2001;45:3322.
Anidulafungin3-6 neutropenic rabbits per groupchallenged iv with C. albicansTreatment for 10 days
Micafungin3 healthy rabbits per groupno immunosuppressionTreatment for 8 days
Brain Tissue Concentration Itraconazole
Tissue concentrations in ratsafter a single dose of 10 mg/kg
Mean tissue/plasma ratios in dogsafter 12 months daily treatment with5, 20, and 80 mg/kg
Heykants J, et al. The pharmacokinetics of itraconazole in animals and man: an overview. In: Fromtling RA, ed. Barcelona, Spain: J.R. Prous Science Publishers; 1987:223-249.
0 8 16 24 32 40 48 56 64 720.01
0.02
0.05
0.1
0.2
0.5
1
2
5
10
20
50
100
HOURS
UD
Brain
Plasma LungLiver
Kidney
Adrenal
0 10 20 30
Fat
Liver
Skin
Pancreas
Kidney
Heart
MuscleStomach
Lung
BrainPlasma
TISSUE / PLASMA CONCENTRATION RATIO
P-gpa Expression in Human Cortex Vessels
Virgintino D, et al. J Histochem Cytochem. 2002;50:1671-1676.
Cortex specimens from patients with high-grade gliomaConfocal laser microscopy
Cortex microvessel
P-gp Caveolin-1 P-gpCaveolin-1
a P-glycoprotein
Itraconazole Brain Concentrationsmdr1 knockout mice (mdr1 -/-)vs
FVB mice (mdr1 +/+)-> Itraconazole 5mg/kg iv
Miyama T, et al, Antimicrob Agents Chemother. 1998;42:1738-1744.
ITZ conc.mdr1 -/-
mdr1 +/+
Rats treated iv with:5mg/kg itraconazole-/+ prior 5mg/kg verapamil
Bra
in ti
ssue
/pla
sma
ratio
Posaconazole CSF Concentrations
Rüping M, et al. J Antimicrob Chemother 2008;62:1468.
3 patients600 – 3200 mg POSA orally per day
1 patientinvasive pulmonary aspergillosis, meningeal leukemia after alloHSCT800 mg POSA orally per day
Reinwald M, et al. Bone Marrow Transplant 2009;44:269.
CSF (µg/mL) Plasma (µg/mL) CSF/plasma0.00118 – 0.00459 0.136 – 0.989 0.0042 – 0.0087
CSF (µg/mL) Serum (µg/mL) CSF/plasma<0.01 0.088 n.a. GvHD, CNS zygomycosis≤0.187 0.396 0.41 – 0.47 Bacterial brain abscess≤0.221 0.0934 2.25 – 2.37 Cerebral aspergillosis
Voriconazole Tissue Distribution in Animals
• Concentrations of radioactivity in male rat tissue at 5 minutes post infusion
• Cerebrospinal fluid/plasma concentrationratio = 0.8 in guinea pigs at steady state after multiple dosing
Tissue concentration μgeq/g Blood 4.3 Brain 8.1 Eye – retina 13.0 Kidney – cortex 10.4 Liver 21.1 Lung 5.8
Jezequel et al. ICAAC 1995
Lutsar, I., et al. Clin Infect Dis. 2003;37:728-732.
Guinea pigs without infection analysed hourly after 5days of2, 4, 10 mg/kg VRC q8h
10mg/kg
4mg/kg
plasma
plasma
CSF
CSF
Penetration of Voriconazole into CSF
Voriconazole Levels Brain Tissue/Abscess
Lutsar I, et al. Clin Infect Dis 2003;37:728.
Age (years) Dosing Brain tissue36 4.5 mg/kg q12h 11.8 µg/g13 7.2 mg/kg q24h 58.5 µg/g
2 patients with invasive pulmonary aspergillosis† 9-10 hours after stop of VRC
1 patientrhinocerebral aspergillosis(4mg/kg q12h)
Elter T, et al. Int J Antimicrob Agents 2006;28:262.
Specimen Brain tissueLiquid abscess 1.4 µg/gSolid abscess 1.2 µg/g
1 patientC. albicansmeningoencephalitis(4mg/kg q12h)
Schwartz S, et al. ICAAC 2007:440 (M-1161).
Specimen Brain tissue Post doseLiquid abscess 5.1 µg/mL 4 hDura mater 1.4 µg/g 3.5 h
Voriconazole Levels Brain
Henry ME, et al., ICAAC. 2009: (A1-421).
Healthy volunteers (n=12)VRC dosingday 1: 2x400mg, day 2: 2x200mg, day 3: 200mg -> MRI
brain conc. (µg/mL)Pre dose (2h) 2.09Post dose (2h) 4.17
N
All aspergillosis 747*CNS aspergillosis 85
clinical trials 37emergency/compass. 48
Certaintydefinite 48probable 33possible 4
All definite/probable 81* All patients treated with voriconazole
Voriconazole in CNS aspergillosis
Schwartz S, et al. Blood 2005;106:2641.
Underlyingcondition N Median Rx
days (range)Satisfactory response %
Hematologicmalignancy 13 96 (5 – 522) 54
Other 14 82 (1 – 946) 50
Chronic immuneSuppression
11 122 (9 – 1128) 45
Solid organtransplant
11 39 (7 – 825) 36
BMT 32 20 (3 – 390) 16*
TOTAL 81 51 (1 – 1128) 35*BMT Vs All others p = 0.004
Schwartz S, et al. Blood 2005;106:2641.
Voriconazole for Cerebral Aspergillosis
Duration of reported survival:3-1,245 days (median: 69 days)
Schwartz S, et al. Blood. 2005;106:2641-2645.
Surv
ival
Fun
ctio
n
1.0
0.8
0.6
0.4
0.2
0.00 200 400 600 800 1000 1200 1400
Time (Days)
Voriconazole for Cerebral Aspergillosis
81 patients with proven/probable cerebral aspergillosis96% with failure or intolerance to previous therapies
Impact of Underlying Conditions
All other U.D. n = 49
BMT n = 32Surv
ival
Fun
ctio
n
1.0
0.8
0.6
0.4
0.2
0.00 200 400 600 800 1000 1200 1400
Time (Days)
Risk ratio: 2.0 (1.1 - 3.6) p=0.02
Schwartz S, et al. Blood 2005;106:2641.
Impact of neurosurgical interventions
Craniotomy/abscess resection (14), abscess drainage (12),ventricular shunt (4), Ommaya-reservoir (1)
1.0
0.8
0.6
0.4
0.2
0.0
Surv
ival
Fun
ctio
n
0 200 400 600 800 1000 1200 1400
Time (Days)
With neurosurgery (n=31)
No/unknown neurosurgery (n=38/12)
Risk ratio 2.1 (1.1-3.9) P=0.02
81 patients with voriconazole for proven/probable cerebral aspergillosis
Schwartz S, et al. Blood 2005;106:2641.
Schwartz S, et al. ICAAC 2009: (M 1056).
• Retrospective analysis• Voriconazole database• Literature from jan. 2002 until dec. 2008
• CNS infections in: • Aspergillosis - 120 patients• Scedosporiosis - 34 patients• Cryptococcosis and others* - 38 patients-> total of 192 patients
* Blastomyces dermatitidis = 5; Cryptococcus neoformans = 11; C. gattii = 1; Coccidioides immitis = 3; Cladophialophora bantiana = 5; Candida spp = 3 (C. albicans = 1, C. krusei = 1, Candida spp = 1); Chrysosporium spp = 1; Curvularia geniculata = 1; Fonsecaea monophora = 1; Fusarium spp = 3 (F. dimerum = 1, F. solani = 1, Fusarium spp = 1); Histoplasma capsulatum = 2; Ochroconis gallopavum = 1; Ramichloridium mackenzie = 1.
Voriconazole in CNS Mycoses
Survival by Fungus Group
Other spp.Scedosporium spp.
Aspergillus spp.
Other spp.
Aspergillus spp.
Schwartz S, et al. ICAAC 2009: (M 1056).
Impact of Neurosurgery on Survival
* ventricular drainage/shunt (7), abscess biopsy/drainage (28), other (37; mostly craniotomy or abscess resection)
Neurosurgery (72)*
No/unknown neurosurgery (119)
Schwartz S, et al. ICAAC 2009: (M 1056).
Publication Bias on Survival?
Published cases (78)
Database cases (114)
Schwartz S, et al. ICAAC 2009: (M 1056).
Thank you for your attention!
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