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!

Questions?