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Cladophialophora bantiana
: a rare cause of fungal brain
abscess. Clinical aspects and new therapeutic options
CHRISTIAN GARZONI*, LYDIA MARKHAM$, PHILIPPE BIJLENGA% & JORGE GARBINO$
*
Infectious Diseases Division, University Hospital of Bern, Bern,
$
Infectious Diseases Division, University Hospitals of Geneva,
Geneva, and
%
Neurosurgery, Department of Clinical Neurosciences, University Hospitals of Geneva, Geneva, Switzerland
Black molds or dematiaceous fungi are rare etiologic agents of intracerebral
abscesses and such infections carry a high mortality of up to 70% despite
combined surgical and antifungal therapy. While the growing use of immuno-
suppressive therapies and organ transplantation have caused an increase in the
incidence of rare fungal cerebral infections, occurrence in immunocompetent
hosts is also possible. We describe a 60-year-old female patient with a cerebral
abscess caused by Cladophialophora bantiana. The case illustrates the clinical and
radiological similarities between glioblastomas and brain abscesses and empha-
sizes the need to perform histological and microbiological studies prior to the
initiation of any form of therapy. Long-term survival from cerebral black mold
abscesses has been reported only when complete surgical resection was possible.
The recommended antifungal treatment involves the use of amphotericin B
combined with a triazole and, if possible, flucytosine. Highly-active new
generation triazole antifungal compounds (voriconazole or posaconazole) are
likely to offer improved survival rates for patients with rare mold infections. In
particular, posaconazole could be a new therapeutic option given its better
tolerance, lower toxicity and fewer drug-drug interactions. We discuss clinical,
microbiological and practical pharmacological aspects and review current and
evolving treatment options.
Keywords brain abscess, Cladophialophora bantiana, dematiaceous fungus,
posaconazole, voriconazole
Introduction
Cladophialophora bantiana is a highly neurotropic
dematiaceous fungus and a rare cause of cerebral
abscesses. Such infections carry a high mortality of
up to 70% and neurosurgical radical resection asso-
ciated with powerful antifungal treatment is the most
successful therapeutic strategy reported to date. We
describe a case involving a 60-year-old woman with an
unresectable C. bantiana brain abscess treated by a
combined approach of CT-guided aspiration and
aggressive antifungal therapy. Sequential imaging sug-
gests that the fungal infection was contained. This case
illustrates the absence of a pathognomonic image of
glioblastoma and the absolute need to obtain histo-
pathological confirmation when possible before initia-
tion of any treatment. Highly active new-generation
antifungal compounds will probably improve the
prognosis of rare mold infections of the central
nervous system (CNS) and we review the microbiolo-
gical and practical pharmacological aspects of these
evolving therapies.
Case Report
A 60-year-old woman was referred to our institution
because of fever and frequent falls ten days after her
arrival in the country. Upon admittance, she was sleepy
Correspondence: Jorge Garbino, Service of Infectious Disease,
University Hospitals of Geneva, 24 Rue Micheli-du-Crest, 1211
Geneva 14, Switzerland. Tel: 41 22 372 9839; Fax: 41 22 372
9832; E-mail: jorge.garbino@hcuge.ch
Received 4 September 2007; Accepted 14 January 2008
– 2008 ISHAM DOI: 10.1080/13693780801914906
Medical Mycology
August 2008, 46, 481486
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and confused. Her medical history included long-term
corticoid therapy (10 mg/d) and cholchicine 1 mg/d for
systemic sclerosis, pulmonary fibrosis and Raynaud’s
phenomenon which was in remission after six months
of cyclophosphamide treatment she received three years
earlier. She had chronic hepatitis C-related cirrhosis,
chronic thrombocytopenia linked to secondary hypers-
plenism (60 G/L, normal range 150350 G/L) and
arterial hypertension.
Neurological examination was normal apart from
drowsiness and confusion, as was the rest of the clinical
examination. Laboratory investigations revealed the
lack of an inflammatory syndrome (normal leucocytes,
C-reactive-protein B1 mg/l). Liver enzymes were
known to be chronically elevated because of active
hepatitis C. A cerebral CT-scan showed a 2 cm diameter
ring-enhancing lesion in the left posterior arm of the
internal capsule compressing the left lateral ventricle
(Fig. 1A & B). Magnetic resonance imaging (MRI) of
the brain showed a ring-enhancing lesion in the body of
the caudate infiltrating the corpus callosum and the
posterior arm of the internal capsule, strongly suggest-
ing the diagnosis of high grade glioma (Fig. 1C & D).
Due to the history of chronic immunosuppressive
therapy with prednisone and previous cyclophospha-
mide treatment for systemic sclerosis, the probability of
a secondary cerebral lymphoma or an opportunistic
infectious process was considered. Antibiotic treatment
with imipenem-cilastatin 500mg i.v. every 6 h associated
with dexamethasone 100 mg was started. Serology for
toxoplasma was negative (IgM and IgG) eliminating the
possible presence of a cerebral toxoplasmosis abscess.
The patient deteriorated during the first week
with the appearance of progressive right hemiparesis,
Fig. 1 Initial imaging of lesion. (A) Axial section of native CT-Scan demonstrating a discrete hypodensity in the left body of the caudate and
mass effect on the lateral ventricule. (B) Contrast-enhanced CT-Scan showing enhancement of the lesion. (C) Axial section of contrast-enhanced
T1-weighted MRI. (D) Coronal reconstruction of contrast-enhanced T1-weighted MRI showing extension within corpus callosum.
– 2008 ISHAM,
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, 46, 481486
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aphasia and a worsening in sensorium. Notwithstand-
ing both the risk of hemorrhage increased by throm-
bocytopenia and radiological features advocating
glioblastoma diagnosis, a neuronavigation-guided fra-
meless needle biopsy was performed under platelet
transfusion. Approximately 5 ml of a total lesion
volume of approximately 67 ml was aspirated. Micro-
scopic analysis of Gram, Calcofluor white and Grocott
silver stained biopsy material revealed a brain abscess
suspected to be caused by a black mold.
The presumptive diagnosis was confirmed by further
analysis. The aspirated liquid was cultured onto
CHROMagar Candida (Beckton Dickinson, New Jer-
sey, USA). After 12 days, 20 mm size colonies were
noted developing in culture. They had a velvety texture
and were olive gray to black on the obverse and black
on the reverse. Microscopic examination of a lactophe-
nol stained slide culture preparation revealed brown
septate hyphae with long, sparsely branched conidio-
phores bearing wavy chains of smooth oval conidia.
The latter did not display dark attachment scars as has
been described for other Cladosporium spp. Aspirated
liquid was also inoculated onto Sabouraud dextrose
agar. The isolate recovered could grow at 428C, a
feature that differentiates C. bantiana from other
morphologically similar saprophytic fungi (Fig. 2). To
corroborate the identification of the species, samples
were subjected to a polymerase chain reaction (PCR)
amplification with ITS (internal transcribed spacer) 1
and ITS4 primers as previously described [1]. The
amplicon was sequenced on an ABI PRISM 310
Genetic Analyser sequencer (Applied Biosystems,
Rotkreuz, Switzerland); the resulting sequence was
analyzed with the FASTA program and compared
with other sequences of the Cladophialophora genus
published in GenBank (NCBI) and SeqWeb2.1.0. [1].
The results confirmed the microbiological diagnosis.
C. bantiana was susceptible to all antifungal agents
apart from fluconazole. The minimal inhibitory con-
centrations (MIC; YeastOne
TM
Trek Diagnostic, Penn-
sylvania, USA) obtained were (mg/ml): amphotericin
B, 1.0 mg/ml (susceptible S); fluconazole, 64 mg/ml
(resistant); itraconazole, 0.023 mg/ml (S); ketoconazole,
0.032 mg/ml (S); flucytosine, 1.0 mg/ml (S); voriconazole
0.064 mg/ml (S); posaconazole, 0.02 mg/ml (S); caspo-
fungin, 0.50 mg/ml (S). Since no breakpoints have been
well established for the different antifungal drugs, it is
difficult to establish a standardized antifungal therapy.
In addition, the efficacy of various antifungal agents
against black molds is not clearly defined in cases
involving humans. However, there has been limited
clinical experience with the newer antifungal com-
pounds like third-generation antifungal triazoles posa-
conazole and voriconazole.
Voriconazole (400 mg p.os b.i.d) and liposomal
amphotericin B (5 mg/kg body weight daily) were
started and gradually increased to 7 mg/kg/day. Vor-
iconazole was preferred over itraconazole because of
better bioavailability (96% vs 55%) and cerebrospinal
fluid penetration (90% vs. 50%). Flucytosine could not
be added to this regimen because of the risk of
myelotoxicity in a patient with chronic thrombocyto-
penia. Aphasia remained unchanged and right hemi-
plegia worsened. Brain MRI performed 5 days after
starting treatment showed an increase in the initial
lesion and new lesions following the biopsy tract (Fig.
3A). The increase in the levels of liver enzymes (ASAT
and ALAT) from 59 and 105 U/l at admission to 176
and 310 U/l, respectively (normal range, 1142 U/l))
confirmed hepatotoxicity and voriconazole was re-
placed by posaconazole (400 mg b.i.d p.os). Ten days
after the change to posaconazole, liver enzymes im-
proved rapidly (ASAT 115 U/l and ALAT 189 U/l).
A third MRI performed 11 days after the introduc-
tion of posaconazole showed control of the growing
brain abscesses. The volume of the lesions was sig-
nificantly reduced and less midline shift was evidenced
(Fig. 3B). Neurological deficits remained stable. Con-
sidering the dynamic of abscess growth before the
introduction of posaconazole, the findings were inter-
preted as evidence of the efficacy of the treatment with
posaconazole. Unfortunately, the patient developed
aspiration nosocomial pneumonia with severe sepsis
and died.
Fig. 2 Histological and cytological (inset) analysis (Grocott silver
stain coloration) revealed invasion of brain structures by septed low
branching hyphae.
– 2008 ISHAM,
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, 46, 481486
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Discussion
Infection of the central nervous system caused by a
dermatiaceous mold is referred to as cerebral phaeo-
hyphomycosis, which may be literally defined as ‘infec-
tion due to dark-walled fungi’, i.e., those with the dark
pigment melanin. While rare, C. bantiana (formerly
Cladosporium bantianum, Cladosporium trichoides and
Xylohypha bantiana) is the most common agent of this
disease.
Although infections caused by dematiaceous fungi
are not common, they are being increasingly recog-
nized as being involved in human disease, particularly
in the immunocompromised host [2,3]. They can cause
soft-tissue infection, sinusitis, mycetoma and CNS
abscesses. In particular, C. bantiana has a high
specificity for the CNS as evidenced in a recent
extensive review of 101 cases of cerebral phaeohypho-
mycosis in which 48 cases were associated with C.
bantiana [2]. The infection usually results from hema-
togenous dissemination from a primary site of inva-
sion, commonly the lung. However, the absence of a
primary focus is not unusual.
Brain abscesses caused by C. bantiana have been
reported in both immunocompetent and immunocom-
promised patients, predominantly in transplant recipi-
ents [413]. Immunosuppression due to corticoid
therapy, neutropenia or diabetes mellitus has also
been associated with infections caused by this mold
[14,15]. Direct inoculation, eye trauma and intravenous
drug use are other known risk factors. Given the
increasing use of immunosuppressive therapies and
organ transplantation, the incidence of rare fungal
diseases, including cerebral mold infections, will cer-
tainly be observed more frequently.
Clinically, patients may present with insidious head-
aches and slow evolving neurological signs. It is
important to stress that fever is not always present
and infection parameters can be normal on admission
of the patient. The abscess can be single or multiple and
is usually easy to identify through CT or MRI studies
[16]. Radiologically, fungal abscesses caused by rare
fungi such as C. bantiana cannot be differentiated with
certitude from bacterial abscesses, primary CNS neo-
plasia or cerebral metastasis. In particular, differentiat-
ing between brain abscesses and cystic brain tumors
such as high-grade gliomas and metastasis is often
difficult, if not impossible [17]. In the immunocompro-
mised host, the differential diagnosis is broader and
opportunistic infections (toxoplasmosis, nocardiosis,
and listeriosis among others) and specific malignancy
like lymphoma should also be considered. Cerebral
biopsy with histological studies and exhaustive micro-
biological cultures for bacteria, mycobacteria and fungi
are considered the gold diagnostic standard and should
always be performed.
The mortality rate of cerebral C. bantiana infection is
high. A recent series confirmed a death rate of 70%
despite surgical resection and systemic antifungal
therapy [1]. Several studies have shown that radical
surgical resection followed by targeted pharmacological
treatment enabled good recovery in some cases [18].
One study of 26 cases of cerebral C. bantiana infections
concluded that radical surgical resection of the CNS
lesions was the best outcome predictor [16]. However,
given that CNS disease by C. bantiana is a rare, life-
threatening condition, recommendations for systemic
antifungal therapy can only be based upon the
experience of isolated cases. Based on a large case
series [16], systemic antifungal treatment does, however,
Fig. 3 MRI coronal reconstruction of T1-weighted contrast-enhanced images at similar rostro-caudal levels. (A) Two days before posoconazole
treatment initiation. Note seeding along biopsy tract. (B) Eleven days after posoconazole treatment the enhancement of the lesions were reduced.
– 2008 ISHAM,
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, 46, 481486
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et al.
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appear to affect outcomes. Antifungal therapy is
evolving rapidly and more efficient and better tolerated
new drugs are now available.
Fluconazole is not active against C. bantiana and the
classical medical treatment is amphotericin B i.v. alone
or associated with flucytosine and itraconazole. In the
largest published review of 48 cases, mortality was
as high as 70% despite the use of these antifungal
agents [2]. The major factor causing such high mortal-
ity rates is the poor penetration of amphotericin B
(either as deoxycholate or liposomal form) and itraco-
nazole across the blood-brain barrier [19,20]. Further-
more, major adverse effects associated with the use of
these drugs often limit and force an interruption of
treatment. Amphotericin B is known for its renal
toxicity and electrolyte disturbances. Flucytosine use
is limited by its high bone marrow toxicity. Itracona-
zole is an azole used as standard treatment but its oral
formulation presents large inter-individual differences
in gastrointestinal absorption which is a major limita-
tion and necessitates monitoring of drug levels.
Voriconazole or posaconazole are new second-gen-
eration triazole compounds and represent very attrac-
tive options to replace itraconazole in C. bantiana
cerebral infections. Both show broad antifungal spec-
trum in vitro, including C. bantiana, with a very good
oral bioavailability, high volume distribution and high
tissue concentration including the CNS [21]. Successful
treatment of C. bantiana cerebral infections with both
compounds has been reported recently [22,23]. The
most common side effects reported with voriconazole
are transient visual disturbances and liver toxicity [24].
Posaconazole is also very active, both in vitro and in
vivo, in other human fungal infections such as asper-
gillosis or zygomycosis [15,21,25]. Efficacy of posaco-
nazole was shown to be superior to itraconazole or
amphotericin B in a recent mouse model of C. bantiana
infection [26]. Posaconazole could be considered as an
alternative to voriconazole in cases of pre-existing liver
disease or side effects during treatment as occurred in
our patient. The case reported herein showed a rapid
reduction in liver enzymes after a switch from vorico-
nazole to posaconazole treatment and signs of radi-
ological improvement following posaconazole
introduction that were not observed during voricona-
zole treatment. Other new antifungals are the echino-
candins, of which three are currently available, i.e.,
caspofungin, micafungin, and anidulafungin. They
have limited toxicity profiles and minimal drugdrug
interactions. Unfortunately, black molds are less sus-
ceptible to them.
New antifungal drugs such as voriconazole or
posaconazole will probably lead to an improvement
of the prognosis of cerebral fungal abscesses but it
should be kept in mind that, whenever possible,
neurosurgical radical removal of the abscess is currently
the treatment of choice and its role will probably not
change despite new compounds.
Conclusions
Although rare, C. bantiana is frequently associated with
CNS abscesses. However, other rare fungal etiologic
agents should not be excluded from the diagnosis even
in the immunocompetent host. Biopsy and microscopic
observations, along with microbiological studies for
bacteria, mycobacteria and fungi should always be
performed to confirm the diagnosis in cases of evolving
intracerebral mass lesions. A multidisciplinary ap-
proach among neurosurgeons, infectious disease spe-
cialists and microbiologists is mandatory in all cases of
rare cerebral fungal disease in order to correctly
interpret test results and optimize antifungal therapy.
The latter is rendered difficult because of the rarity of
such diseases, difficulties in extrapolating drug efficacy
from in vitro susceptibility testing, availability of several
new potent drugs, experience in adverse events and
drug-drug interactions. Promising new therapies are
currently available and additional studies will confirm
soon if their introduction into clinical practice will
really translate into improved survival. Despite the
often fatal outcome, we encourage clinicians to con-
sider newer therapeutic approaches for these life-
threatening infections when resection is not possible.
Acknowledgements
We are grateful to Kalthum Bouchuigui-Waf for her
microbiological support.
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This paper was first published online on iFirst on 5 March 2008.
– 2008 ISHAM,
Medical Mycology
, 46, 481486
486 Garzoni
et al.
Med Mycol Downloaded from informahealthcare.com by University of Geneva on 10/05/11
For personal use only.