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Acr emonium Species: A Review of the Etiological Agents of Emerging

Hyalohyphomycosis

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DOI: 10.1007/s11046-010-9334-1 · Source: PubMed

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Acremonium Species: A Review of
the Etiological Agents of Emerging
Hyalohyphomycosis

Mycopathologia

ISSN 0301-486X
Volume 170
Number 6

Mycopathologia (2010)
170:361-375
DOI 10.1007/
s11046-010-9334-1

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 Author's personal copy
Mycopathologia (2010) 170:361–375
DOI 10.1007/s11046-010-9334-1
Acremonium Species: A Review of the Etiological Agents
of Emerging Hyalohyphomycosis
Shukla Das • Rumpa Saha • Sajad Ahmad Dar
V. G. Ramachandran
Received: 1 February 2010 / Accepted: 9 June 2010 / Published online: 25 June 2010
Ó Springer Science+Business Media B.V. 2010
Abstract Unusual fungal agents that exist environ-
mentally as saprophytes can often lead to opportunis-
tic infections. Hyalohyphomycosis is a group of fungal
infections caused by fungi characterized by hyaline
septate hyphae and can infect both immunocompetent
as well as immunocompromised patients. Many a
times it becomes difficult to distinguish a pathogenic
and a contaminant fungus, because many such agents
can assume clinical significance depending on cir-
cumstances. Subcutaneous and invasive fungal infec-
tion due to the emerging hyalohyphomycotic fungus,
Acremonium, has drawn the attention of clinicians and
microbiologists, as a potential pathogen in patients
with and without underlying risk factors. Generally
considered to be minimally invasive in the past, genus
Acremonium has been responsible for eumycotic
mycetomas and focal infections in otherwise healthy
individuals. It has also been increasingly implicated in
systemic fungal diseases. The management with
different antifungals in various clinical situations has
been very conflicting and hence needs to be carefully
evaluated. This overview is an endeavor to consolidate
the available clinical infections due to Acremonium
and the recommendations on treatment.
S. Das (&)
R. Saha
S. A. Dar
V. G. Ramachandran
Department of Microbiology, University College
of Medical Sciences (University of Delhi) and Guru Teg
Bahadur Hospital, Delhi 110095, India
e-mail: shukladas_123@yahoo.com
•
Keywords Acremonium
Hyalohyphomycosis

Antifungals
Introduction
Recent years have witnessed steady changes in the
spectrum of clinically important fungal infections. In
addition to the well-established fungal pathogens, a
number of soil saprophytes and plant pathogens have
also been associated with a variety of human infec-
tions. Immunocompromised individuals are the targets
of these agents; however, apparently healthy individ-
uals with no underlying risk factors also fall prey.
The term hyalohyphomycosis is specially desig-
nated for infections caused by ubiquitous saprophytes
such as Fusarium, Scedosporium, Scopulariopsis,
Penicillium marneffei and Acremonium, which appear
as hyaline, septate mycelial elements, with branched
or intertwined hyphae. Although these filamentous
fungi are common environmental saprophytes, they
cause a variety of infections mostly thought to be
secondary to prior colonization and increased host
susceptibility [1, 2]. Following introduction by
penetrating trauma or abrasions in the immunocom-
petent individuals, they usually cause localized infec-
tions. However, disseminated infections tend to occur
among severely immunocompromised hosts such as
those undergoing transplantation or in patients with
AIDS [3]. Among these hyaline fungi, the number and
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362
diversity of infections caused by Acremonium species
have increased in recent years, resulting in a wide
spectrum of clinical diseases.
Acremonium is an opportunistic environmental
pathogen and its existence in soil or air can often lead
to superficial infections. Substantial data exists on its
clinical and geographical distribution in immunocom-
petent population as well. However, its association in
serious infections in severely immunocompromised
patients has given this genus a special status among the
hyaline fungi. Clinically, it has been associated with
diseases like onychomycosis, otomycosis and compli-
cations in burn patients [4]. It is also a well-recognized
etiological agent of mycetoma [5, 6]. Infections
caused by hyalohyphomycetes are being increasingly
reported; the reason for the increase in occurrence
could probably be related to intervention such as
antifungal prophylaxis or the use of medical devices
and increased awareness in identifying these agents by
clinical laboratories.
The genus Acremonium (also known as Cephalo-
sporium) isolated from dead plant material and soil
includes approximately 150 species. The earliest
documented reports of Acremonium dates back to
1839. Corda named it first as Acremonium cephalo-
sporium. There was a little evidence of the pathoge-
nicity of Acremonium until the twentieth century.
During investigation of their antimicrobial property in
1953, they were eventually identified as the fungal
agent Cephalosporium Acremonium, which culmi-
nated in the development of cephalosporin group of
drugs. Only in 1971, the genus Acremonium followed
the criteria of standard taxonomical nomenclature and
was accorded a separate genus [7]. Quite belatedly, in
1971, the status of Acremonium as a separate genus
became operational following the criteria of standard
taxonomical nomenclature. Recently, it was demon-
strated by DNA sequence analysis that one of the species
A. strictum displays a broad genetic polymorphism.
Taxonomy
Acremonium is a cosmopolitan environmental contam-
inant. Its pathogenicity evolves with the inoculation of
the fungus via a penetrating injury and often leads to a
granuloma formation with or without sinus tract.
Sometimes there may be an underlying predisposing
immunological deficit favoring to its opportunistic role.
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Mycopathologia (2010) 170:361–375
Of the 150 known species, nine are implicated as
human pathogens—falciforme (currently known as
Fusarium falciforme), A. recifei, A. kiliense, A. potronii,
A. roseogriseum, A. strictum, A. alabmensis, A. blochi,
A. astrogriseum [8]. A. kiliense and A. falciforme have
by far been the most common species reported to be
associated with clinical disease. However, as opportu-
nistic pathogens, A. roseogriseum and A. srtictum have
also caused human infection. Recent data on compar-
ison of the phylogenetic affinities of opportunistic
pathogens based on sequencing of the ribosomal
large subunit (LSU) has considered A. falciforme as a
variant of Fusarium solani. This recognition based on
molecular criteria underpins the importance of correct
detection of such emerging pathogens for appropriate
management [9] and epidemiology.
Mycological Characteristics
The synanamorph features are characterized by phi-
alidic mode of conidiogenesis and the presence of
phialoconidia, phialides and hyphae, which are con-
sistent with Acremonium species. Yeast like syna-
namorph of Acremonium, observed by the occurrence
of a phenomenon of single fungus exhibiting adven-
titious forms, in-vitro versus in-vivo, is unique rem-
iniscent of the forms seen in Exophiala jeanselmei and
Fusarium solani [10]. Such a release of propagules is
stated to be forms responsible for dissemination of
infection. Sporulation in-situ of filamentous ana-
morphs has been observed in pulmonary infection
with Aspergilllus, Fusarium moniliforme and Paeci-
lomyces lilacinus [11]. Such variable forms can be
helpful in diagnosing these hyaline fungi but are often
mistaken with yeast, leading to erroneous manage-
ment. Mycological analyses of such filamentous fungi
from various specimens are possible as per standard
laboratory procedures [12].
Acremoniun species can be easily isolated on
modified SDA (Sabouraud’s dextrose agar) at a
temperature of 25–37°C (optimum 30°C). It grows
as a smooth, waxy or velvety colony with varying
colors after 4–5 days of incubation. Delicate thin
hyaline septate hyphae, forming inter-twining ropes,
bearing slender unbranched tapering (3 lm from the
base) conidiophores at right angles to the hyphae with
elliptical or crescent shape unicellular conidia are the
microscopic characteristics of this genus.
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Mycopathologia (2010) 170:361–375
Clinical Infections and Pathogenesis
The epidemiology of invasive fungal infections has
shown a changing trend during the past several years.
Their incidence has increased, and the patients at risk
have expanded with different underlying medical
conditions, such as immunosuppressive therapy, major
surgeries including transplantation. The exact reasons
for these changes are not completely clear. The clinical
forms are classified as superficial, locally invasive or
disseminated. Acremonium may be a mere colonizer or
infection may result in disease. They are further
categorized into the following forms of diseases:
allergic; ocular; mycetoma; invasive and systemic
[13]. From the available data given in Table 3, it
appears that localized infections account for nearly
two-thirds of the Acremonium cases reported world-
wide, most of which occured in immunocompetent
individuals and only one-third were reported as
disseminated infection in immunocompromised hosts.
Localized Infections
Environmental factors like relative density of fungi in
the soil, rainfall, temperature, humidity and type of
vegetation are relevant in mycetomas. They are the
commonest presentations of Acremonium species,
occurring mostly after sustained penetrating skin
injury. They appear either as subcutaneous nodules
with discharging sinuses or uncommonly as pseud-
omycetomas. Most of these are due to A. kiliense or
A. falciforme, while other species, such as A. blochii
and A. recifei, have also been implicated [6, 14]. In
India, 5–6% of the cases of subcutaneous hyalohy-
phomycosis have been associated with Acremonium
infections [15]. The majority of Acremonium myceto-
mas are chronic infections of distal extremities,
usually affecting young adults living in tropical or
subtropical regions. However, due to its ubiquitous
presence in environment, its presence as a laboratory
contaminant or as an etiological agent of mycetoma
needs to be established with care. Moreover, the
clinical presentation of an Acremonium mycetoma is
not distinctive, and it commonly presents as pale grain
eumycetomas, producing white to pale-yellow grains,
which may be confused with morphologically similar
fungi like Fusarium or Pseudalleshcheria species.
However, careful microscopical examination of the
363
hyphal and conidial elements, along with growth
characteristics, can abate the confusions. Ability to
form grains and provoking an inflammatory response
gives it an advantage in establishing mycetomas in
humans. Recently, Acremonium has been also recog-
nized as an important cause of superficial white
onychomycosis and distal or lateral sub-ungual ony-
chomycosis [16]. Mycotic keratitis and endophthal-
mitis account for other major entities of this fungus,
after trauma or surgical abrogation of ocular defenses.
Suppurative arthritis, sinusitis or osteomyelitis and
kerion due to Acremonium species have also been
reported, though sporadically, as a complication in
trauma because of the presence of its environmental
habitat. However, in conditions characterized by
underlying immunodeficiency, rare localized infec-
tions have been reported in neutropenia, leukemia,
CAPD (continuous ambulatory peritoneal dialyses)
and after steroid therapy. Similar to other hyaline
fungi (e.g. Aspergillus species), colonizing Acremo-
niasis occurring as a pulmonary fungal ball in healthy
individuals or resulting in bezoar formation in gastro-
intestinal tract, is one of the rare presentations that
often may lead to misdiagnosis at presentation [17].
Allergic Acremonium infections resulting in hyper-
sensitivity and Acremonium lung disease have been
attributed to chronic contamination of dwelling units
and improper sewage disposal. Total recovery ensues
following a change of residence and improved
environmental conditions. Fungal sinusitis in immu-
nocompetent patients is not rare. The first case of
Acremonium as a causative agent of AFRS (Allergic
fungal rhino sinusitis) with unilateral vision loss was
reported by Mulwafu et al. [18]. Although a rare
association with Acremonium species, it was amena-
ble to cure by surgery and I/V antifungals.
Disseminated Infections
In general, the recognition of disseminated fungal infec-
tions is difficult because specific signs and symptoms
may not exist and recognition of the etiology is delayed
until autopsy. The low virulence of the agent and the
rarity with which it contaminates wounds may have
contributed to paucity in scientific literature of this
agent. Majority of disseminated infections occur in
immunosuppressed patients. Pneumonia, arthritis, oste-
omyelitis, endocarditis, meningitis, peritonitis and
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364
sepsis in the immunodeficient (organ transplant reci-
pient, diabetes, mycetoma, leukemia or on immunosup-
pressive therapy) patients have been reported with
Acremonium species [19]. Endocarditis, cerebritis,
meningitis due to A. strictum and A. alabamensis,
pulmonary infection by A. kiliense in a chronic granu-
lomatous disease of a child and peritonitis in a CAPD
patient are among the fatal infections caused by this
genus, giving it a fascinating spectrum of disease
manifestation [20]. Acremonium infection in bone
marrow transplant recipients has also been reported,
with remission after appropriate antifungal treatment.
Blood stream infections due to Acremonium are quite
common in the immunocompromised; however, occa-
sional reports of fungemia in patients with sub-clavian
catheter, after mitral valve replacement or infection of
pacemaker pocket, have been reported in patients with
no apparent immune depletion [21–23]. Tables 1 and 2
depict the infections caused by Acremonium species
throughout the world.
Mixed Infections and Hospital-Associated
Infections
Nosocomial fungal infections have also been identified
with Acremonium (11%) in association with Malas-
sezia, Trichosporon and Fusarium, accounting for
almost 9% of all hospital infections [99]. Risk factors
commonly associated with hospitalized patients, espe-
cially in ICU, oncology section and dialysis unit,
contribute to the increasing secular trends in nosoco-
mial fungal infection rates. Table 3 depicts the distri-
bution of localized and disseminated infections due
to Acremonium reported in immunocompetent and
immunosuppressed individuals.
Our tertiary health care facility receives about
150–200 clinical samples (biopsy) for fungal patho-
gens annually. Onychomycosis, mycotic keratitis and
occasional mycetoma due to Acremonium species
account for 6, 3 and 2%, respectively, of all infections.
Most frequently, these infections have been docu-
mented in immunocompetent individuals. In the
immunosuppressed patients, the critical factor is
recovery from immunosuppression, with surgical
resection of localized lesions and appropriate anti-
fungal therapy playing an important adjunctive role.
The controversy surrounding the pathogenesis of
Acremonium infections takes into account various host
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Mycopathologia (2010) 170:361–375
and agent factors. Still little is known by what
mechanism do these fungi cause disease, particularly
in immunocompetent individuals. The immune status
of the host able to localize the lesion and release
multiple cytokines and growth factors contributes to
perpetuating the inflammatory process. As proposed
by Mulwafu et al., the role of eosinophils, sensitization
to fungal antigens, fungal spores trapped in nasal
mucus and damage to mucosa facilitating bacterial
super-infection in AFRS has been well established.
Wound integrity also seems to be an important feature
influencing the risk especially for developing endoph-
thalmitis and intraocular infections. Acremonium
remains viable in the anterior chamber despite surgical
removal of the bulk of the fungal mass and treatment
with antifungals, both topical and systemic. However,
suture-less vitrectomy and intravitreal injection along
with long-term antifungal medication results in good
visual outcome [26]. Although low in virulence,
underlying multiple factors in the host and environment
can contribute to the pathogenicity of Acremonium.
Laboratory Diagnosis
Mycological analyses of filamentous fungi from
various specimens are processed as per standard
procedures [12]. Acremonium has been isolated from
varied specimens ranging from biopsy, nail and
corneal scrapings, blood, bone marrow, CSF to
sputum depending upon the clinical manifestations.
Acremonium species have also been reported to
colonize certain sites (e.g.: contact lenses). Keeping
these in mind, it becomes necessary that only appro-
priate clinical samples should be submitted for culture
and isolation. These fungi are not nutritionally
demanding and can be isolated on any standard
mycology media like SDA (Sabouraud dextrose agar)
without antimicrobial and cycloheximide or brain
heart infusion agar. Occasionally, additional media
(e.g. potato dextrose agar, potato flakes agar) may be
used to enhance development of particular features
like conidiation for appropriate identification. Bipha-
sic brain heart infusion medium should be used for
blood culture. Acremonium species usually grow
within 5 days on SDA at 30°C. Morphologically
similar fungi in other genera like Fusarium, Paecilo-
myces and Pseudallescheria species that are also
likely to be encountered in clinical cases may be
 Table 1 Worldwide clinical infections caused by different species of Acremonium
Type of infection Species Place Year Treatment Outcome References

Fungemia A. strictum France 2010 Liposomal AmB, Vori Cured [24]

Onychomycosis Acremonium spp. Switzerland 2010 Ter, Itra Not cured [25]
Intraocular infection Acremonium spp. Korea 2010 Vitrectomy, Vori Cured [26]
Fungemia A. strictum Scandinavia 2009 Not known Died [22]
Fungemia Acremonium spp. Turkey 2009 Vori Cured [23]
Peritonitis A. strictum Turkey 2008 Not known Not known [27]
Peritonitis in infant A. strictum Turkey 2008 Liposomal AmB Cured [28]
Mycopathologia (2010) 170:361–375

Mycetoma Acremonium spp. Brazil 2008 Surgery, Itra and Keto, Not known [29]
New azoles
Chronic LRTI Acremonium spp. Nigeria 2007 AmB Cured [30]
Fungemia due to CV catheter Acremonium spp. Mexico 2007 AmB, Itra Not known [31]
Vertebral osteomyelitis Acremonium spp. Israel 2007 Vori Not known [32]
Fungemia in ALL A. strictum Germany 2007 AmB Cured [33]
Mycetoma in heart transplant case Acremonium spp. USA 2006 Not known Not known [34]
Invasive infection in a bone A. strictum Greece 2006 AmB Cured [35]
marrow transplant patient.
Mycetoma A. kiliense Buenos Aires 2006 Keto, Itra, Clotri Cured [36]
A. recifei
A. falciforme
Keratoconjunctivitis Acremonium spp. France 2006 Vori Cured [37]
Keratitis A. strictum Senegal 2006 Azoles, Povidone, Iodine Cured [38]
Author's personal copy

Allergic fungal sinusitis Acremonium spp Cape town 2006 Spheno-ethmoidectomy, Cured [18]
I/V AmB, Flu
Mycetoma Acremonium spp. Argentina 2005 Not known Cured [39]
Endophthalmitis A. strictum USA 2005 Cured [40]
ALL with keratitis Acremonium spp. China 2005 AmB, Caspofungin [41]
Pyomyositis Acremonium sp Taiwan 2005 AmB Cured [42]
Recalcitrant hyalohyphomycosis A. strictum Turkey 2005 1% Imiquimod cream Cured [43]
Onychomycosis Acremonium spp. Turkey 2005 AmB, Granulocyte colony-stimulating Cured [44]
factor (G-CSF) & surgical drainage
Dermatomycosis Acremonium spp. China 2004 Amorolfine Cured [12]
Cutaneous hyalohyphomycosis Acremonium spp. UK 2004 Not known Not known [45]
Corneal ulcer Acremonium spp. Paraguay 2004 Not known Not known [46]
365

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 Table 1 continued
366

Type of infection Species Place Year Treatment Outcome References

123
Onychomycosis Acremonium spp. France 2003 Not known Not known [47]
Fatal mycoses A. strictum USA 2003 AmB, Itra Not cured [48]
Septic arthritis Acremonium spp. France 2003 AmB, Itra Not cured [49]
Fungemia Acremonium spp. Italy 2003 AmB, Vori Cured [50]
Fatal disseminated mycoses A. strictum Turkey 2003 AmB, Flu Not cured [51]
Infectious keratitis Acremonium spp Korea 2002 Not known Not known [52]
Pulmonary infection in a leukemic patient A. strictum France 2002 Posa Cured [53]
Onychomycosis Acremonium spp. Brazil 2002 Not known Not known [54]
Pacemaker pocket infection Acremonium spp. Greece 2002 Not known Not known [21]
Subcutaneous hyalohyphomycosis A. strictum Turkey 2001 AmB Not cured [1]
on cheek
Onychomycosis Acremonium spp. Italy 2000 Itra, Ter Cured [55]
Traumatic keratitis Acremonium spp. USA 2000 Keratoplasty Cured [56]
Endophthalmitis Acremonium spp. USA 2000 AmB Cured [57]
Keratitis in herpetic corneal disease Acremonium spp. Greece 2000 Not known Not known [58]
Fungemia A. strictum Norway 2000 AmB, Ter, Vori Cured [59]
Podalic mycetoma A. kiliense Brazil 1999 Itra Cured [60]
Peritonitis in a patient of CAPD A. strictum Turkey 1998 AmB Cured [61]
Cutaneous infection Acremonium spp. Israel 1998 Not known Not known [62]
Infection of esophagus Acremonium spp. Pennsylvania 1997 Keto, AmB Cured [63]
Disseminated infection in Neutropenia A. strictum Carolina 1996 AmB, Keto Cured [64]
Author's personal copy

patient
Blood infection in neuroblastoma case Acremonium spp. Italy 1995 Liposomal AmB, Flu Cured [65]
and ALL patient
Mycetoma A. recifei Brazil 1995 Itra Cured [66]
Peritonitis in CAPD patient A. kiliense Brazil 1995 Catheter removal, AmB, Keto Cured [67]
GIT infection in BMT A. falciforme USA 1995 AmB, Itra, GM-CSF Cured [68]
Subcutaneous leg abscess in A. falciforme Brazil 1994 Surgery, Keto Cured [69]
renal transplant
Blood infection in ALL patient Acremonium spp. Italy 1993 Liposomal AmB Cured [70]
Fungemia Acremonium spp. UK 1992 None Cured [71]
Infection of lung in AML Acremonium spp. Georgia 1991 AmB, Rifampicin Cured [6]
Mycetoma A. kiliense Hungary 1991 Surgery, Itra Cured [72]
Mycopathologia (2010) 170:361–375
 Table 1 continued
Type of infection Species Place Year Treatment Outcome References

Knee abscess Acremonium spp. Brazil 1990 AmB, surgery Cured [73]
Mycetoma A. strictum France 1988 Flu, Nystatin, AmB Cured [74]
Arthritis in knee Acremonium spp. USA 1988 Surgery, Nystatin, Itra Cured [75]
Landry Guillain Barre syndrome A. strictum Hungary 1987 AmB Died [76]
Osteomyelitis A. kiliense Kansas 1985 Surgery, AmB, Keto Cured [77]
Cerebritis A. alabamensis USA 1984 Steroid Died [78]
Pneumonitis, Chronic A. strictum Not known 1984 AmB, Keto Cured [20]
Mycopathologia (2010) 170:361–375

granulomatous dis.
Peritonitis Acremonium spp. Indiana 1982 AmB Died [79]
Allergic Pneumonitis Acremonium spp. Milwaukee, Chicago 1981 None Cured [80]
Prosthetic heart valve A. kiliense Brazil 1981 Surgery, AmB, 5FC Cured [81]
Renal transplant Acremonium spp. New York 1979 AmB Cured [82]
Endophthalmitis Acremonium spp. California 1979 Vitrectomy, Topical AmB Cured [83]
Mycetoma A. falciforme California 1976 Not known Cured [84]
Keratitis A. potronii Miami, Florida 1975 Keratoplasty Cured [85]
GIT fungus ball Acremonium spp. Finland 1975 Not known Not known [17]
Pulmonary fungus ball Acremonium spp. Australia 1972 Resection of lung Cured [86]
Endocarditis Acremonium spp. France 1971 AmB Died [87]
Keratitis Acremonium spp. Florida 1971 Graft, Keratotomy Cured [88]
AmB, amphotericin B; 5FC, 5-flurocytosine; Vori, voriconazole; Keto, ketoconazole; Itra, itraconazole; Ter, terbinafine; Flu, fluconazole; Clotri, clotrimazole; Posa,
posaconazole; BMT, bone marrow transplant; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; GIT, gastrointestinal tract; CAPD, continuous ambulatory
Author's personal copy

peritoneal dialysis
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368 Mycopathologia (2010) 170:361–375

Table 2 Prominent Indian studies with Acremonium infections

Type of infection Species Location in India Year Treatment Outcome References

Onychomycosis Acremonium spp. Delhi 2008 Flu, Itra, Ter Cured [89]
Onychomycosis Acremonium spp. Shimla 2007 Flu, Itra, Ter Cured [90]
Keratitis Acremonium spp. Delhi 2006 Itra, Ter Cured [91]
Onychomycosis Acremonium spp. NE India 2003 Ter Cured [92]
Endophthalmitis A. kiliense Chandigarh 2003 Surgery, AmB Cured [93]
Endophthalmitis Acremonium spp. Chennai 1999 Vitrectomy, azoles Cured [94]
Mycetoma A. kiliense, Madras 1995 Not known Cured [95]
A. falciforme
Corneal ulcer Acremonium spp. Chandigarh 1994 Not known Cured [96]
Mycetoma A. recifie South India 1979 Surgery, Keto Cured [97]
Mycetoma Acremonium spp. Madras 1977 Itra Cured [15]
Madura foot Cephalosporium madurae South India 1966 Not known Cured [98]

confused during microscopic identification. Colony
characteristics of Acremonium species vary according
to their growth, ranging from white powdery suede-
like colonies or smooth, waxy and velvety colony with
color varying from white to gray to rose with light
yellow or light pink on reverse after 4–5 days of
incubation. Conidial morphology is the other diag-
nostic feature that can help differentiate species from
each other. Characteristic tapering phialides arising
from septate hyphae measuring \1.5–2 lm in diam-
eter with clustered spheres of one-celled ellipsoidal
conidia can be present or they may occur in chains
[100]. A. falciforme (Fig. 1) has crescentic conidia that
are either non-septate or have a single septum [10].
A. recifei has curving and sickle-shaped conidia with
apiculate base, and A.kiliense exhibit awl-shaped
phialides bearing one-celled ellipsoidal conidia with
rounded edges accumulating as slimy heads [96]
(Fig. 2). Delicate thin hyaline septate hyphae, forming
inter-twining ropes, bearing slender unbranched taper-
ing (3 lm from the base) conidiophores at right angles
to the hyphae with elliptical or crescent shape
unicellular conidia are the microscopic characteristics
of this genus. A mucoid substance holds the conidia in
a spherical cluster (slimy balls) at the tip of the
phialide. However, a dry medium shows only short
chains of conidia.
The tissue form of Acremonium can consist of
granules as seen in mycetoma or can be simple hyphae
that may or may not be accompanied by unicellular
yeast-like forms. Histopathological staining shows
granulomatous reaction with palisade arrangement of
hyphae in eumycetomas. PAS-positive hyphae in the
cement substance can also be seen. Pathological
examination can reveal elongated hyphae and spores
on methenamine silver and periodic acid-Schiff stains.
Molecular Techniques in Laboratory Diagnosis
Rapid identification of fungal pathogens is important
for appropriate treatment with antifungal agents and
with the number of new antifungals steadily increas-
ing; accuracy in identification of the etiology assumes
additional significance. The detection of microbial
DNA and amplification of gene sequences by PCR is
without doubt one of the most powerful tools for the
early diagnosis and identification of different types of
human pathogens. Genetic analysis by DNA-PCR
using panfungal primers and sequencing are tools that
have classified genus Acremonium in a polyphyletic
group of genetically distantly related fungi [49].
Availability of data from genomic sequencing projects
for different fungi, probes for highly conserved
regions, as well as genus- and species-specific variable
regions in recent times has added a measure of
certainty in the recognition of the fungi. A recent
study by Keynan et al. [32] describing DNA amplifi-
cation by nested PCR using primers for ITS1 and ITS4,
which are the internal transcribed spacer regions of
rDNA, followed by digestion with HaeIII endonucle-
ases in RFLP analysis, has revealed unique restriction
pattern (193 and 92 bp) that was found compatible with
Acremonium species. ITS sequencing is a sensitive tool

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Table 3 Clinical infections of Acremonium based on immune status of the patients

Immune status Clinical infection
Localized (references) Disseminated (references)

Immunocompetent Involvement of the eye: Keratitis [28, 56, 85, 88, 91], Blood stream infection involving the
Keratoconjunctivitis [37], Endophthalmitis [26, 40, 57, pacemaker pocket: [21] Catheter-related
83, 93, 94], Corneal ulcer [46, 96] fungemia: [23]
Involvement of the skin: Cutaneous infections [45] Fungemia after mitral valve replacement:
Sub-cutaneous infection: Cheek [1], Face(43), Mycetoma [22]
[15, 19, 29, 36, 39, 60, 66, 72, 74, 90, 95, 97]
Involvement of the nail: Dermatomycosis [12]
Onychomycosis [44, 47, 54, 55, 89, 90, 92]
Involvement of the bone & joints: Knee arthritis
[75],Vertebral Osteomyelitis [32, 77], Knee abscess [73]
Peritonitis: [27]
Pneumonitis: [80]
Sinusitis: [18]
Immunocompromised ALL with keratitis: [41, 58, 88] Fungemia: [24, 31, 33, 35, 50, 59, 64, 65,
Neutropenia Pyomyositis: [42] 70, 71, 82]
Treatment with—steroids Mycetoma in heart transplant case: [34] Septic arthritis: [48]
chemotherapy Cutaneous infection: [61] Pulmonary infection: [6, 20, 53]
ALL, AML Chronic LRTI: [30] Peritonitis: [28, 61, 67, 79] prosthetic
Transplant (Heart, Kidney, heart valve infection: [81]
GIT: [17, 68]
Bone marrow) Pulmonary fungal ball: [86]
Subcutaneous abscess in leg: [69]
Herpetic corneal disease
CAPD patient
cGD
GBS
Infant
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; LRTI, lower respiratory tract infection; GIT, gastrointestinal tract;
CAPD, continuous ambulatory peritoneal dialysis; cGD, chronic granulomatous disease; GBS, Guillain Barre syndrome; CRF,
chronic renal failure

for accurate identification. Coupled with endonuclease
restriction digestion and RFLP, the technique can be
extended to strain typing as well. The DNA sequence
analysis may at least be able to distinguish the genera.
The principal advantage of this method is obvious;
identification as well as the possibility of strain typing
of Acremonium species with its unique restriction
pattern. The gene sequences of these regions are
available in GenBank database. Phenotypic resem-
blance between filamentous fungi often poses diffi-
culty in distinguishing one from the other. The
phylogenetic analysis of LSU of rDNA sequence
chromatographs and their association with sequences
downloaded from GenBank (http://www.ncbi.nlm.
nih.gov/) can also assist in accurate analysis. Oligo-
nucleotide array has also been developed but is
technically demanding and time-consuming and inac-
curate identification can occur sometimes. This is
because a single morphological species can contain
multiple biological or phylogenetic species as descri-
bed by Taylor et al. [101]. Also, strains belonging to the
same species may display different morphological
characteristics at different growth stages and can often
lead to misidentification. However, since fungal ITS
sequences have low intraspecies variation and high
interspecies divergence, the performance (sensitivity
and specificity) of microarray in this genus has been
rated good [102]. It is recommended that mycotic
elements should be demonstrated in multiple speci-
mens from the same or related site in case of infections
in immunocompetent host. Thus, owing to the com-
plexity of various patient groups at risk for infection,

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370
Fig. 1 Lactophenol cotton blue (LPCB) mount of Acremonium
falciforme (magnification 4009). The figure shows crescentic
conidia that are either non-septate or showing a single septum on
unbranched phialides
Fig. 2 LPCB mount of Acremonium kiliense (magnification
4009). The figure shows long, awl-shaped phialides having
one-celled ellipsoidal conidia with rounded edges accumulat-
ing as heads
opportunistic mycoses pose a considerable diagnostic
challenge to both clinicians and microbiologists.
Current Management Strategies
Acremonium is one of the important hyaline fungal
agents, which when unidentified often proves fatal
with excessive empirical management. There are no
standard therapies for infections caused by Acremo-
nium with regard to choice of agent or duration of
therapy The fungus is susceptible to nystatin, keto-
conazole, itraconazole and amphotericin B. Optimum
therapy of surgical resection and a 6-month ketocon-
azole has been successful in treating a case of
abscess. Another case of subcutaneous infection
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Mycopathologia (2010) 170:361–375
following trauma could be managed with a 3-month
course of itraconazole alone. Appropriate treatment
of Acremonium infection is imprecise because of
limited number of documented reports and conflicting
results of therapies. The susceptibility testing of
filamentous fungi is also poorly standardized, and
very often results do not correlate with clinical cure.
Despite various reports of in-vitro resistance of these
fungi to azoles, many case reports indicate resolution
with combination of surgery (wherever indicated) and
azole derivatives given for prolonged periods.
A study determining the minimum inhibitory con-
centration (MIC) and minimum fungicidal concentra-
tion (MFC) of different antifungals, against 33 strains of
Acremonium, indicated amphotericin B as the most
effective drug followed by itraconazole, miconazole
and ketoconazole [13]. Fluconazole and 5-fluorocyto-
sine were ineffective in most cases among different
strains of Acremonium except in onychomycosis treated
with azoles. The discrepancy in the MIC values may be
due to different methodologies used to determine the
antifungal susceptibility testing. Hence, these methods
should be standardized for filamentous fungi in each
laboratory following CLSI guidelines (NCCLS, CLSI)
[103]; though in-vitro susceptibility to antifungal agents
have a limited value. Clinical efficacy of the drugs has
not been very encouraging, yet the susceptibility testing
can be a useful guide in infections due to rare fungal
agents. Length of therapy is generally based on clinical
response and may range from several weeks to months
or longer.
Medical management has been a constant challenge
for the clinicians in mycetomas due to Acremonium
species. Immunocompromised patients like renal and
heart transplant recipients and diabetics have been
successfully treated with amphotericin B and keto-
conazole. Unusual recalcitrant hyalohyphomycosis of
the face in an immunocompetent patient in Turkey
caused by A. strictum was reported unresponsive to
itraconazole and cryotherapy. An antiviral imiquimod
(imidazoquinoline derivative) 5% ointment was for
the first time reported to have effected cure in an
immunocompetent patient who had failed to respond
to various antifungals and cryotherapy [43]. Overall
clinical data shows that amphotericin B has proven to
be the best therapeutic option [48]. However, failures
have been reported with it and success seen with
itraconazole [13]. Hence, in addition to amphotericin
B, ketoconazole or fluconazole has been preferred for
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Mycopathologia (2010) 170:361–375
therapy at times. Nevertheless, there are also docu-
mented reports of Acremonium with high-level resis-
tance to fluconazole and itraconazole. Therefore, for a
favorable course and cure of Acremonium infections,
choice of antifungals may vary and success of
treatment may not be consistent with the same agents
in all cases. Reports suggest that the new triazole drug
voriconazole and caspofungin have in-vitro activities
against Acremonium species but the efficacies of
these drugs remain to be determined [104]. The value
of combination therapy also needs to be further
investigated along with amphotericin B, especially in
life-threatening situation. In immunosuppressive or
neutropenic patients, the fungi can prove fatal and
disseminate due to formation of conidia in-vivo. In
such situations, the antifungals have to be given for a
prolonged duration. Based on the scattered data
available of Acremonium infections (probably due to
underreporting), it is difficult to establish the optimal
antifungal therapy. Amphotericin B, ketoconazole,
itraconazole, fluconazole, 5-flurocytosine, voriconaz-
ole, posaconazole and combination with amphotericin
B have been recommended in serious infections.
Acremonium infections in immunocompromised
patients with various manifestations like cardiac,
neurological, ocular or pulmonary are usually difficult
to treat with drugs alone. In cases with poor outcome
or recurrent Acremonium infection due to surgery or
prostheses removal, amphotericin B is recommended.
Moreover, other drugs like itraconazole have been
reported to interact antagonistically at times, therefore
may not always be a successful combination with
amphotericin B. Topical application of antifungals,
intravenous amphotericin B and appropriate surgeries
like iridectomy, keratoplasty, incision and drainage,
vitrectomy, spheno-ethmoidectomy debridement have
satisfactorily resolved cases of keratitis, endophthal-
mitis, and rare case of ARFS. Mycetomas have been
successfully treated with amphotericin B in associa-
tion with surgeries, but those treated only with
antifungals have led to failures. In immunosuppressed
patients, despite amphotericin B, fatalities are often
inevitable. In immunocompetent patients, a combina-
tion of amphotericin B with other azoles has shown
favorable results in several cases.
In our experience, a case of pseudomycetoma due to
A. kiliense, a diabetic individual, needed fluconazole
and terbinafine for a prolonged period. Although the
infection did not disseminate systemically, it resolved
371
Table 4 Treatment modalities available for Acremonium
infections
Drugs Surgery
Topical Systemic
Nystatin Amphotericin B Resection
Terbinafine Azoles-Ketoconazole Cryotherapy
Imiquimod Itraconazole Keratotomy
5% Fluconazole Keratoplasty
Clotrimazole Voriconazole Vitrectomy
Posaconazole Spheno-ethmoidectomy
Terbinafine
5-Flurocytosine
after an indolent course of 18 months (Das S et al.,
manuscript communicated). Eumycetomas are prefer-
ably treated with itraconazole; however, a combination
therapy with amphotericin B has proven to be useful
depending on the extent of manifestations in develop-
ing countries. Newer azoles like voriconazole are
preferred but due to unaffordability by our population,
it is not given as a drug of choice in tertiary care
hospitals. The treatment modalities available for
Acremonium infections are listed in Table 4.
Conclusion
Among hyalohyphomycosis, Acremonium is a signif-
icant cause of different types of infections akin to
Fusarium and Scedosporium species. The current
diagnostic approach including clinical suspicion,
culture of appropriate samples from suitable sites,
histopathological examination of relevant sections
and imaging techniques become absolutely essential
to optimize diagnosis and treatment of these infec-
tions, especially in compromised hosts. Due to low
susceptibility to antifungal drugs, it is essential to
identify these agents correctly and accordingly for-
mulate a therapeutic plan for each patient, which may
not necessarily be always based upon documented
data of treated patients. Identified agents may even be
deposited with reference laboratories for future
studies. Nevertheless, these infections may be sus-
pected clinically on the basis of a constellation of
clinical and laboratory findings, which should lead to
prompt treatment.
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372
The twin advantage of specificity of identification
due to its inherent discriminatory power and the
possibility of isolate characterization in a single test
format makes nucleic acid amplification–based iden-
tification an attractive option. Moreover, as sequence
databases become more robust, molecular methods
will become the acceptable method of identification
by microbiologists. Further, this procedure makes
available a large window of opportunity for optimiz-
ing clinical management by cutting down the time
required for the identification of the etiological agent
and minimizing the confusion relating to its identi-
fication with morphologically similar-looking fungi.
Case reporting of clinical experiences is important in
attempting to better define optimal therapy for these
infections.
Opportunistic infections with fungi are on the rise
largely attributable to aggressive and injudicious
treatment with a variety of antibiotics irrespective of
their optimal activity. Speed and accuracy in their
identification would improve the intervention modal-
ity and provide useful epidemiological database for
empirical management as well. Much additional work
is needed to better understand the pathogenic mech-
anisms underlying hyalohyphomycosis and to opti-
mize treatment for these often refractory infections.
Methodology
Literatures searches were conducted on PubMed (http://
www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed) using a
variety of key words such as Acremonium, Acremonium
infections, emerging fungal infections and hyalohypho-
mycetes. Articles from 1966 to 2010 were included in this
review.
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