Mycopathologia (2010) 170:361375 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 Springer Science+Business Media B.V. 2010

Abstract Unusual fungal agents that exist environmentally as saprophytes can often lead to opportunistic 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 difcult to distinguish a pathogenic and a contaminant fungus, because many such agents can assume clinical signicance depending on circumstances. Subcutaneous and invasive fungal infection 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 conicting 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.

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 infections. Immunocompromised individuals are the targets of these agents; however, apparently healthy individuals with no underlying risk factors also fall prey. The term hyalohyphomycosis is specially designated 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 lamentous 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 immunocompetent individuals, they usually cause localized infections. 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

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

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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 supercial infections. Substantial data exists on its clinical and geographical distribution in immunocompetent 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 complications 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 Cephalosporium) isolated from dead plant material and soil includes approximately 150 species. The earliest documented reports of Acremonium dates back to 1839. Corda named it rst as Acremonium cephalosporium. There was a little evidence of the pathogenicity of Acremonium until the twentieth century. During investigation of their antimicrobial property in 1953, they were eventually identied as the fungal agent Cephalosporium Acremonium, which culminated 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 demonstrated by DNA sequence analysis that one of the species A. strictum displays a broad genetic polymorphism.

Of the 150 known species, nine are implicated as human pathogensfalciforme (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 opportunistic pathogens, A. roseogriseum and A. srtictum have also caused human infection. Recent data on comparison of the phylogenetic afnities 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 phialidic mode of conidiogenesis and the presence of phialoconidia, phialides and hyphae, which are consistent with Acremonium species. Yeast like synanamorph of Acremonium, observed by the occurrence of a phenomenon of single fungus exhibiting adventitious forms, in-vitro versus in-vivo, is unique reminiscent 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 lamentous anamorphs has been observed in pulmonary infection with Aspergilllus, Fusarium moniliforme and Paecilomyces lilacinus [11]. Such variable forms can be helpful in diagnosing these hyaline fungi but are often mistaken with yeast, leading to erroneous management. Mycological analyses of such lamentous fungi from various specimens are possible as per standard laboratory procedures [12]. Acremoniun species can be easily isolated on modied SDA (Sabourauds dextrose agar) at a temperature of 2537C (optimum 30C). It grows as a smooth, waxy or velvety colony with varying colors after 45 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.

Taxonomy Acremonium is a cosmopolitan environmental contaminant. 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 decit favoring to its opportunistic role.

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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 classied as supercial, 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 worldwide, 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 pseudomycetomas. 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, 56% of the cases of subcutaneous hyalohyphomycosis have been associated with Acremonium infections [15]. The majority of Acremonium mycetomas 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

hyphal and conidial elements, along with growth characteristics, can abate the confusions. Ability to form grains and provoking an inammatory response gives it an advantage in establishing mycetomas in humans. Recently, Acremonium has been also recognized as an important cause of supercial white onychomycosis and distal or lateral sub-ungual onychomycosis [16]. Mycotic keratitis and endophthalmitis 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 immunodeciency, rare localized infections 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 Acremoniasis occurring as a pulmonary fungal ball in healthy individuals or resulting in bezoar formation in gastrointestinal tract, is one of the rare presentations that often may lead to misdiagnosis at presentation [17]. Allergic Acremonium infections resulting in hypersensitivity 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 immunocompetent patients is not rare. The rst 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 amenable to cure by surgery and I/V antifungals.

Disseminated Infections In general, the recognition of disseminated fungal infections is difcult because specic 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 scientic literature of this agent. Majority of disseminated infections occur in immunosuppressed patients. Pneumonia, arthritis, osteomyelitis, endocarditis, meningitis, peritonitis and

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sepsis in the immunodecient (organ transplant recipient, diabetes, mycetoma, leukemia or on immunosuppressive 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 granulomatous 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, occasional 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 [2123]. Tables 1 and 2 depict the infections caused by Acremonium species throughout the world.

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 inammatory 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 inuencing the risk especially for developing endophthalmitis 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.

Mixed Infections and Hospital-Associated Infections Nosocomial fungal infections have also been identied with Acremonium (11%) in association with Malassezia, Trichosporon and Fusarium, accounting for almost 9% of all hospital infections [99]. Risk factors commonly associated with hospitalized patients, especially in ICU, oncology section and dialysis unit, contribute to the increasing secular trends in nosocomial fungal infection rates. Table 3 depicts the distribution of localized and disseminated infections due to Acremonium reported in immunocompetent and immunosuppressed individuals. Our tertiary health care facility receives about 150200 clinical samples (biopsy) for fungal pathogens 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 documented in immunocompetent individuals. In the immunosuppressed patients, the critical factor is recovery from immunosuppression, with surgical resection of localized lesions and appropriate antifungal therapy playing an important adjunctive role. The controversy surrounding the pathogenesis of Acremonium infections takes into account various host

Laboratory Diagnosis Mycological analyses of lamentous 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 appropriate 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 akes agar) may be used to enhance development of particular features like conidiation for appropriate identication. Biphasic brain heart infusion medium should be used for blood culture. Acremonium species usually grow within 5 days on SDA at 30C. Morphologically similar fungi in other genera like Fusarium, Paecilomyces and Pseudallescheria species that are also likely to be encountered in clinical cases may be

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Table 1 Worldwide clinical infections caused by different species of Acremonium Species A. strictum Acremonium spp. Acremonium spp. A. strictum Acremonium spp. A. strictum A. strictum Acremonium spp. Acremonium spp. Acremonium spp. Acremonium spp. A. strictum Acremonium spp. A. strictum A. kiliense A. recifei A. falciforme Acremonium spp. France Senegal Cape town Argentina USA China Taiwan Turkey Turkey China UK Paraguay 2006 2005 2005 2005 2005 2005 2005 2004 2004 2004 AmB, Caspofungin AmB 1% Imiquimod cream AmB, Granulocyte colony-stimulating factor (G-CSF) & surgical drainage Amorolne Not known Not known Cured Cured Cured Cured Not known Not known 2006 2006 A. strictum Acremonium spp Acremonium spp. A. strictum Acremonium spp. Acremonium sp A. strictum Acremonium spp. Acremonium spp. Acremonium spp. Acremonium spp. Vori Azoles, Povidone, Iodine Spheno-ethmoidectomy, I/V AmB, Flu Not known Cured Cured Cured Cured Cured [37] [38] [18] [39] [40] [41] [42] [43] [44] [12] [45] [46] Buenos Aires 2006 Keto, Itra, Clotri Greece 2006 AmB USA 2006 Not known Germany 2007 AmB Israel 2007 Vori Mexico 2007 AmB, Itra Nigeria 2007 AmB Brazil 2008 Surgery, Itra and Keto, New azoles Turkey 2008 Liposomal AmB Turkey 2008 Not known Cured Not known Cured Not known Not known Cured Not known Cured Cured Turkey 2009 Vori Cured Not known Scandinavia 2009 Not known Died Korea 2010 Vitrectomy, Vori Cured Switzerland 2010 Ter, Itra Not cured France 2010 Liposomal AmB, Vori Cured [24] [25] [26] [22] [23] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] Place Year Treatment Outcome References

Type of infection

Fungemia

Onychomycosis

Intraocular infection

Fungemia

Fungemia

Peritonitis

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Peritonitis in infant

Mycetoma

Chronic LRTI

Fungemia due to CV catheter

Vertebral osteomyelitis

Fungemia in ALL

Mycetoma in heart transplant case

Invasive infection in a bone marrow transplant patient.

Mycetoma

Keratoconjunctivitis

Keratitis

Allergic fungal sinusitis

Mycetoma

Endophthalmitis

ALL with keratitis

Pyomyositis

Recalcitrant hyalohyphomycosis

Onychomycosis

Dermatomycosis

Cutaneous hyalohyphomycosis

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Corneal ulcer

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Table 1 continued Species Acremonium spp. A. strictum Acremonium spp. Acremonium spp. A. strictum Acremonium spp A. strictum Acremonium spp. Acremonium spp. A. strictum Acremonium spp. Acremonium spp. Acremonium spp. Acremonium spp. A. strictum A. kiliense A. strictum Acremonium spp. Acremonium spp. A. strictum Acremonium spp. A. recifei A. kiliense A. falciforme A. falciforme Acremonium spp. Acremonium spp. Acremonium spp. A. kiliense Brazil USA Brazil Italy UK Georgia Hungary Brazil Italy Carolina Pennsylvania 1997 1996 1995 1995 1995 1995 1994 1993 1992 1991 1991 Israel 1998 Turkey 1998 Brazil 1999 Itra AmB Not known Keto, AmB AmB, Keto Liposomal AmB, Flu Itra Catheter removal, AmB, Keto AmB, Itra, GM-CSF Surgery, Keto Liposomal AmB None AmB, Rifampicin Surgery, Itra Norway 2000 Greece 2000 Not known AmB, Ter, Vori USA 2000 AmB USA 2000 Keratoplasty Italy 2000 Itra, Ter Turkey 2001 AmB Greece 2002 Not known Brazil 2002 Not known France 2002 Posa Korea 2002 Not known Cured Not known Not known Not cured Cured Cured Cured Not known Cured Cured Cured Not known Cured Cured Cured Cured Cured Cured Cured Cured Cured Cured Cured Turkey 2003 AmB, Flu Not cured Not known Italy 2003 AmB, Vori Cured France 2003 AmB, Itra Not cured USA 2003 AmB, Itra Not cured France 2003 Not known Not known [47] [48] [49] [50] [51] [52] [53] [54] [21] [1] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [6] [72] Place Year Treatment Outcome References

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Type of infection

Onychomycosis

Fatal mycoses

Septic arthritis

Fungemia

Fatal disseminated mycoses

Infectious keratitis

Pulmonary infection in a leukemic patient

Onychomycosis

Pacemaker pocket infection

Subcutaneous hyalohyphomycosis on cheek

Onychomycosis

Traumatic keratitis

Endophthalmitis

Keratitis in herpetic corneal disease

Fungemia

Podalic mycetoma

Peritonitis in a patient of CAPD

Cutaneous infection

Infection of esophagus

Disseminated infection in Neutropenia patient

Blood infection in neuroblastoma case and ALL patient

Mycetoma

Peritonitis in CAPD patient

GIT infection in BMT

Subcutaneous leg abscess in renal transplant

Blood infection in ALL patient

Fungemia

Infection of lung in AML

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Mycetoma

Table 1 continued Species Acremonium spp. A. strictum Acremonium spp. A. strictum A. kiliense A. alabamensis A. strictum Acremonium spp. Acremonium spp. A. kiliense Acremonium spp. Acremonium spp. A. falciforme A. potronii Acremonium spp. Acremonium spp. Acremonium spp. Acremonium spp. Florida 1971 France 1971 Australia 1972 Finland 1975 Miami, Florida 1975 Not known Resection of lung AmB Graft, Keratotomy California 1976 Not known Keratoplasty California 1979 Brazil New York 1981 1979 Surgery, AmB, 5FC AmB Vitrectomy, Topical AmB Milwaukee, Chicago 1981 None Indiana 1982 AmB Not known 1984 AmB, Keto USA 1984 Steroid Died Cured Died Cured Cured Cured Cured Cured Cured Not known Cured Died Cured Kansas 1985 Surgery, AmB, Keto Cured Hungary 1987 AmB Died USA 1988 Surgery, Nystatin, Itra Cured France 1988 Flu, Nystatin, AmB Cured Brazil 1990 AmB, surgery Cured [73] [74] [75] [76] [77] [78] [20] [79] [80] [81] [82] [83] [84] [85] [17] [86] [87] [88] Place Year Treatment Outcome References

Type of infection

Knee abscess

Mycetoma

Arthritis in knee

Landry Guillain Barre syndrome

Osteomyelitis

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Cerebritis

Pneumonitis, Chronic granulomatous dis.

Peritonitis

Allergic Pneumonitis

Prosthetic heart valve Renal transplant

Endophthalmitis

Mycetoma

Keratitis

GIT fungus ball

Pulmonary fungus ball

Endocarditis

Keratitis

AmB, amphotericin B; 5FC, 5-urocytosine; Vori, voriconazole; Keto, ketoconazole; Itra, itraconazole; Ter, terbinane; Flu, uconazole; Clotri, clotrimazole; Posa, posaconazole; BMT, bone marrow transplant; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; GIT, gastrointestinal tract; CAPD, continuous ambulatory peritoneal dialysis

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368 Table 2 Prominent Indian studies with Acremonium infections Type of infection Onychomycosis Onychomycosis Keratitis Onychomycosis Endophthalmitis Endophthalmitis Mycetoma Corneal ulcer Mycetoma Mycetoma Madura foot Species Acremonium spp. Acremonium spp. Acremonium spp. Acremonium spp. A. kiliense Acremonium spp. A. kiliense, A. falciforme Acremonium spp. A. recie Acremonium spp. Cephalosporium madurae Chandigarh South India Madras South India 1994 1979 1977 1966 Location in India Delhi Shimla Delhi NE India Chandigarh Chennai Madras Year 2008 2007 2006 2003 2003 1999 1995 Treatment

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Outcome Cured Cured Cured Cured Cured Cured Cured Cured Cured Cured Cured

References [89] [90] [91] [92] [93] [94] [95] [96] [97] [15] [98]

Flu, Itra, Ter Flu, Itra, Ter Itra, Ter Ter Surgery, AmB Vitrectomy, azoles Not known Not known Surgery, Keto Itra Not known

confused during microscopic identication. Colony characteristics of Acremonium species vary according to their growth, ranging from white powdery suedelike 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 45 days of incubation. Conidial morphology is the other diagnostic feature that can help differentiate species from each other. Characteristic tapering phialides arising from septate hyphae measuring \1.52 lm in diameter 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 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. 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 identication of fungal pathogens is important for appropriate treatment with antifungal agents and with the number of new antifungals steadily increasing; accuracy in identication of the etiology assumes additional signicance. The detection of microbial DNA and amplication of gene sequences by PCR is without doubt one of the most powerful tools for the early diagnosis and identication of different types of human pathogens. Genetic analysis by DNA-PCR using panfungal primers and sequencing are tools that have classied 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-specic 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 amplication by nested PCR using primers for ITS1 and ITS4, which are the internal transcribed spacer regions of rDNA, followed by digestion with HaeIII endonucleases 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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Mycopathologia (2010) 170:361375 Table 3 Clinical infections of Acremonium based on immune status of the patients Immune status Clinical infection Localized (references) Immunocompetent Involvement of the eye: Keratitis [28, 56, 85, 88, 91], Keratoconjunctivitis [37], Endophthalmitis [26, 40, 57, 83, 93, 94], Corneal ulcer [46, 96] Involvement of the skin: Cutaneous infections [45] Sub-cutaneous infection: Cheek [1], Face(43), Mycetoma [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 Neutropenia Treatment withsteroids chemotherapy ALL, AML Transplant (Heart, Kidney, Bone marrow) Herpetic corneal disease CAPD patient cGD GBS Infant ALL with keratitis: [41, 58, 88] Pyomyositis: [42] Mycetoma in heart transplant case: [34] Cutaneous infection: [61] Chronic LRTI: [30] GIT: [17, 68] Subcutaneous abscess in leg: [69] Disseminated (references)

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Blood stream infection involving the pacemaker pocket: [21] Catheter-related fungemia: [23] Fungemia after mitral valve replacement: [22]

Fungemia: [24, 31, 33, 35, 50, 59, 64, 65, 70, 71, 82] Septic arthritis: [48] Pulmonary infection: [6, 20, 53] Peritonitis: [28, 61, 67, 79] prosthetic heart valve infection: [81] Pulmonary fungal ball: [86]

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 identication. 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; identication 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 resemblance between lamentous fungi often poses difculty 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. Oligonucleotide array has also been developed but is

technically demanding and time-consuming and inaccurate identication can occur sometimes. This is because a single morphological species can contain multiple biological or phylogenetic species as described 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 misidentication. However, since fungal ITS sequences have low intraspecies variation and high interspecies divergence, the performance (sensitivity and specicity) of microarray in this genus has been rated good [102]. It is recommended that mycotic elements should be demonstrated in multiple specimens from the same or related site in case of infections in immunocompetent host. Thus, owing to the complexity of various patient groups at risk for infection,

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Fig. 1 Lactophenol cotton blue (LPCB) mount of Acremonium falciforme (magnication 4009). The gure shows crescentic conidia that are either non-septate or showing a single septum on unbranched phialides

Fig. 2 LPCB mount of Acremonium kiliense (magnication 4009). The gure shows long, awl-shaped phialides having one-celled ellipsoidal conidia with rounded edges accumulating 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 unidentied often proves fatal with excessive empirical management. There are no standard therapies for infections caused by Acremonium with regard to choice of agent or duration of therapy The fungus is susceptible to nystatin, ketoconazole, itraconazole and amphotericin B. Optimum therapy of surgical resection and a 6-month ketoconazole has been successful in treating a case of abscess. Another case of subcutaneous infection

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 conicting results of therapies. The susceptibility testing of lamentous 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 concentration (MIC) and minimum fungicidal concentration (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-uorocytosine 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 lamentous fungi in each laboratory following CLSI guidelines (NCCLS, CLSI) [103]; though in-vitro susceptibility to antifungal agents have a limited value. Clinical efcacy 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 ketoconazole. 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 rst 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 uconazole has been preferred for

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Mycopathologia (2010) 170:361375

371 Table 4 Treatment modalities available for Acremonium infections Drugs Topical Nystatin Terbinane Imiquimod 5% Clotrimazole Systemic Amphotericin B Itraconazole Fluconazole Voriconazole Posaconazole Terbinane 5-Flurocytosine Resection Keratotomy Keratoplasty Vitrectomy Spheno-ethmoidectomy Surgery

therapy at times. Nevertheless, there are also documented reports of Acremonium with high-level resistance to uconazole 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 efcacies 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 difcult to establish the optimal antifungal therapy. Amphotericin B, ketoconazole, itraconazole, uconazole, 5-urocytosine, voriconazole, 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 difcult 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, endophthalmitis, and rare case of ARFS. Mycetomas have been successfully treated with amphotericin B in association 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 combination 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 uconazole and terbinane for a prolonged period. Although the infection did not disseminate systemically, it resolved

Azoles-Ketoconazole Cryotherapy

after an indolent course of 18 months (Das S et al., manuscript communicated). Eumycetomas are preferably treated with itraconazole; however, a combination therapy with amphotericin B has proven to be useful depending on the extent of manifestations in developing 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 significant 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 infections, especially in compromised hosts. Due to low susceptibility to antifungal drugs, it is essential to identify these agents correctly and accordingly formulate a therapeutic plan for each patient, which may not necessarily be always based upon documented data of treated patients. Identied agents may even be deposited with reference laboratories for future studies. Nevertheless, these infections may be suspected clinically on the basis of a constellation of clinical and laboratory ndings, which should lead to prompt treatment.

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Mycopathologia (2010) 170:361375 5. Green WO, Adams TE. Mycetoma in the US: a review of report of seven additional cases. Am J Clin Pathol. 1964; 42:7591. 6. Fincher RME, Fisher JF, Lovell RD, Newman CL, Espinellngroff A, Shadomy HJ. Infection due to fungus Acremonium (Cephalosporium). Medicine (Baltimore). 1991;70: 398409. 7. Gams W. Cephalosporiumartige Schimmelpize (Hyphomycetes). Stuttgart: Gustav Fischer Verlag; 1971. p. 262. 8. Zaias N. Supercial white onychomycosis. Sabroudia. 1966;5:99103. 9. Summerbell RC, Schroers HJ. Analysis of phylogenetic relationship of Cylidrocarpon lichenicola and Acremonium falciforme to the Fusarium solani species complex and review of similarities in the spectrum of opportunistic infections caused by these fungi. J Clin Microbiol. 2002;40: 286675. 10. Jicinska E. Dimorphic and yeast like mutants of the genus cephalosporium Cda. Folia Microbiol. 1974;19:14. 11. Li RY, Wan Z, Wang AP, Shen YN, Lu CM, Li M, et al. In-vitro susceptibility testing of amorolne in pathogenic fungi isolated from dermatomycosis patients in China. Mycoses. 2004;47:4026. 12. Rippon JW. Mycetoma. In: Medical mycology: the pathogenic fungi and the pathogenic Actinomycetes. Philadelphia: WB Saunders Co; 1982. p. 79114. 13. Guarro J, Gams W, Pujol I, Gene J. Acremonium species new emerging fungal opportunists in-vitro antifungal susceptibilities and review. Clin Infect Dis. 1997;25:12229. 14. Matruchot L. Un nouveau champignon pathogene pour lhomme. C R Hebd Seances Acad Sci. 1911;152:3257. 15. Venugopal TV, Venugopal PV, Parmasivan CN, Shetty BM, Subramanium S. Mycetomas in madras. Sabouraudia. 1997;15:1722. 16. Gupta AK, Summerbell RC. Combined distal and lateral subungual and white supercial onychomycosis in toenails. J AM Acad Dermatol. 1999;41:93844. 17. Pertalla Y, Peltokallio P, Leiviska T, Sipponen J. Yeast bezoar formation following gastric surgery. Am J Roentgenol Radium Ther Nucl Med. 1975;125:36573. 18. Mulwafu WK, Lubbe DE, Garb M. Allergic fungal sinusitis secondary to Acremonium species causing unilateral visual loss. East Central Afr J Surg. 2006;11:624. 19. Haide C, Padhye AA, Haley LD, Rinaldi MG, Kay D. Acremonium falciforme as a cause of mycetoma. Sabourodia. 1976;14:31926. 20. Boltansky H, Kwon-Chung KJ, Macher AM, Gallin JI. Acremonium strictum related pulmonary infection in a patient with chronic granulomatous disease. J Infect Dis. 1984;149:653. 21. Kouvousis N, Lazaros G, Christoforatou E, Deftereos S, Petropoulou MD, Lelekis M. Pacemaker pocket infection due to Acremonium species. Pacing Clin Electrophysiol. 2002;25:3789. J, Cano J, Gonza lez CG. A 22. Guarro J, Del Palacio A, Gene case of colonization of a prosthetic mitral valve by Acremonium strictum. Rev Iberoam Micol. 2009;26:1468. 23. Purnak T, Beyazit Y, Sahin GO, Shorbagi A, Akova M. A novel fungal pathogen under the spotlightAcremonium species associated fungaemia in an immunocompetent host. Mycoses 2009; [Epub ahead of print].

The twin advantage of specicity of identication due to its inherent discriminatory power and the possibility of isolate characterization in a single test format makes nucleic acid amplicationbased identication an attractive option. Moreover, as sequence databases become more robust, molecular methods will become the acceptable method of identication by microbiologists. Further, this procedure makes available a large window of opportunity for optimizing clinical management by cutting down the time required for the identication of the etiological agent and minimizing the confusion relating to its identication with morphologically similar-looking fungi. Case reporting of clinical experiences is important in attempting to better dene 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 identication would improve the intervention modality and provide useful epidemiological database for empirical management as well. Much additional work is needed to better understand the pathogenic mechanisms underlying hyalohyphomycosis and to optimize 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 hyalohyphomycetes. Articles from 1966 to 2010 were included in this review.

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