27
Subcutaneous mycoses Flavio Queiroz-Telles, MD a , Michael R. McGinnis, MD b, * , Ira Salkin, MD c , John R. Graybill, MD d a Hospital de Clı ´nicas da Universidade Federal do Parana ´, Curitiba, PR, Brazil b Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555–0609, USA c Information From Science, West Sand Lake, NY 12196, USA d University of Texas Health Science Center and Audie L. Murphey Veterans Administration Hospital, 7400 Merton Minter Boulevard, San Antonio, TX 78284, USA Subcutaneous mycoses include a heterogeneous group of fungal infec- tions that develop at the site of transcutaneous trauma. Infection slowly evolves as the etiologic agent survives and adapts to the adverse host tissue environment. The main subcutaneous fungal infections include sporo- trichosis, chromoblastomycosis, mycetoma, lobomycosis, rhinosporidiosis, subcutaneous zygomycosis, and subcutaneous phaeohyphomycosis. Diag- nosis rests on clinical presentation, histopathology, and culture of the etiologic agents. This article considers sporotrichosis, chromoblastomycosis, and mycetoma. Epidemiology Sporotrichosis Sporothrix schenckii commonly occurs in nature as a saprophyte on dead plant material. Although this dimorphic mold is worldwide in distribution, it primarily grows in warm temperate and tropical climates. Its pathogenic potential was first reported by Schenck in 1898 [1] at Johns Hopkins Hospital in Baltimore. When Schenck described it, he thought it resembled a ‘‘sporotrichia.’’ Today, the fungus is known as S schenckii. Sporothrix schenckii most commonly gains entrance into the host through traumatic inoculation as a contaminant on thorns, splinters, barbs, grasses, Infect Dis Clin N Am 17 (2003) 59–85 * Corresponding author. E-mail address: [email protected] (M.R. McGinnis). 0891-5520/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0891-5520(02)00066-1

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Subcutaneous mycoses

Flavio Queiroz-Telles, MDa,Michael R. McGinnis, MDb,*,

Ira Salkin, MDc, John R. Graybill, MDd

aHospital de Clınicas da Universidade Federal do Parana, Curitiba, PR, BrazilbDepartment of Pathology, University of Texas Medical Branch,

301 University Boulevard, Galveston, TX 77555–0609, USAcInformation From Science, West Sand Lake, NY 12196, USA

dUniversity of Texas Health Science Center and Audie L. Murphey Veterans Administration

Hospital, 7400 Merton Minter Boulevard, San Antonio, TX 78284, USA

Subcutaneous mycoses include a heterogeneous group of fungal infec-tions that develop at the site of transcutaneous trauma. Infection slowlyevolves as the etiologic agent survives and adapts to the adverse host tissueenvironment. The main subcutaneous fungal infections include sporo-trichosis, chromoblastomycosis, mycetoma, lobomycosis, rhinosporidiosis,subcutaneous zygomycosis, and subcutaneous phaeohyphomycosis. Diag-nosis rests on clinical presentation, histopathology, and culture of theetiologic agents. This article considers sporotrichosis, chromoblastomycosis,and mycetoma.

Epidemiology

Sporotrichosis

Sporothrix schenckii commonly occurs in nature as a saprophyte on deadplant material. Although this dimorphic mold is worldwide in distribution,it primarily grows in warm temperate and tropical climates. Its pathogenicpotential was first reported by Schenck in 1898 [1] at Johns HopkinsHospital in Baltimore. When Schenck described it, he thought it resembleda ‘‘sporotrichia.’’ Today, the fungus is known as S schenckii.

Sporothrix schenckii most commonly gains entrance into the host throughtraumatic inoculation as a contaminant on thorns, splinters, barbs, grasses,

Infect Dis Clin N Am 17 (2003) 59–85

* Corresponding author.

E-mail address: [email protected] (M.R. McGinnis).

0891-5520/03/$ - see front matter � 2003, Elsevier Science (USA). All rights reserved.

doi:10.1016/S0891-5520(02)00066-1

or sphagnum moss. The predominant clinical manifestation of the diseaseis lymphocutaneous sporotrichosis, which occurs chiefly in those whoseoccupation or vocation involves contact with vegetation and soil [2]. Inaddition, this form of the disease is generally associated with immunocom-petent individuals 35 years’ of age or younger and in approximately equalnumbers of males and females [3]. There is virtually no description of humanto human transmission.

In contrast, disseminated sporotrichosis occurs in patients who areimmunosuppressed. In the AIDS era epidemic, the numbers of such cases inHIV-infected patients is increasing [4–6].

Pulmonary sporotrichosis is found primarily in men, with a 6:1 male tofemale ratio. This form of the disease has been linked in one series of casesto alcohol abuse. Pulmonary sporotrichosis is probably caused by theinhalation of fungal conidia developing on vegetation, a situation similar topulmonary infections caused by other dimorphic fungal pathogens [7].

Osteoarticular disease also has a male to female ratio of from 6:1 to ashigh as 9:1. Malignant disease and immunosuppressive therapy have beenreported as predisposing factors. Most patients also have cutaneous andsubcutaneous lesions, although some patients do not have histories ofcutaneous disease.

The largest and most well-documented sporotrichosis epidemic occurredin South Africa between 1941 and 1944. Over 3000 gold miners acquired thelymphocutaneous form of the disease through contact with fungal-colonizedmine timbers (Simson FW, unpublished data). The epidemic ended throughtreatment of the timbers with fungicides. Similar outbreaks have beendescribed in the United States among individuals handling evergreenseedlings packed in sphagnum moss. The largest such epidemic occurred in1988 and involved 84 forestry workers and home gardeners from 15 states[8,9]. The fungus seems to initiate infections only after the postharvestdrying of the sphagnum moss for 4 to 24 months.

Chromoblastomycosis

Chromoblastomycosis refers to subcutaneous infections caused by darklypigmented (dematiaceous) molds, which form thick-walled, dark-colored,multicelled structures called muriform cells or sclerotic bodies in tissue. Asadditional similar cutaneous and subcutaneous diseases were reportedhaving only hyphal and yeast cells in tissue, these other infections wererenamed phaeohyphomycosis [10,11].

Following the initial reports, a number of dematiaceous molds have beenassociated with subcutaneous lesions containing muriform cells. The mostcommon of the etiologic agents are Cladophialophora carrionii and Fonsecaeapedrosoi. Less common pathogens include Fonsecaea compactum, Phialo-phora verrucosa, Rhinocladiella aquaspersa, Exophiala jeanselmei, Exophialaspinifera, and Wangiella dermatitidis [12]. To complicate matters further, as

60 F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

illustrated in the following example, several of these molds may also causeother mycotic diseases and the diagnosis is not always straightforward.

A 38-year-old white man presented with a history of chronic lesions at thebuttocks. He stated that the disease started 15 years ago, when he workedas a rural worker in the hinterlands of the State of Parana, South Regionof Brazil. During 2 years he was treated with two courses of amphotericin B(2 and 1.5 g) with partial response. He complained of pruritus and local pain.Erythematous, scaly, slightly elevated plaque, and cicatricial lesions on thebuttocks were observed (Fig. 1). A skin biopsy showed muriform cells inthe middle of microabscesses (Fig. 2). The cultivation of tissue fragmentsyielded black yeast, which was later identified as E jeanselmei (Fig. 3 A, B).This patient has chromoblastomycosis. Exophiala, however, are classicallycauses of phaeohyphomycosis and mycetoma. When causing phaeohypho-mycosis, pigmented yeast cells, vesicular structures, and septate hyphae areseen. In mycetoma, hyphae occur as compact dark aggregates.

Chromoblastomycosis is generally found in tropical and subtropicalareas and in populations that do not routinely wear shoes. The etiologicagents gain entrance through puncture wounds, predominantly on thelower extremities. Dead plant contact is the major risk factor, although theremay be some genetic susceptibility [13]. The primary pathogens includeF pedrosoi and C carrionii. Both are common in tropical areas of the world,although F pedrosoi is seen in humid forests, whereas C carrionii is found indrier climates of Madagascar, Australia, China, Mexico, Cuba, and Africa.The largest series of chromoblastomycosis was collected in Madagascar byEsterre et al [31,70]. Over 40 years 1343 cases were identified, with 98%confirmed by the characteristic histopathology, and 69% by culture ofF pedrosoi. Its frequency is 1 per 920 inhabitants. In a separate hot and dryregion of southern Madagascar, C carrionii is the most common pathogen.

Fig. 1. Violaceous plaque lesions and scarring on the buttocks.

61F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

The risk of infection is higher here, because only 5% of the Madagascarpopulation resides in this area, but more than a third of the total cases werefrom this region (1 per 480 inhabitants).

In a series of 325 cases from the humid Amazon region of Brazil, 77 of 78culture-confirmed cases were caused by F pedrosoi [14]. Most of the patientswere male agriculture workers, and 81% developed lesions on the legs orfeet. Londero and Ramos [15] found that most of their 35 patients in RioGrande do Sul in Brazil resided in the northern part of the state, whereasthere were few in the southern part, where people are engaged in cattleranching and usually wear shoes. Occasionally, dissemination may occurto lymph nodes, the lung, and even the brain. The disease is commonlydiagnosed after 1 to 4 years of slow evolution, but the lesions may slowlyenlarge or persist for decades before diagnosis [16]. Spontaneous resolutionis rare [17]. Queiroz-Telles et al [18] have reviewed 71 patients seen in theState of Parana, in the South Region of Brazil chromoblastomycosis arecharacterized in Brazil, between 1985 and 1996. Table 1 summarizes theseand other reports from Brazilian studies.

The disease was prevalent among males (12:1) with the mean age at thebeginning of infection of 41.3 years (range 9 to 71 years). In 32 patients(45%), the infection was associated with trauma. Isolation of the etiologicagent was possible in 67 (94%) of the cases. F pedrosoi was identified in 64(95%) cases.

Fig. 2. Skin biopsy showing a typical muriform cell in a microabscess. PAS, original magnifi-

cation � 1500.

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Mycetoma

Mycetoma is a syndrome involving cutaneous and subcutaneous tis-sues, fascia, and bone, caused by soil-inhabiting bacteria (actinomycoticmycetoma) or fungi (eumycetoma). Although the author who first des-cribed this disease remains in dispute, it was unquestionably originallyfound among Indian farmers [19] where it was called ‘‘Madura foot’’ ormaduromycosis [20]. Mycetoma is the recognized general name of thedisease whose clinical manifestations are described next [3,7].

Fig. 3. Micromorphology of Exophiala jeanselmei during the yeast-like phase (A) and the

mycelial phase (B). One-celled annelloconidia accumulated in balls at the apices of terminal and

intercalary tapered annellides (B).

Table 1

Chromoblastomycosis in Brazil

State

No. of cases/years

of observation

(cases per year)

Sex M/F

distributiona Age

Duration

in years Reference

Rio Grande

do Sul

73/28 (2,6) 7:1 40–50 1–40 [15]

Maranhao 13/03 (4,3) 5,5:1 50–60 0–15

Parana 71/11 (6,4) 12:1 40–50 1–50 [18,75]

PAara 325/55 (5,9) 13:1 50–60 ? [14]

a male:female.

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Approximately 50% of all cases of mycetoma are caused by true fungi,the most common of which are Madurella mycetomatis and Madurella grisea.Less frequent etiologic agents of mycetomata include Acremonium kiliense;E jeanselmei; Leptosphaeria senegalensis; Pseudallescheria boydii, also knownas Scedosporium apiospermum; and species in more than 10 other fungalgenera [19]. The other 50% of infections called actinomycosis or actino-mycotic mycetoma are caused by aerobic actinomycetes, primarily Actino-madura madurae and Nocardia brasiliensis.

As is the case for chromoblastomycosis, these fungi gain entrance to thehost through penetrating trauma, abrasions, or contact with other sharpobjects. Actinomycetoma and eumycetoma are most common in tropicaland subtropical areas and are endemic to India and several countries inAfrica and South America. For example, in a series of 21 patients observedin the State of Parana, Brazil, 14 (67%) were caused by bacteria (actino-mycetoma) and 7 (33%) were caused by fungi. The mean age was 46.4 years(range 22 to 77), and lower limbs were involved in more than 90% ofpatients. Both forms of mycetoma have been reported from temperateclimates, however, including the United States. The young to middle agemale prevalence likely reflects more occupational contact [19].

Pathogenesis

Sporotrichosis

Sporothrix schenckii may gain entrance by either direct entry into tissuefollowing traumatic injury, or by inhalation leading to pulmonary infection.S schenckii grows on dead, not living, plant material where it producesabundant hyphae and conidia. The hyphae and conidia serve as theinoculum that initiates cutaneous and lymphocutaneous sporotrichosis [21].In contrast, conidia most likely initiate pulmonary sporotrichosis because oftheir small size and aerodynamic properties. Virulence of conidia is relatedto cell wall composition that is influenced by the age of the cells and thesubstrate the fungus was growing on [21]. The differential susceptibilityseems to correlate with the amount of melanin present on the conidial wall.Melanin reduces phagocytosis and scavenging of oxygen and nitrogenspecies, which is protective for the fungus [22]. On entry into human tissue,the inoculum converts to a yeast form that elicits a local suppurative andgranulomatous tissue response with nodule development spreading alongthe local lymphatic system. The use of local heat seems to be effective in themanagement of sporotrichosis because it increases the polymorphonuclearneutrophil leukocyte (PMN) killing ability [23]. Immediate and delayed-typehypersensitivity reactions are elicited by yeast surface alfa-L-rhamnopyr-anosyl units. Delayed-type hypersensitivity is one of the important hostdefense mechanisms that help prevent the spread of the fungus. The cell-mediated immune response against S schenckii is expressed mainly by

64 F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

macrophages activated by CD4+ T cells, resulting in a Th1 expression in thelesion [24,25].

Chromoblastomycosis

Chromoblastomycosis is essentially a miniature form of mycetoma.Chromoblastomycosis has muriform cells, whereas in mycetoma multicel-lular sclerotia are present. The structural architecture of muriform cells andsclerotia (granules composed of fungal cells) contribute to the recogni-tion of the respective diseases (Fig. 4A). Muriform cells are expelledto the surface of the lesion by transepithelial elimination, whereas sclerotiaare expelled through fistulae. Lesions consist of abscesses; have a granulo-matous tissue response; and are noncontagious, chronic, and difficult tomanage, especially in advanced infections. The etiologic agents of chro-moblastomycosis are phylogenetically related fungi that are darklypigmented in tissue because of the presence of melanin in their cell walls.Melanin may play an important role in the pathogenesis of infections causedby dematiaceous fungi. This pigment inhibits intracellular killing ofWangiella dermatitidis and blocks neutrophil oxidation [26]. Granulomatousand suppurative components of the patient’s tissue consist of lymphocytes,plasma cells, eosinophils, and Langerhans’ cells (see Fig. 4A). The fungus iseither free, within phagocytic cells, or a combination of both [27]. In thedermis, muriform cells in microabscesses often show cell wall damage thatmay be the result of PMNs, in contrast to hyphal forms in the epi-dermis [28].

Rozental et al [29] have observed that once activated macrophages adhereto the cell wall of F pedrosoi, a respiratory burst occurs. The activity of therespiratory burst was detected in the macrophage plasma membrane portionthat was in contact with the fungus, and within the phagocytic vacuoles.Even though the activated macrophages did not kill ingested fungal cells,

Fig. 4. (A) Langerhans’ cell containing a muriform cell. H & E stain. (B) Muriform cells of

chromoblastomycosis. H & E stain.

65F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

they delayed germination and hyphal development. Muriform cells ofF pedrosoi may remain viable for up to 18 months after epidermal tissue iscollected from the patient [30], demonstrating the resistant nature of thesestructures.

Specific antibodies to particular antigens of C carrionii (23.5 and 33 kd)and F pedrosoi (18.5 kd) correlate with the extent of lesions on the patientand the chronic nature of the infection. Some patients with chromoblas-tomycosis have had positive antibody for a year following antifungaltherapy. A diagnosis of infection following a year of therapy can be detectedusing a quantitative ELISA test developed by Esterre et al [31].

Mycetoma

Fungi that cause eumycetoma are phylogenetically diverse. Sclerotiaexhibit distinctive morphologic architecture, typically with cells havingthickened cell walls toward the periphery of the sclerotium. Because ofthe irregular shape of sclerotia, the infection can be maintained in tissueby fragments of sclerotia breaking free from the parent structure andbeing dispersed locally either within the diseased area, or to adjacent tissue.PMNs are the predominant cell type in the inflammatory infiltrate that sur-rounds the sclerotia in tissue. Mycetomata are in essence granulomatoustumors [32].

Laboratory diagnosis

Sporotrichosis

The tissue phase consists of oval- to elongate-shaped budding yeast-likecells (Fig. 4B). Given the low numbers found in pus, exudates, or aspiratesfrom lesions, however, fungal cells are rarely observed in potassium hy-droxide or Gram-stained preparations. The use of celluflour or calcoflour-white, a nonspecific florescent stain, may enhance detection in clinicalspecimens.

Clinical diagnosis is dependent on culture using standard mycologic iso-lation media, (eg, Sabouraud’s glucose agar, Mycosel, blood agar) andincubated at 25�C to 30�C. S schenckii readily grows on these media within 5to 7 days, although plates should be held 3 to 4 weeks. Colonies are initiallymoist and smooth, somewhat similar to those of yeasts, but become dry,wrinkled, folded, and tough in texture as they age. The black colony color iscaused by the pigmentation in the conidial walls [3,7,33].

Because other molds are similar in their colony and microscopicmorphology to S schenckii, it is important to demonstrate the dimorphiccapabilities of the fungus. To do such, portions of hyphae and conidia fromthe mold phase are transferred to rich organic media, such as brain-heartinfusion agar and incubated at 37�C to induce transformation to yeasts.Yeast colonies are dull white in color, smooth in texture, and composed of

66 F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

spherical to oval budding cells, occasionally with multiple buds on a singleyeast cell [3,7,33,34].

Chromoblastomycosis

Laboratory diagnosis is relatively easy because muriform cells are usuallyobservable by direct microscopic examination of clinical specimens. Biopsyspecimens show hyperkeratosis and parakeratosis, with central neutrophilicabscesses and granulomas. Tissue infiltrates may present with variablepigmented fungal structures, such as muriform cells (Medlar bodies, copperpennies, and fumagoid bodies). The muriform cells are the main diagnosticfeature, and are defined as dematiaceous cells dividing in more that oneplane (see Fig. 4A) [21]. They may be clustered with necrotic tissue as ‘‘blackdots’’ seen on the surface of lesions.

Mycetoma

Exudate, pus, and biopsy tissue should be examined grossly for thepresence of sclerotia (grains, granules), which are characteristic of bothforms of mycetoma (Fig. 5). These are mounted on a microscope slide inpotassium hydroxide and crushed under the coverslip. The sclerotia ofactinomycetomata are composed of narrow filaments, generally less than1 lm in diameter, along with coccoid elements. In contrast, the filaments thatform the sclerotia of eumycetomata are from 2 to 6 lm in diameter. Inaddition, some of these hyphae may bear terminal swollen cells.

To isolate the etiologic agents of eumycetomata, sclerotia first should betransferred through several sterile water rinses containing antibacterialagents to decrease contamination that may inhibit fungal development.They can be inoculated directly into the mycologic media. To avoid con-tamination, tissue is best obtained from deep biopsy. Cultures should be in-cubated at 25�C and 37�C. Because the fungi that cause eumycetomata

Fig. 5. Mycetoma grain. H & E stain.

67F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

are very slow growing, cultures are to be maintained for upward of 6 weeksbefore being discarded as negative.

Clinical manifestations

Sporotrichosis

Lesions are most commonly encountered as fixed cutaneous (Fig. 6) andlymphocutaneous (Fig. 7). The typical course of disease begins days toweeks after inoculation by the formation of a nodule or ulcer at the primarysite of inoculation. Lesions enlarge slowly, and form satellite nodules track-ing proximally along the regional lymphatics. Regional adenopathy mayoccur. The lesions of cutaneous sporotrichosis are characteristic but notpathognomonic. They may remit spontaneously, but often recur. Nocardiaspecies can cause a very similar process (sporotrichoid nocardiosis [Fig. 8])and rarely this can be seen with actinomycosis or with Staphylococcus infec-tion [35,36]. Nocardiosis and actinomycosis can be identified readily bymodified acid-fast stains of tissue biopsy specimens or abscess drainage. Thedifferential diagnosis of nodular lesions with regional lymphatic involve-ment is broad enough to include certain nontuberculous mycobacteria,especially M marinum and M fortuitum complex, cat-scratch disease, andblastomycosis. The differential diagnosis of fixed and lymphocutaneousforms of sporotrichosis are as follows:

Infectious diseasesFungiParacoccidioidomycosisBlastomycosisChromoblastomycosisCoccidioidomycosisPhaeohyphomycosisGranulomatous trichophytosisBacteriaTuberculosis

Fig. 6. (A,B) Fixed sporotrichosis of the hand.

68 F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

SyphilisNocardiosisEctimaMycobacteriosis (M marinum or M fortuitum)Staphylococcus lymphangitisProtozoaLeishmaniasisNoninfectious diseasesBasal cellular carcinomaSarcoidosis

Lymphocutaneous disease may progress slowly over months. Bursitismay develop under the lesions, commonly in the olecranon or prepatellarsites [37–39]. Osteoarticular disease is less common, and may occur fromdirect extension from a cutaneous site, or may be blood borne. There maybe no apparent primary focus for pulmonary or cutaneous disease [40].Absence of sentinel skin lesions may lead to long delays in diagnosis. Theseries by Crout et al [40] had a mean of 25 months until diagnosis.Misdiagnosis may lead to intra-articular steroid injections, with temporaryrelief. Various surgical procedures may also be done before diagnosis [40].

Fig. 7. Lymphocutaneous sporotrichosis of the leg.

Fig. 8. Sporotrichoid nocardiosis.

69F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

Monoarthritic joint synovial swelling and effusion also are the usualmanifestations, with the knee, ankle, wrist, and elbow being involved indescending order of frequency. Multiple joint involvement and widespreaddisease are usually seen in patients with underlying immune suppression.Fever is uncommon. Radiographs show bone erosions and osteoporosis[40,41]. Synovial fluid and tissue biopsy specimens are positive in culture.Organisms are seen far less commonly [40]. Nonarticular osteomyelitis mayoccur, usually under a site of local superficial trauma, and often without anyoverlying skin lesion [42].

Chronic pulmonary sporotrichosis is the least common manifestationof sporotrichosis; is most commonly a consequence of inhalation; and ismarked by productive cough, dyspnea, and occasional hemoptysis (Fig. 9)[43]. Chronic cavitary disease and fibrosis are similar to chronic pulmonaryforms of histoplasmosis, blastomycosis, coccidioidomycosis, or mycobacte-rial disease. Fibrocavitary disease is confined to the lungs and disseminationis uncommon. Underlying chronic pulmonary disease is common. Chronicpulmonary sporotrichosis is slow in onset and very slow in response.Residual fibrosis is common.

Disseminated sporotrichosis may spread from scratch inoculation atremote sites, from inhalation, or hematogenously (Fig. 10). Lynch et al [43]reported that none of their eight patients with arthritis had overlying skin

Fig. 9. Pulmonary sporotrichosis.

70 F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

lesions. Widespread dissemination with meningitis occurs occasionally inimmune-suppressed patients [44,45].

Chromoblastomycosis

Chromoblastomycosis and phaeohyphomycosis are chronic infectionsdiffering in clinical presentation and in parasitic morphology. Lesions,which develop at the site of inoculation and may occasionally spread bylymphatic and autoinoculation at remote sites, include the following:

Nodular typeModerately elevated, fairly soft, dull to pink violaceous growths; smooth,verruciform, or scaly surface; with time they may become graduallytumorous.

Tumorous typeTumor-like masses, prominent, papillomatous, sometimes lobulated;cauliflower-like; on the lower extremities tend to be more exuberant;the surface is partly or wholly covered with epidermal debris andcrusts.

Verruciform typeHyperkeratosis is the outstanding feature; frequently encountered alongthe border of the foot; dry lesion.

Cicatricial typeNonelevated centrifugal growths that enlarge by peripheral extension atthe center with atrophic or sclerotic scarring while healing takes place;tend to cover extensive areas of the body; usually present annular,arciform, or serpiginous contour.

Plaque typeSlightly elevated with variously sized and shaped areas of infiltration;generally found on the higher portions of the limbs; reddish toviolaceous in color presenting a scaly surface; sometimes showsmarked lines of cleavage.

Fig. 10. (A) Disseminated sporotrichosis of face in patient with AIDS. (B) Skin lesions of same

patient.

71F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

Lesions may be graded both by type of lesion and by severity. The mostsevere lesions respond more slowly to treatment. The severity criteria ofchromoblastomycosis lesions are as follows:

Mild formA solitary plaque or nodule measuring less than 5 cm in diameterModerate formSolitary or multiple lesions: nodular, verruciform, or plaque types,

existing alone or in combination, covering one or two adjacentcutaneous regions, measuring less than 15 cm in diameter

Severe formAny type of lesion alone or in combination, covering extensive cutaneous

regions whether adjacent or nonadjacent

At the site of inoculation, lesions develop as warty papules or plaques(Fig. 11). They evolve over weeks to many months to thick, verrucousmasses (Fig. 12). Older lesions may have central clearing, which reflectsextensive scar formation or central ulcers (Fig. 13) [17]. Most lesions aresolitary. The lesions of chromoblastomycosis can be grouped according totheir severity or type, as shown previously [46]. This was useful in predictingthe clinical response to itraconazole [18]. From the 71 patients, 17 (24%)presented mild forms; 32 (45%) moderate forms; and 22 (31%) severeforms. Their mean time of evolution was 9 (range 1 to 26) years; 15.7 (range1 to 50) years; and 19.5 (range 5 to 40) years. A common misdiagnosis invery chronic lesions is cutaneous malignancy or premalignant conditions[17,47,48]. Comorbidities, such as leprosy or malignancy, can lead to poortherapeutic responses. Like sporotrichosis, the differential includes many in-fectious and noninfectious possibilities. The correct diagnosis is usually madewith characteristic histopathology, and may be confirmed with cultures.

Mycetoma

Eumycetoma is distinguished clinically by an even slower course andgreater destruction than chromoblastomycosis. Mycetoma remains the leastcommon of these infections, although it has a wide distribution, pre-

Fig. 11. (A,B) Chromoblastomycosis plaques.

72 F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

dominantly in countries with hot climates and a protracted dry season [32].Seventy percent of cases involve the foot. As with chromoblastomycosis, theillness is defined by the clinical presentation and pathology, not just by theorganism isolated. The initial lesion may develop slowly or rapidly, witha painless papule or nodule followed by development of draining sinus tractswith visible grains (Fig. 14A). The sinus tracts rarely appear before 3months, but are usually present by the end of the first year. Sclerotia mayalso be seen in pus discharging from the lesions (Fig. 14B). Sclerotia area mix of fungal and host matrix components, and may include granulomaand fungal polysaccharide cytoskeleton products [49,50]. Although thelesions commonly do not spread beyond the initial focus, they graduallyextend into deep tissues, extending along fascial planes to bone. Small pittedlesions develop in bones, and the cavities may become filled with sclerotia(Fig. 15). Secondary bacterial osteomyelitis may occur. The fungus mayoccasionally spread secondarily along lymphatics to involve viscera.

Treatment

Sporotrichosis

In a recent article, members of the Mycoses Study Group reviewed thedata on treatment of sporotrichosis and put forth their recommendations[51]. Treatment options for sporotrichosis include hyperthermia, saturated

Fig. 13. (A,B) Chromoblastomycosis with central clearing.

Fig. 12. (A,B) Chromoblastomycosis mass lesion.

73F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

solution of potassium iodide (SSKI), ketoconazole, itraconazole, flucona-zole, the two newer triazoles posaconazole and voriconazole, and terbinafine[2]. For lymphocutaneous disease, the least expensive treatment is SSKI,increasing from 5 to 40 drops three times a day or the maximally tolerateddose for 3 to 6 months (Table 2). SSKI is less effective or ineffective forother forms of sporotrichosis. The other systemic drug used specifically forskin infections is terbinafine. Initial reports were encouraging, with res-ponses in five of five patients given 250 mg/d for 8 weeks [52]. In anotherstudy, however, at 250 mg/d responses occurred in only about two of threepatients and it has not been aggressively pressed [53]. There are no data formore severe forms of sporotrichosis.

Of the azoles, ketoconazole was the first explored. It is least well-toleratedand least effective of the entire class, and the only thing favoring its use is thelow price. In one small study of seven patients, two responded, three failed,and two relapsed [54]. In another similar study, Calhoun et al [55] foundthat sustained remissions were noted in six of eight patients with systemicdisease, but late relapses occurred. Fluconazole is much better tolerated, buteven at doses of greater than 400 mg/d the response rate was only 71% forlymphocutaneous and osteoarticular disease [56]. Neither of these drugs isstrongly recommended.

Fig. 14. (A) Mycetoma lesion. (B) Grains of lesion.

Fig. 15. (A) Mycetoma foot lesion. (B) Radiograph of same lesion with lucencies in bone.

74 F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

The most effective triazole by far is itraconazole, for both lymphocuta-neous disease (responses 100% at 6 months’ treatment) [57] or for osteo-articular disease (about 85% to 100% response in several series [Table 3])[57–60]. Pulmonary sporotrichosis is uncommon, and it may be difficult toevaluate improvement in people with extensively damaged lungs. Itracona-zole may be useful, although experience is small. It is anticipated that bothvoriconazole and posaconazole, with potent extended spectra in otherfilamentous mycoses, will be highly effective; however, this is presentlyspeculation with no supporting evidence.

For patients with the most acutely life-threatening disseminated disease,and those few with meningitis, amphotericin B has been recommended[2,43]. Patients with meningeal sporotrichosis are commonly immunesuppressed, with such diseases as AIDS. Lifelong therapy may be requiredfor these patients. Lifelong therapy with amphotericin B is a very un-attractive proposition, and even in the absence of AIDS, there are reports ofrelapse [45]. Some recommend conversion to itraconazole when the patientis stable [2,51]. Although cerebrospinal fluid penetration of itraconazole isexceedingly low, itraconazole has been used successfully for treatment ofboth cryptococcal meningitis and coccidioidal meningitis. Pharmacokineticarguments should not prevent clinical exploration. Except for lymphocuta-neous disease, the length of treatment is not clearly defined. In the paucity ofdata, for osteoarticular disease and pulmonary disease the authors suggest

Table 2

Treatment options for sporotrichosis

Form of disease Primary

Dose and

duration Alternatives Dose and duration

Lymphocutaneous Itraconazole 100 mg/d

3 to 6 mo

SSKI 40 drops TID 3 to 6 mo

Bone and joint Itraconazole 200 mg BID

until well

Amphotericin B �0.5 mg/kg/d until well

Pulmonary Resection if

possible

— Itraconazole

Amphotericin B

200 mg BID until well

�0.5 mg/kg/d until

stable or resolved

Meningitis Amphotericin B Unclear Itraconazole 200 mg BID until resolved

and perhaps lifetime

Table 3

Itraconazole efficacy in sporotrichosis

Reference Lymphocutaneous Bone and joint

[59] 10/10 12/17

[60] 6/6

[39] 0/3

Total 100% of 10 71% of 26

Responses/total number are given.

75F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

treatment of disseminated disease until the process is inactive, then forperhaps 6 additional months. This is obviously easier for triazoles than foramphotericin B, and the authors reserve amphotericin B for the mostseriously ill. None of the triazoles are recommended in pregnancy, andeither SSKI (skin disease), hyperthermia (awkward to perform), oramphotericin B are the major alternatives. Finally, some manifestations ofsporotrichosis, particular bone and bursal disease, may warrant surgicalresection or debridement [39,42].

Chromoblastomycosis

Patients with chromoblastomycosis are a true therapeutic challenge forclinicians. Before the availability of a broad range of antifungal agents,Yanase and Yamada [61] successfully treated a case of chromoblastomy-cosis caused by F pedrosoi by applying localized heat to the skin lesionswith a pocket warmer. Subsequently, a number of patients in Japan whohad disease caused by F pedrosoi were successfully treated with local heat,and in at least one instance with local heat and antifungal agents. Eventhough a number of patients had a complete cure, some had only localimprovement. Local heat seems to be successful because F pedrosoi does notgrow beyond approximately 37�C to 40�C, whereas local applied heat isapproximately 46�C [62,63].

Cryosurgery has also been successful. Pimentel et al [64] treated 11patients infected by F pedrosoi. The five cases having localized lesions werecompletely cured; three patients with generalized lesions attained clinicaland mycologic remission for up to 26 months, whereas the three remainingpatients with generalized lesions had significant improvement. Similarresults have been reported by others [65]. Cryosurgery in conjunction withantifungal agents, such as itraconazole, has been successful [66,67].

The usefulness of local heat or cryosurgery is ideal for the managementof small lesions (mild forms), whereas antifungal agents, such as itraconazoleor terbinafine, are used for large lesions (moderate or severe forms). Fluco-nazole has been used successfully in a few patients [17,68]. Flucytosinehas been used, with mixed results [69]. Unfortunately, even with systemictherapy, cure rates are not high. Bonifaz and Carrasco-Gerard [66] describedtheir results for 51 cases from a 17-year period as 31% cured, 57% improved,and 12% failure based on cryosurgery, itraconazole, or a combination ofboth. Esterre et al [70] reported 47.2% cure with terbinafine in 43 patients.

Therapeutic success can be related to the etiologic agent (C carrionii ismore sensitive than F pedrosoi); to the severity of the disease (edema anddermal fibrosis can reduce the antifungal tissue levels); and to the choice ofthe antifungal drug [18,71].

There are no comparative trials in chromoblastomycosis. In most of theclinical trials the lesions are not graded according to severity, nor did thedifferent authors dealing with this mycosis use standardized criteria of cure.

76 F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

Bayles [72] from South Africa introduced some years ago clinical,mycologic, and histopathologic criteria for the interruption of antifungaltherapy in chromoblastomycosis patients. Queiroz-Telles et al [18] have beenusing these criteria and believe that they are very helpful for clinicians.

ClinicalDisappearance of pain and itching and complete healing of all lesionswith scarring

MycologicAbsence of parasites on direct examinationNo fungal isolation on culturePersistence of these findings in three consecutive monthly biopsyspecimens

HistologicAbsence of parasitesAtrophy of the epidermisDisappearance of microabscesses and granulomaReplacement of granulomatous infiltrate by chronic inflammation andfibrosis

Persistence of all these findings in three consecutive monthly biopsyspecimens

Itraconazole alone or combined with flucytosine or topical liquidnitrogen (cryotherapy) seems to be the best treatment for chromoblas-tomycosis [73–76]. Borelli [71] published a small experience, the first withitraconazole. Restrepo et al [77] reported successes with itraconazole inchromoblastomycosis, with smaller lesions responding more rapidly thanvery large ones. Queiroz-Telles et al [18] reported 19 cases caused byF pedrosoi, with 42% cure with itraconazole. Those data have beenexpanded in number and follow-up to include now 30 patients (Tables 4,5). The final assessment showed that eight patients (89%) with mildforms achieved clinical and mycologic cure after 10.9 months of therapy(range 7 to 17.6 months). No relapses were observed in this group afterthe mean time of 31.2 months (12 to 72 months). Similar responses wereobserved in 11 (91%) of the 12 patients with moderate forms after 12.9months, on average (range 5 to 31 months of continuous treatment). Inthis group only one patient relapsed after 6.3 months of follow-up, andthe remaining did not relapse in 12 to 60 months of follow-up. Amongthe nine patients with severe lesions of chromoblastomycosis, four (44%)had clinical and mycologic response after a mean of 30 months (range 10to 51 months), and the remaining patients were significantly improved.One relapse was observed during the follow-up (after 35 months), butthe patient improved again after resumption of therapy. No signifi-cant changes in the values of hematologic and biochemical tests wereobserved.

77F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

In another series of 12 patients, 11 with cultures positive for F pedrosoi,lesions with areas less than 15 cm were treated with itraconazole, 300 mg/d[67]. Of four patients receiving just itraconazole, two were cured and twoimproved with courses of 8 to 14 months. Another group of four patientswith similar-sized lesions received cryosurgery, with cures in all. In a thirdgroup, with larger lesions, itraconazole was used to reduce the size oflesions, which were then treated with liquid nitrogen. Others have usedcryosurgery alone [65]. Two of four patients were cured, and two wereimproved. Other small case reports show success. A few cases have beentreated with fluconazole, with some success, but experience is too small fora recommendation [68].

Flucytosine has been used successfully in a number of patients, often withamphotericin B or combined with itraconazole or resection [73,78]. It maybe less well tolerated than the triazoles, however, and is not uniformlyavailable in developing countries.

Terbinafine may be the best of all therapies. Esterre et al [70] havepublished a series of 43 patients from Madagascar, 37 with F pedrosoi andthe others with C carrionii. Terbinafine was given at 500 mg/d for 6 to 12months. Results showed efficacy in as short a time as 4 months in patients,half of whom had disease more than 10 years, and many of them azolefailures. Sixty-five percent had achieved clinical cure by 1 year (Table 6).This has recently been tried in the United States, with one patient suc-

Table 4

Clinical and demographic characteristics of 30 patients with chromoblastomycosis treated with

itraconazole

Clinical

form

Number of

patients (%)

Median age

(years)

Duration of

illness (years)

Previous

treatmenta (%)

Mild 9 (30) 57 (34–81) 7.5 (1–19) 4 (44)

Moderate 12 (40) 57 (42–70) 20 (6–50) 5 (42)

Severe 9 (30) 59 (50–75) 24 (18–40) 7 (78)

Total 30 56.5 17.2 16 (53)

a Surgery, cryotherapy, amphotericin B, flucytosine, and ketoconazole.

Table 5

Efficacy of itraconazole in 30 patients with chromoblastomycosis

Clinical and

mycologic

cure (%)

Duration of

therapya Improvement

Relapses

posttherapeutic

followupa

Mild 8 (89) 10,9 (7–16,6) 8 0

31.2 (12–72)

Moderate 11 (91) 12,9 (5–31) 1 1

63

Severe 4 (44) 30 (10–51) 5 1

35

a median of months.

78 F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

cessfully treated, and a similar experience in Japan with good efficacyin three of four patients reported [78,79]. Conclusions from these studiesmust be guarded, however, for several reasons. First, Esterre did not gradethe severity of his patients, and he did not use histopathologic criteria forinterruption of terbinafine. Second, the clinical specimens he used asmycologic criteria of response were just scrapings of the lesions. Finally,there are only preliminary findings and not long-term follow-up forrelapse. In addition to cryosurgery with liquid nitrogen, hyperthermia hasbeen used to treat chromoblastomycosis in very mild forms of disease[17,80]. Heat pads and even disposable pocket warmers have been usedsuccessfully [81].

Finally, the organisms seem sufficiently susceptible to amphotericin Bthat large oral doses might be used. Iijima et al [82] report one patient withF pedrosoi treated with up to 2400 mg/d (24 tablets) of amphotericin B. Hissmall lesions cleared on this treatment. Amphotericin B concentrations inthe bloodstream were only 0.089 lg/mL after a month of 300 mg/d, then0.138 lg/mL after 2 weeks at 1200 mg/d. Clearly, this small amount ofabsorbed amphotericin B was sufficient to cure the patient. In the future, thenew antifungal drugs under development may play an important role in thetreatment of chromoblastomycosis. In vitro, dematiaceous fungi are verysensitive to the new triazoles voriconazole and posaconazole [83,84]. Theresults published to date suggest that these new agents have broad-spectrumactivities in vitro; however, their effectiveness in the treatment of humanmycoses remains to be determined.

Mycetoma

Eumycetoma is an extremely difficult infection to manage (Fig. 16).Because of its chronic course, surgical management does not have to beinstigated before determining the identity of the etiologic agent. The agentsof fungal mycetoma tend to respond differently to antifungal drugs [85].This is a different situation than in chromoblastomycosis, where theetiologic agents are phylogenetically closely related to each other. Medicaltreatment is difficult because of the chronic nature of the disease, fibrosis

Table 6

Response of chromoblastomycosis to terbinafine

0 Months 4 Months 12 Months

Fungal cell score (0–4+ grade

score on no. cells/25 fields)

1.8 � 0.7 0.5 � 0.5 0.1 � 0.4

% Mycologic cure/N 0/29 41/29 85/27

% Clinical cure/N 0/29 6/29 65/29

Data from Esterre P, Inzan CK, Ramarcel ER. Treatment of chromoblastomycosis with

terbinafine: preliminary results of an open pilot study. Br J Dermatol 2001;134:33–6.

79F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

and tissue damage, and the presence of the etiologic as sclerotia that serve asa protective structure for these fungi [32].

Management of fungal mycetoma is either medical, surgical, or acombination of both [32,86]. Depending on the severity and duration of theinfection, the response to these modalities varies from complete cure tofailure. Del Giudice [87] and Smith and Kutbi [88] recommend that severalyears may be required before a decision regarding final outcome is possible.When considering the chronic nature and slow progress of the disease,ample time must be allowed for the potential subsequent development ofsymptoms if the etiologic agent is still viable in the patient’s tissues. Surgerymay result in mutilating excision to amputation with frequent recurrenceinvolving regional lymph nodes and surrounding tissue because of in-adequate adjacent tissue removal [44]. Small mycetomata are more success-fully managed by surgery than are larger and more extensively developedones [89]. Typically, antifungal agents are used in conjunction with surgicalmanagement.

Amphotericin B is thought ineffective, and fluconazole has produced onlytemporary improvement [56,86,90]. Ketoconazole has been thought to bethe best drug for mycetoma, with 72% of Sudanese patients showing someimprovement, but the data were generated before newer triazoles wereavailable [91]. Itraconazole and terbinafine are presently the major anti-fungal agents considered for the medical management of fungal mycetoma

Fig. 16. (A) Pretreatment eumycetoma. (B) Posttreatment same lesion. (C) Grains in a sinus

tract

80 F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

[44,88,92]. According to Poncio Mendes et al [93], itraconazole seems to bemore effective than ketoconazole. In animal models of disseminated myco-ses, the authors have found posaconazole highly effective against P boydii(Gonzales G, Graybill JR, unpublished data), and there are some clinicalresponses documented to voriconazole [94]. It seems appropriate to developthese agents as alternatives, given the poor responses to date.

References

[1] Schenck BR. On refractory subcutaneous abscesses caused by a fungus possibly related to

sporotrichia. Bulletin of the Johns Hopkins Hospital 1898;9:286–90.

[2] Kauffman CA. Sporotrichosis. Clin Infect Dis 1999;29:231–7.

[3] Rippon JW. The pathogenic fungi and pathogenic actinomycetes. Philadelphia: WB

Saunders; 1988.

[4] Al-Tawfiq JA, Woods KK. Disseminated sporotrichosis and Sporothrix schenckii fumegmia

as the initial presentation of human immunodeficiency virus infection. Clin Infect Dis

1998;26:1403–6.

[5] Bolao F, Podzamczer D, Ventin M, Gudiol F. Efficacy of acute phase and maintenance

therapy with itraconazole in an AIDS patient with sporotrichosis. Eur J Clin Microbiol

Infect Dis 1994;13:609–12.

[6] Donabedian RM, O’Donnell E, Olszewski C, MacArthur RD, Budd N. Disseminated

cutaneous and meningeal sporotrichosis in an AIDS patient. Diagn Microbiol Infect Dis

1994;18:111–5.

[7] Kwon-Chung KJ, Bennett JE. Medical mycology. Philadelphia: Lea and Febiger; 1992.

[8] Cooper CR, Breslin BJ, Dixon DM. DNA typing of isolates associated with the 1988

sporotrichosis epidemic. J Clin Microbiol 1992;30:1631–5.

[9] Dixon DM, Salkin IF, Duncan RA, Hurd NJ, Haines JH, Kemna ME, et al. Isolation

and characterization of Sporothrix schenckii from clinical and environmental sources

associated with the largest U.S. epidemic of sporotrichosis. J Clin Microbiol 1991;

29:1106–13.

[10] Ajello L. Phaeohyphomycosis: definition and etiology. Pan American Health Organization

Scientific Bulletin 1975;304:126–33.

[11] McGinnis MR. Chromoblastomycosis and phaeohyphomycosis: new concepts, diagnosis,

and mycology. J Am Acad Dermatol 1983;8:1–6.

[12] Padhye AA, Hampton AA, Hampton MT, Hutton NW, Prevost-Smith E, Davis MS.

Chromoblastomycosis caused by Exophiala spinifera. Clin Infect Dis 1996;22:331–5.

[13] Tsuneto LT, Arce-Gomez B, Queiroz-Telles F. HLA-A29 and genetic susceptibility to

chromoblastomycosis. J Med Vet Mycol 1989;27:181–5.

[14] Silva JP, De Souza W, Rozental S. Chromoblastomycosis: a retrospective study of 325

cases on Amazonic Region (Brazil). Mycopathologia 1998;143:171–5.

[15] Londero AT, Ramos CD. Chromoblastomicose no interior do estado do Rio Graande do

Sul. Annaies Brasiliense de dermatologia 1989;64:155–8.

[16] Shin JH, Shin DH, Song JW, Kee SJ, Suh SP, Ryang DW. Electrophoretic karyotype

analysis of sequential Candida parapsilosis isolates from patients with persistent or

recurrent fungemia. J Clin Microbiol 2001;39:1258–63.

[17] Elgart GW. Chromoblastomycosis. Dermatol Clin 1996;14:77–83.

[18] Queiroz-Telles F, Purin K, Fillus JN. Itraconazole in the treatment of chromoblastomy-

cosis due to Fonsecaea pedrosoi. Int J Dermatol 1992;31:805–12.

[19] Padhye AA, McGinnis MR. Fungi causing eumycetomic mycetoma. In: Murray PR,

Baron EJ, Pfaller MA, Tenover FC, Yolken RH, editors. Manual of clinical microbiology.

Washington: ASM Press; 1999. p. 1318–26.

[20] Carter HV. On mycetoma or the fungus disease of India. London: Churchill; 1874.

81F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

[21] Zhang X, Andrews JH. Evidence for growth of Sporothrix schenckii on dead but not on

living sphagnum moss. Mycopathologia 1993;123:87–94.

[22] Romero-Martinez R, Wheeler M, Guerrero-Plata A, Rico G, Torres-Guerrero H.

Biosynthesis and functions of melanin in Sporothrix schenckii. Infect Immunol 2000;

68:3696–703.

[23] Hiruma M, Kagawa S. Effects of hyperthermia on phagocytosis and intracellular killing of

Sporothrix schenckii by polymorphonuclear leukocytes. Mycopathologia 1986;95:93–100.

[24] Fujimura T, Asai T, Miyata T. Local expression of migration inhibitory factor and Th1

type cytokines mRNA in sporotrichosis lesions. Acta Dermatol Venereol 1996;76:

321–35.

[25] Tachibana T, Matsuyama T, Mitsuyama M. Involvement of CD4+ T cells and macro-

phages in acquired protection against infections with Sporothrix schenckii in mice. Med

Mycol 1999;37:397–404.

[26] Schnitzler N, Peltroche-Llacsahuanga H, Bestier N, Zundorf J, Luttiken R, Haase G.

Effect of melanin and carotenoids of Exophiala (Wangiella) dermatitidis on phagocytosis,

oxidative burst, and killing by human neutrophils. Infect Immunol 1999;67:94–101.

[27] Alviano CS, Farbiarz SR, deSouza W. Characterization of Fonsecaea pedrosoi melanin.

J Gen Microbiol 1991;137:837–44.

[28] Okuda C, Ito M, Oka K. Relationship between tissue reaction and morphological changes

of the fungi in chromoblastomycosis: morphometry and electron microscopy. Arch

Dermatol Res 1992;284:95–9.

[29] Rozental S, Alviano CS, deSouza W. The in vitro susceptibility of Fonsecaea pedrosoi to

activated macrophages. Mycopathologia 1994;126:85–91.

[30] Rosen T, Overholt M. Persistent viability of the Medlar body. Int J Dermatol 1996;

14:479–83.

[31] Esterre P, Jahevitra M, Andriantsimahavandy A. Humoral response in chromoblastomy-

cosis during and after therapy. Clin Diagn Lab Immunol 2000;7:497–500.

[32] McGinnis MR. Mycetoma. Dermatol Clin 1996;14:97–104.

[33] Perfect JR, Schell WA. The new fungal opportunists are coming. Clin Infect Dis

1996;22(suppl 2):S112–8.

[34] Schell W. Fusarium causing extremity infections in immunocompromised patients.

Editorial comment: an emerging, difficult fungus. Infect Med 1998;15:697.

[35] De Granda MEC, Richard C, Conde E, Iriondo A, De Lucas FM, Salesa R, et al.

Endocarditis caused by Scedosporium prolificans after autologous peripheral blood stem cell

transplantation. Eur J Clin Microbiol Infect Dis 2001;20:215–7.

[36] Salonen JH, Rimpilainen M, Lehtonen L, Lehtonen OP, Nikoskelainen J. Measurement of

the D-arabinitol/L-arabinitol ratio in urine of neutropenic patients treated empirically with

amphotericin B. Eur J Clin Microbiol Infect Dis 2001;20:179–84.

[37] Moyne AL, Shelby R, Cleveland TE, Tuzun S. Bacillomycin D: an iturin with antifungal

activity against Aspergillus flavus. J Appl Microbiol 2001;90:622–9.

[38] Staib P, Moran GP, Sullivan DJ, Coleman DC, Morschhauser J. Isogenic strain

construction and gene targeting in Candida dubliniensis. J Bacteriol 2001;183:2859–65.

[39] Wang JP, Granlund KF, Bozzette SA, Botte MJ, Fierer J. Bursal sporotrichosis: case

report and review. Clin Infect Dis 2000;31:615–6.

[40] Crout JE, Brewer NS, Tompkins RB. Sporotrichosis arthritis: clinical features in seven

patients. Ann Intern Med 1977;86:294–7.

[41] Wasylnka JA, Simmer MI, Moore MM. Differences in sialic acid density in pathogenic and

non-pathogenic Aspergillus species. Microbiology 2001;147:869–77.

[42] Govender S, RasoolMN,NgcelwaneM.Osseous sporotrichosis. J Infect Dis 1989;19:273–6.

[43] Lynch PJ, Voorhees JJ, Harrell R. Systemic sporotrichosis. Ann Intern Med 1970;73:

23–30.

[44] Mahgoub ES, Gumaa SA. Ketoconazole in the treatment of eumycetoma due to Madurella

mycetomatis. Trans R Soc Trop Med Hyg 1984;78:376–9.

82 F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

[45] Gullberg RM, Quintanilla A, Levin ML, Williams J, Phair JP. Sporotrichosis: recurrent

cutaneous, articular, and central nervous system infection in a renal transplant recipient.

Rev Infect Dis 1987;9:369–75.

[46] Carrion AL. Chromoblastomycosis. Ann N Y Acad Sci 1950;50:1255–82.

[47] Boekhout T, Theelen B, Diaz M, Fell JW, Hop WCJ, Abeln ECA, et al. Hybrid

genotypes in the pathogenic yeast Cryptococcus neoformans. Microbiology 2001;147:

891–907.

[48] Petrikkou E, Rodrıguez-Tudela JL, Cuenca-Estrella M, Gomez A, Molleja A, Mellado E.

Inoculum standardization for antifungal susceptibility testing of filamentous fungi

pathogenic for humans. J Clin Microbiol 2001;39:1345–7.

[49] Hay RJ, Collins MJ. An ultrastructural study of pale eumycetoma grains. Sabouradia

1983;21:261.

[50] Wong SSY, Ho TYC, Ngan AHY, Woo PCY, Que TL, Yuen KY. Biotyping of Penicillium

marneffei reveals concentration-dependent growth inhibition by galactose. J Clin Microbiol

2001;39:1416–21.

[51] Kauffman CA, Hajjeh R, Chapman SW, Mycoses SG. Practice guidelines for the

management of patients with sporotrichosis. Clin Infect Dis 2000;30:684–7.

[52] Hull PR, Vismer HF. Treatment of cutaneous sporotrichosis with terbinafine. Br J

Dermatol 1992;126(suppl 39):51–5.

[53] Pappas P, Restrepo A, Dietze R, Tiraboschi N, Bustamente D, Nolazco D, et al.

Terbinafine treatment of cutaneous sporotrichosis: initial results from a phase II/III trial

[abstract J-96]. Presented at the Thirty Eighth Interscience Conference on Antimicrobial

Agents and Chemotherapy, 1998.

[54] Dismukes WE, Stamm AM, Graybill JR, Craven PC, Stevens DA, Stiller RL, et al.

Treatment of systemic mycoses with ketoconazole: emphasis on toxicity and clinical

response in 52 patients. Ann Intern Med 1983;98:13–20.

[55] Calhoun DL, Waskin H, White MP, Bonner JR, Mulholland JH, Rumans LW,

et al. Treatment of systemic sporotrichosis with ketoconazole. Rev Infect Dis 1991;13:

47–51.

[56] Diaz M, Negroni R, Montero-Gei F, Castro LGM, Sampaio SAP, Borelli D, et al. A pan-

American 5-year study of fluconazole therapy for deep mycoses in the immunocompetent

host. Clin Infect Dis 1992;14(suppl 1):S68–76.

[57] Restrepo A, Robledo J, Gomez I, Tabare AM, Gutierrez R. Itraconazole therapy in

lymphangitic and cutaneous sporotricosis. Arch Dermatol 1986;122:413–7.

[58] Kauffman CA, Pappas PG, McKinsey DS, Greenfield RA, Perfect JR, Cloud GA, et al.

Treatment of lymphocutaneous and visceral sporotrichosis with fluconazole. Clin Infect

Dis 1996;22:46–50.

[59] Sharkey-Mathis PK, Kauffman CA, Graybill JR, Stevens DA, Hostetler JS, Cloud GA,

et al. Treatment of sporotrichosis with itraconazole. Am J Med 1993;95:279–85.

[60] Winn RE, Anderson JG, Piper J, Aronson NE, Pluss J. Systemic sporotrichosis treated

with itraconazole. Clin Infect Dis 1993;17:210–7.

[61] Yanase K, Yamada M. Pocket-warmer therapy of chromomycosis. Arch Dermatol

1978;114:1095.

[62] Kinbara T, Fukushiro R, Eryu Y. Chromomycosis: report of two cases successfully treated

with topical heat therapy. Mykosen 1982;25:689–94.

[63] Tagami H, Ginoza M, Imaizumi S. Successful treatment of chromoblastomycosis with

topical heat therapy. J Am Acad Dermatol 1984;10:615–9.

[64] Pimentel ER, Castro LG, Cuce LC. Treatment of chromomycosis by cryosurgery with

liquid nitrogen: a report on eleven cases. J Dermatol Surg Oncol 2001;15:72–7.

[65] Lubritz R, Spence JE. Chromoblastomycosis: cure by cryosurgery. Int J Dermatol

1978;17:830–2.

[66] Bonifaz A, Carrasco-Gerard SA. Chromoblastomycosis: clinical and mycologica

experience of 51 cases. Mycoses 2001;44:1–7.

83F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

[67] Bonifaz A, Martinez-Soto E, Carrasco-Gerard E, Peniche J. Treatment of chromoblas-

tomycosis with itraconazole, cryosurgery, and a combination of both. Int J Dermatol

1997;36:542–7.

[68] Yu RY, Gao L. Chromoblastomycosis successfully treated with fluconazole. Int J

Dermatol 1994;33:716–9.

[69] Lopes CF, Alvarenga RJ, Cisalpino EC, Resende MR, Gonzalago OL. Six years of

experience in the treatment of chromoblastomycosis with 5-fluorocytosine. Int J Dermatol

1978;17:414.

[70] Esterre P, Inzan CK, Ramarcel ER. Treatment of chromoblastomycosis with terbinafine:

preliminary results of an open pilot study. Br J Dermatol 2001;134:33–6.

[71] Borelli D. A clinical trial of itraconazole in the treatment of deep mycoses and

leishmaniasis. Rev Infect Dis 1987;9:S57–63.

[72] Bayles M. Tropical mycoses. Chemotherapy 1992;38(suppl 1):27–34.

[73] Bolzinger T, Pradinaude R, Sainte-Marie DDB, Shwetzoff E. Traitement de quatre cas de

chromomicose a Fonsecaea pedrosoi par l’associatyion 5-fluorocytosine-itraconazole. Les

Nouvelles Dermatologiques 1991;10:462–6.

[74] Cuce LC, Wroclawski EL, Sampaio SAP. Treatment of paracoccidioidomysosis,

candidiasis, chromoblastomycosis, lobomycosis, and mycetomas with ketoconazole. Int J

Dermatol 1980;19:405–8.

[75] De Hoog GS, Queiroz-Tellez F, Haase G. Black fungi: clinical and pathogenic approaches.

Med Mycol 2000;38(suppl 1):243–50.

[76] Kullavanijaya E, Rojanavanich V. Successful treatment of chromoblastomycosis due to

Fonsecaea pedrosoi by itraconazole and cryotherapy. Int J Dermatol 1995;34:804–7.

[77] Restrepo A, Gomez I, Arango MD, deBedout C. Treatment of chromoblastomycosis with

itraconazole. Ann NY Acad Sci 1988;544:504–16.

[78] Tanuma H, Hiramutsu M, Mukai H, Abe M, Nishiyama S, Katsuoka K. Case report:

a case of chromoblastomycosis effectively treated with terbinafine. Mycoses 1999;43:79–83.

[79] Sevigny GM, Ramos-Caro FA. Treatment of chromoblastomycosis due to Fonsecaea

pedrosoi with low-dose terbinafine. Cutis 2000;66:45–6.

[80] Tuffanelli L, Milburn P. Treatment of chromoblastomycosis. J Am Acad Dermatol

1990;23:728.

[81] Hiruma M, Kawada A, Yoshida M, Kouya M. Hyperthermic treatment of chromomycosis

with disposable chemical pocket warmers. Mycopathologia 1993;122:107–14.

[82] Iijima S, Takase T, Otsuka F. Treatment of chromomycosis with oral high-dose

amphotericin B. Arch Dermatol 1995;131:399–401.

[83] Espinel-Ingroff A. Comparison of in vitro activities of the new triazole SCH56592 and the

echinocandins MK-0991 (L-743,872) and LY303366 against opportunistic filamentous and

dimorphic fungi and yeasts [abstract]. J Clin Microbiol 1998;36:2950–6.

[84] Marco F, Pfaller MA, Messer AF, Jones RN. Antifungal activity of a new triazole,

voriconazole (UK-109,496) compared with three other antifungal agents against clinical

isolates of filamentous fungi. Med Mycol 1998;36:433–61.

[85] McGinnis M, Pasarell L. In vitro testing of susceptibilities of filamentous ascomycetes to

voriconazole, itraconazole, and amphotericin B, with consideration of phylogenetic

implications. J Clin Microbiol 1998;36:2353–5.

[86] Restrepo A. Treatment of tropical mycoses. J Am Acad Dermatol 1994;31(suppl):

S91–S102.

[87] Del Giudice P. Treatment of eumycetoma. J Am Acad Dermatol 1996;34(suppl 46):33–6.

[88] Smith EL, Kutbi S. Improvement of eumycetoma with itraconazole. J Am Acad Dermatol

1995;33:917–9.

[89] Welsh O, Salinas MC, Rodriguez MA. Treatment of eumycetoma and actinomycetoma.

Curr Top Med Mycol 1995;6:47–71.

[90] Rios-Fabra A, Restrepo A, Isturiz E. Fungal infections in Latin American countries. Infect

Dis Clin North Am 1994;8:129.

84 F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85

[91] Hay RJ. Ketoconazole in the treatment of fungal infections: clinical and laboratory studies.

Am J Med 1983;74(suppl 1B):16.

[92] Hay RJ. Therapeutic potential of terbinafine in subcutaneous and systemic mycoses. Br J

Dermatol 1999;141(suppl 56):36–40.

[93] Poncio Mendes R, Negroni R, Bonifaz A. New aspects of some endemic mycoses. Med

Mycol 2000;38(suppl 1):237–41.

[94] Munoz P, Marın M, Tornero P, Rabadan PM, Rodrıguez-Creixems M, Bouza E.

Successful outcome of Scedosporium apiospermum disseminated infection treated with

voriconazole in a patient receiving corticosteroid therapy. Clin Infect Dis 2000;

31:1499–501.

85F. Queiroz-Telles et al / Infect Dis Clin N Am 17 (2003) 59–85