Fungal Infections Merck Manual Lungs and other organs

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Paracoccidioidomycosis

(South American Blastomycosis)

A progressive mycosis of skin, mucous membranes, lymph nodes, and

internal organs caused by Paracoccidioides brasiliensis.

Infections occur only in discrete foci in South and Central America,

most often in men aged 20 to 50, especially coffee growers of

Colombia, Venezuela, and Brazil. Although a relatively unusual

opportunistic infection, paracoccidioidomycosis sometimes occurs in

immunocompromised patients, including those with AIDS.

Although specific natural sites for P. brasiliensis remain

undefined, it is presumed to exist in soil as a mold, with

infections thought to follow inhalation of conidia (spores). These

convert into invasive yeasts within the lungs at 37° C (98.6° F) and

are assumed to spread to other sites hematogenously and via

lymphatics.

Symptoms and Signs

Mucocutaneous infections most often involve the face, especially at

the nasal and oral mucocutaneous borders. Yeasts are usually

abundantly present within pinpoint lesions throughout granular bases

of slowly expanding ulcers. Regional lymph nodes enlarge, become

necrotic, and discharge necrotic material through the skin.

Lymphatic infections mainly involve painless enlargement of

cervical, supraclavicular, or axillary nodes. Visceral infections

are characterized by focal lesions causing enlargement mainly of the

liver, spleen, and abdominal lymph nodes, sometimes with

accompanying abdominal pain. Mixed infections involve combinations

of all three patterns.

Diagnosis, Prognosis, and Treatment

Culture is diagnostic, although the presence in specimens of large

(often > 15 µm) yeasts forming characteristic multiple buds provides

strong presumptive evidence.

Clinically apparent infections are generally chronic and progressive

but not usually fatal. Azoles are highly effective. Oral

itraconazole is generally considered the drug of choice. IV

amphotericin B also can eliminate the infection and is often used in

very severe cases. Sulfonamides, which are widely used in some

countries because they are inexpensive, can suppress growth and

improve lesions but are not curative.

Sporotrichosis

An infection caused by the saprophytic mold Sporothrix schenckii,

usually initiated at cutaneous sites of trauma that spreads via

lymphatics to form nodules that break down into abscesses and ulcers

if untreated.

S. schenckii is found on rose or barberry bushes and sphagnum moss

or other mulches. Horticulturists, gardeners, farm laborers, and

timber workers are most often infected.

Symptoms and Signs

Lymphocutaneous infections are most common. They can occur on any

body site but characteristically involve one hand and arm, although

primary lesions may occur on exposed surfaces of the feet or face.

Occasionally, without primary lymphocutaneous lesions, the lungs are

involved or hematogenous spread leads to involvement of other sites,

especially peripheral joints. A primary lesion may appear as a

small, nontender papule or, occasionally, as a slowly expanding

subcutaneous nodule that eventually becomes necrotic and sometimes

ulcerates. Typically, a few days or weeks later, a chain of draining

lymph nodes begins to enlarge slowly but progressively, forming

movable subcutaneous nodules. If untreated, overlying skin reddens

and may later necrose, sometimes causing an abscess, ulceration, and

bacterial superinfection. Systemic signs and symptoms of infection

are notably absent. Lymphocutaneous lesions seldom, if ever, lead to

hematogenous dissemination to other sites. However, rare cases of

dissemination do occur, usually causing indolent infections of

multiple peripheral joints, sometimes bones, and, less often,

genitalia, liver, spleen, kidney, or meninges. Rarely, inhalation of

spores causes chronic pneumonia, manifested by localized infiltrates

or cavities, most often in patients with preexisting chronic lung

disease.

Diagnosis, Prognosis, and Treatment

The illness must be differentiated from local infections caused by

Mycobacterium tuberculosis, atypical mycobacteria, Nocardia, or

other organisms. Culture from the active infection site provides the

definitive diagnosis. S. schenckii yeasts can be seen only rarely in

fixed tissue specimens, even with special staining. Serologic tests

are not widely available. Delay in proper treatment commonly occurs

because, during the early, nondisseminated stage, the primary lesion

is misdiagnosed as a spider bite, especially in regions known to be

infested with spider species that cause necrotic arachnidism.

Lymphocutaneous sporotrichosis is chronic and indolent, but

potentially fatal only if bacterial superinfections cause sepsis.

Oral itraconazole is the treatment of choice, replacing prolonged

administration of saturated solution of potassium iodide, which is

less effective and causes troubling toxic effects far more

frequently. IV amphotericin B has been successful in clearing most

systemic cases, but relapses are frequent. Itraconazole may prove to

be more effective, but experience is limited.

Cryptococcosis

(Torulosis; European Blastomycosis)

An infection acquired by inhalation of soil contaminated with the

encapsulated yeast Cryptococcus neoformans, which may cause a self-

limited pulmonary infection or disseminate, especially to the

meninges, but sometimes to the skin, bones, viscera, or other sites.

Etiology and Incidence

Distribution is worldwide. Cryptococcosis is a defining

opportunistic infection for AIDS, although patients with Hodgkin's

or other lymphomas or sarcoidosis or those receiving long-term

corticosteroid therapy are also at increased risk. Progressive

disseminated cryptococcosis also sometimes affects those who are not

obviously immunocompromised, more frequently men > 40 yr. In such

cases, chronic meningitis is most common, usually without clinically

evident pulmonary lesions. Typically, meningeal inflammation is not

extensive, and microscopic multifocal intracerebral lesions are

present. Meningeal granulomas and larger focal brain lesions may be

evident.

Symptoms and Signs

Although most cryptococcal infections have a self-limited, subacute,

or chronic course, AIDS-associated cryptococcal infection may

present with severe, progressive pneumonia with acute dyspnea and an

x-ray pattern suggestive of Pneumocystis infection. Disseminated

cutaneous involvement may occur in any infected person, causing

pustular, papular, nodular, or ulcerated lesions, sometimes

resembling acne, molluscum contagiosum, or basal cell carcinoma.

Focal sites of dissemination also may become apparent in

subcutaneous nodules, the ends of long bones, joints, liver, spleen,

kidneys, prostate, and other tissues. Involved tissues typically

contain cystic masses of yeasts that appear gelatinous because of

accumulated cryptococcal capsular polysaccharide, but with minimal

or no acute inflammatory changes, especially in the brain.

Primary lesions in the lungs are usually asymptomatic and self-

limited. In immunocompetent persons, clinically apparent isolated

pulmonary lesions sometimes heal spontaneously without

disseminating, even without antifungal therapy. Pneumonia usually

causes cough and other nonspecific respiratory symptoms. Rarely,

pyelonephritis occurs with renal papillary necrosis development.

Besides skin lesions, focal lesions in bone, abdominal viscera, or

other tissues usually cause little or no symptoms.

Most symptoms of cryptococcal meningitis are attributable to brain

swelling and are usually nonspecific, including headache, blurred

vision, confusion, depression, agitation, or other behavioral

changes. Except for ocular or facial palsies, focal signs are rare

until relatively late in the course of infections. Blindness may

develop due to brain swelling or direct involvement of the optic

tracts. Fever is usually low-grade and frequently absent. AIDS

patients may have minimal or no symptoms and completely normal CSF

parameters except for the presence of many yeasts. However, elevated

CSF protein and a mononuclear cell pleocytosis are usual, although

neutrophilia occasionally predominates. Glucose is frequently low,

and encapsulated yeasts forming narrow-based buds can be seen on

India ink smears in most cases. Cryptococcal capsular polysaccharide

antigen is detectable in CSF and/or serum in > 90% of meningitis

cases.

Diagnosis

Culture is definitive. CSF, sputum, and urine yield organisms most

often, and blood cultures may be positive in heavy infections,

particularly in association with AIDS. The diagnosis is strongly

suggested by identification of encapsulated budding yeasts by

experienced observers in smears of body fluids, secretions,

exudates, or other specimens. In fixed tissue specimens,

encapsulated yeasts may also be identified and confirmed as C.

neoformans by positive mucicarmine or Masson-Fontana staining. The

latex test for capsular antigen is positive in CSF and/or blood

specimens from > 90% of patients with meningitis and is generally

specific, although false-positive results may occur, usually with

titers <= 1:8, especially in the presence of rheumatoid factor. In

disseminated cryptococcosis with meningitis, C. neoformans is

frequently cultured from urine, and prostatic foci of infection

sometimes persist despite successful clearance of organisms from the

CNS.

Treatment

Patients who are not immunocompromised may need no treatment if

there is only localized pulmonary involvement, confirmed by normal

CSF parameters, negative CSF and urine cultures, and no suggestion

of cutaneous, bone, or other extrapulmonary lesions. In the absence

of meningitis, localized lesions in skin, bone, or other sites

require systemic antifungal therapy, but optimum regimens have not

been defined in comparative experiments. Amphotericin B with or

without flucytosine has proven effective in most cases, but

successful therapy with oral therapy has been reported more recently.

For meningitis in non-AIDS patients, the standard regimen is 6 wk of

0.3 mg/kg/day amphotericin B IV combined with 100 to 150 mg/day

flucytosine po (25 to 37.5 mg q 6 h). Renal and hematologic function

must be evaluated before and regularly during therapy. Ideally,

flucytosine blood levels should be monitored to avoid accumulation

of toxic levels. It is more difficult to administer flucytosine

safely to patients with preexisting renal failure or bone marrow

dysfunction. Higher doses of amphotericin B, usually 0.6 mg/kg/day,

are given to patients who do not tolerate flucytosine. Fluconazole

is also effective in patients with mild infections and no apparent

risk factors.

AIDS patients more often have suboptimal therapeutic responses.

Amphotericin B and flucytosine are, nonetheless, recommended as

initial treatment in AIDS patients at least for 2 wk. Oral

fluconazole (200 to 400 mg/day) can be used thereafter. In AIDS

patients with cryptococcosis, initial treatment with fluconazole was

associated with more early deaths than occurred in patients who

received amphotericin B. Most cases relapse if treatment is stopped,

so chronic suppressive therapy is needed, preferably with

fluconazole 200 to 400 mg/day po. Weekly doses of IV amphotericin B

also can be used to prevent relapse. Higher doses of fluconazole are

being tried and may be more effective. In general, cultures should

become and remain negative for at least 2 wk before treatment is

ended in non-AIDS patients.

For cryptococcal meningitis, optimum fluconazole dosage and duration

of therapy still must be defined for treating non-AIDS patients.

Itraconazole also has been used successfully for maintenance or

overall therapy of cryptococcal meningitis but seems somewhat less

effective than fluconazole. In the absence of AIDS, antigen titers

should steadily decline during successful therapy.

Systemic Candidiasis

(Candidosis; Moniliasis)

Invasive infections caused by Candida sp, most often C. albicans,

manifested by fungemia, endocarditis, meningitis, and/or focal

lesions in liver, spleen, kidneys, bone, skin, and subcutaneous or

other tissues.

Mucocutaneous candidiasis is discussed in Chs. 113 and 164; chronic

mucocutaneous candidiasis, in Ch. 147.

Etiology and Incidence

Candida sp are commensal organisms that colonize the normal GI tract

and sometimes the skin. Unlike other systemic mycoses, candidiasis

is an endogenous organism and is not generally acquired from the

surrounding environment.

Infections due to Candida sp account for about 80% of all major

systemic fungal infections. Candida is now the fourth most prevalent

organism found in bloodstream infections and is the most common

cause of fungal infections in immunocompromised people. The

frequency of nosocomial candidiasis has risen at least fivefold in

the 1980s, making it one of the most common hospital-acquired

infections. Although often a benign, self-limited problem, it may be

associated with excess mortality of >= 40% (ie, deaths attributable

to candidiasis rather than to underlying diseases) and prolongation

of hospitalizations.

Invasive candidiasis usually occurs in immunosuppressed patients and

is most often caused by C. albicans or C. tropicalis. However,

infections caused by C. glabrata (formerly Torulopsis glabrata) and

other Candida sp are increasing in frequency. Oral candidiasis

(thrush) commonly affects patients with AIDS or with other causes of

compromised T-cell-mediated immune defense mechanisms and

occasionally affects others. Candidiasis involving the esophagus,

trachea, bronchi, or lungs is a defining opportunistic infection in

AIDS. Mucocutaneous candidiasis frequently complicates AIDS, but

hematogenous dissemination is unusual until immunocompromise becomes

profound. Vaginal candidiasis commonly affects women, including

those with normal immunity, especially after antibiotic use.

Neutropenic patients receiving cancer chemotherapy are at high risk

for developing life-threatening disseminated candidiasis. Candidemia

and especially hematogenous endophthalmitis are frequent nosocomial

infections in non-neutropenic patients who have prolonged

hospitalizations; infection is often related to multiple trauma or

surgical procedures, multiple courses of broad-spectrum

antibacterial therapy, and/or IV hyperalimentation. IV lines and the

GI tract are the usual portals of entry. Endocarditis may occur in

relation to IV drug abuse, valve replacement, or intravascular

trauma. Fungemia may lead to meningitis as well as to focal

involvement of skin, subcutaneous tissues, bones, joints, liver,

spleen, kidneys, eyes, and other tissues.

Symptoms and Signs

Esophagitis is most often manifested by dysphagia. Symptoms of

respiratory tract infections are nonspecific, such as cough. Vaginal

infections cause itching, burning, and discharge. Candidemia usually

causes fever, but other symptoms are typically nonspecific.

Sometimes, a syndrome develops resembling bacterial sepsis, with a

fulminating course that may include shock, oliguria, renal shutdown,

and disseminated intravascular coagulation. Hematogenous

endophthalmitis starts as white retinal plaques that can cause

blindness as destructive inflammation progresses, extending to

opacify the vitreous and causing potentially irreversible scarring.

Most often, there are no symptoms in early stages of Candida

endophthalmitis. If treatment is not begun before symptoms appear,

significant or even total loss of vision is likely to occur in the

affected eye. In neutropenic patients, eye involvement is more often

manifested by retinal hemorrhages; papulonodular, erythematous, and

vasculitic skin lesions may also develop.

Diagnosis

Because Candida sp are commensals, their culture from sputum, the

mouth, the vagina, urine, stool, or skin does not necessarily

signify an invasive, progressive infection. A characteristic

clinical lesion must also be present, histopathologic evidence of

tissue invasion documented, or other causes excluded. Positive

cultures of blood, CSF, pericardium or pericardial fluid, or tissue

biopsy specimens provide definitive evidence that systemic therapy

is needed. Histopathologic appearance of typical combined yeasts,

pseudohyphae, and/or hyphae in tissue specimens also is diagnostic.

However, antifungal therapy often is started presumptively. Various

serologic assays to detect antibodies or antigens have been

developed, but none has sufficient specificity or sensitivity to be

useful for rapid diagnosis or diagnostic exclusion in seriously ill

patients.

Prognosis and Treatment

All forms of disseminated candidiasis should be considered serious,

progressive, and potentially fatal. Predisposing conditions such as

neutropenia, malnutrition, or uncontrolled diabetes should be

reversed or controlled whenever possible. IV amphotericin B, alone

or in combination with flucytosine, is recommended for the most

severely ill, especially those who are markedly immunocompromised.

Fluconazole is as effective as amphotericin B for treating

candidemia in non-neutropenic patients, and preliminary data suggest

that fluconazole also can be effective in those with neutropenia.

However, infections caused by C. cruzii do not respond to

fluconazole and should be treated with amphotericin B; some other

species of Candida are less sensitive to fluconazole than are C.

albicans, particularly C. glabrata. For initial therapy, high doses

of oral, or if necessary, IV fluconazole (600 mg/day or more) can be

used pending species identification and results of in vitro

susceptibility tests, except in hospitals that have high prevalences

of infections caused by C. cruzii or other fluconazole-resistant

organisms. In these cases, amphotericin B should be used for initial

therapy. However, comparative trials are incomplete, and the optimum

fluconazole dosage for treating systemic candidiasis still is

undefined. Most experts recommend using 400 to 800 mg/day (po, or if

necessary, IV), especially since some Candida sp are more resistant

to fluconazole than are C. albicans. In particular, hospitals with

high frequencies of C. cruzii infection should use amphotericin B

for initial therapy until in vitro sensitivity test results are

available. Other azoles may also be effective, but comparative data

on efficacy are unavailable. Candida endocarditis almost always

requires valve replacement, although long-term suppressive therapy

with fluconazole may be tried.

Controlled studies are not available to determine the optimal

treatment regimen for other forms of disseminated candidiasis. Most

experts would recommend amphotericin B, but high-dose fluconazole

may be equally effective. Standard regimens for Candida meningitis

have not been established. Amphotericin B IV has been successful in

some patients, but intrathecal administration has been required in

many cases. Fluconazole has also been reported to be effective.

Usually, 400 to 800 mg/day (po, or if necessary, IV) is used. Some

cases of Candida meningitis have resolved spontaneously without any

specific antifungal therapy.

Aspergillosis

Opportunistic infections caused by Aspergillus sp and inhaled as

mold conidia, leading to hyphal growth and invasion of blood

vessels, hemorrhagic necrosis, infarction, and potential

dissemination to other sites in susceptible patients.

Aspergillus sp are among the most common environmental molds, found

frequently in decaying vegetation (compost heaps), on insulating

materials (in walls or ceilings around steel girders), in air

conditioning or heating vents, in operating pavilions and patient

rooms, on hospital implements, or in airborne dust. Invasive

infections are usually acquired in susceptible patients by

inhalation of conidia or, occasionally, by direct invasion at sites

of damaged skin. Major risk factors include neutropenia, long-term

high-dose corticosteroid therapy, organ transplantation (especially

bone marrow transplantation), hereditary disorders of neutrophil

function, such as chronic granulomatous disease, or, occasionally,

AIDS.

Symptoms and Signs

Noninvasive or, rarely, minimally locally invasive colonization of

preexisting cavitary pulmonary lesions also may occur in the form of

fungus ball (aspergilloma) formation or chronic progressive

aspergillosis. Fungus ball (aspergilloma) is a characteristic

saprophytic, noninvasive growth of tangled masses of hyphae, with

fibrin exudate and few inflammatory cells, typically encapsulated by

fibrous tissue. Aspergillomas usually arise and may enlarge

gradually within pulmonary cavities originally caused by

bronchiectasis, neoplasm, TB, other chronic pulmonary infections, or

even resolving invasive aspergillosis. Rarely, chronic necrotizing

invasive pulmonary lesions occur, usually in association with

corticosteroid therapy.

Primary superficial invasive aspergillosis is uncommon but may occur

in burns, beneath occlusive dressings, after corneal trauma

(keratitis), or in the sinuses, nose, or ear canal. Invasive

pulmonary aspergillosis usually extends rapidly, causing

progressive, ultimately fatal respiratory failure unless treated

promptly and aggressively. A. fumigatus is the most common causative

species. Extrapulmonary disseminated aspergillosis may involve the

liver, kidneys, brain, or other tissues and is usually fatal.

Primary invasive aspergillosis may also begin as an invasive

sinusitis, usually caused by A. flavus, presenting as fever with

rhinitis and headache. Necrosing cutaneous lesions may overlie the

nose or sinuses, palatal or gingival ulcerations may be present,

signs of cavernous sinus thrombosis may develop, and pulmonary or

disseminated lesions may occur. An allergic form of pulmonary

aspergillosis results in inflammatory infiltrates unrelated to

fungal invasion of tissues (see Allergic Bronchopulmonary

Aspergillosis in Ch. 76).

Diagnosis

Since Aspergillus sp are common in the environment, positive sputum

cultures may be due to environmental contamination by airborne

spores or noninvasive colonization in patients with chronic lung

disease. Sputum from patients with aspergillomas often does not

yield Aspergillus in cultures because cavities are likely to be

walled off from airways. A movable fungus ball within a cavitary

lesion is characteristic on x-ray or CT scan, although other

saprophytic molds also may cause it. Sputum cultures are even less

likely to be positive in patients with invasive pulmonary

aspergillosis, presumably because the disease progresses mainly by

vascular invasion and tissue infarction. However, a positive culture

from sputum or bronchial washings provides strong presumptive

evidence of invasive aspergillosis if obtained from patients with

increased susceptibility due to neutropenia, corticosteroid therapy,

or AIDS. Most lesions are focal and solid, although x-rays or CT

scans sometimes detect a halo sign, a thin air shadow surrounding a

nodule representing cavitation within a necrotic lesion. Diffuse,

generalized infiltrates occur in some patients. Progression usually

is extremely rapid. However, chronic invasive aspergillosis

occasionally occurs, notably in patients with the hereditary

phagocytic cell defect, chronic granulomatous disease.

Many patients at high risk for invasive aspergillosis are

thrombocytopenic, and respiratory insufficiency is common, so biopsy

specimens may be difficult to obtain. In addition, both cultures and

histopathology may be negative with biopsy specimens taken from

infected tissues because limited samples may miss small foci of

vascular invasion, showing only nonspecific necrosis within areas of

secondary infarction. Therefore, most decisions to treat are based

on strong presumptive clinical evidence. Histopathology with silver

or PAS staining can reveal characteristic blood vessel invasion by

septate hyphae with regular diameters and dichotomous (Y-shaped)

branching patterns. However, other less common causes of

opportunistic mycoses may be similar histopathologically.

Invasive sinusitis can be strongly suggested by CT scan and

diagnosed by anterior rhinoscopy with confirmatory cultures and

histopathology from biopsied necrotic lesions. Other invasive

superficial lesions can be diagnosed by culture and histopathology.

Blood cultures are almost always negative, even with rare cases of

endocarditis. Large vegetations often release sizable emboli that

may occlude blood vessels and providing specimens for diagnosis.

Various serologic assays have been developed but have been of

limited value for rapid diagnosis of acute, life-threatening

invasive aspergillosis. Detection of antigens such as galactomannans

can be specific but is not sufficiently sensitive to identify most

cases early enough.

Prognosis and Treatment

Fungus balls neither require nor respond to systemic antifungal

therapy but may require resection because of local effects,

especially hemoptysis. Invasive infections generally require

aggressive treatment with IV amphotericin B, although oral

itraconazole (but not fluconazole) can be effective in some cases.

Acute, rapidly progressive invasive aspergillosis is often rapidly

fatal, so high doses of amphotericin B should be started as early as

possible (usually 1.0 mg/kg/day, but up to 1.5 mg/kg/day, usually

given in divided doses). Addition of flucytosine may benefit some

patients, but renal failure inevitably caused by high-dose

amphotericin B increases flucytosine accumulation and the likelihood

of toxicity. Flucytosine doses should be adjusted to renal status.

Several newer lipid-associated formulations of amphotericin B are

approved for use in cases of invasive aspergillosis that are

unresponsive to the standard colloidal formulation. If progressive

renal failure requires reduction in amphotericin B doses to

suboptimal levels, the newer lipid formulations are less nephrotoxic

than amphotericin B deoxycholate and have been shown to be

effective. However, direct comparative studies of the different

formulations have not been completed.

Itraconazole is being evaluated in comparative trials but has been

used successfully in moderately severe cases. Generally, complete

cure requires reversal of immunosuppression (eg, resolution of

neutropenia, discontinuation of corticosteroids). Recrudescence

commonly occurs in patients who redevelop neutropenia.

Mucormycosis

(Zygomycosis; Phycomycosis)

Infection with tissue invasion by broad, nonseptate, irregularly

shaped hyphae of diverse fungal species, including Rhizopus,

Rhizomucor, Absidia, and Basidiobolus.

Infection is most common in immunosuppressed persons, in patients

with poorly controlled diabetes, and in patients receiving the iron-

chelating drug desferrioxamine.

Symptoms and Signs

Rhinocerebral mucormycosis is the most common form, but primary

cutaneous, pulmonary, or GI lesions sometimes develop, and

hematogenous dissemination to other sites can occur. Rhinocerebral

infections are usually fulminant and frequently fatal. Necrotic

lesions usually appear on the nasal mucosa or sometimes the palate.

Vascular invasion by hyphae leads to progressive tissue necrosis

that may involve the nasal septum, palate, and bones surrounding the

orbit or sinuses. Manifestations may include pain, fever, orbital

cellulitis, proptosis, purulent nasal discharge, and mucosal

necrosis. Progressive extension of necrosis to involve the brain can

cause signs of cavernous sinus thrombosis, convulsions, aphasia, or

hemiplegia. Patients with diabetic ketoacidosis are most often

affected, but opportunistic infections may also develop in

association with renal desferrioxamine therapy in chronic renal

disease or with immunosuppression, particularly with neutropenia or

high-dose corticosteroid therapy. Pulmonary infections resemble

invasive aspergillosis. Cutaneous Rhizopus infections have developed

under occlusive dressings.

Diagnosis and Treatment

Diagnosis requires a high index of suspicion and painstaking

examination of tissue samples for large nonseptate hyphae with

irregular diameters and branching patterns, because much of the

necrotic debris contains no organisms. For unclear reasons, cultures

usually are negative, even when hyphae are clearly visible in

tissues. CT scans and x-rays often underestimate or miss significant

bone destruction.

Effective antifungal therapy requires that diabetes be controlled

or, if at all possible, immunosuppression reversed or

desferrioxamine discontinued. IV amphotericin B must be used,

because azoles are ineffective. Surgical debridement of necrotic

tissue may be needed, because amphotericin B cannot penetrate into

these avascular areas to clear remaining organisms.

Mycetoma

(Maduromycosis; Madura Foot)

A chronic, progressive, local infection caused by fungi or bacteria,

involving the feet, upper extremities, or back and characterized by

tumefaction and formation of multiple sinus tracts.

Bacteria, primarily Nocardia sp and other actinomycetes, cause more

than half the cases; the remainder are caused by about 20 different

fungal species. Mycetoma occurs mainly in tropical or subtropical

areas, including the southern USA, and is acquired by entry of

organisms through sites of local trauma on bare skin of the feet as

well as on the extremities or backs of workers carrying contaminated

vegetation or other objects. Men aged 20 to 40 are most often

affected, presumably because of trauma incurred during work

outdoors. Infections spread through contiguous subcutaneous areas,

resulting in tumefaction and formation of multiple draining sinuses

that exude characteristic " grains " that comprise clumped organisms.

Microscopic tissue reactions may be primarily suppurative or

granulomatous depending on the specific causative agent.

Symptoms and Signs

The first lesion may be a papule, a fixed subcutaneous nodule, a

vesicle with an indurated base, or a subcutaneous abscess that

ruptures to form a fistula to the skin surface. Fibrosis is common

in and around early lesions. There is little or no tenderness in the

absence of acute suppurative bacterial superinfection. Infection

progresses slowly over the course of months or even years, with

gradual, progressive extension to and destruction of contiguous

muscles, tendons, fascia, and bones. There is neither systemic

dissemination nor signs and symptoms suggesting generalized

infection. Eventually, muscle wasting, deformity, and tissue

destruction prevent use of affected limbs. In advanced infections,

involved extremities appear grotesquely swollen, forming a club-

shaped mass of cystic areas with multiple draining and

intercommunicating sinus tracts and fistulas that discharge thick or

serosanguinous exudates containing characteristic grains.

Diagnosis, Prognosis, and Treatment

Causative agents can be identified presumptively by gross and

microscopic examination of grains, which are irregularly shaped,

variably colored 0.5- to 2-mm granules from exudates. Crushing and

culture of these granules provide definitive identification.

Specimens may yield multiple bacteria and fungi, some of which are

potential causes of superinfections.

The course may be prolonged for > 10 yr. Death may occur in

neglected cases due to bacterial superinfection and sepsis.

Sulfonamides and certain other antibacterial drugs, sometimes in

combination, are used to treat Nocardia (see Nocardiosis in Ch.

157). Among those infections caused by fungi, so-called eumycetomas,

certain of the potential causative organisms may respond at least

partially to amphotericin B or to itraconazole or ketoconazole, but

many are resistant to all available antifungal drugs. Relapses occur

after antifungal therapy in most cases, and many cases do not

improve or worsen during treatment. Surgical debridement is

necessary, and limb amputation may be needed to prevent potentially

fatal severe secondary bacterial infections.

Chromomycosis And Phaeohyphomycosis

(Chromoblastomycosis; Verrucous Dermatitis; Hematomycosis)

Infections of subcutaneous tissues, sinuses, brain, and other

tissues caused by dark, melanin-pigmented dematiaceous fungi

(including species of Bipolaris, Cladophialophora, Cladosporium,

Drechslera, Exophiala, Fonsecaea, Phialophora, Xylohypha,

Ochroconis, Rhinocladiella, Scolecobasidium, and Wangiella).

Symptoms and Signs

Chromomycosis is a cutaneous infection affecting normal,

immunocompetent persons mostly in tropical or subtropical areas,

characterized by formation of papillomatous nodules that tend to

ulcerate. Most infections begin on the foot or leg, but other

exposed body parts may be infected, especially where the skin is

broken. Early small, itchy, enlarging papules may resemble

dermatophytosis (ringworm). These extend to form dull red or

violaceous, sharply demarcated patches with indurated bases. Several

weeks or months later, new lesions, projecting 1 to 2 mm above the

skin, may appear along paths of lymphatic drainage. Hard, dull red

or grayish cauliflower-shaped nodular projections may develop in the

center of patches, gradually extending to cover extremities over

periods as long as 4 to 15 years. Lymphatic obstruction may occur,

itching may persist, and secondary bacterial superinfections may

cause ulcerations and, occasionally, septicemia.

Dematiaceous fungi also may cause other patterns of infection in

normal hosts and have been increasingly recognized as opportunists

affecting immunocompromised patients. Most mycology texts

distinguish these extracutaneous infections as phaeohyphomycosis.

Invasive sinusitis, sometimes with bony necrosis, as well as

subcutaneous nodules or abscesses, keratitis, lung masses,

osteomyelitis, mycotic arthritis, intramuscular abscess,

endocarditis, brain abscess, or chronic meningitis, may occur.

Diagnosis, Prognosis, and Treatment

Late chromomycosis lesions have a characteristic appearance, but

early involvement may be mistaken for dermatophytoses.

Phaeohyphomycosis must be distinguished by histopathology and

culture from the myriad other causes of facial extracutaneous

infectious and noninfectious conditions. Dematiaceous fungi are

frequently discernible in tissue specimens stained with conventional

hematoxylin and eosin, appearing as septate, brownish bodies

reflecting their natural melanin content. Masson-Fontana staining

for melanin confirms their presence. Culture is needed to identify

the causative species.

Dematiaceous fungi only rarely cause fatal infections in those who

have normally intact host defense mechanisms; life-threatening

illnesses occur more often in immunocompromised patients.

Itraconazole is the most effective antifungal drug, although not all

patients respond. Flucytosine is sometimes useful for ancillary

therapy, because some lesions may respond rapidly but generally

relapse. Fluconazole seldom causes lesions to regress, and

amphotericin B is ineffective. Many cases require surgical excision

for cure.