1685CHAPTER 218 Mucormycosis

of either agent for infections outside the brain, although LAmB may

be less nephrotoxic than ABLC.

Starting dosages of 1 mg/kg per day for AmB deoxycholate

and 5 mg/kg per day for LAmB and ABLC are commonly given

to adults and children to treat mucormycosis. Dose escalation of

LAmB to 7.5 or 10 mg/kg per day for CNS mucormycosis may be

considered in light of the limited penetration of polyenes into the

brain. Because of autoinduction of metabolism, which results in

paradoxically lower drug levels, there is no advantage to escalating

the LAmB dose above 10 mg/kg per day, and doses of 5 mg/kg per

day are probably adequate for nonbrain infections. ABLC dose

escalation above 5 mg/kg per day is not advisable given the lack of

relevant data and the drug’s potential toxicity.

In multiple studies, various combinations of lipid polyenes

(both ABLC and LAmB) plus echinocandins (e.g., caspofungin,

micafungin, and anidulafungin) improved survival rates among

mice with disseminated mucormycosis (including CNS disease).

Furthermore, combination lipid polyene–echinocandin therapy

was associated with significantly better outcomes than polyene

monotherapy in a retrospective clinical study involving patients

with rhino-orbital-cerebral mucormycosis (including CNS disease).

The effect of echinocandins appears to be to downmodulate the

virulence of the fungus and reduce tissue necrosis and destruction

from fungal invasion. On the basis of such data, some experts prefer combination lipid polyene–echinocandin therapy as a first-line

option. However, at least one retrospective study did not find an

advantage of any combination regimens (including polyene-azole,

polyene-echinocandin, or others) in patients who primarily had

malignancy as the underlying disease. Ultimately definitive randomized controlled trials are needed to establish whether the combination is superior in efficacy to monotherapy for mucormycosis.

When used, echinocandins should be administered at standard,

FDA-approved doses since dose escalation has resulted in paradoxical loss of efficacy in preclinical models.

In contrast to deferoxamine, the iron chelator deferasirox is fungicidal against clinical isolates of the Mucorales. In mice with DKA

and disseminated mucormycosis, combination deferasirox–LAmB

therapy resulted in synergistic improvement of survival rates and

reduced the fungal burden in the brain. Unfortunately, a small

randomized, double-blind, phase 2 safety clinical trial of adjunctive

therapy with deferasirox (plus LAmB) documented excess mortality

among patients treated with deferasirox. Of note, the study population included primarily patients with active malignancy, and few

patients in the study had diabetes mellitus as their only risk factor.

TABLE 218-2 Antifungal Options for the Treatment of Mucormycosisa

DRUG RECOMMENDED DOSAGE ADVANTAGES AND SUPPORTING STUDIES DISADVANTAGES

First-Line Antifungal Therapy

AmB deoxycholate 1.0–1.5 mg/kg once per day • >5 decades of clinical experience

• Inexpensive

• FDA approved for treatment of mucormycosis

• Highly toxic

• Poor CNS penetration

LAmB 5–10 mg/kg once per day • Less nephrotoxic than AmB deoxycholate

• Better CNS penetration than AmB deoxycholate or

ABLC

• Better outcomes than with AmB deoxycholate in

murine models and a retrospective clinical review

• Expensive

ABLC 5 mg/kg once per day • Less nephrotoxic than AmB deoxycholate

• Murine and retrospective clinical data suggest benefit

of combination therapy with echinocandins

• Expensive

• Possibly less efficacious than LAmB for

CNS infection

Second-Line/Salvage Option

Isavuconazole 200 mg of isavuconazole (372

mg of isavuconazonium sulfate),

load q8h × 6 followed by

once-daily dosing

• Efficacy similar to that of LAmB in mouse models

• FDA approved for treatment of mucormycosis

• May be a rational empirical option when septate mold

vs mucormycosis is not yet established

• Much less clinical experience

• Clinical study supporting approval was

small and historically controlled

Posaconazole 200 mg four times per day • In vitro activity against the Mucorales, with lower MICs

than isavuconazole

• Retrospective data for salvage therapy in

mucormycosis

• Substantially lower blood levels than

isavuconazole

• No data on initial therapy for

mucormycosis, and no evidence for

combination therapy with posaconazole

• Experience limited, potential use for

salvage therapy

Combination Therapyb

Echinocandin plus lipid

polyene

Standard echinocandin doses • Favorable toxicity profile

• Synergistic in murine disseminated mucormycosis

• Retrospective clinical data suggest superior outcomes

for rhino-orbital-cerebral mucormycosis.

• Limited clinical data on combination

therapy

Lipid polyene plus

azole (posaconazole or

isavuconazole)

Standard doses • Favorable toxicity profile • Limited efficacy data, with no available

evidence of superiority vs monotherapy

Triple therapy (lipid

polyene plus echinocandin

plus azole)

Standard doses • Maximal aggressiveness • Limited efficacy data, with no available

evidence for superiority vs monotherapy

or dual therapy

a

Primary therapy should generally include a polyene. Non-polyene-based regimens may be appropriate for patients who refuse polyene therapy or for relatively

immunocompetent patients with mild disease (e.g., isolated suprafascial cutaneous infection) that can be surgically eradicated. b

Prospective randomized trials are

necessary to confirm the suggested benefit (from animal and small retrospective human studies) of combination therapy for mucormycosis. Dose escalation of any

echinocandin is not recommended because of a paradoxical loss of benefit of combination therapy at echinocandin doses of ≥3 mg/kg per day.

Abbreviations: ABLC, AmB lipid complex; AmB, amphotericin B; CNS, central nervous system; FDA, U.S. Food and Drug Administration; LAmB, liposomal AmB; MIC, minimal

inhibitory concentration.

Source: Modified from B Spellberg et al: Clin Infect Dis 48:1743, 2009.

1686 PART 5 Infectious Diseases

Deferasirox is therefore contraindicated as therapy in patients with

active malignancy, but its role in patients who have diabetes mellitus without malignancy (the setting in which its preclinical efficacy

was optimal) remains uncertain.

Posaconazole and isavuconazole are the only FDA-approved

azoles with reliable in vitro activity against the Mucorales. However, there are limited data regarding the efficacy of posaconazole

monotherapy for mucormycosis, and in contrast to polyeneechinocandin therapy, there are no data to support the use of combination posaconazole-polyene regimens. Although the minimal

inhibitory concentrations of isavuconazole against the Mucorales

are four- to eightfold higher than those of posaconazole, blood

levels may be higher with standard isavuconazole dosing than with

posaconazole. Isavuconazole is FDA approved for the treatment

of mucormycosis on the basis of a small, historically controlled

study. Given this limited data set, many experts continue to think

that lipid polyenes are first-line options and that isavuconazole,

like posaconazole, is best reserved for oral stepdown therapy in

patients whose condition has substantially improved on polyenebased therapy or for salvage therapy in patients who are intolerant of polyene-based regimens or whose infection is refractory to

these regimens. As with posaconazole, no data support the use

of combination isavuconazole-polyene regimens in lieu of polyene monotherapy or polyene-echinocandin combination regimens.

Some experts use triple therapy with a polyene, echinocandin,

and either posaconazole or isavuconazole for patients who have

extensive disease or whose disease has progressed on prior therapy.

Empirical, dual lipid polyene–azole therapy is a rational choice in

a patient with likely invasive mold infections when septate molds

and mucormycosis are both in the differential diagnosis and the

etiologic agent has not yet been confirmed. Alternatively, initial

therapy with isavuconazole monotherapy may be reasonable for a

brief period of time in a stable patient if mucormycosis is felt to be

possible, but less likely than a septated mold infection.

The roles of recombinant cytokines and neutrophil transfusions

in the primary treatment of mucormycosis are not clear, although

it is intuitive that earlier recovery of neutrophil counts should

improve survival rates. Limited data from uncontrolled case series

support the use of hyperbaric oxygen in centers with the appropriate technical expertise and facilities; its efficacy remains undefined.

As mentioned previously, one study in mice with DKA found that

administration of sodium bicarbonate improved survival from

mucormycosis; however, because insulin was not administered to

the mice, it is unclear whether the therapeutic effect is clinically

relevant.

In general, antifungal therapy for mucormycosis should be continued until resolution of clinical signs and symptoms of infection and resolution of underlying immunosuppression. However,

after several weeks of daily therapy in a patient who is clinically

improving, it is reasonable to consider switching to thrice-weekly

lipid polyene doses—with ultimate weaning down to twice-weekly

doses—for maintenance therapy. For patients with mucormycosis who are receiving immunosuppressive medications, secondary

antifungal prophylaxis is typically continued for as long as the

immunosuppressive regimen is administered. Stepdown to azoles

for chronic suppression is a reasonable alternative to continuing

polyene therapy in this setting, with reinitiation of polyenes during

periods of deep neutropenia.

One common source of error in the long-term management of

mucormycosis is follow-up radiology. Analysis of data from the

DEFEAT Mucor study indicated that early radiographic progression (within the first 2 weeks) did not predict long-term survival.

Changing the therapeutic plan based on early radiographic changes

can result in therapeutic errors. For example, it is common for CNS

Mucorales to cavitate in the brain parenchyma over time. This does

not necessarily reflect therapeutic failure, but rather may reflect

increased immune reactivity to the fungus, particularly in patients

recovering from neutropenia or with removal of immune suppression. Thus, it may not be advisable to obtain serial radiographic

studies in the short term, and if such studies are obtained, caution should be used in reacting to their results. Greater emphasis

should be placed on clinical response, particularly within the first

2–4 weeks after initiation of therapy.

■ PROGNOSIS

Over the past two decades, the prognosis of mucormycosis has substantially improved with aggressive antifungal therapy. Even CNS

infection is often successfully treated. As mentioned, the key driver of

outcome may be control of the patient’s predisposing condition.

■ FURTHER READING

Cornely O et al: Global guideline for the diagnosis and management

of mucormycosis: An initiative of the European Confederation of

Medical Mycology in cooperation with the Mycoses Study Group

Education and Research Consortium. Lancet Infect Dis 19:e405,

2019.

Pettrikos G et al: Epidemiology of mucormycosis in Europe. Clin

Microbiol Infect 20(S3):67, 2014.

Spellberg B et al: Novel perspectives on mucormycosis: Pathophysiology, presentation, and management. Clin Microbiol Rev 18:556, 2005.

Spellberg B et al: Combination therapy for mucormycosis: Why,

what, and how? Clin Infect Dis 54(S1):S73, 2012.

Spellberg B et al: Risk factors for mortality in patients with mucormycosis. Med Mycol 50:611, 2012.

ENDEMIC MYCOSES (DIMORPHIC FUNGI)

Dimorphic fungi exist in discrete environmental niches as molds that

produce conidia, which are their infectious form. In tissues and at temperatures of >35°C, the mold converts to the yeast form. Other endemic

mycoses—histoplasmosis, coccidioidomycosis, and blastomycosis—

are discussed in Chaps. 212, 213, and 214, respectively.

■ SPOROTRICHOSIS

Etiologic Agent, Epidemiology, and Pathogenesis Sporothrix

schenckii complex is comprised of six closely related organisms;

S. schenckii and S. brasiliensis are the species that cause most human

infection. Sporothrix species are found worldwide in sphagnum moss,

decaying vegetation, and soil. Sporotrichosis most commonly affects

persons who participate in outdoor activities such as landscaping, gardening, and tree farming. Infected animals can transmit S. schenckii to

humans. A large ongoing outbreak of sporotrichosis in Rio de Janeiro

caused by S. brasiliensis has been traced to cats, which are highly

susceptible to this infection. Sporotrichosis is primarily a localized

infection of skin and subcutaneous tissues that follows traumatic

inoculation of conidia. Osteoarticular sporotrichosis is uncommon,

occurring most often in middle-aged men who abuse alcohol, and

pulmonary sporotrichosis occurs almost exclusively in persons with

chronic obstructive pulmonary disease who have inhaled the organism

from the environment. Dissemination occurs almost entirely in markedly

immunocompromised patients, especially those with AIDS.

Clinical Manifestations and Differential Diagnosis Days

or weeks after inoculation, a papule develops at the site and then

usually ulcerates but is not very painful. Similar lesions develop

sequentially along the lymphatic channels proximal to the original

219 Less Common Systemic

Mycoses and Superficial

Mycoses

Carol A. Kauffman

1687CHAPTER 219 Less Common Systemic Mycoses and Superficial Mycoses

FIGURE 219-1 Several nodular lesions that developed after a young boy pricked

his index finger with a thorn. A culture yielded S. schenckii. (Courtesy of Dr. Angela

Restrepo.)

TABLE 219-1 Suggested Treatment for Endemic Mycoses

DISEASE FIRST-LINE THERAPY ALTERNATIVES/COMMENTS

Sporotrichosis

Cutaneous,

lymphocutaneous

Itraconazole, 200 mg/d

until 2–4 weeks after

lesions resolve

SSKI, increasing dosesa

Terbinafine, 500 mg bid

Pulmonary,

osteoarticular

Itraconazole, 200 mg bid

for 12 months

Lipid AmBb

 for severe

pulmonary disease until

stable; then itraconazole

Disseminated,

central nervous

system

Lipid AmBb

 for 4–6 weeks Itraconazole, 200 mg bid after

AmB for 12 months

AIDS patients: itraconazole

maintenance, 200 mg/d until

CD4+ T cell count is >200/μL

for ≥12 months

Paracoccidioidomycosis

Chronic (adult form) Itraconazole, 100–200 mg/d

for 6–12 months

Voriconazole, 200 mg bid for

6–12 months

Posaconazole, 300 mg/d for

6–12 months

TMP-SMX, 160/800 mg bid for

12–36 months

Acute (juvenile

form)

AmBc

 or lipid AmBb

 until

improvement

Itraconazole, 200 mg bid after

AmB for 12 months

Voriconazole or posaconazole

at doses noted above may

be used

Talaromycosis (Penicilliosis)

Mild or moderate Itraconazole, 200 mg bid

for 12 weeks

Voriconazole, 200 mg bid

Severe Lipid AmBb

 or AmBc

 until

improvement

Itraconazole, 200 mg bid after

AmB for 12 weeks

Maintenance

therapy (AIDS)

200 mg/d until CD4+ T cell

count is >100/μL for

≥6 months

a

The starting dosage is 5–10 drops tid in water or juice. The dosage is increased

weekly by 10 drops per dose, as tolerated, up to 40–50 drops tid. b

The dosage of lipid

AmB is 3–5 mg/kg daily; the higher dosage should be used when the central nervous

system is involved. c

The dosage of AmB deoxycholate is 0.6–1.0 mg/kg daily.

Abbreviations: AmB, amphotericin B; SSKI, saturated solution of potassium iodide;

TMP-SMX, trimethoprim-sulfamethoxazole.

lesion (Fig. 219-1). Some patients develop a fixed cutaneous lesion

that can be verrucous or ulcerative and that remains localized without

lymphatic extension. The differential diagnosis of lymphocutaneous

sporotrichosis includes nocardiosis, tularemia, nontuberculous mycobacterial infection (especially that due to Mycobacterium marinum),

and leishmaniasis. Osteoarticular sporotrichosis can present as chronic

synovitis or septic arthritis. Pulmonary sporotrichosis must be differentiated from tuberculosis and other fungal pneumonias. Numerous

ulcerated skin lesions, with or without spread to visceral organs

(including the central nervous system [CNS]), are characteristic of

disseminated sporotrichosis.

Diagnosis S. schenckii usually grows readily as a mold on Sabouraud’s agar when material from a cutaneous lesion is incubated at

room temperature. Histopathologic examination of biopsy material

shows a mixed granulomatous and pyogenic reaction, and tiny oval or

cigar-shaped yeasts sometimes can be seen with special stains.

Treatment and Prognosis Guidelines for the management of the

various forms of sporotrichosis have been published by the Infectious

Diseases Society of America (Table 219-1). Itraconazole is the drug

of choice for lymphocutaneous and cutaneous sporotrichosis. Fluconazole is less effective, voriconazole is not effective, and posaconazole

has been used successfully in a small number of patients. Saturated

solution of potassium iodide (SSKI) continues to be used for lymphocutaneous infection because it costs much less than itraconazole.

However, SSKI is poorly tolerated because of adverse reactions, including metallic taste, salivary gland swelling, rash, and fever. High-dose

terbinafine may be effective for lymphocutaneous infection. Treatment

for lymphocutaneous sporotrichosis is continued for 2–4 weeks after

all lesions have resolved, usually for a total of 3–6 months. The success

rate for treatment of lymphocutaneous sporotrichosis is 90–100%.

Pulmonary and osteoarticular forms of sporotrichosis are treated

with itraconazole for at least 1 year. Severe pulmonary infection and

disseminated sporotrichosis, including that involving the CNS, should

be treated initially with amphotericin B (AmB), with a switch to itraconazole after improvement has been noted. Lifelong suppressive therapy

with itraconazole often is required for AIDS patients. These forms of

sporotrichosis respond poorly to antifungal therapy.

■ PARACOCCIDIOIDOMYCOSIS

Etiologic Agent, Epidemiology, and Pathogenesis Paracoccidioides brasiliensis and the less frequently reported Paracoccidioides

lutzii are thermally dimorphic fungi found in humid areas of Central

and South America, especially in Brazil. A striking male-to-female ratio

varies from 14:1 to as high as 70:1 in various reports. Most patients are

middle-aged or elderly men from rural areas. Paracoccidioidomycosis

develops after the inhalation of aerosolized conidia encountered in the

environment. For most patients, disease rarely develops at the time of

the initial infection but appears years later, presumably after reactivation of a latent infection.

Clinical Manifestations Two major syndromes are associated

with paracoccidioidomycosis: the acute or juvenile form and the

chronic or adult form. The acute form is uncommon, occurs mostly

in persons <30 years old, and manifests primarily as disseminated

infection of the reticuloendothelial system. Immunocompromised

individuals also develop this type of rapidly progressive disease. The

chronic form of paracoccidioidomycosis accounts for ~90% of cases

and predominantly affects older men. The primary manifestations

are progressive pulmonary disease, primarily in the lower lobes, with

fibrosis and ulcerative and nodular mucocutaneous lesions that occur

primarily in mucous membranes of the upper respiratory tract and that

must be differentiated from leishmaniasis (Chap. 226) and squamous

cell carcinoma (Chap. 76).

Diagnosis The diagnosis is established by growth of the mold form

of P. brasiliensis in culture at room temperature. A presumptive diagnosis can be made by detection of the distinctive thick-walled yeast,

which has multiple narrow-necked buds attached circumferentially, in

purulent material or tissue biopsies.

Treatment and Prognosis Itraconazole is the treatment of

choice for paracoccidioidomycosis (Table 219-1). Voriconazole and

1688 PART 5 Infectious Diseases

posaconazole also are effective. Sulfonamides have been used for years

and are the least costly agents; however, the response is slower and

the relapse rate higher. Seriously ill patients should be treated with

AmB initially. Patients with paracoccidioidomycosis have an excellent

response to therapy, but pulmonary fibrosis can be progressive in those

with chronic disease.

■ TALAROMYCOSIS (PENICILLIOSIS)

Etiologic Agent, Epidemiology, and Pathogenesis Talaromyces

marneffei (formerly Penicillium marneffei) is a thermally dimorphic

fungus that is endemic in the soil in certain areas of Vietnam, Thailand, and

other southeastern Asian countries. The epidemiology of talaromycosis

is linked to bamboo rats that are infected with the fungus but rarely

manifest disease. The disease occurs most often among persons living

in rural areas in which the rats are found, but there is no evidence for

transmission of the infection directly from rats to humans. Infection is

rare in immunocompetent hosts, and most cases are reported in persons who have advanced AIDS. Infection results from the inhalation

of conidia from the environment. The organism converts to the yeast

phase in the lungs and then spreads hematogenously throughout the

reticuloendothelial system.

Clinical Manifestations The clinical manifestations of talaromycosis mimic those of disseminated histoplasmosis and include fever,

fatigue, weight loss, dyspnea, lymphadenopathy, hepatosplenomegaly,

and skin lesions, which appear as papules that often umbilicate and

resemble molluscum contagiosum (Chap. 196).

Diagnosis Talaromycosis is diagnosed by culture of T. marneffei

from blood or from biopsy samples of skin, bone marrow, or lymph

node. The organism usually grows within 1 week as a mold producing

a distinctive red pigment that diffuses into the agar. Histopathologic

examination of tissues and smears of blood or material from skin

lesions shows oval or elliptical yeast-like organisms with central septation and can quickly establish a presumptive diagnosis.

Treatment and Prognosis For mild or moderate infection, itraconazole is the drug of choice; voriconazole can also be used. Severe

infection should be treated with AmB until improvement occurs; then

therapy can be changed to itraconazole (Table 219-1). For patients with

AIDS, suppressive therapy with itraconazole is recommended until the

CD4+ T cell count has been >100 cells/μL for at least 6 months. Disseminated talaromycosis is usually fatal if not treated. With treatment,

the mortality rate is ~10%.

PHAEOHYPHOMYCOSES

Dematiaceous or brown-black fungi, the common soil organisms that

cause phaeohyphomycoses, contain melanin, which causes the hyphae

and conidia to be darkly pigmented. The term phaeohyphomycosis is

used to describe any infection with a pigmented mold. This definition

encompasses two specific syndromes—eumycetoma and chromoblastomycosis—as well as all other types of infections caused by these

organisms. It is important to note that eumycetomas can be caused by

hyaline molds as well as by brown-black molds and that only about half

of all mycetomas are due to fungi. Actinomycetes cause the remainder

(Chap. 174). Most dematiaceous fungi cause localized subcutaneous

infections after direct inoculation, but disseminated infections and

serious focal visceral infections do occur, especially in immunocompromised patients.

Etiologic Agents, Epidemiology, and Pathogenesis A large

number of pigmented molds can cause human infection. Most are

found in the soil or on plants, and some cause economically important

plant diseases. Alternaria, Exophiala, Curvularia, and Wangiella species

are among the more common molds reported to cause human infection. In 2012, Exserohilum species caused a large outbreak in the United

States of severe and in some patients fatal CNS infections after the

injection of methylprednisolone contaminated with this fungus. The

most common cause of eumycetoma is Madurella species. Fonsecaea,

Phialophora, and Cladophialophora species are responsible for most

cases of chromoblastomycosis. Infections with dematiaceous molds

are acquired by traumatic inoculation into the eye or through the skin,

by inhalation, or by injection of contaminated medication. Melanin

is a virulence factor for all the pigmented molds. Several organisms,

specifically Cladophialophora bantiana and Rhinocladiella mackenziei,

are neurotropic and likely to cause CNS infection. When a patient is

immunocompromised or when a pigmented mold is injected directly

into a deep structure, these organisms become opportunists, invading

blood vessels and mimicking better-known opportunistic infections,

such as aspergillosis. Eumycetoma and chromoblastomycosis are

acquired by inoculation through the skin; these two syndromes are

seen almost entirely in tropical and subtropical areas and occur mostly

in rural laborers who are frequently exposed to the organisms.

Clinical Manifestations Dematiaceous molds are the most common cause of allergic fungal sinusitis and a less common cause of

invasive fungal sinusitis. Keratitis occurs with traumatic corneal

inoculation. Even in many immunocompromised patients, inoculation

through the skin generally produces only localized nodular lesions at

the entry site. However, other immunocompromised patients develop

pneumonia, brain abscess, or disseminated infection. In the outbreak

mentioned above, epidural injection of Exserohilum-contaminated

glucocorticoids led to meningitis, basilar stroke, epidural abscess and

phlegmon, vertebral osteomyelitis, and arachnoiditis.

Eumycetoma is a chronic subcutaneous and cutaneous infection

that usually occurs on the lower extremities and is characterized by

swelling, the development of sinus tracts, and the appearance of grains

that are actually colonies of fungi discharged from the sinus tract. As

the infection progresses, adjacent fascia and bony structures become

involved. The disease is indolent and disfiguring, progressing slowly

over years. Complications include fractures of infected bone and bacterial superinfection.

Chromoblastomycosis is an indolent subcutaneous infection characterized by nodular, verrucous, or plaque-like painless lesions that

occur predominantly on the lower extremities and grow slowly over

months to years. There is hardly ever extension to adjacent structures,

as is seen with eumycetoma. Long-term consequences include bacterial

superinfection, chronic lymphedema, and (rarely) the development of

squamous cell carcinoma.

Diagnosis The specific diagnosis of infection with a pigmented

mold is established by growth of the organism in culture, which is

essential to differentiate infection with a hyaline mold (e.g., Aspergillus or Fusarium) from that due to a pigmented mold. A tentative

clinical diagnosis of mycetoma can be made when a patient presents

with a lesion characterized by swelling, sinus tracts, and grains. Histopathologic examination and culture are necessary to confirm that the

etiologic agent is a mold and not an actinomycete. In chromoblastomycosis, the diagnosis rests on the histologic demonstration of sclerotic

bodies (dark brown, thick-walled, septate fungal forms that resemble

large yeasts) in the tissues; culture establishes which pigmented mold is

causing the infection. PCR assays are increasingly used in the diagnosis

of infection due to dematiaceous molds but are available only through

fungal reference laboratories.

Treatment and Prognosis The choice of antifungal agent to treat

disseminated and focal visceral infections with brown-black molds is

based on the location and extent of the infection, in vitro test results,

and clinical experience with the specific infecting organism. AmB

is not effective against many of these organisms but has been used

successfully against some species (Table 219-2). Itraconazole, voriconazole, or posaconazole can be used in the treatment of localized

infections. Voriconazole is preferred when infections involve the CNS

because this drug reaches adequate concentrations at that site. Voriconazole or posaconazole could be used for disseminated infection; these

agents are available as both IV and well-absorbed oral formulations.

Disseminated and focal visceral infections, especially those involving

the CNS, are associated with high mortality rates.

Treatment of eumycetoma and chromoblastomycosis involves both

surgical extirpation of the lesion and use of antifungal agents. Surgical

1689CHAPTER 219 Less Common Systemic Mycoses and Superficial Mycoses

removal of the lesions is most effective if performed before extensive

spread has occurred. In chromoblastomycosis, cryosurgery and laser

therapy have been used with variable success. Eumycetoma has been

treated with itraconazole, voriconazole, posaconazole, and less commonly terbinafine with variable rates of success. Itraconazole, terbinafine, and flucytosine have been used to treat chromoblastomycosis,

again with variable success. Chromoblastomycosis and eumycetoma

are chronic indolent infections that are difficult to cure, and the cost of

antifungal treatment can be prohibitively expensive.

OPPORTUNISTIC FUNGAL INFECTIONS

Three genera of hyaline (nonpigmented) molds, Fusarium, Scedosporium, and Lomentospora, and one yeast-like genus, Trichosporon, have

become prominent pathogens among immunocompromised patients.

Invasive infections caused by these hyaline molds mimic aspergillosis

in their clinical manifestations and their histopathologic appearance

in tissues. In the immunocompetent host, these fungi cause localized

infections of skin, skin structures, and subcutaneous tissues, but their

role as causes of infection in immunocompromised patients will be

emphasized in this section.

■ FUSARIOSIS

Etiologic Agent, Epidemiology, and Pathogenesis Fusarium

species, which are found worldwide in soil and on plants, have emerged

as major opportunists in markedly immunocompromised patients.

Most human infections follow inhalation of conidia, but ingestion

and direct inoculation also can lead to disease. An outbreak of severe

Fusarium keratitis among soft contact lens wearers was traced back

to a particular brand of contact lens solution and individual contact

lens cases that had been contaminated with this mold. Disseminated

infection is reported most often in patients who have a hematologic

malignancy, are neutropenic, have received a hematopoietic cell or

solid-organ transplant, or have severe burn wounds.

Clinical Manifestations In immunocompetent persons, Fusarium

species cause localized infections of various organs. These organisms

are a common cause of fungal keratitis, which can extend into the anterior chamber of the eye, cause loss of vision, and require corneal transplantation. Onychomycosis due to Fusarium species, while basically an

annoyance in immunocompetent patients, is a source of subsequent

hematogenous dissemination and should be aggressively sought and

treated in neutropenic patients. In profoundly immunocompromised

patients, fusariosis is angioinvasive, and clinical manifestations mimic

those of aspergillosis. Pulmonary infection is characterized by multiple

nodular lesions. Sinus infection is likely to lead to invasion of adjacent

structures. Disseminated fusariosis occurs primarily in neutropenic

patients with hematologic malignancies and in allogeneic hematopoietic cell transplant recipients. Disseminated fusariosis differs from

disseminated aspergillosis in that skin lesions are extremely common

with fusariosis; the lesions are nodular or necrotic, are usually painful,

and appear over time in different locations (Fig. 219-2).

Diagnosis The diagnostic approach usually includes both documentation of the growth of Fusarium species from involved tissue and

demonstration of invasion by histopathologic techniques that show

septate hyphae in tissues. The organism is difficult to differentiate from

Aspergillus species in tissues; thus, identification with culture is imperative. An extremely helpful diagnostic clue is growth in blood cultures,

which are positive in as many as 50% of patients with disseminated

fusariosis.

Treatment and Prognosis Fusarium species are resistant to

many antifungal agents. A lipid formulation of AmB, voriconazole, or

posaconazole is recommended. Many physicians use both a lipid formulation of AmB and either voriconazole or posaconazole because susceptibility information is not standardized and is not always predictive

of clinical response. Serum drug levels should be monitored with either

azole to ensure that absorption is adequate and with voriconazole to

avoid toxicity. Mortality rates for disseminated fusariosis have been

as high as 85%. With the improved antifungal therapy now available,

mortality rates have fallen to ~50%. However, if neutropenia persists,

the mortality rate approaches 100%.

■ SCEDOSPORIOSIS AND LOMENTOSPORIOSIS

Etiologic Agent, Epidemiology, and Pathogenesis Scedosporium apiospermum complex, which is composed of several related

species, is reported more often as a cause of human infection than

Lomentospora prolificans, formerly Scedosporium prolificans, but both

are major pathogens in immunocompromised hosts, causing pneumonia, disseminated infection, and brain abscess. Organisms of

the S. apiospermum complex are found worldwide in temperate climates in tidal flats, swamps, ponds, manure, and soil. L. prolificans also

is found in soil but is more geographically restricted. Infection occurs

predominantly through inhalation of conidia, but direct inoculation

through the skin or into the eye also can occur.

Clinical Manifestations Among immunocompetent persons,

Scedosporium and Lomentospora species are a prominent cause of

eumycetoma. Keratitis as a result of accidental corneal inoculation

is a sight-threatening infection. In patients who have hematologic

malignancies (especially acute leukemia with neutropenia), recipients

of solid-organ or hematopoietic cell transplants, and patients receiving

glucocorticoids, these organisms are angioinvasive, causing pneumonia

and widespread dissemination. Pulmonary infection mimics aspergillosis; nodules, cavities, and lobar infiltrates are common. Disseminated

FIGURE 219-2 Painful necrotic foot lesion that developed over a week in a woman

who had acute leukemia and who had been neutropenic for 2 months. Fusarium

species were grown from a punch biopsy. (Courtesy of Dr. Nessrine Ktaich.)

TABLE 219-2 Suggested Treatment for Phaeohyphomycoses and

Opportunistic Infections

DISEASE FIRST-LINE THERAPY

ALTERNATIVES/

COMMENTS

Phaeohyphomycoses Voriconazole, 200 mg bid

Itraconazole, 200 mg bid

Posaconazole, 300 mg/d

Lipid AmB may be

effective against some

mold species.

Fusariosis Voriconazole, 200–300 mg

bid

Lipid AmB, 5 mg/kg per day

Posaconazole, 300 mg/d

Lipid AmB plus

voriconazole or

posaconazole is used by

some physicians for initial

therapy.

Scedosporiosis/

lomentosporiosis

Voriconazole, 200–300 mg

bid

Posaconazole, 300 mg/d

Not susceptible to AmB

Lomentospora prolificans

is resistant to almost all

antifungal drugs.

Trichosporonosis Voriconazole, 200–300 mg

bid

Posaconazole, 300 mg/d

Abbreviation: AmB, amphotericin B.

1690 PART 5 Infectious Diseases

infection involves the skin, heart, brain, and many other organs. Skin

lesions are not as common or as painful as those of fusariosis.

Diagnosis Diagnosis depends on the growth of Scedosporium or

Lomentospora species from involved tissue and the histologic demonstration of septate hyphae invading tissues. Culture evidence is essential because these molds are difficult to differentiate from Aspergillus in

tissues, and demonstration of tissue invasion is essential because these

ubiquitous environmental molds can be mere contaminants or colonizers. L. prolificans can grow in blood cultures, but S. apiospermum

usually does not.

Treatment and Prognosis Scedosporium and Lomentospora

species are resistant to AmB, echinocandins, and some azoles. Voriconazole is the agent of choice for S. apiospermum, and posaconazole also

can be used for this infection. L. prolificans is resistant in vitro to almost

every available antifungal agent; the addition of agents such as terbinafine to a voriconazole regimen has been attempted because in vitro data

suggest possible synergy against some strains of L. prolificans. Mortality

rates for invasive S. apiospermum infection are ~50%, but those for

invasive L. prolificans infection remain as high as 85–100%.

■ TRICHOSPORONOSIS

Etiologic Agent, Epidemiology, and Pathogenesis The genus

Trichosporon contains many species, some of which cause localized

infection of hair and nails. The major pathogen responsible for invasive

infection is Trichosporon asahii. Trichosporon species grow as yeastlike colonies in vitro; in vivo, however, hyphae, pseudohyphae, and

arthroconidia, in addition to yeast forms, can be seen. These yeasts are

commonly found in soil, sewage, and water and in rare instances can

colonize human skin and the human gastrointestinal tract. Most infections follow inhalation or entry via central venous catheters. Systemic

infection occurs almost exclusively in immunocompromised hosts,

including those who have hematologic malignancies, are neutropenic,

have received a solid-organ or hematopoietic cell transplant, or are

receiving glucocorticoids.

Clinical Manifestations Disseminated trichosporonosis resembles invasive candidiasis, and fungemia is often the initial manifestation of infection. Pneumonia, skin lesions, and sepsis are common.

The skin lesions begin as papules or nodules surrounded by erythema

and progress to central necrosis. A chronic form of infection mimics

hepatosplenic candidiasis (chronic disseminated candidiasis).

Diagnosis The diagnosis of systemic Trichosporon infection is

established by growth of the organism from involved tissues or from

blood. Histopathologic examination of a skin lesion showing a mixture of yeast forms, arthroconidia, and hyphae can lead to an early

presumptive diagnosis of trichosporonosis. The serum cryptococcal

antigen latex agglutination test may be positive in patients with disseminated trichosporonosis, because T. asahii and Cryptococcus

neoformans share polysaccharide antigens.

Treatment and Prognosis Rates of response to AmB have been

disappointing, and many Trichosporon isolates are resistant in vitro.

Voriconazole is the antifungal agent of choice. The mortality rates for

disseminated Trichosporon infection have been as high as 70% but are

decreasing with the use of voriconazole; however, patients who remain

neutropenic are likely to succumb to this infection.

SUPERFICIAL CUTANEOUS INFECTIONS

Fungal infections of the skin and skin structures are caused by molds

and yeasts that do not invade deeper tissues but rather cause disease

merely by inhabiting the superficial layers of skin, hair follicles, and

nails. These agents are the most common fungal infections of humans

but only rarely cause serious infections.

■ YEAST INFECTIONS

Etiologic Agents, Epidemiology, and Pathogenesis Malassezia

species, primarily M. furfur and M. pachydermatis, are lipophilic yeasts

that generally cause only minor skin infections but, on occasion, can

cause invasive infection. Malassezia species are part of the indigenous

human microbiota found in the stratum corneum of the back, chest,

scalp, and face—areas rich in sebaceous glands. The organisms do

not invade below the stratum corneum and generally elicit little if any

inflammatory response.

Clinical Manifestations Malassezia species cause tinea versicolor

(also called pityriasis versicolor), folliculitis, and seborrheic dermatitis. Tinea versicolor presents as flat round scaly patches of hypo- or

hyperpigmented skin on the neck, chest, or upper arms. The lesions

are usually asymptomatic but can be pruritic. They can be mistaken

for vitiligo, but the latter is not scaly. Folliculitis occurs on the back and

chest and mimics bacterial folliculitis. Seborrheic dermatitis manifests

as erythematous pruritic scaly lesions in the eyebrows, moustache,

nasolabial folds, and scalp (dandruff). Seborrheic dermatitis can be

severe in patients with advanced AIDS. Fungemia and disseminated

infection occur rarely with Malassezia species, and almost always this

occurs in premature neonates receiving parenteral lipid preparations

through a central venous catheter.

Diagnosis Malassezia infections are diagnosed clinically in most

cases. If scrapings are collected on a microscope slide on which a drop

of potassium hydroxide has been placed, a mixture of budding yeasts

and short septate hyphae is seen. In order to culture Malassezia from

those patients in whom disseminated infection is suspected, sterile

olive oil must be added to the medium.

Treatment and Prognosis Topical creams and lotions, including

selenium sulfide shampoo, ketoconazole shampoo or cream, and terbinafine cream, are effective in treating Malassezia infections and are

usually given for 2 weeks. Other more expensive antifungal creams

are rarely needed. Mild topical steroid creams are sometimes used to

treat seborrheic dermatitis. For extensive disease, oral itraconazole or

fluconazole (200 mg daily) can be used for 5–7 days. The rare cases

of fungemia caused by Malassezia species are treated with AmB or

an azole, such as voriconazole, prompt removal of the catheter, and

discontinuance of parenteral lipid infusions. Malassezia skin infections

are benign and self-limited, although recurrences are the rule. The

outcome of systemic infection depends on the host’s underlying conditions, but most infected neonates do well.

■ DERMATOPHYTE (MOLD) INFECTIONS

Etiologic Agents, Epidemiology, and Pathogenesis The molds

that cause skin infections in humans include the genera Trichophyton,

Microsporum, and Epidermophyton. These organisms, which are not

components of the normal skin microbiota, can live within the keratinized structures of the skin—hence the term dermatophytes. Dermatophytes occur worldwide, and infections with these organisms are

extremely common. Some organisms cause disease only in humans and

can be transmitted by person-to-person contact and by fomites, such as

hairbrushes or wet floors, that have been contaminated by infected individuals. Several species cause infections in cats and dogs and can readily

be transmitted from these animals to humans, and others are spread

from contact with soil. The characteristic ring shape of cutaneous lesions

is the result of the organisms’ outward growth in a centrifugal pattern in

the stratum corneum. Fungal invasion of the nail usually occurs through

the lateral or superficial nail plates and then spreads throughout the nail;

when hair shafts are invaded, the organisms can be found either within

the shaft or surrounding it. Symptoms are caused by the inflammatory

reaction elicited by fungal antigens and not by tissue invasion. Dermatophyte infections occur more commonly in males than in females, and

progesterone has been shown to inhibit dermatophyte growth.

Clinical Manifestations Dermatophyte infection of the skin is

often called ringworm. This term is confusing because worms are not

involved. Tinea, the Latin word for worm, describes the serpentine

nature of the skin lesions. Tinea is a less confusing term and can be

used with the name of the body part affected—e.g., tinea capitis (head),

tinea pedis (feet), tinea corporis (body), tinea cruris (crotch), and tinea

1691CHAPTER 220 Pneumocystis Infections

TABLE 219-3 Suggested Oral Treatment for Extensive Tinea Infections

and Onychomycosis

ANTIFUNGAL

AGENT

SUGGESTED

DOSAGE COMMENTS

Extensive Tinea Infection

Terbinafine 250 mg/d for

1–2 weeks

Adverse reactions minimal with short

treatment period

Itraconazolea 200 mg/d for

1–2 weeks

Adverse reactions minimal with short

treatment period except for drug

interactions

Onychomycosis

Terbinafine 250 mg/d for

3 months

Slightly superior to itraconazole;

monitor for hepatotoxicity

Itraconazolea 200 mg/d for

3 months or 200 mg

bid for 1 week each

month for 3 months

Drug interactions frequent; monitor

for hepatotoxicity; rarely causes

hypokalemia, hypertension, edema;

use with caution in patients with

congestive heart failure

a

Itraconazole capsules require food and gastric acid for absorption, whereas

itraconazole solution is taken on an empty stomach.

■ DEFINITION AND DESCRIPTION

Pneumocystis is an opportunistic pathogen that is an important cause

of pneumonia in immunocompromised hosts, particularly those with

HIV infection (Chap. 202), organ transplants, or hematologic malignancies and those receiving high-dose glucocorticoids or certain

immunosuppressive monoclonal antibodies. Pneumocystis was discovered in rodents in 1909 and was initially believed to be a protozoan.

Because Pneumocystis cannot be cultured, our understanding of its

biology has been limited, but molecular techniques have demonstrated

that the organism is actually a fungus. Formerly known as Pneumocystis

carinii, the species infecting humans has been renamed Pneumocystis

jirovecii.

■ EPIDEMIOLOGY

Pneumocystis jirovecii pneumonia (PCP) came to medical attention

in the early 1950s when pathologists in Czechoslovakia recognized

Pneumocystis in the alveolar exudates of infants involved in nursery

outbreaks of interstitial pneumonia, outbreaks that had been described

in Europe since the 1920s. Among adults, PCP was rarely recognized

until the populations of immunosuppressed adults increased due to the

development of immunosuppressive therapies for solid-organ transplantation, bone marrow transplantation, cancer, and autoimmune

disorders, and the development of better pulmonary diagnostic techniques such as bronchoscopy. In 1981, PCP was first reported in men

who had sex with men and in intravenous (IV) drug users who had no

obvious cause of immunosuppression. These cases were subsequently

220 Pneumocystis Infections

Alison Morris, Henry Masur

unguium (nails, although infection at this site is more often termed

onychomycosis).

Tinea capitis occurs most commonly in children 3–7 years old.

Children with tinea capitis usually present with well-demarcated

scaly patches in which hair shafts are broken off right above the skin;

alopecia can result. Tinea corporis is manifested by well-demarcated,

annular, pruritic, scaly lesions that undergo central clearing. Usually

one or several small lesions are present. However, in some patients,

tinea corporis can involve much of the trunk. The rash should be differentiated from contact dermatitis, eczema, and psoriasis. Tinea cruris

is seen almost exclusively in men. The perineal rash is erythematous

and pustular, has a discrete scaly border, is without satellite lesions, and

is usually pruritic. The rash must be differentiated from intertriginous

candidiasis, erythrasma, and psoriasis.

Tinea pedis also is more common among men than among women.

It usually starts in the web spaces of the toes; peeling, maceration, and

pruritus are followed by development of a scaly pruritic rash along the

lateral and plantar surfaces of the feet. Hyperkeratosis of the soles of the

feet often ensues. Tinea pedis has been implicated in lower-extremity

cellulitis, as streptococci and staphylococci can gain entrance to the tissues through fissures between the toes. Onychomycosis affects toenails

more often than fingernails and is most common among persons who

have tinea pedis. The nail becomes thickened and discolored and may

crumble; onycholysis almost always occurs. Onychomycosis is more

common in older adults and in persons with vascular disease, diabetes

mellitus, and trauma to the nails. Fungal infection must be differentiated from psoriasis, which can mimic onychomycosis but usually has

associated skin lesions.

Diagnosis Many dermatophyte infections are diagnosed by their

clinical appearance. If the diagnosis is in doubt, scrapings should be

taken from the edge of a lesion with a scalpel blade, transferred to a

slide to which a drop of potassium hydroxide is added, and examined

under a microscope for the presence of hyphae. Cultures are indicated

if an outbreak is suspected or the patient does not respond to therapy.

Treatment and Prognosis Dermatophyte infections usually

respond to topical therapy. Lotions or sprays are easier than creams to

apply to large or hairy areas. Particularly for tinea cruris, the affected

area should be kept as dry as possible. When patients have extensive

skin lesions, oral itraconazole or terbinafine can hasten resolution

(Table 219-3). Terbinafine interacts with fewer drugs than itraconazole

and is generally the first-line agent.

Onychomycosis generally does not respond to topical therapy,

although efinaconazole topical solution applied to the affected nail

for as long as a year has been shown to be beneficial in several trials.

Itraconazole and terbinafine both accumulate in the nail plate and can

be used to treat onychomycosis (Table 219-3). The major decision to be

made with regard to therapy is whether the extent of nail involvement

justifies the use of systemic antifungal agents that have adverse effects,

may interact with other drugs, and are very costly. Treating for cosmetic reasons alone is discouraged. Relapses of tinea cruris and tinea

pedis are common and should be treated as early as possible with topical creams to avoid development of more extensive disease. Relapses of

onychomycosis follow treatment in 25–30% of cases.

■ FURTHER READING

Bonifaz A, Tirado-Sanchez A: Cutaneous disseminated and

extracutaneous sporotrichosis: Current status of a complex disease.

J Fungi 3:6, 2017.

De Almeida Junior JN, Hennequin C: Invasive Trichosporon infections: A systematic review on a re-emerging fungal pathogen. Front

Microbiol 7:1629, 2016.

Nelson KE et al: Penicilliosis, in Essentials of Clinical Mycology, 2nd ed.

CA Kauffman et al (eds). New York, Springer, 2011, pp 399–411.

Nucci M et al: Fusariosis. Semin Respir Crit Care Med 36:706, 2015.

Ramirez-Garcia A et al: Scedosporium and Lomentospora: An updated

overview of underrated opportunists. Med Mycol 56(suppl 1):

102, 2018.

Revankar SG et al: A Mycoses Study Group international prospective

study of phaeohyphomycosis: An analysis of 99 proven/probable

cases. Open Forum Infect Dis 4:ofx200, 2017.

Shikanai-Yasuda MA et al: Brazilian guidelines for the clinical

management of paracoccidioidomycosis. Rev Soc Bras Med Trop

50:715, 2017.

Theelan B et al: The Malassezia genus in skin and systemic diseases.

Med Mycol 56:510, 2018.

Woo TE et al: Diagnosis and management of cutaneous tinea infections. Adv Skin Wound Care 32:350, 2019.