ACP medicine, 3rd Edition

Infectious Disease

Mycotic Infections

Carol A. Kauffman MD, FACP1

Professor

1Department of Internal Medicine, University of Michigan Medical School

The author has received grant or research support from Merck & Co., Inc., Astellas Pharma, Inc., and Enzon Pharmaceuticals, Inc., and participates in the speakers' bureaus for Pfizer, Inc., Astellas Pharma, Inc., Merck & Co., Inc., and Schering-Plough Corp.

May 2006

Overview of Endemic Mycoses

The endemic mycoses include histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis. Paracoccidioidomycosis is indigenous to South America and is not discussed in this chapter. Sporotrichosis, which is technically not an endemic mycosis but is often included with these diseases, is discussed.

All of these diseases are caused by fungi that share several important characteristics. These fungi are all dimorphic, existing as molds in the environment and as either yeasts or spherules in tissues. Each organism occupies a different ecological niche and has a distinct geographic distribution. Infection is directly related to exposure to the mycelial or mold phase of the organism in the environment. These fungi are true pathogens in that they are capable of causing infection in otherwise healthy persons. The severity of infection is determined both by the extent of the exposure to the organism and by the immune status of the patient. Histoplasma capsulatum, Blastomyces dermatitidis, andCoccidioides immitis/Coccidioides posadasii are inhaled, have the propensity to disseminate hematogenously, and are able to reactivate years later; Sporothrix schenckii usually causes primary infection after cutaneous inoculation and does not reactivate. Although all four diseases share many clinical manifestations, each of the four has its own distinctive characteristics.

Early recognition of these diseases can be challenging. The endemic mycoses mimic many common infections involving lungs, skin, and other organs. Because of the mobility of the United States population, coupled in some cases with the ability of these diseases to remain dormant in the body for long stretches of time, patients with one of the endemic mycoses often present outside the classic endemic area. When faced with an elderly retiree who spends winters in Arizona and who has developed fever, headache, and visual complaints, a physician who practices in Ohio and who may have never seen coccidioidomycosis must remember that this fungal infection causes chronic meningitis. Similarly, an AIDS patient with fever, hepato splen o megaly, and pancytopenia who lives in Seattle but who spent his childhood in Arkansas and has not returned there for the past 20 years may well be experiencing reactivation of histoplasmosis.

The most useful diagnostic tests differ for each of the endemic mycoses, but as a general rule, histopathologic demonstration of the fungi in biopsy specimens is the most expeditious way to make a diagnosis, especially in a severely ill patient; growth of the organism in vitro is definitive. For most patients with an endemic mycosis, treatment is with an azole antifungal agent. For those who are severely ill, initial therapy with amphotericin B followed by consolidation therapy with an azole is standard. Echinocandins (e.g., caspofungin) have no role in the treatment of the endemic mycoses.

A review of antifungal agents and guidelines for their use in the treatment of mycotic infections is found after the descriptions of specific manifestations of each endemic mycosis [see Antifungal Therapy, below].

Histoplasmosis

EPIDEMIOLOGY

  1. capsulatumis a dimorphic fungus that every year infects hundreds of thousands of persons in the United States. The organism is endemic in the Mississippi and Ohio River valleys and in Central America, and it also exists in microfoci in Canada and the eastern United States. Soil containing high concentrations of bird or bat guano supports the profuse growth of the mycelial phase of H. capsulatum. Exposure typically occurs as a result of activities that generate aerosols containing the organism. Infection is very common in the endemic area, most persons having been infected before adulthood. Although most cases are sporadic and the exact source of exposure is unknown, many point-source outbreaks have been well described in association with disruption of soil; the cleaning of attics, bridges, or barns; tearing down old structures laden with guano; and spelunking.1,2A massive outbreak of infection with H. capsulatum occurred in Indianapolis when urban demolition exposed hundreds of thousands of people to the organism.1

PATHOGENESIS

During the mycelial phase of the organism's life cycle, the microconidia are inhaled into the alveoli, causing a localized pulmonary infection. Neutrophils and macrophages phagocytize the organism, which converts to the yeast phase; the organism is then able to survive and travel within the macrophage. Spread to the hilar and mediastinal lymph nodes ensues, and hematogenous dissemination subsequently occurs throughout the reticuloendothelial system before specific immunity has developed. After several weeks, cell-mediated immunity that is specific for H. capsulatum activates macrophages, which then kill the organism.3 Of all the human mycoses, histoplasmosis exemplifies best the pivotal importance of the cell-mediated immune system. The corollary of this observation is that most patients with severe infection are those with cellular immune deficiencies.

The extent of disease is determined by the number of conidia that are inhaled and the immune response of the host. A healthy person may develop life-threatening pulmonary infection if a large number of conidia are inhaled. This might occur during demolition or renovation of an old building or as a result of spelunking in a heavily infested cave. Conversely, a small inoculum can cause severe pulmonary infection or progress to acute symptomatic disseminated histoplasmosis in a patient with advanced HIV infection whose cell-mediated immune system is unable to contain the organism.

Most persons who have been infected with H. capsulatum experience asymptomatic dissemination; only rarely will this lead to symptomatic acute or chronic disseminated histoplasmosis. However, by virtue of this dissemination, latent infection can persist for a lifetime. Reactivation of quiescent infection can occur years later if immunosuppression occurs.4 Reinfection has also been documented, though rarely, in persons previously known to have had histoplasmosis. Such reinfection almost always occurs in the setting of exposure to a heavy inoculum of H. capsulatum conidia.

CLINICAL PRESENTATION

Pulmonary Histoplasmosis

Infection is asymptomatic in the vast majority of persons who have been infected with H. capsulatum. Most patients who have symptomatic pulmonary infection will have a self-limited illness characterized by fever, chills, and cough that is usually nonproductive; such infection is often associated with anterior chest discomfort, myalgias, arthralgias, and fatigue. Chest radiography will show a patchy lobar or multilobar nodular infiltrate.5 The diagnosis is usually not made in individual cases until the patient fails to respond to several courses of antibiotics given for atypical pneumonia.

The diagnosis of acute pulmonary histoplasmosis is more easily made when the patient has been involved in an outbreak.2 A careful history of the patient's activities as well as the patient's colleagues' activities—especially if the history reveals participation in outdoor activities, activities around a demolition site, or spelunking several weeks before the onset of symptoms—may point to histoplasmosis. High, spiking fever, prostration, dyspnea, and cough are prominent in severe cases in which the number of conidia inhaled is large. Diffuse nodular infiltrates are noted on the chest radiograph, and development of the acute respiratory distress syndrome (ARDS) can ensue.

In patients with cell-mediated immune deficiencies, including those who have advanced HIV infection, those with a hematologic malignancy, those who have received a transplant, and those who are receiving immunosuppressive medications, pulmonary infection is more severe than in otherwise healthy patients. Although pulmonary infection may be the only manifestation of histoplasmosis, in most immunosuppressed patients, pulmonary involvement is merely one component of widespread dissemination.6 Prostration, fever, chills, marked dyspnea, and hypoxemia are prominent, and chest radiographs show diffuse infiltrates.

Chronic cavitary pulmonary histoplasmosis is a progressive form of histoplasmosis that usually develops in older patients who have chronic obstructive pulmonary disease (COPD). Typical symptoms include fever, fatigue, anorexia, weight loss, cough that is productive of purulent sputum, and hemoptysis.7 On chest radiography, infiltrates can be either unilateral or bilateral and are almost always located in the upper lobes. Cavities may be multiple and are frequently quite large; extensive fibrosis occurs in the lower lobes. Unless treated, the condition is fatal.

Disseminated Histoplasmosis

Hematogenous dissemination typically occurs in immunosuppressed patients and young children early in the course of infection with H. capsulatum. Patients who have HIV infection and whose CD4+ T cell counts are less than 150/mm3 are at greatest risk for developing histoplasmosis, which almost always presents as disseminated infection.6 Severe disseminated histoplasmosis has also been reported in patients receiving treatment with the tumor necrosis factor-α (TNF-α) antagonists infliximab and entanercept.8,9

Symptoms and signs of acute disseminated histoplasmosis include chills, fever, malaise, anorexia, weight loss, dyspnea, hepatosplenomegaly, and skin and mucous membrane lesions. Pancytopenia, diffuse pulmonary infiltrates on chest radiographs, and blood cultures that yield H. capsulatum are common.4 Adrenal insufficiency may also be present.

A chronic, progressive disseminated form of histoplasmosis that occurs mostly in middle-aged to elderly men who have no known immunosuppressive illness is characterized by fever, night sweats, weight loss, and fatigue.10 Patients appear chronically ill and frequently have hepatosplenomegaly, mucocutaneous ulcerations, and signs of adrenal insufficiency. Typical findings include an increase in the erythrocyte sedimentation rate, an elevation in the alkaline phosphatase level, pancytopenia, and diffuse pulmonary infiltrates on chest radiography. If not diagnosed and treated appropriately, this form of histoplasmosis is fatal.

DIAGNOSIS

Culture

The definitive diagnostic test for histoplasmosis is growth of H. capsulatum in culture, which, unfortunately, may take as long as 6 weeks.4Sputum, bronchoalveolar lavage fluid, or tissue biopsy specimens should be sent to the laboratory for culture. For those patients who have evidence of dissemination, cultures of blood are useful. The best yield is with the lysis-centrifugation system (i.e., the Isolator aerobic blood culture system). The laboratory should be informed that pulmonary histoplasmosis is a diagnostic consideration, so that a special medium that decreases the growth of commensal fungi, such as Candida, can be used for the culture of pulmonary samples. As soon as growth of a mold has been detected, a DNA probe specific for H. capsulatum confirms the identity of the organism.

Serologic Studies

In contrast to several other endemic mycoses, serology plays an important adjunctive role in the diagnosis of histoplasmosis.11 Both complement fixation (CF) and immunodiffusion (ID) tests are available through reference laboratories. These assays should not be obtained through commercial laboratories. ID is more specific than CF (> 95% specificity versus 85% to 90%); both are only modestly sensitive (75% to 85% sensitivity). Serologic tests should not be relied upon in immunosuppressed patients who cannot mount an antibody response. However, most patients with pulmonary histoplasmosis are not immunosuppressed, and thus, in this group, antibody tests are helpful.

Patients with chronic cavitary pulmonary histoplasmosis almost always have an elevated CF antibody titer (> 1:32) and either an M precipitin band or both H and M precipitin bands. In a patient with acute pneumonia, a documented fourfold increase in CF titer or the appearance of an M precipitin band on ID establishes the diagnosis of histoplasmosis. Serologic tests are not definitive in patients with only mediastinal lymphadenopathy and should always be confirmed by tissue biopsy. False positive test results occur in patients with lymphoma, tuberculosis, sarcoidosis, and other fungal infections, all of which may present as mediastinal masses. In most patients with the chronic disseminated form of histoplasmosis, both precipitin and CF antibodies are present.

Antigen Tests

An enzyme immunoassay for the detection of H. capsulatum polysaccharide antigen in urine and serum is extremely helpful in the diagnosis of disseminated histoplasmosis.11 The assay is often positive in patients with acute pulmonary histoplasmosis, but it is usually negative in those with chronic pulmonary histoplasmosis. The test in urine is more sensitive than that in serum. Cross-reactivity occurs in a small number of patients with blastomycosis, paracoccidioidomycosis, and penicilliosis.

Tissue Biopsy

For an acutely ill patient, evidence of H. capsulatum on tissue biopsy allows the physician to make the diagnosis of histoplasmosis in a timely fashion. The organisms appear as distinctive, fairly uniformly shaped, oval budding yeasts 2 to 4 µm in diameter. Tissue biopsy is most useful for the diagnosis of disseminated disease; bone marrow, liver, and mucocutaneous lesions reveal many organisms [see Figures 1a and 1b]. For most patients with acute pulmonary histoplasmosis, biopsy is not indicated unless the patient is severely ill. For patients with chronic pulmonary histoplasmosis or granulomatous mediastinitis, biopsy of lung or lymph nodes may reveal the organism. Routine hematoxylin-eosin staining will not show the tiny H. capsulatum yeasts; biopsy material must be stained with methen amine-silver stain or periodic acid—Schiff stain. In contrast to larger yeasts, such as B. dermatitidis, it is extremely unusual to find H. capsulatum on cytologic examination of sputum or bronchoalveolar lavage fluid.

 

Figure 1. Shown are biopsy samples from an elderly man with chronic progressive disseminated histoplasmosis. (a) Tongue ulcer stained with methenamine-silver stain shows several budding yeast forms measuring 2 to 4 µm. (a) A smear from a lung biopsy sample, which is stained with Giemsa stain, shows small intracellular yeasts inside a macrophage.

DIFFERENTIAL DIAGNOSIS

Acute pulmonary histoplasmosis is most difficult to differentiate from acute pulmonary blastomycosis. The clinical and radiographic findings of these two diseases are similar, the regions in which these diseases are endemic overlap, and the CF antibody tests for the two organisms show cross-reactivity. For either disease, culture of the causative organism from sputum is diagnostically definitive. However, results of sputum cultures are often negative for patients with acute pneumonia caused by either fungus. Treatment, fortunately, is the same for the two diseases.

Atypical pneumonias caused by Mycoplasma, Legionella, and Chlamydia are included in the differential diagnosis of acute pulmonary histoplasmosis. Hilar and mediastinal lymphadenopathy, which is very common with histoplasmosis, is uncommon in patients with atypical pneumonia caused by these other organisms.

Chronic pulmonary histoplasmosis mimics tuberculosis in regard to symptoms, signs, and radiographic findings. Other chronic fungal pneumonias, especially blastomycosis and sporotrichosis, and nontuberculous mycobacterial infections also must be differentiated from this form of histoplasmosis. Sputum culture and serology are most useful in differentiating these infections.

Patients with acute disseminated histoplasmosis can present with a sepsis syndrome associated with ARDS and disseminated intravascular coagulation that is indistinguishable from sepsis of any bacterial or viral etiology. Helpful findings supporting the diagnosis of histoplasmosis are pancytopenia, diffuse nodular pulmonary infiltrates, and hepatosplenomegaly; the hematology laboratory may make the diagnosis when they find small yeasts inside white cells on the peripheral smear. In AIDS patients, the main infections that must be excluded are those caused by cytomegalovirus, Mycobacterium avium complex, and M. tuberculosis. Biopsy of involved tissues should be performed as soon as possible to help differentiate between these conditions. Culture of blood by means of lysis-centrifugation (i.e., the Isolator system) for fungus and mycobacteria and use of urinary antigen testing for H. capsulatum are very helpful diagnostic tests in this circumstance.

Patients with chronic disseminated histoplasmosis usually present with fever of unknown origin. The disease that mimics histoplasmosis most closely is miliary tuberculosis; lymphoma, brucellosis, and sarcoidosis also must be excluded. Serology is helpful, but histopathologic evidence of yeasts in tissue granulomas and confirmatory culture of the organism from bone marrow, mucous membrane lesions, or liver are definitive. It should be emphasized that the diagnosis of sarcoidosis requires firm evidence that the patient does not have histoplasmosis or tuberculosis; corticosteroid use for the treatment of suspected sarcoidosis in patients who in fact have histoplasmosis frequently leads to defervescence for a short period, followed by further worsening of the infection.12

TREATMENT

Guidelines for the treatment of histoplasmosis have been published by the Mycoses Study Group and the Infectious Diseases Society of America.13 Efficacy has been defined primarily by open-label trials in patients with and without AIDS and through anecdotal experience14,15,16,17,18; there are no studies that directly compare azoles with amphotericin B. The only blinded, randomized treatment trial that compared liposomal amphotericin B with amphotericin B deoxycholate involved a very restricted patient population: AIDS patients with severe disseminated histoplasmosis.19 In spite of the lack of controlled treatment trials, clinical experience has clearly defined itraconazole as the treatment of choice for most patients with histoplasmosis.14,15,16

Fluconazole should be considered a second-line agent; primary response rates are lower for fluconazole in patients with and without AIDS, and relapse rates for AIDS patients receiving fluconazole are higher than those noted in previous studies with itraconazole.17,18 If a patient does not tolerate itraconazole, fluconazole can be used, but the dosage should be 400 to 800 mg daily.

Voriconazole, the most recently approved azole, is of uncertain value in the treatment of histoplasmosis. The same is true of posaconazole, which is available in Europe and should soon be approved for use in the United States. Patients have been treated successfully with these agents, but case series have been small.20

Side effects, drug absorption, and drug-drug interactions are important considerations in antifungal therapy [see Antifungal Therapy,below].

Pulmonary Histoplasmosis

Treatment recommendations are based on the type of histoplasmosis and the immune status of the host.13 Treatment is generally not recommended for patients with acute pulmonary histoplasmosis; in fact, the diagnosis is often not made until after the patient's symptoms have resolved. However, if the patient remains symptomatic after 4 weeks, therapy with itraconazole, 200 mg daily for 6 to 12 weeks, is recommended. Children with acute pulmonary histoplasmosis should be treated with itraconazole, 5 to 7 mg/kg/day.

In acute outbreaks of histoplasmosis, most patients who develop pneumonia will recover without treatment. Patients with severe infection should receive treatment, however. Immunosuppressed patients with acute pulmonary histoplasmosis should always be treated. For initial therapy, either amphotericin B, 0.7 mg/kg/day, or a lipid formulation of amphotericin B, 3 to 5 mg/kg/day, should be used. After a favorable response is noted, which usually occurs quite soon after initiation of therapy, therapy can be changed to oral itraconazole. Treatment should continue until the infiltrate has resolved.

Antifungal therapy is required for all patients with chronic pulmonary histoplasmosis.13 Itraconazole, 200 mg once or twice daily for 12 to 24 months, is the treatment of choice. Even with appropriate antifungal therapy, outcome is poor because of the underlying pulmonary disease.

Disseminated Histoplasmosis

All patients with symptomatic disseminated histoplasmosis should receive antifungal therapy.13 Patients with acute disseminated disease who have only mild to moderate symptoms and most patients with chronic progressive disseminated histoplasmosis should be treated with itraconazole, 200 mg twice daily; this recommendation applies both to patients with AIDS and to those who do not have AIDS. For patients who do not have AIDS, a total of 12 months of therapy is usually adequate, but the length of therapy will be determined by the patient's clinical course; this is especially true for patients with chronic progressive disease. AIDS patients should initially receive itraconazole twice daily for 12 weeks; after that period, they should receive a maintenance course of suppressive therapy with itraconazole, 200 mg daily, until their CD4+ T cell count has been above 200/mm3 for at least a year, at which point it is safe to stop suppressive therapy.21

Young infants, who frequently have overwhelming infection, and immunosuppressed patients with moderately severe to severe symptoms should be treated initially with amphotericin B, 0.7 to 1.0 mg/kg/day, or lipid-formulation amphotericin B, 3 to 5 mg/kg/day. A blinded, randomized clinical trial in AIDS patients with severe disseminated histoplasmosis compared liposomal amphotericin B, 3 mg/kg/day, with amphotericin B deoxycholate, 0.7 mg/kg/day, as initial therapy; duration of fever and mortality were lower for patients given liposomal amphotericin B.19 The only drawback to the use of lipid formulations of amphotericin B is that they are much more expensive than the standard formulation. For most adults, therapy can be changed to itraconazole after they become afebrile and are able to take oral medications.13 Infants should receive a full course of amphotericin B because experience with itraconazole is limited in this population group.

COMPLICATIONS

Granulomatous mediastinitis, in which lymphadenopathy persists for months, is an uncommon complication of pulmonary histoplasmosis.4,5The enlarged nodes can erode into the esophagus, can lead to the formation of a tracheoesophageal fistula, and can cause a traction diverticulum. Chest radiography or CT scanning in these patients reveals enlarged hilar and mediastinal lymph nodes; necrosis and calcium deposition in the nodes are commonly noted on CT scan. Mediastinoscopy and biopsy reveal caseous material, which may contain a few yeastlike organisms typical of H. capsulatum. In most patients, the disease follows a self-limited, although protracted, course. Fibrosing mediastinitis does not develop as a consequence of granulomatous mediastinitis. Patients may benefit from itraconazole, 200 mg twice daily, but there are no clinical trials proving efficacy.13

Fibrosing mediastinitis is a rare complication of pulmonary histoplasmosis in which an excessive amount of fibrosis develops in the mediastinal lymph nodes in response to infection.22,23 The exuberant fibrous tissue entraps the great vessels, causing heart failure, pulmonary emboli, and superior vena cava syndrome. Odynophagia, dyspnea, cough, wheezing, and hemoptysis are common. For some patients, stenting of great vessels provides relief from obstruction.5,22 Antifungal agents play no role in the treatment of this condition.

Pericarditis is a self-limited illness that occurs as an inflammatory response to acute pulmonary histoplasmosis.4 Pleural effusions and mediastinal lymphadenopathy are commonly noted with pericarditis. The pericardial fluid is exudative. Drainage is required if tamponade occurs, but this is rare. Pericarditis should be treated with nonsteroidal anti-inflammatory drugs; cortico steroids should be used for severe cases. Antifungal agents should not be used.13 The long-term outcome is excellent; constrictive pericarditis rarely occurs.

PROGNOSIS

Most patients with histoplasmosis respond quite well to antifungal agents. Even patients with advanced AIDS respond quickly and completely to therapy.

Patients with chronic progressive disseminated histoplasmosis usually experience a return to their baseline function, although this often takes months. The patients who do poorly are those whose underlying illness precludes a return to normal function. For example, patients with chronic cavitary pulmonary histoplasmosis frequently have progressive respiratory insufficiency because of their severe underlying emphysema and the fibrosis caused by the fungal infection.

Blastomycosis

EPIDEMIOLOGY

Although the dimorphic fungus B. dermatitidis is present in many diverse geographic areas worldwide, most cases of blastomycosis are reported from the south central and north central United States.24 The endemic area for blastomycosis overlaps that for histoplasmosis but extends farther north into Wisconsin, Minnesota, and the southern portions of the Canadian provinces of Manitoba, Saskatchewan, and Alberta. Most cases are reported from Arkansas, Mississippi, and Kentucky.

The ecology of B. dermatitidis is not as well understood as that of the other endemic mycoses. The natural niche is assumed to be soil, but the yield of soil cultures is quite low. Most cases occur sporadically, but several well-described outbreaks have helped define the presumed natural habitat.25,26 The largest outbreak to date involved 95 students in northern Wisconsin who camped along a beaver pond and explored a beaver lodge.25 Decomposed wood on the pond bank and samples from the lodge yielded B. dermatitidis.

Most, but certainly not all, patients who develop blastomycosis are men who have an outdoor occupation or hobby. Cases have been described in hunters and their dogs; in these cases, it is presumed that the hunters and their dogs were exposed to the same environmental source. For most sporadic cases, the source of exposure to the fungus is unknown.

PATHOGENESIS

Most patients with blastomycosis have no underlying illnesses, but the disease is more severe in immunosuppressed patients.27Blastomycosis is acquired by inhaling the conidia of B. dermatitidis into the alveoli. The organisms change to the yeast form in the lungs and then reproduce by budding. The immune response to B. dermatitidis appears to include both neutrophils and cell-mediated immune mechanisms involving T cells and macrophages.

Even though a major clinical manifestation of blastomycosis is cutaneous lesions, blastomycosis is only very rarely spread through inoculation. Examples of such cases include accidental inoculation in laboratory workers, conjugal inoculation from a genital lesion, and inoculation from the bite of an infected dog. In almost all cases, the organism travels through the bloodstream to the skin and other common target organs, including osteoarticular structures and the genitourinary tract. Most persons infected with B. dermatitidis are asymptomatic or have mild pulmonary symptoms. Hematogenous dissemination occurs without clinical manifestations, and only later do patients present with skin lesions in the absence of other obvious organ involvement.

CLINICAL PRESENTATION

Pulmonary Blastomycosis

Blastomycosis begins as a pulmonary infection, but many patients never develop symptoms, and others have an acute illness with fever, cough, and a pulmonary infiltrate that is diagnosed as an atypical pneumonia. Overwhelming pulmonary disease with ARDS can occur.28Whether severe infection occurs because of exposure to a large number of conidia or a defective immune response has not been clarified.

A more common presentation is a subacute to chronic pulmonary infection. Fever, night sweats, weight loss, and fatigue are common symptoms. Cough, sputum production, hemoptysis, and dyspnea are noted. The lesions may be cavitary, nodular, fibrotic, or masslike in appearance.29,30 Hilar and mediastinal lymphadenopathy and pleural effusions are uncommonly seen.

Disseminated Blastomycosis

Many patients with blastomycosis have no pulmonary symptoms.24,29 They present with cutaneous lesions that are well circumscribed, nonpainful papules, nodules, or plaques that often become verrucous and develop punctate drainage areas in the center. The lesions are common on the face and extremities but can appear anywhere. There may be only a single lesion, or there may be multiple lesions. An uncommon manifestation seen mostly in immunocompromised patients is the appearance of hundreds of acute pustular lesions associated with widespread visceral involvement and an acute downhill course.

Additional manifestations of disseminated blastomycosis include prostatitis, septic arthritis, osteomyelitis, laryngeal and oropharyngeal nodules, and, less commonly, central nervous system involvement. Genitourinary involvement may be asymptomatic, or it may be associated with signs of prostatism. Although osteoarticular infection can be associated with a contiguous skin lesion, bone involvement often occurs at sites distant from the cutaneous lesions. It is helpful to obtain a bone scan for all patients with disseminated blastomycosis because of the propensity of the organism to seed into bone and because osteomyelitis requires prolonged antifungal therapy. All patients with manifestations of dissemination, even patients with only one skin lesion, need to be treated with systemic antifungal therapy to prevent progression of disease.31

DIAGNOSIS

Culture

The most definitive method for diagnosing blastomycosis is growth of the organism from an aspirate, tissue biopsy, sputum, or body fluid.32For patients with disseminated blastomycosis, urine obtained before and after prostatic massage should be sent for fungal culture. B. dermatitidis generally takes several weeks to grow at room temperature. Once growth has occurred, highly specific and sensitive DNA probes are used to rapidly identify the mold as B. dermatitidis.

Biopsy and Cytologic Studies

Biopsy specimens of skin lesions characteristically show pseudoepitheliomatous hyperplasia; when distinctive, large, thick-walled yeasts with a single broad-based bud are seen, a firm diagnosis of blastomycosis can be made before the results of cultures are known. In patients who have pulmonary lesions, the distinctive yeast forms should be sought by performing Calcofluor white or Papanicolaou stains on sputum or bronchoalveolar lavage fluid and by methenamine-silver or periodic acid—Schiff stains on lung biopsy specimens [see Figures 2a and 2b].

 

Figure 2. Thick-walled, broad-based budding yeasts typical for B. dermatitidis are seen on biopsy material; they allow a definitive diagnosis of blastomycosis. (a) A lung biopsy specimen is stained with periodic acid—Schiff stain. The patient presented with a mass lesion in the right lower lobe and was initially thought to have lung carcinoma. (b) Purulent material was aspirated from one of numerous skin lesions in a patient with disseminated blastomycosis. Lactophenol cotton blue stain was used to prepare the slide.

Serologic Studies

Standard CF and ID serologic assays for blastomycosis are neither sensitive nor specific. A urinary antigen enzyme immunoassay has been developed, but it is not clear what its role will be in the diagnosis of blastomycosis at this time.33

DIFFERENTIAL DIAGNOSIS

The skin lesions of blastomycosis clinically mimic those caused by mycobacteria, especially nontuberculous mycobacteria; other fungal infections, especially coccidioidomycosis or paracoccidioidomycosis; mycosis fungoides; squamous cell carcinoma; the lesions associated with bromide use; and atypical pyoderma granulosum. The histopathologic characteristics of pseudoepitheliomatous hyperplasia occur in response to other chronic infections and to bromoderma. Culture of biopsy material is of crucial importance in differentiating between these conditions.

Acute pulmonary blastomycosis is almost always misdiagnosed as a bacterial or atypical pneumonia and is treated with antibiotics. Development of skin lesions is a strong clue suggesting blastomycosis. The masslike pulmonary lesion that often occurs in blastomycosis is usually thought to be lung cancer until biopsy results are reported. Likewise, lesions in the upper airways, which are usually firm and nodular, are frequently assumed to be squamous cell carcinoma until biopsy is performed. The clinical and radiographic signs and symptoms of patients with chronic pulmonary blastomycosis must be differentiated from those associated with tuberculosis, histoplasmosis and other fungal infections, and sometimes sarcoidosis.

TREATMENT

Guidelines for the treatment of blastomycosis have been published by the Mycoses Study Group under the auspices of the Infectious Diseases Society of America.31 The current recommendations are based on several multicenter, nonrandomized, open-label treatment trials and a few retrospective and prospective reports from individual institutions.14,34,35 There have been no trials comparing amphotericin B with azoles for the treatment of blastomycosis.

In general, patients with pulmonary or disseminated forms of blastomycosis can be treated in a similar manner.31 Those patients who have mild to moderate illness should be treated with an azole. Patients who have severe blastomycosis (either pulmonary or disseminated), patients who are immunosuppressed, and all patients with CNS involvement should receive amphotericin B as initial therapy.31

Itraconazole is the drug of choice for the treatment of mild to moderate blastomycosis.14,31 Although lesions often begin to resolve within the first month of therapy, treatment should be continued for 6 to 12 months to achieve a mycologic cure and to prevent relapse. The usual dosage is 200 mg once or twice daily for 6 to 12 months. Children with blastomycosis should be treated with itraconazole, 5 to 7 mg/kg/day. Osteoarticular involvement requires therapy for at least a year. Fluconazole is not as effective as itraconazole for blastomycosis.34,35However, if a patient is unable to take itraconazole because of drug interactions or problems with absorption, fluconazole can be used; the dosage should be high—a total daily dosage of 400 to 800 mg given in once-daily or twice-daily doses for 6 to 12 months. Voriconazole has been reported to be effective in two cases of blastomycosis meningitis.36,37 However, there is too little experience with this agent to support its use as initial therapy for blastomycosis; the same is true of posaconazole, whose drug application was granted 6-month priority review by the Food and Drug Administration in February 2006.

When amphotericin B is used to treat blastomycosis, the daily dosage is 0.7 to 1.0 mg/kg or a lipid formulation at 3 to 5 mg/kg/day. After the patient has improved, therapy can be changed to itraconazole, 200 mg twice daily, for a total of 6 to 12 months of therapy.

Side effects, drug absorption, and drug-drug interactions are important considerations in the use of antifungal therapy [see Antifungal Therapy, below].

PROGNOSIS

In patients with pulmonary and cutaneous manifestations of blastomycosis who undergo treatment with itraconazole, the clinical and mycologic response rates are 90% to 95%. If relapse occurs, a second treatment course with itraconazole is generally successful. Most reported deaths from blastomycosis occur early in the course of disease in patients who present with overwhelming pneumonia and ARDS. The outcome for patients with osteoarticular infection is good, but antifungal therapy should be given for at least a year to ensure a successful outcome.

Coccidioidomycosis

EPIDEMIOLOGY

The Coccidioides species that cause coccidioidomycosis—C. immitis (California isolates) and C. posadasii (isolates from elsewhere)—occupy the most specific ecological niche of the endemic mycotic pathogens commonly seen in the United States.38,39 These organisms grow in the semiarid desert regions known as the Lower Sonoran Life Zone, which encompasses portions of California, Arizona, New Mexico, Nevada, and western Texas. The organisms are also found in discrete areas of Central and South America.

The mycelial form of Coccidioides produces arthroconidia that can be widely dispersed and are highly infectious. Although persons who work outdoors are at highest risk for infection, the wide dispersal of arthroconidia ensures that most of the people who live in the endemic areas become infected before they reach adulthood. As the allure of the sunbelt has increased, there has been an increase in coccidioidomycosis in older adults. A case-control analysis of patients with and without coccidioidomycosis showed that the greatest risk factor for the development of infection was a recent move into an area endemic for Coccidioides species.40

Periodic outbreaks of coccidioidomycosis in the endemic area have been reported; these outbreaks are related to environmental cycles of rain and drought in the desert. Severe infection can follow massive exposure, as might occur during participation in activities such as anthropologic excavations, in which many arthroconidia are dispersed. In addition, catastrophic dust storms and earthquakes have been linked to the spread of Coccidioides species to areas far beyond those normally considered endemic for the disease.41

PATHOGENESIS

Coccidioidomycosis is acquired after the arthroconidia are inhaled into the alveoli. In the lung, the arthroconidia undergo morphologic changes that result in the formation of spherules, which are large (20 to 80 µm), thick-walled structures that become filled with huge numbers of endospores. When filled, the spherule ruptures, releasing the endospores, each of which forms a new spherule and thus propagates the infection. Coccidioides species do not form yeasts in tissues, as do other endemic mycotic pathogens.

The primary host defense against Coccidioides species is cell-mediated immunity. Neutrophils are present in most lesions but are ineffective at eradicating spherules. In hosts with deficient T cell immunity, such as patients with AIDS, the organism has the propensity to disseminate widely by the hematogenous route. Not yet elucidated is the reason for the well-known observation that dark-skinned races are at high risk for dissemination and severe infection. The highest risk appears to be among African Americans; higher but less dramatic risk of dissemination is also noted in persons from the Philippines, Native Americans, and Hispanics. Women who develop primary coccidioidomycosis while pregnant, especially in the third trimester, are also at increased risk for disseminated infection.

CLINICAL PRESENTATIONS

Pulmonary Coccidioidomycosis

Most persons with acute infection with coccidioidomycosis have no symptoms or have symptoms that are common to many types of pneumonia, such as fever, nonproductive cough, chest pain, dyspnea, fatigue, myalgias, and arthralgias.38 Chest radiographs show a patchy pneumonitis. Erythema nodosum occurs during acute pulmonary coccidioidomycosis in as many as 25% of women and a smaller percentage of men and is a clue to the diagnosis. For most otherwise healthy patients, acute pulmonary coccidioidomycosis is a self-limited infection.

In rare cases, when exposure to the organism is extensive or the host is immunosuppressed, Coccidioides infection may result in acute, overwhelming pneumonia, characterized by high fevers, hypoxemia, and diffuse reticulonodular infiltrates. This occurs most commonly in patients with advanced HIV infection; in many cases, the pulmonary symptoms are merely one manifestation of widely disseminated infection.42

It is estimated that fewer than 5% of patients will have residual manifestations of the acute pulmonary infection. Other than nodules or coccidioidomas, the most common manifestations are cavitary lesions that persist for months to years. These are generally asymptomatic, solitary, thin-walled, peripherally located lesions. Although almost half of these cavities will resolve, for some patients they can last for years and cause hemoptysis, with or without the presence of a mycetoma; they rarely rupture into the pleural cavity. Chronic progressive coccidioidal pneumonia is rare but is more likely to occur in older patients who have COPD and diabetes mellitus; clinically and radiographically, this form of coccidioidomycosis mimics tuberculosis or chronic cavitary histoplasmosis.38,43

Disseminated Coccidioidomycosis

As with other endemic mycoses, hematogenous dissemination of Coccidioides species is probably common and mostly asymptomatic. However, approximately one in every 200 infected persons will develop symptoms of extrapulmonary coccidioidomycosis.38 The manifestations of extrapulmonary infection with Coccidioides species are protean; they may be focal and related to only one organ system that has been seeded, or they may be systemic. The sites involved most often are skin, bones, subcutaneous tissues, and the meninges. In one study, risk factors for disseminated disease included African-American race, low socioeconomic status, and pregnancy.43 Other studies have noted an increased risk of dissemination in patients who have been treated with TNF-α antagonists, those with hematologic malignancies, those who have received an organ transplant, and, not surprisingly, those with AIDS.9,42,44,45

The skin lesions of coccidioidomycosis are typically papular or pustular initially and then become plaquelike or verrucous; facial lesions are common. Ulceration can occur, but drainage is usually minimal. Subcutaneous abscesses are commonly noted in disseminated coccidioidomycosis. Sinus tracts form and may drain intermittently for years. There often is underlying osteomyelitis contiguous with these subcutaneous abscesses. Bony lesions may be single or multiple and can appear in any area of the body; vertebral involvement is particularly common. Although skin and soft tissue abscesses respond fairly well to antifungal therapy, osteomyelitis and coccidioidal arthritis are characterized by an indolent, relapsing course in spite of antifungal therapy.

Coccidioides can infect any organ system, but the most dreaded complication of dissemination is meningitis.46 Chronic progressive meningeal infection is typically concentrated in the basilar area. Meningitis may be only one of several manifestations of severe disseminated coccidioidomycosis, or it may be the sole manifestation. The symptoms include headache, cranial nerve palsies, and signs of increased intracranial pressure. Vasculitis occurs in arteries of the brain in a minority of patients with coccidioidal meningitis, and spinal cord involvement at any level of the spinal cord is not uncommon. If not treated, this form of coccidioidomycosis is fatal in virtually all patients within 2 years of diagnosis. Even with treatment, which must be lifelong, the outcomes are poor.

DIAGNOSIS

Culture

The definitive diagnostic test is growth of the organism. Coccidioides that is in the mold phase grows within several days to a week on most laboratory media. DNA probes can identify the organism very specifically once growth has occurred. Also very helpful is histopathologic identification of the very distinctive large spherules in tissue biopsy specimens, on Calcofluor preparations from sputum, or on potassium hydroxide (KOH) smears from purulent material from an abscess [see Figure 3].

 

Figure 3. Shown is a transbronchial lung biopsy specimen, stained with hematoxylin-eosin stain, from a patient with advanced HIV infection and diffuse reticulonodular pulmonary infiltrates. Large spherules (measuring 60 to 80 µm) of C. immitis in various stages of maturation are evident.

Serologic Studies

Serology is quite helpful in the diagnosis of various forms of coccidioidomycosis.47 For serologic tests to be as useful as possible, it is important that they be sent to a reference laboratory that is experienced in performing fungal serologic analyses. Early appearance of IgM antibodies, detected through an ID test, is helpful for the diagnosis of acute coccidioidomycosis, but this test is not always sensitive enough to detect early infection. An enzyme immunoassay that is not standardized appears to be more sensitive, but false positive results are common.39 An IgG CF assay is generally used to diagnose chronic infections and to follow the course of infection. A decrease in the CF antibody titer or reversion to a negative titer is associated with a good clinical response, whereas a stable high titer (> 1:16) or a rising titer is a poor prognostic sign. A positive CF antibody titer obtained on cerebro spinal fluid is diagnostic of coccidioidal meningitis; cultures of CSF very infrequently yield Coccidioides species.

DIFFERENTIAL DIAGNOSIS

Coccidioidomycosis mimics many other infections. Acute pulmonary coccidioidomycosis is often diagnosed as an atypical pneumonia caused by a virus, Mycoplasma, or Chlamydia. Chronic cavitary pneumonia is radiographically similar to tuberculosis and other endemic mycoses. The diffuse pulmonary infiltrates seen in immunosuppressed patients are no different from those noted in patients with Pneumocystis jiroveci infection, histoplasmosis, tuberculosis, nocardiosis, and many other infections. The importance of tissue biopsy for histopathology and culture in these settings cannot be overemphasized.

The cutaneous lesions can appear similar to those of blastomycosis, or they can mimic squamous or basal cell carcinomas. The bone involvement associated with coccidioidomycosis, which is frequently accompanied by subcutaneous abscesses, is typical of that seen in patients with blastomycosis or tuberculosis. The differential diagnosis of chronic coccidioidal meningitis includes tuberculosis, other fungal infections (i.e., cryptococcosis, histoplasmosis, and, rarely, sporotrichosis or blastomycosis), and sarcoidosis and other disorders of noninfectious etiology.

TREATMENT

The Mycoses Study Group and the Infectious Diseases Society of America have published guidelines for the treatment of coccidioidomycosis.48

Except for one randomized, blinded comparative trial,49 the appropriate treatment of various forms of coccidioidomycosis has been defined by open-label, nonrandomized, multicenter trials and anecdotal reports from experienced clinicians who practice in areas endemic for coccidioidomycosis.50,51,52 In contrast to the other endemic mycoses, coccidioidomycosis can be treated with either fluconazole or itraconazole. A head-to-head, blinded, randomized comparison of fluconazole and itraconazole (each given in dosages of 400 mg daily for 1 year) showed no overall statistically significant difference in efficacy between the drugs.49 However, for skeletal coccidioidomycosis, itraconazole was significantly superior to fluconazole, with response rates of 70% versus 30% after 1 year of therapy. The role of the new broad-spectrum triazoles voriconazole and posaconazole in the treatment of coccidioidomycosis is not clear. Voriconazole successfully treated a small number of patients, some of whom had meningitis, whose disease had not responded to standard therapy.53,54 There has been one published report and a small open-label unpublished trial that showed benefit from posaconazole treatment. In the published report, five of six patients with refractory infection responded to posaconazole.55 Side effects, drug absorption, and drug-drug interactions are important considerations in the use of antifungal therapy [see Antifungal Therapy, below].

Pulmonary Coccidioidomycosis

Most patients with acute pulmonary coccidioidomycosis do not require therapy with an antifungal agent; in fact, most are not seen by a physician, or the diagnosis is not made until after improvement has occurred. For patients who have symptoms lasting 3 to 4 weeks and who show no improvement, therapy with either itraconazole, 200 mg twice daily, or fluconazole, 400 mg daily, for 3 to 6 months is recommended.48 Any patient with underlying immunosuppression, especially immunosuppression associated with HIV infection, solid-organ or stem cell transplantation, or corticosteroid therapy, should be treated because the risk of dissemination is high. Pregnant women are also at risk for dissemination and should be treated. However, azoles cannot be used in pregnant women; rather, amphotericin B, which is safe in pregnancy, is required. Consideration should be given to the treatment of African-American and Filipino patients because of the high risk of dissemination in these populations.

When diffuse pulmonary infiltrates are present, patients should receive amphotericin B, 0.7 mg/kg/day, or a lipid formulation at 3 to 5 mg/kg/day, followed by azole therapy, for a total of at least 1 year of therapy.48 Patients who have chronic cavitary coccidioidomycosis should receive therapy with itraconazole, 200 mg twice daily, or fluconazole, 400 mg daily, for 1 to 2 years, depending on the patient's response. However, patients with asymptomatic cavities are often observed, and treatment with an azole is begun only if the cavities increase in size or complications such as rupture into the pleural cavity seem imminent. Surgical removal of cavities is preferred if the patient is a good operative candidate.

Disseminated Coccidioidomycosis

Disseminated coccidioidomycosis should always be treated.48 Patients who are seriously ill require therapy with amphotericin B, 0.7 mg/kg/day, or a lipid formulation at 3 to 5 mg/kg/day; patients with mild to moderate symptoms can be treated with an azole. Treatment should be given for at least 1 year; for some patients, especially those with HIV infection and African Americans, lifelong azole therapy may be required to prevent relapse.42

The most difficult form of coccidioidomycosis to treat is meningitis. The preferred treatment is fluconazole; the dosage probably should be 800 mg or more daily, although initial studies of this therapy employed doses of only 400 mg daily.46,48,52 Itraconazole has been reported to be as effective as fluconazole, but experience with itraconazole is limited, and most physicians prefer fluconazole. Approximately 20% to 25% of patients will not respond to fluconazole. Amphotericin B administered by both the intravenous and the intrathecal routes is used for those in whom fluconazole therapy fails. Intrathecal amphotericin B is not well tolerated. Repeated administration of amphotericin B into the lumbar area leads to arachnoiditis, and this is an inefficient method of delivering drug to the basilar meninges. Ideally, the drug should be administered into the cistern, but most physicians cannot perform this procedure. An alternative method is delivery through an intraventricular reservoir, but this method also does not deliver drug to the basilar meninges as efficiently as intracisternal injection. Therapy must be individualized and must be given for life.46,48

PROGNOSIS

Of all the endemic mycoses, infection with C. immitis is the least responsive to currently available antifungal agents. Success rates with azoles are highest in patients with soft tissue infections; approximately 70% of such patients respond after 12 months of therapy. Patients with chronic pulmonary infection have response rates of 50% to 60%. Relapses are more common with coccidioidomycosis than with other endemic mycoses. For patients with chronic relapsing disease, who are often of African-American descent, lifelong azole therapy may be required. For patients with meningitis, cures are rare, and suppressive therapy must be continued indefinitely.

Sporotrichosis

EPIDEMIOLOGY

The dimorphic fungus Sporothrix schenckii is found worldwide. The environmental niches for the organism include sphagnum moss, decaying vegetation, hay, and soil. Infection is seen most often in persons whose vocation or avocation brings them into contact with the environment. Landscaping, rose gardening, Christmas tree farming, topiary production, baling hay, and motor vehicle accidents have all been associated with sporotrichosis.56,57 Less commonly, pulmonary sporotrichosis results from inhalation of S. schenckii conidia from soil. Cases of sporotrichosis usually occur sporadically, but outbreaks have been described. The largest outbreak in the United States involved 84 patients in 25 states and was traced back to conifer seedlings that had been packed in sphagnum moss from Wisconsin.56

  1. schenckiican also be acquired through exposure to animals that are either infected or are able to passively transfer the organism from soil through scratching or biting. A variety of animals have been reported to transmit sporotrichosis, but cats with ulcerated skin lesions appear to be the most infectious. Clusters of sporotrichosis involving families and veterinarians caring for infected cats have been described.58,59

PATHOGENESIS

Sporotrichosis typically develops in an otherwise healthy person who is exposed to the fungus while outdoors. The typical clinical picture is that of localized cutaneous or lymphocutaneous disease. After inoculation of S. schenckii conidia, the organism converts to the yeast form, which reproduces by budding. Strains that grow poorly at temperatures higher than 35°C tend to be found in fixed cutaneous lesions; these strains do not have the ability to spread along lymphatics, as do most strains of S. schenckii.60

In patients with underlying illnesses, including alcoholism, diabetes mellitus, COPD, and HIV infection, S. schenckii can disseminate to involve osteoarticular structures, lungs, meninges, and other organs. Neutrophils and macrophages are able to ingest and kill the yeast phase of S. schenckii in the absence of antibodies. A role for cell-mediated immunity as a host defense against S. schenckii is suggested by the observation that sporotrichosis is more severe in those with HIV infection.61

CLINICAL PRESENTATIONS

Lymphocutaneous Sporotrichosis

Days to weeks after cutaneous inoculation of the fungus, a papule develops at the site of inoculation. The primary lesion can become nodular, but most often, it ulcerates. The drainage is not grossly purulent and has no odor, and the lesion is not terribly painful. Similar lesions subsequently occur along the lymphatic channels proximal to the original lesion. A fixed cutaneous lesion that is verrucous or ulcerative and that is not associated with lymphatic extension can also occur.62

Visceral Sporotrichosis

Pulmonary sporotrichosis occurs most often in middle-aged men who have COPD and abuse alcohol.63 In contrast to most forms of sporotrichosis, systemic symptoms, including fever, night sweats, weight loss, and fatigue, are common. Dyspnea, cough, purulent sputum, and hemoptysis are common respiratory symptoms. A chest radiograph shows unilateral or bilateral upper-lobe cavities with variable amounts of fibrosis and nodular lesions.

Osteoarticular sporotrichosis is found most often in middle-aged men and occurs more frequently in patients with alcoholism.64 Although some patients experience osteoarticular involvement after local inoculation, this form of infection most often develops through hematogenous spread. Infection may involve one joint or multiple joints. The joints most commonly affected are the knee, elbow, wrist, and ankle. Isolated cases of bursitis and tenosynovitis, sometimes presenting as nerve entrapment syndromes, have been reported.

  1. schenckiihas rarely been reported to cause localized infection of the meninges, pericardium, eye, perirectal tissues, larynx, breast, epididymis, spleen, liver, bone marrow, or lymph nodes.60Disseminated sporotrichosis is very uncommon, with cases occurring primarily in patients with advanced HIV infection. Most patients have widespread ulcerative cutaneous lesions and may or may not have visceral dissemination.

DIAGNOSIS

Culture

Growth of S. schenckii from material aspirated from a lesion, a tissue biopsy specimen, sputum, or body fluid is the most sensitive method for establishing a diagnosis of sporotrichosis. Growth of the mold phase of S. schenckii is usually evident a few days to a week after inoculation onto Sabouraud agar. Synovial tissue provides a better yield than synovial fluid.

Biopsy

Histopathologic examination of biopsy material shows a mixed granulomatous and pyogenic process. The organisms often are not visualized, even with special stains for fungi, because they are rarely present in large numbers. When visualized, S. schenckii yeasts are 3 to 5 µm in diameter; they are oval to cigar-shaped and may show multiple buds.

Serologic Studies

Serology is not useful in the diagnosis of sporotrichosis.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of lymphocutaneous sporotrichosis includes atypical mycobacterial infections, especially M. marinum infections;Nocardia infections, particularly N. brasiliensis infections; Leishmania brasiliensis infections; and tularemia. Both clinically and radiographically, pulmonary sporotrichosis mimics tuberculosis; nontuberculous mycobacterial infections; other fungal infections, especially histoplasmosis; and sarcoidosis. Osteoarticular sporotrichosis is often misdiagnosed as a bacterial infection and treated with antibiotics, to no avail. Growth of the organism in culture is the most important method of differentiating between these conditions.

TREATMENT

Guidelines for the management of the various forms of sporotrichosis have been published by the Mycoses Study Group and the Infectious Diseases Society of America.65 No randomized, blinded treatment trials have been performed comparing various antifungal agents for the treatment of sporotrichosis. The guidelines are based entirely on open treatment trials and anecdotal experience.64,66,67,68,69 Because mostS. schenckii infections are subacute to chronic and are localized, oral antifungal agents are preferred; amphotericin B is reserved for the uncommon visceral infections.

Lymphocutaneous Sporotrichosis

Itraconazole is the drug of choice for lymphocutaneous sporo trichosis.65 The usual dosage is 100 to 200 mg/day. Treatment should continue for several weeks after all lesions have disappeared, usually for a total of 3 to 6 months.64,67 Fluconazole is less active against S. schenckiibut may be effective when a daily dose of 400 mg is used.68 Saturated solution of potassium iodide (SSKI) is also effective and is much less costly than therapy with an azole. The initial dosage is 5 to 10 drops three times daily in water or juice; the dosage is increased each week to a maximum of 40 to 50 drops three times daily. SSKI is difficult for many patients to administer and tolerate; side effects include a metallic taste, salivary gland swelling, rash, and fever.66 Terbin afine appears to be effective for sporotrichosis, but few patients have been treated with this agent to date.69 Local hyperthermia, induced by a variety of different warming devices or baths, also has been used with minimal side effects for localized cutaneous sporotrichosis.70

Visceral Sporotrichosis

For a seriously ill patient with pulmonary sporotrichosis, amphotericin B, 0.7 to 1.0 mg/kg/day or a lipid formulation at 3 to 5 mg/kg/day, should be used as initial therapy.65 After the patient has shown improvement, therapy can be changed to itraconazole, 200 mg twice daily. Azole therapy should be continued for at least 1 to 2 years. For patients who are not acutely ill, therapy can be initiated with itraconazole, 200 mg twice daily. Surgical resection has proved to be useful for patients who have focal lesions and whose pulmonary function is adequate to withstand a lobectomy.66

Almost all patients who have osteoarticular sporotrichosis can be treated with itraconazole, 200 mg twice daily.65 Therapy should continue for 1 to 2 years. Other azoles are less effective, and SSKI is ineffective. Intravenous amphotericin B is rarely required.

Amphotericin B, 0.7 to 1.0 mg/kg/day or a lipid formulation at 3 to 5 mg/kg/day, is the drug of choice for disseminated sporotrichosis, including meningeal infection.65 Itraconazole, 200 mg twice daily, can be used in those patients with disseminated skin lesions and other nonmeningeal manifestations as soon as the patient's condition has stabilized. AIDS patients with disseminated sporotrichosis should receive lifelong maintenance therapy with itraconazole, 200 mg daily.

PROGNOSIS

The success rate for the treatment of lymphocutaneous sporotrichosis is 90% to 100%, but it is much lower for all other forms of the disease. This is undoubtedly related to delays in diagnosis, as well as to the underlying diseases of the hosts who have noncutaneous forms of sporotrichosis. Joint function after cure of sporotrichal arthritis is often poor, and pulmonary function after treatment of pulmonary sporotrichosis is often marginal. The outcome of disseminated sporotrichosis in patients with HIV infection has been poor, but almost all reports are from studies conducted before the era of highly active antiretroviral therapy. Presumably, antifungal therapy along with highly active antiretroviral therapy would improve the prognosis.

Antifungal Therapy

For treatment of the endemic mycoses, the choice of azoles or amphotericin B depends on the severity of the infection, the presence of underlying diseases, and the immune status of the host. In general, most mild to moderately ill patients can be very effectively treated with an azole; most severely ill patients should receive amphotericin B as initial therapy. Amphotericin B is most often administered as a lipid formulation to decrease the risk of nephrotoxicity. Induction amphotericin B therapy can almost always be followed by consolidation therapy with an azole. The length of therapy is measured in months to years and is obviously managed primarily in the outpatient setting. Thus, issues of compliance, absorption, and drug-drug interactions assume great importance in current treatment regimens for the endemic mycoses.

USE OF AZOLES TO TREAT ENDEMIC MYCOSES

Four azole antifungal agents are currently available in the United States: ketoconazole, itraconazole, voriconazole, and fluconazole. A fifth azole, posaconazole, was granted 6-month priority review by the FDA in February 2006. Ketoconazole, which is available only in tablet form, is used infrequently because of its greater toxicity, poor absorption, and modest spectrum of antifungal activity when compared with the other azoles; it will not be discussed further. Itraconazole has supplanted ketoconazole because it is both more effective and better tolerated. Fluconazole is less active than itraconazole against most of the endemic mycoses, and except for coccidioidomycosis, it is a second-line agent. Voriconazole and posaconazole have in vitro activity against B. dermatitidis, C. immitis/C. posadasii, and H. capsulatum. Voriconazole is not active against S. schenckii; posaconazole has modest activity against S. schenckii.71,72 Both agents have been used successfully in small numbers of patients with histoplasmosis, blastomycosis, and coccidioidomycosis.

Side Effects

Hepatitis, which is sometimes severe, can occur with all azoles. This is an idiosyncratic response for most azoles, but hepatitis appears to be related to serum levels of drug in the case of voriconazole.73 Liver enzyme and bilirubin levels should be measured before therapy is started, after several weeks of therapy, and then every 1 to 2 months in patients receiving long-term therapy. Mild elevations in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (i.e., a twofold to threefold increase over normal levels) do not require discontinuance of the drug, but such increases do require very careful follow-up. If the levels continue to rise, the drug should be discontinued. If therapy with an azole is required, another azole can be cautiously given after the enzyme levels return to normal. Liver enzyme levels should be assessed weekly, and the drug must be stopped if they again rise threefold or more while the patient is receiving the second azole.

Uncommonly, itraconazole causes hypertension, edema, and hypokalemia; this triad usually occurs in older adults and requires discontinuance of the drug. Whether these effects are related to the myocardial dysfunction noted with itraconazole has not been elucidated.74

Rash can occur with all azoles. Voriconazole has a greater propensity to cause rash than the other azoles; the rash can manifest itself as severe photosensitivity requiring discontinuance of the drug.73 Long-term therapy with fluconazole has been associated with alopecia, which is reversible when the drug is discontinued.75 All azoles are contraindicated during pregnancy; teratogenicity in animals has been noted, and several cases of fetal malformations have been reported in women taking fluconazole during pregnancy.76

Unique to voriconazole is photopsia, a condition in which a patient sees wavy lines or bright spots or merely experiences blurry vision approximately 30 minutes after the drug is administered.73 The effect lasts for minutes to hours and gradually lessens as the drug is continued for weeks. There are no long-term consequences from this phenomenon.

Absorption Issues

The capsule formulation of itraconazole requires both gastric acid and food for absorption. Therefore, histamine receptor antagonists (e.g., H2 receptor blockers), antacids, and proton pump inhibitors cannot be administered to patients receiving these agents. Older adults, who are often achlorhydric, may not absorb itraconazole capsules. The oral-suspension formulation of itraconazole was developed specifically to overcome the poor absorption characteristics of the capsules. The suspension requires neither acid nor food for absorption and should be taken on an empty stomach. For the treatment of endemic mycoses, itraconazole is commonly used at a daily dose of 400 mg; regardless of whether solution or capsules are prescribed, the drug should be administered in twice-daily doses of 200 mg, rather than a once-daily dose of 400 mg, to achieve appropriate serum drug levels. At doses higher than 200 mg, decreased absorption of the drug occurs. Compliance with long-term use of the oral suspension is often difficult, but the suspension is preferred to ensure adequate serum levels. Serum itraconazole levels should be obtained at a reference mycology laboratory to ensure that absorption is adequate.

Use of the intravenous formulation of itraconazole, solubilized in cyclodextrins, avoids absorption problems. However, it is recommended that the intravenous formulation be used for only 2 weeks and and that it not be given to patients whose creatinine clearance is less than 30 ml/min because of concerns about the nephrotoxicity of the cyclodextrin vehicle. Intravenous therapy is usually followed by treatment with the oral-suspension formulation.

Fluconazole, which is nearly 100% bioavailable, has none of the absorption problems that have been so troublesome with itraconazole. The drug is distributed into most body compartments, including the eye and the CSF; is excreted as active drug in the urine; and can be given as a once-daily dose, either intravenously or orally.

Voriconazole is approximately 95% bioavailable when given orally, if given on an empty stomach; food decreases the absorption of the drug. The intravenous formulation in cyclodextrin cannot be given to patients whose creatinine clearance level is below 50 ml/min. Both intravenous and oral formulations are given twice daily.

Posaconazole is currently manufactured only as an oral suspension that must be taken with fatty food to ensure absorption. It is given two or four times daily. The maximum dose that can be absorbed daily is 800 mg.

Drug-Drug Interactions

The azoles interact with many other drugs, primarily through their interactions with cytochrome P-450 enzymes; some azoles also interact with P-glycoprotein. Voriconazole is especially problematic because it is metabolized by cytochromes 3A4, 2C9, and 2C19.73 Posaconazole appears to have fewer interactions than the other azoles.72 These interactions can be serious and even life-threatening. It is absolutely essential that the patient's concomitant medications be reviewed and the package insert read before use of any azole for the treatment of any fungal infection. Major interactions for the azoles are detailed [see Tables 1 and 2].

Table 1 Effects of Concomitantly Administered Drugs on Serum Levels of Azoles

Drugs Affecting Azole Serum Levels

Effects That Other Drugs Have on Azole Serum Levels

Itraconazole

Fluconazole

Voriconazole

Antituberculous drugs

Rifampin

Decreased

Decreased

Decreased

Rifabutin

Decreased

No effect

Decreased

Antiretroviral drugs

Efavirenz

Likely decreased

No effect

Decreased

Nevirapine

Decreased

No effect

Likely decreased

Ritonavir

None known

No effect

Decreased

Anticonvulsants

Phenytoin

Decreased

None known

Decreased

Carbamazepine

Decreased

None known

Decreased

Long-acting barbiturates

Decreased

None known

Decreased

Gastric acid-–lowering agents*

Antacids

Decreased

No effect

No effect

H2 receptor blockers

Decreased

No effect

No effect

Proton pump inhibitors

Decreased

No effect

No effect

*Gastric acid–lowering agents should not be used with itraconazole capsules; if necessary, they can be used with itraconazole suspension.
These agents should not be used together, because azole levels will be markedly low or interaction could cause severe reaction.

Table 2 Effects of Azoles on Serum Levels of Other Drugs

Drugs Affected by Azoles

Effects That Azoles Have on Other Drugs' Serum Levels

Itraconazole

Fluconazole

Voriconazole

Immunosuppressants

Cyclosporine

Increased*

Increased*

Increased*

Tacrolimus

Increased*

Increased*

Increased*

Sirolimus

Increased*

Likely increased*

Increased

Anticonvulsants

Phenytoin

Increased*

Increased*

Increased*

Carbamazepine

Increased*

Increased*

Increased

Sedatives

Triazolam

Increased

Increased*

Increased*

Midazolam

Increased

Increased*

Increased*

Cholesterol-lowering agents

Lovastatin

Increased

None known

Increased*

Simvastatin

Increased

None known

Increased*

Antiretroviral agents

Indinavir

Increased

None known

No effect

Saquinavir

Increased

None known

No effect

Ritonavir

Increased

No effect

No effect

Efavirenz

None known

None known

Increased

Antituberculous drugs

Rifampin

No effect

No effect

No effect

Rifabutin

Increased*

Increased*

Increased

Other drugs

Warfarin

Increased*

Increased*

Increased*

Digoxin

Increased*

No effect

None known

Sulfonylureas

Increased*

Increased*

Increased*

Quinidine

Increased

None known

Increased

Omeprazole

No effect

No effect

Increased*

Methadone

No effect

No effect

Increased*

Ergot alkaloids

None known

None known

Increased

Calcium channel blockers

Increased*

No effect

Increased*

*Significant interaction; monitoring of drug serum levels, clinical status, or both is required.
Life-threatening interaction; these agents should not be used together.

Itraconazole and voriconazole have the most drug-drug interactions, but fluconazole shares several significant interactions. Increased serum levels of warfarin, phenytoin, and oral hypoglycemic agents occur when azoles are given with these commonly used drugs. Itraconazole increases serum levels of digoxin in some but not all patients. Thus, serum levels of these agents or the effects of these agents must be closely monitored in patients receiving an azole.

Itraconazole and voriconazole should never be given to patients receiving statins, because of the potential for life-threatening rhabdomyolysis, or to patients receiving midazolam or triazolam, because of the possibility of markedly increased sedation. Several commonly used drugs have the effect of inducing the metabolism of the azoles and thus decreasing serum azole concentrations and diminishing effectiveness. This has been reported with rifampin, phenytoin, carbamazepine, and long-acting barbiturates. These agents should not be given with an azole, or if they are needed, the dosing of the azole should be modified.

USE OF AMPHOTERICIN B TO TREAT ENDEMIC MYCOSES

Amphotericin B is fungicidal against a broad range of fungi. The major drawbacks are the need for intravenous administration and the inherent toxicity of the drug. Some, but not all, of the infusion-related reactions to amphotericin B can be minimized with the use of preinfusion medications77; however, nephrotoxicity remains a common and potentially severe side effect, especially with higher doses and increasing duration of therapy.78

In an attempt to decrease the toxicity of amphotericin B, the drug has been incorporated into liposomes and other lipid-delivery vehicles. Three formulations are currently available: liposomal amphotericin B (AmBisome, L-AmB); amphotericin B lipid complex (Abelcet, ABLC); and amphotericin B colloidal dispersion (Amphotec or Amphocil, ABCD). Each differs from the others and from amphotericin B deoxycholate with regard to composition, pharmacologic parameters, toxicity, recommended dosages, and cost.79,80 All of these preparations are clearly less nephrotoxic than amphotericin B deoxycholate, and two of the three cause fewer infusion-related reactions than amphotericin B deoxycholate. Amphotericin B colloidal dispersion causes as many infusion reactions as amphotericin B deoxycholate and is rarely used. All of these agents are much more costly than standard amphotericin B.

Other than two studies that show liposomal amphotericin B to be superior to amphotericin B deoxycholate for the treatment of severe histoplasmosis in AIDS patients and for the empirical treatment of febrile neutropenic patients,19,81 there is little evidence to suggest that lipid formulations of amphotericin B are more efficacious than the standard formulation; they should be considered to be equally efficacious as amphotericin B deoxycholate.

Diminished creatinine clearance is the major manifestation of nephrotoxicity, but profound hypokalemia and hypomagnesemia are also common. Patients with underlying renal disease show a more rapid rise in creatinine levels than patients with normal renal function. Use of other nephrotoxic drugs, such as aminoglycosides, cisplatin, cyclosporine, or tacrolimus, should be avoided if at all possible when amphotericin B is used.

Sodium loading is routinely employed in an attempt to decrease nephrotoxicity82 [see Table 3]. Potassium and magnesium losses can be large and can contribute to other organ dysfunction; for this reason, electrolytes should be monitored carefully and should be replaced as soon as the serum levels show even a slight decrease. In many patients, intravenous repletion is ultimately required to keep pace with the renal loss.

Table 3 Administration of Amphotericin B for Treatment of the Endemic Mycoses

General Guidelines

    Do not use in-line filters; no need to cover drug while infusing

    Use central I.V. catheter if at all possible.

    For the initial dose, infuse very slowly for the first 20 min and assess for the rare occurrence of anaphylaxis or arrhythmias

    Infuse drug over 2 to 4 hr; for patients with infusion-related reactions, slower infusion times are often better tolerated; for others, 2-hr infusion times are appropriate

    For subacute or chronic infections, start with a lower dose and increase daily by the same increment until the desired daily dose is reached; use pretreatment medications only if required

    For life-threatening infections, give the desired daily dose within the first 24 hr; preinfusion medications should be given before the first dose because reactions are frequent

Measures to Decrease Infusion-Related Reactions (chills, fever, nausea and vomiting, headache, myalgia)

    Medications before beginning infusion of amphotericin B: acetaminophen (650 mg p.o.), diphenhydramine (50 mg p.o.), prochlorperazine (25 mg p.o. for nausea and vomiting), and meperidine (50–75 mg I.V. or I.M. for rigors); administer hydrocortisone (25–50 mg I.V.) if reactions do not improve with the above drugs

Measures to Reduce Nephrotoxicity

    Assess volume status before treatment; stop diuretics, if possible; do not restrict sodium

    Before each dose, infuse 500 ml 0.9% saline over 1 hr

Required Laboratory Studies to Assess Toxicity

    Baseline creatinine, blood urea nitrogen, potassium, magnesium levels; blood count, liver function tests

    Monitor creatinine, blood urea nitrogen, potassium, magnesium levels every other day

    Monitor blood count weekly; repeat liver function tests if clinically indicated

Infusion-related reactions include chills or rigors, fever, nausea, headache, and myalgias. These side effects can be diminished by prescribing a variety of medications before infusion of amphotericin B [see Table 3].

Patients with life-threatening infections that require immediate treatment with large doses of amphotericin B are more likely to have infusion-related reactions. Pretreatment medications should be given before the first dose of amphotericin B in these patients. For others who have subacute to chronic infections, the dosage of amphotericin B can be increased gradually over a few days, decreasing the risk of immediate reactions.

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Editors: Dale, David C.; Federman, Daniel D.