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Mycotic Infections Samuel A. Shelburne, MD, PhD Richard J. Hamill, MD

Fungal infections have assumed an increasingly important role as use of broad-spectrum antimicrobial agents has increased and the number of immunodeficient patients has grown. Some pathogens (eg, Cryptococcus, Candida, Pneumocystis, Fusarium) rarely cause serious disease in normal hosts. Other endemic fungi (eg, Histoplasma, Coccidioides, Paracoccidioides) commonly cause disease in normal hosts but tend to be more aggressive in immunocompromised ones. Superficial mycoses are discussed in Chapter 6.

Successful management of most systemic fungal infections requires knowledge of the natural history of these diseases as well as familiarity with the unique pharmacokinetics, adverse effects, and drug interactions of the various therapeutic agents. Furthermore, most affected individuals usually have significant underlying illnesses. Conse­ quently, clinicians with extensive experience in the management of these disorders should be routinely consulted.

CANDIDIASIS

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Essentials of diagnosis

Common normal flora but opportunistic pathogen.

Gastrointestinal mucosal disease, particularly esophagitis, most common.

Intravenous catheter-associated fungemia occurs in patients who have sustained cutaneous or mucosal injury, undergone instrumentation, or received broad-spectrum antibiotics.

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``General Considerations Candida albicans can be cultured from the mouth, vagina, and feces of most people. Cutaneous and oral lesions are discussed in Chapters 6 and 8, respectively. The risk factors for invasive candidiasis include prolonged neutropenia, recent abdominal surgery, broad-spectrum antibiotic therapy, advanced chronic kidney disease, and the presence of

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intravascular catheters (especially when providing total parenteral nutrition). Cellular immunodeficiency predisposes to mucocutaneous disease. When no other underlying cause is found, persistent oral or vaginal candidiasis should arouse a suspicion of HIV infection.

``Clinical Findings A. Mucosal Candidiasis Esophageal involvement is the most frequent type of significant mucosal disease. Presenting symptoms include substernal odynophagia, gastroesophageal reflux, or ­nausea without substernal pain. Oral candidiasis, though often associated, is not invariably present. Diagnosis is best confirmed by endoscopy with biopsy and culture.

Vulvovaginal candidiasis occurs in an estimated 75% of women during their lifetime. Risk factors include pregnancy, uncontrolled diabetes mellitus, broad-spectrum antimicrobial treatment, corticosteroid use, and HIV infection. Symptoms include acute vulvar pruritus, burning vaginal discharge, and dyspareunia.

B. Candidal Funguria Most cases of candidal funguria are asymptomatic and represent specimen contamination or bladder colonization. However, signs and symptoms of true Candida urinary tract infections are indistinguishable from bacterial urinary tract infections and can include urgency, hesitancy, fever, chills, or flank pain.

C. Disseminated Candidiasis The diagnosis of disseminated Candida infection is problematic because Candida species are often isolated from mucosal sites in the absence of invasive disease while blood cultures are positive only 50% of the time in disseminated infection. Serologic tests have not proved useful for distinguishing colonization from invasive disease.

Isolation of Candida species from blood cultures may represent a benign, self-limited process, but until proven otherwise it should be considered a sign of serious, complicated disease.

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Another form of invasive disease is hepatosplenic candidiasis. This results from aggressive chemotherapy and prolonged neutropenia in patients with underlying hematologic cancers. Typically, fever and variable abdominal pain present weeks after chemotherapy, when neutrophil counts have recovered. Blood cultures are generally negative. Hepatic enzymes reveal an alkaline phosphatase elevation that may be marked.

D. Candidal Endocarditis Candidal endocarditis is a rare infection that is most frequently associated with exposure to a healthcare setting.

Candidal endocarditis occurs with increased frequency on prosthetic valves in the first few months following surgery.

The diagnosis is established definitively by culturing Candida from emboli or from vegetations at the time of valve replacement.

``Treatment A. Mucosal Candidiasis Therapy of esophageal candidiasis depends on the severity of disease. If patients are able to swallow and take adequate amounts of fluid orally, fluconazole, 100 mg/d (or itraconazole solution, 10 mg/mL, 200 mg/d), for 10–14 days usually suffices. In the individual who is more ill or in whom esophagitis has developed while taking fluconazole, options include oral or intravenous voriconazole, 200 mg twice daily; intravenous amphotericin B, 0.3 mg/kg/d; intravenous caspofungin, 50 mg/d; intravenous anidulafungin, 100 mg on day 1, then 50 mg/d; or intravenous micafungin, 150 mg/d. Relapse is common with all agents when there is underlying HIV infection without adequate immune reconstitution.

Various topical azole preparations (eg, clotrimazole, 100 mg vaginal tablet for 7 days, or miconazole, 200 mg vaginal suppository for 3 days) are effective against vulvovaginal candidiasis. One 150 mg oral dose of fluconazole has been shown to have equivalent efficacy with better patient acceptance. Disease recurrence is common but can be decreased with weekly fluconazole therapy (150 mg weekly).

B. Candidal Funguria Candidal funguria frequently resolves with discontinuance of antibiotics or removal of bladder catheters. Clinical benefit from treatment of asymptomatic candiduria has not been demonstrated, but persistent funguria should raise the suspicion of disseminated infection.

When symptomatic funguria persists, oral fluconazole, 200 mg/d for 7–14 days, can be used. Newer generation azoles (eg, voriconazole) and echinocandins are not considered standard therapy for candidal urinary tract infections due to low levels of active drug in the urine.

C. Disseminated Candidiasis The decision to treat for disseminated Candida when organisms are isolated from urine or sputum (or both) needs to be individualized for each patient. A randomized

trial of empiric fluconazole for patients at high risk for, but not proven to have, disseminated candidiasis showed no clinical benefit compared with placebo.

The 2009 guidelines for treatment of invasive candidiasis recommend fluconazole (loading dose of 800 mg [12 mg/kg] intravenously, then 400 mg [6 mg/kg] intravenously daily) for less critically ill patients who have had no recent azole exposure. For patients with moderately severe to severe illness or for patients who have had recent azole exposure, an echinocandin such as caspofungin (loading dose of 70 mg intravenously once, then 50 mg intravenously daily), micafungin (100 mg intravenously daily), anidulafungin (loading dose of 200 mg intravenously once, then 100 mg intravenously daily) is favored. Therapy for candidemia should be continued for 2 weeks after the last positive blood culture and resolution of symptoms and signs of infection. A dilated fundoscopic examination is recommended for all patients with candidemia to exclude endophthalmitis and repeat blood cultures should be drawn to demonstrate organism clearance. Once patients have become clinically stable, parenteral therapy can be discontinued and oral fluconazole, 200–800 mg orally given as one or two doses daily, is used to complete treatment for isolates known to be or likely to be susceptible to fluconazole. Removal or exchange of intravascular catheters is generally recommended for non-neutropenic patients, since this may decrease the duration of candidemia and overall mortality, which approaches 30%.

Non-albicans species of Candida account for over 50% of clinical bloodstream isolates and often have resistance patterns that are different from C albicans. An echinocandin is recommended for treatment of Candida glabrata infection with a transition to oral fluconazole or voriconazole reserved for patients whose isolates are known to be susceptible to these agents. Similarly, Candida krusei is generally fluconazoleresistant and so should be treated with an alternative agent, such as echinocandin or voriconazole. Fluconazole is the treatment of choice for Candida parapsilosis due to possible echinocandin resistance in such isolates.

Treatment for hepatosplenic candidiasis is with fluconazole, 400 mg orally daily, or a lipid formulation of amphotericin B should be given until clinical and radiographic improvement occurs.

D. Candidal Endocarditis Amphotericin, either in a lipid or standard formulation, has long been considered the optimal therapy for candidal endocarditis, given in a dosage of 0.5–1 mg/kg/d intravenously, and can be given along with 5-flucytosine (25 mg/ kg four times daily). Alternatively, fluconazole can be added to amphotericin B at dosages greater than 400 mg/d, followed by long-term oral suppressive therapy. Aggressive surgical intervention appears to be beneficial. There are now more data regarding the usefulness of echinocandins in this setting.

In high-risk patients undergoing induction chemotherapy, bone marrow transplantation, or liver transplantation, prophylaxis with antifungal agents has been shown to prevent invasive fungal infections although the effect on mortality and the preferred agent remain debated.

Mycotic Infections

Oude Lashof AM et al. Ocular manifestations of candidemia.

Clin Infect Dis. 2011 Aug 1;53(3):262–8. [PMID: 21765074] Reboli AC et al. Anidulafungin compared with fluconazole for treatment of candidemia and other forms of invasive candidiasis caused by Candida albicans: a multivariate analysis of factors associated with improved outcomes. BMC Infect Dis. 2011 Sep 30;11:261. [PMID: 21961941] Smego RA Jr et al. The role of fluconazole in the treatment of Candida endocarditis: a meta-analysis. Medicine (Baltimore).

2011 July;90(4):237–49. [PMID: 21694646]

HISTOPLASMOSIS

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Essentials of diagnosis

Epidemiologically linked to bird droppings and bat exposure; common along river valleys (especially the Ohio River and the Mississippi River valleys).

Most patients asymptomatic; respiratory illness most common clinical problem.

Widespread disease especially common in AIDS or other immunosuppressed states, with poor prognosis.

Biopsy of affected organs with culture or urinary polysaccharide antigen most useful in disseminated disease.

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``General Considerations Histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus that has been isolated from soil contaminated with bird or bat droppings in endemic areas (central and eastern United States, eastern Canada, Mexico, Central America, South America, Africa, and southeast Asia). Infection presumably takes place by inhalation of conidia. These convert into small budding cells that are engulfed by phagocytes in the lungs. The organism proliferates and undergoes lymphohematogenous spread to other organs.

``Clinical Findings A. Symptoms and Signs Most cases of histoplasmosis are asymptomatic or mild and thus go unrecognized. Past infection is recognized by pulmonary and splenic calcification noted on incidental radiographs. Symptomatic infection may present with mild influenza-like illness, often lasting 1–4 days.

Moderately severe infections are frequently diagnosed as atypical pneumonia. These patients have fever, cough, and mild central chest pain lasting 5–15 days.

Clinically evident infections occur in several forms: (1) Acute histoplasmosis frequently occurs in epidemics, often when soil containing infected bird or bat droppings is disturbed. It is a relatively severe disease manifested by marked prostration, fever, and comparatively few pulmonary complaints even when radiographs show diffuse

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pneumonia. The illness may last from 1 week to 6 months but is almost never fatal. (2) Progressive disseminated histoplasmosis is commonly seen in patients with underlying HIV infection (with CD4 cell counts usually < 100 cells/mcL) or other conditions causing immunosuppression. Disseminated histoplasmosis has been more frequently reported in patients from endemic areas taking tumor necrosis factor (TNF)-blocking agents. It is characterized by fever and multiple organ system involvement.

Chest radiographs may show a miliary pattern. Presentation may be fulminant, simulating septic shock, with death ensuing rapidly unless treatment is provided. Symptoms usually consist of fever, dyspnea, cough, loss of weight, and prostration. Ulcers of the mucous membranes of the oropharynx may be present. The liver and spleen are nearly always enlarged, and all the organs of the body are involved, particularly the adrenal glands, though this infrequently results in adrenal insufficiency. Gastrointestinal involvement may mimic inflammatory bowel disease. (3) Subacute/chronic progressive pulmonary histoplasmosis is usually seen in older patients with various lesions including apical cavities, infiltrates, and nodules found on radiographs. (4) Chronic progressive disseminated histoplasmosis usually occurs in middle-aged to elderly men with no known condition causing immunosuppression.

Presentation is similar to acute disseminated histo­plasmosis except for the chronicity of symptoms; it can result in death if not treated. (5) Complications of pulmonary histoplasmosis include granulomatous mediastinitis characterized by persistently enlarged mediastinal lymph nodes and fibrosing mediastinitis in which an excessive fibrotic response to Histoplasma infection results in compromise of the great vessels.

B. Laboratory Findings Most patients with progressive pulmonary disease show anemia of chronic disease. Bone marrow involvement may be prominent in disseminated forms with occurrence of pancytopenia. Alkaline phosphatase and marked lactate dehydrogenase (LDH) and ferritin elevations are also common as are mild elevations of serum aspartate aminotransferase, although alanine aminotransferase is often normal.

With pulmonary involvement, sputum culture is rarely positive except in chronic disease; antigen testing of bronchoalveolar lavage fluid may be helpful in acute disease.

The combination of a urine and serum antigen assay has an 83% sensitivity for the diagnosis of acute pulmonary histoplasmosis. Blood or bone marrow cultures from immun­ ocompromised patients with acute disseminated disease are positive more than 80% of the time but may take several weeks for growth. The urine antigen assay has a sensitivity of > 90% for disseminated disease in immunocompromised patients and a declining titer can be used to follow response to therapy.

``Treatment For progressive localized disease and for mild to moderately severe nonmeningeal disseminated disease in immunocompetent or immunocompromised patients,

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itraconazole, 200–400 mg/d orally divided into two doses, is the treatment of choice with an overall response rate of approximately 80%. The oral solution is better absorbed than the capsule formulation, which requires gastric acid for absorption. Duration of therapy ranges from weeks to several months depending on the severity of illness.

Intravenous amphotericin B formulations are used in patients with more severe illness such as meningitis, with guidelines favoring the use of liposomal or lipid complex amphotericin formulations at a dose of 3 mg/kg/d over amphotericin B deoxycholate. Patients with AIDS-related histoplasmosis require lifelong suppressive therapy with itraconazole, 200–400 mg/d orally, although secondary prophylaxis may be discontinued if immune reconstitution occurs in response to antiretroviral therapy. There is no clear evidence that antifungal or anti-inflammatory agents are of benefit for patients with granulomatous mediastinitis or fibrosing mediastinitis although oral itraconazole is often used. Reported outcomes in patients with fibrosing mediastinitis treated with either surgical procedures or nonsurgical intravascular interventions appear to be relatively good.

Hage CA et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis. 2011 Sep;53(5):448–54.

[PMID: 21810734] Knox KS et al. Histoplasmosis. Proc Am Thorac Soc. 2010 May; 7(3):169–72. [PMID: 20463244] Peikert T et al. Fibrosing mediastinitis: clinical presentation, therapeutic outcomes, and adaptive immune response.

Medicine (Baltimore). 2011 Nov;90(6):412–23. [PMID: 22033450]

COCCIDIOIDOMYCOSIS

``

Essentials of diagnosis

Influenza-like illness with malaise, fever, backache, headache, and cough.

Erythema nodosum common with acute infection.

Dissemination may result in meningitis, bony lesions, or skin and soft tissue abscesses.

Chest radiograph findings vary from pneumonitis to cavitation.

Serologic tests useful; spherules containing endospores demonstrable in sputum or tissues.

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``General Considerations Coccidioidomycosis should be considered in the diagnosis of any obscure illness in a patient who has lived in or visited an endemic area.

Infection results from the inhalation of arthroconidia of Coccidioides immitis or C posadasii; both organisms are molds that grow in soil in certain arid regions of the southwestern United States, in Mexico, and in Central and South America.

Less than 1% of immunocompetent persons show dissemination, but among these patients, the mortality rate is high.

In HIV-infected people in endemic areas, coccidioidomycosis is a common opportunistic infection. In these patients, disease manifestations range from focal pulmonary infiltrates to widespread miliary disease with multiple organ involvement and meningitis; severity is inversely related to the extent of control of the HIV infection.

``Clinical Findings A. Symptoms and Signs Symptoms of primary coccidioidomycosis occur in about 40% of infections. Symptom onset (after an incubation period of 10–30 days) is usually that of a respiratory tract illness with fever and occasionally chills.

Coccidioidomycosis is a common, frequently unrecognized, etiology of community-acquired pneumonia in endemic areas.

Arthralgia accompanied by periarticular swelling, often of the knees and ankles, is common. Erythema nodosum may appear 2–20 days after onset of symptoms. Persistent pulmonary lesions, varying from cavities and abscesses to parenchymal nodular densities or bronchiectasis, occur in about 5% of diagnosed cases.

Disseminated disease occurs in about 0.1% of white and 1% of nonwhite patients. Filipinos and blacks are especially susceptible, as are pregnant women of all races. Any organ may be involved. Pulmonary findings usually become more pronounced, with mediastinal lymph node enlargement, cough, and increased sputum production. Lung abscesses may rupture into the pleural space, producing an empyema. These may also extend to bones and skin, and pericardial and myocardial involvement has been occasionally observed. Fungemia may occur and is characterized clinically by a diffuse miliary pattern on chest radiograph and by early death. The course may be particularly rapid in immunosuppressed patients. Clinicians caring for immunosuppressed patients in endemic areas need to consider that patients may be latently infected.

Meningitis occurs in 30–50% of cases of dissemination.

Subcutaneous abscesses and verrucous skin lesions are especially common in fulminating cases. Lymphadenitis may occur and may progress to suppuration. HIV-infected persons with disseminated disease have a higher incidence of miliary infiltrates, lymphadenopathy, and meningitis, but skin lesions are uncommon.

B. Laboratory Findings In primary coccidioidomycosis, there may be moderate leukocytosis and eosinophilia. Serologic testing is useful for both diagnosis and prognosis. The immunodiffusion tube precipitin test and enzyme-linked immunosorbent assay (ELISA) detect IgM antibodies and are both useful for diagnosis early in the disease process. Historically, a persistent rising IgG complement fixation titer (≥ 1:16) has been considered suggestive of disseminated disease; in addition, complement fixation titers can be used to assess the adequacy of therapy. Serum complement fixation titer may be

Mycotic Infections low when there is meningitis but no other disseminated disease. In patients with HIV-related coccidioidomycosis, the false-negative rate may be as high as 30%.

Demonstrable complement-fixing antibodies in spinal fluid are diagnostic of coccidioidal meningitis. These are found in over 90% of cases. Spinal fluid findings include increased cell count with lymphocytosis and reduced glucose. Spinal fluid culture is positive in approximately 30% of meningitis cases. Spherules filled with endospores may be found in biopsy specimens of soft tissues and bone; though they are not infectious, they convert to the highly contagious arthroconidia when grown in culture media.

Blood cultures are rarely positive.

C. Imaging Radiographic findings vary, but patchy, nodular pulmonary infiltrates and thin-walled cavities are most common.

Hilar lymphadenopathy may be visible and is seen in localized disease; mediastinal lymphadenopathy suggests dissemination. There may be pleural effusions and lytic lesions in bone with accompanying complicated soft-tissue collections.

``Treatment General symptomatic therapy is given as needed for disease limited to the chest with no evidence of progression. For progressive pulmonary or extrapulmonary disease, amphotericin B intravenously is used although oral azoles may be used for mild cases (see Chapter 30). Duration of therapy is determined by a declining complement fixation titer and a favorable clinical response. For meningitis, treatment usually is with high-dose oral fluconazole (400–800 mg/d, or higher) although lumbar or cisternal intrathecal administration of amphotericin B daily in increasing doses up to 1–1.5 mg/d is used initially by some physicians or in cases refractory to fluconazole. Systemic therapy with amphotericin B, 0.6 mg/kg/d intravenously, is generally given concurrently with intrathecal therapy but is not sufficient alone for the treatment of meningeal disease. Voriconazole or posaconazole may be alternatives to intrathecal amphotericin B in patients who do not respond to fluconazole.

Once the patient is clinically stable, oral therapy with an azole, usually with fluconazole (400 mg daily) and given lifelong, is the recommended alternative to intrathecal amphotericin B therapy.

Itraconazole, 400 mg orally daily divided into two doses, or fluconazole, 200–400 mg, or higher, orally once or twice daily should be given for disease in the chest, bones, and soft tissues; however, therapy must be continued for 6 months or longer after the disease is inactive to prevent relapse. In some patients with disease refractory to itraconazole or fluconazole, voriconazole or posaconazole may be beneficial. Response to therapy should be monitored by following the clinical response and progressive decrease in serum complement fixation titers.

Surgical drainage is necessary for management of soft tissue abscesses, necrotic bone and complicated pulmonary disease (eg, rupture of coccidioidal cavity).

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``Prognosis The prognosis for patients with limited disease is good, but persistent pulmonary cavities may cause complications such as hemoptysis or rupture producing pyopneumothorax. Nodules, cavities, and fibrotic residuals may rarely progress after long periods of stability or regression. Serial complement fixation titers should be performed after therapy for patients with coccidioidomycosis; rising titers warrant reinstitution of therapy because relapse is likely.

Late central nervous system complications of adequately treated meningitis include cerebral vasculitis and hydrocephalitis that may require shunting. Disseminated and meningeal forms still have mortality rates exceeding 50% in the absence of therapy.

Bercovitch RS et al. Coccidioidomycosis during pregnancy: a review and recommendations for management. Clin Infect Dis. 2011 Aug 15;53(4):363–8. [PMID: 21810749] Kim MM et al. Treatment of refractory coccidioidomycosis with voriconazole or posaconazole. Clin Infect Dis. 2011 Dec; 53(11):1060–6. [PMID: 22045955] Ruddy BE et al. Coccidioidomycosis in African Americans. Mayo Clin Proc. 2011 Jan;86(1):63–9. [PMID: 21193657] Taljanovic MS et al. Musculoskeletal coccidioidomycosis.

Semin Musculoskelet Radiol. 2011 Nov;15(5):511–26.

[PMID: 22081286]

PNEUMOCYSTOSIS (Pneumocystis jiroveci Pneumonia)

``

Essentials of diagnosis

Fever, dyspnea, nonproductive cough.

Bilateral diffuse interstitial disease without hilar adenopathy by chest radiograph.

Bibasilar crackles on auscultation in many cases; others have no findings.

Reduced partial pressure of oxygen.

P jiroveci in sputum, bronchoalveolar lavage fluid, or lung tissue.

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``General Considerations Pneumocystis jiroveci, the Pneumocystis species that affects humans, is distributed worldwide. Although symptomatic P jiroveci disease is rare in the general population, serologic evidence indicates that asymptomatic infections have occurred in most persons by a young age. The overt infection is an acute interstitial plasma cell pneumonia that occurs with high frequency among two groups: (1) as epidemics of primary infections among premature or debilitated or marasmic infants on hospital wards in underdeveloped parts of the world, and (2) as sporadic cases among older children and adults who have an abnormal or altered cellular immunity. Cases occur most commonly in patients with cancer or severe malnutrition and

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debility, in patients treated with immunosuppressive or cytotoxic drugs or irradiation for the management of organ transplants and cancer and, most frequently, in patients with AIDS (see Chapter 31).

The mode of transmission in primary infection is unknown, but the evidence suggests airborne transmission.

Following asymptomatic primary infection, latent and presumably inactive organisms are sparsely distributed in the alveoli. Whether acute disease in older children and adults results from de novo infection or from reactivation of latent infection is not entirely clear, although both mechanisms probably contribute.

Pneumocystis pneumonia occurs in up to 80% of AIDS patients not receiving prophylaxis and is a major cause of death. Its incidence increases in direct proportion to the fall in CD4 cells, with most cases occurring at CD4 cell counts < 200/mcL. In non-AIDS patients receiving immunosuppressive therapy, symptoms frequently begin after corticosteroids have been tapered or discontinued.

``Clinical Findings A. Symptoms and Signs Findings are usually limited to the pulmonary parenchyma; extrapulmonary disease is reported rarely. In the sporadic form of the disease associated with deficient cellmediated immunity, the onset is typically abrupt, with fever, tachypnea, shortness of breath, and usually nonproductive cough. Pulmonary physical findings may be slight and disproportionate to the degree of illness and the radiologic findings; many patients have bibasilar crackles, but others do not. Without treatment, the course is usually one of rapid deterioration and death. Adult patients may present with spontaneous pneumothorax, usually in patients with previous episodes or those receiving aerosolized pentamidine prophylaxis. Patients with AIDS will usually have other evidence of HIV-associated disease, including fever, fatigue, and weight loss, for weeks or months preceding the illness.

B. Laboratory Findings Chest radiographs most often show diffuse “interstitial” infiltration, which may be heterogeneous, miliary, or patchy early in infection. There may also be diffuse or focal consolidation, cystic changes, nodules, or cavitation within nodules. Pleural effusions are not seen. About 5–10% of patients with Pneumocystis pneumonia have normal chest films. High-resolution chest CT scans may be quite suggestive of P jiroveci pneumonia, helping distinguish it from other causes of pneumonia.

Arterial blood gas determinations usually show hypoxemia with hypocapnia but may be normal; however, rapid desaturation occurs if patients are exercised before samples are drawn. Isolated elevation or rising levels of serum LDH are very sensitive but not specific findings for P jiroveci.

Serologic tests are not helpful in diagnosis, but several studies have suggested that elevated (1→3)-β-D-glucan levels have reasonably good sensitivity and specificity for the diagnosis of Pneumocystis pneumonia. Specific

diagnosis depends on morphologic demonstration of the organisms in clinical specimens using specific stains. The organism cannot be cultured. Adequate specimens can sometimes be obtained with induced sputum by having patients inhale an aerosol of hypertonic saline (3%) produced by an ultrasonic nebulizer. Specimens are then stained with Giemsa stain or methenamine silver, either of which allows detection of cysts. The use of monoclonal antibody with immunofluorescence has increased the sensitivity of diagnosis. Alternative techniques for obtaining specimens include bronchoalveolar lavage (sensitivity 86–97%) followed by transbronchial lung biopsy (85–97%), if necessary. Open lung biopsy and needle lung biopsy are infrequently done but may need to be performed to dia­ gnose a granulomatous form of Pneumocystis pneumonia.

``Treatment See Table 31–5. It is appropriate to start empiric therapy for P jiroveci pneumonia if the disease is suspected clinically; however, in both AIDS patients and non-AIDS patients with mild to moderately severe disease, continued treatment should be based on a proved diagnosis because of clinical overlap with other infections, the toxicity of therapy, and the possible coexistence of other infectious organisms. Oral trimethoprim-sulfamethoxazole (TMP-SMZ) is the preferred agent because of its low cost and excellent bioavailability in both AIDS patients and non-AIDS patients with mild to moderately severe disease. Patients suffering from nausea and vomiting or intractable diarrhea should be given intravenous TMP-SMZ until they can tolerate the oral formulation. The impact of resistance of Pneumocystis to TMP-SMZ is unclear, although increasing rates of mutations in the DHFR gene that mediate TMPSMZ resistance have been reported. The best-studied second-line option is a combination of primaquine and clindamycin, although dapsone/trimethoprim, pentamidine, and atovaquone have also been used. Therapy should be continued with the selected drug for at least 5–10 days before considering changing agents, as fever, tachypnea, and pulmonary infiltrates persist for 4–6 days after starting treatment. Some patients have a transient worsening of their disease during the first 3–5 days, which may be related to an inflammatory response secondary to the presence of dead or dying organisms. Early addition of corticosteroids may attenuate this response (see Chapter 31).

Some clinicians prefer to treat episodes of AIDS-associated Pneumocystis pneumonia for 21 days rather than the usual 14 days recommended for non-AIDS cases.

A. Trimethoprim-Sulfamethoxazole The dosage of TMP/SMZ is 15–20 mg/kg/d (based on trimethoprim component) given orally or intravenously daily in three or four divided doses for 14–21 days.

Patients with AIDS have a high frequency of hypersensitivity reactions (approaching 50%), which may include fever, rashes (sometimes severe), malaise, neutropenia, hepatitis, nephritis, thrombocytopenia, hyperkalemia, and hyperbilirubinemia.

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B. Primaquine/Clindamycin

``Prevention

Although there are strong data indicating that trimethoprimsulfamethoxazole is optimal first-line therapy for Pneumocystis pneumonia, the data on alternative agents is less clear. A meta-analysis suggested that primaquine, 15–30 mg/d, plus clindamycin, 600 mg three times daily, is the best second-line therapy with superior results when compared with pentamidine. Primaquine may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD)-deficiency.

Primary prophylaxis for Pneumocystis pneumonia in HIVinfected patients should be given to persons with CD4 counts < 200 cells/mcL, a CD4 percentage below 14%, or weight loss or oral candidiasis (see Table 31–4). Primary prophylaxis is often used in patients with hematologic malignancy and transplant recipients, although the clinical characteristics of persons with these conditions who would benefit from Pneumocystis prophylaxis have not been clearly defined. Patients with a history of Pneumocystis pneumonia should receive secondary prophylaxis until they have had a durable virologic response to antiretroviral therapy for at least 3–6 months and maintain a CD4 count of > 200 cells/mcL.

C. Pentamidine Isethionate The use of pentamidine has decreased as alternative agents have been studied. This drug is administered intravenously (preferred) or intramuscularly as a single dose of 3–4 mg (salt)/kg/d for 14–21 days. Pentamidine causes side effects in nearly 50% of patients. Hypoglycemia (often clinically inapparent), hyperglycemia, hyponatremia, and delayed nephrotoxicity with azotemia may occur. Rarely, a variety of other severe adverse reactions may occur, including anemia, thrombocytopenia, ventricular arrhythmias, and fatal pancreatitis. Blood glucose levels should be monitored.

Inadvertent rapid intravenous infusion may cause precipitous hypotension.

D. Atovaquone Atovaquone is approved by the US Food and Drug Administration (FDA) for patients with mild to moderate disease who cannot tolerate TMP-SMZ or pentamidine, but failure is reported in 15–30% of cases. Mild side effects are common, but no serious reactions have been reported.

The dosage is 750 mg three times daily for 21 days.

Atovaquone should be administered with a fatty meal.

E. Other Drugs Trimethoprim, 15 mg/kg/d in three divided doses daily, plus dapsone, 100 mg/d, is an alternative oral regimen for mild to moderate disease or for continuation of therapy after intravenous therapy is no longer needed.

F. Prednisone Based on studies done in patients with AIDS, prednisone is given for moderate to severe pneumonia (when Pao2 on admission is < 70 mm Hg or oxygen saturation is < 90%) in conjunction with antimicrobials. The dosage of prednisone is 40 mg twice daily orally for 5 days, then 40 mg daily for 5 days, and then 20 mg daily until therapy is completed.

The role of prednisone in non-AIDS patients is unclear, especially in patients in whom symptoms developed following tapering doses of corticosteroids.

``Prognosis In the absence of early and adequate treatment, the fatality rate for the endemic infantile form of Pneumocystis pneumonia is 20–50%; for the sporadic form in immunodeficient persons, the fatality rate is nearly 100%. Early treatment reduces the mortality rate to about 3% in the former and 10–20% in AIDS patients. The mortality rate in other immunodeficient patients is still 30–50%, probably because of failure to make a timely diagnosis. In immunodeficient patients who do not receive prophylaxis, recurrences are common (30% in AIDS).

Huang L et al; International HIV-associated Opportunistic Pneumonias (IHOP) Study; Lung HIV Study. HIV-associated Pneumocystis pneumonia. Proc Am Thorac Soc. 2011 Jun; 8(3):294–300. [PMID: 21653531] Sax PE et al; AIDS Clinical Trials Group Study A5164 Team.

Blood (1→3)-β-D-glucan as a diagnostic test for HIV-related Pneumocystis jirovecii pneumonia. Clin Infect Dis. 2011 Jul 15;53(2):197–202. [PMID: 21690628]

CRYPTOCOCCOSIS

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G. Supportive Care Oxygen therapy is indicated to maintain the oxygen saturation over 90% by pulse oximetry.

Most common cause of fungal meningitis.

Predisposing factors: Hematologic cancer chemotherapy, Hodgkin disease, corticosteroid therapy, transplant recipients, TNF inhibitor therapy, HIV infection.

Symptoms of headache, abnormal mental status; meningismus seen occasionally, though rarely in HIV-infected patients.

Demonstration of capsular polysaccharide antigen in cerebrospinal fluid is diagnostic; 95% of HIVinfected and solid-organ transplant patients also have a positive serum antigen.

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Essentials of diagnosis

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``General Considerations Cryptococcosis is mainly caused by Cryptococcus neoformans, an encapsulated budding yeast that has been found worldwide in soil and on dried pigeon dung.

C gattii is a closely related species that also causes disease in humans although C gattii may affect more immunocompetent persons. It has been emerging as a major cause of cryptococcosis in the Pacific Northwestern region of the United States and may result in more severe disease than C neoformans.

Infections are acquired by inhalation. In the lung, the infection may remain localized, heal, or disseminate.

Clinically apparent cryptococcal pneumonia rarely develops in immunocompetent persons, except in those individuals infected by C gattii. Progressive lung disease and dissemination most often occur in the setting of cellular immunodeficiency, including underlying hematologic cancer under treatment, Hodgkin disease, long-term corticosteroid therapy, solid-organ transplant, TNF-inhibitor therapy, or HIV infection.

``Clinical Findings A. Symptoms and Signs Pulmonary disease ranges from simple nodules to widespread infiltrates leading to respiratory failure.

Disseminated disease may involve any organ, but central nervous system disease predominates. Headache is usually the first symptom of meningitis. Confusion and other mental status changes as well as cranial nerve abnormalities, nausea, and vomiting may be seen as the disease progresses. Nuchal rigidity and meningeal signs occur about 50% of the time but are uncommon in HIVinfected patients. Communicating hydrocephalus may complicate the course. C gattii infection frequently presents with neurologic signs caused by space-occupying lesions. Primary C neoformans infection of the skin may mimic bacterial cellulitis, especially in immunocompromised persons. Clinical worsening associated with improved immunologic status has been reported in HIVpositive and transplant patients with cryptococcosis; this entity has been labeled the immune reconstitution inflammatory syndrome (IRIS).

B. Laboratory Findings Respiratory tract disease is diagnosed by culture of respiratory secretions or pleural fluid. For suspected meningeal disease, lumbar puncture is the preferred diagnostic procedure. Spinal fluid findings include increased opening pressure, variable pleocytosis, increased protein, and decreased glucose, though as many as 50% of AIDS patients have no pleocytosis. Gram stain of the cerebrospinal fluid usually reveals budding, encapsulated fungal cells. Cryptococcal capsular antigen in cerebrospinal fluid and culture together establish the diagnosis over 90% of the time. Patients with AIDS often have the antigen in both cerebrospinal fluid and serum, and extrameningeal disease (lungs, blood, urinary tract) is common. In patients with AIDS, the serum

cryptococcal antigen is also a sensitive screening test for meningitis, being positive in over 95% of cases. MRI is more sensitive than CT in finding central nervous system abnormalities such as cryptococcomas.

``Treatment Because of decreased efficacy, initial therapy with an azole alone is not recommended for treatment of acute cryptococcal meningitis. Consequently, amphotericin B, 0.7–1 mg/kg/d intravenously is used for 14 days, followed by an additional 8 weeks of fluconazole, 400 mg/d orally. This regimen has been quite effective, achieving clinical responses and cerebrospinal fluid sterilization in about 70% of patients. Lipid amphotericin B preparations (eg, liposomal amphotericin B, 3–4 mg/kg/d) have equivalent efficacy to conventional amphotericin B with reduced nephrotoxicity. The addition of flucytosine has been associated with improved survival, but toxicity is common.

Flucytosine is administered orally at a dose of 100 mg/kg/d divided into four equal doses and given every 6 hours.

Hematologic parameters should be closely monitored during flucytosine therapy, and it is important to adjust the dose for any decreases in renal function. Fluconazole (800–1200 mg orally daily) may be given with amphotericin B when flucytosine is not available or patients cannot tolerate it. Frequent, repeated lumbar punctures or ventricular shunting should be performed to relieve high cerebrospinal fluid pressures or if hydrocephalus is a complication. Failure to adequately relieve raised intracranial pressure is a major cause of morbidity and mortality. The end points for amphotericin B therapy and for switching to oral fluconazole are a favorable clinical response (decrease in temperature; improvement in headache, nausea, vomiting, and mini-mental status scores), improvement in cerebrospinal fluid biochemical parameters and, most importantly, conversion of cerebrospinal fluid culture to negative.

A similar approach is reasonable for patients with cryptococcal meningitis in the absence of AIDS, though the mortality rate is considerably higher. Therapy is generally continued until cerebrospinal fluid cultures become negative. Maintenance antifungal therapy is important after treatment of an acute episode in HIV-related cases, since otherwise the rate of relapse is > 50%. Fluconazole, 200 mg/d orally, is the maintenance therapy of choice, decreasing the relapse rate approximately tenfold compared with placebo and threefold compared with weekly amphotericin B in patients whose cerebrospinal fluid has been sterilized by the induction therapy. After successful therapy of cryptococcal meningitis, it is possible to discontinue secondary prophylaxis with fluconazole in individuals with AIDS who have had a satisfactory response to antiretroviral therapy (eg, CD4 cell count > 100–200 cells/ mcL for at least 6 months). Among practitioners treating patients without AIDS, there has been a trend in recent years to prescribe a course (eg, 6–12 months) of fluconazole as maintenance therapy following successful treatment of the acute illness; recently published guidelines suggest this as an option.

Mycotic Infections

``Prognosis Factors that indicate a poor prognosis include the activity of the predisposing conditions, older age, organ failure, lack of spinal fluid pleocytosis, high initial antigen titer in either serum or cerebrospinal fluid, decreased mental status, increased intracranial pressure, and the presence of disease outside the nervous system.

Harris JR. Cryptococcus gattii in the United States: clinical aspects of infection with an emerging pathogen. Clin Infect Dis. 2011 Dec;53(12):1188–95. [PMID: 22016503] Loyse A et al. Comparisons of the early fungicidal activity of high-dose fluconazole, voriconazole and flucytosine as second line drugs given in combination with amphotericin B for the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis. 2012 Jan;54(1):121–8. [PMID: 22052885] Perfect JR et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291–322. [PMID: 20047480]

ASPERGILLOSIS

``

Essentials of diagnosis

Most common cause of non-candidal invasive fungal infection in stem cell or organ transplant patients.

Predisposing factors: leukemia, bone marrow or organ transplant, late HIV infection.

Pulmonary, sinus, and CNS are most common disease sites.

Demonstration of galactomannan or β-D-glucan in serum or other body fluid samples is useful for early diagnosis and treatment.

``

``

``

``

``General Considerations Aspergillus fumigatus is the usual cause of aspergillosis, though many species of Aspergillus may cause a wide spectrum of disease. The lungs, sinuses, and brain are the organs most often involved. Clinical illness results either from an aberrant immunologic response or tissue invasion.

``Clinical Findings A. Allergic Bronchopulmonary Aspergillosis This form of aspergillosis occurs in patients with preexisting asthma who develop worsening bronchospasm and fleeting pulmonary infiltrates accompanied by eosinophilia, high levels of IgE, and IgG Aspergillus precipitins in the blood. It also may complicate cystic fibrosis.

B. Invasive Aspergillosis Invasive manifestations may be seen in immunocompetent or only mildly immunocompromised adults. These include

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chronic sinusitis, colonization of preexisting pulmonary cavities (aspergilloma), and chronic necrotizing pulmonary aspergillosis.

1. Sinusitis—Sinus involvement is usually diagnosed histologically after patients with chronic sinus disease undergo surgery.

2. Aspergillomas—Aspergillomas of the lung occur when preexisting lung cavities become secondarily colonized with Aspergillus species. These may be found by incidental radiographic studies but may also present with significant hemoptysis.

3. Chronic necrotizing aspergillosis—This invasive manifestation is a relatively rare disease seen in patients with some degree of immunocompromise and presents with a protracted course compared with the more common acute invasive form of the disease. Fibrosis and cavity formation may be prominent.

4. Life-threatening invasive aspergillosis—Severe invasive aspergillosis most commonly occurs in profoundly immunodeficient patients, particularly in patients who have undergone hematopoietic stem cell transplants; in those with prolonged, severe neutropenia; and in patients with chronic granulomatous disease. Specific risk factors in patients who have undergone a hematopoietic stem cell transplant include cytopenias, corticosteroid use, iron overload, cytomegalovirus disease, and graft-versus-host disease. Pulmonary disease is most common, with patchy infiltration leading to a severe necrotizing pneumonia.

Invasive sinus disease also occurs. There is often tissue infarction as the organism grows into blood vessels; clues to this are the development of pleuritic chest pain and elevation of serum LDH. At any time, there may be hematogenous dissemination to the central nervous system, skin, and other organs. Early diagnosis and reversal of any correctable immunosuppression are essential. Blood cultures have very low yield. Detection of galactomannan by ELISA or β-Dglucan, or both, has been used for the early diagnosis of invasive disease, though multiple determinations should be done. Higher galactomannan levels are correlated with increased mortality. False-positive galactomannan tests have been reported in patients receiving β-lactam antibiotics. Isolation of Aspergillus from pulmonary secretions does not necessarily imply invasive disease, although its positive predictive value increases with more advanced immunosuppression. Therefore, a definitive diagnosis requires demonstration of Aspergillus in tissue or culture from a sterile site. CT scan of the chest may show characteristics quite suggestive of invasive aspergillosis (eg, “halo sign”).

``Prevention The high mortality rate and difficulty in diagnosis of invasive aspergillosis often leads clinicians to institute prophylactic therapy for patients with profound immunosuppression.

The best-studied agents include fluconazole, itraconazole, voriconazole, and posaconazole, although patient and agent selection criteria remain undefined. Widespread use of broad-spectrum azoles raises concern for development of invasive disease by highly resistant fungi.

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``Treatment

MUCORMYCOSIS

A. Allergic Bronchopulmonary Aspergillosis

The term “mucormycosis” (zygomycosis, phycomycosis) is applied to opportunistic infections caused by members of the genera Rhizopus, Mucor, Absidia, and Cunninghamella.

Predisposing conditions include hematologic malignancy, stem cell transplantation, solid organ transplantation, diabetic ketoacidosis, chronic kidney disease, desferoxamine therapy, and treatment with corticosteroids or cytotoxic drugs. These organisms appear in tissues as broad, branching nonseptate hyphae. Biopsy with histologic examination is almost always required for diagnosis; cultures are frequently negative. Invasive disease of the sinuses, orbits, and the lungs may occur. Widely disseminated disease is seen in patients who have received aggressive chemotherapy and broad-spectrum antifungal prophylaxis. A prolonged course of a lipid preparation of amphotericin B should be started early. Based on in vitro susceptibility and reports of successful salvage therapy, there may be a role for posaconazole in the treatment of these infections following control of acute infection by amphotericin. Other azoles are not effective. There are limited data suggesting beneficial synergistic activity when amphotericin and caspofungin are used in combination for mucormycosis. Despite favorable animal studies, a recent pilot study in humans incorporating adjunctive iron chelation therapy with deferasirox demonstrated a higher mortality rate than antifungal therapy alone. Control of diabetes and other underlying conditions, along with extensive repeated surgical removal of necrotic, nonperfused tissue, is essential. Even when these measures are introduced in a timely fashion, the prognosis is poor, with a 30–50% mortality rate for localized disease and higher rates in disseminated cases.

For acute exacerbations, oral prednisone is begun at a dose of 1 mg/kg/d and then tapered slowly over several months.

Itraconazole at a dose of 200 mg daily for 16 weeks appears to improve pulmonary function and decrease corticosteroid requirements in these patients, although voriconazole may become the preferred oral agent. Some patients treated with the anti-IgE monoclonal antibody omalizumab have shown improvement in respiratory symptoms and lung function.

B. Invasive Aspergillosis 1. Sinusitis—These patients may require protracted courses of antifungals (itraconazole, 200 mg twice daily, for weeks to months) in addition to the surgical debridement.

2. Aspergilloma—The most effective therapy for symptomatic aspergilloma remains surgical resection.

3. Chronic necrotizing aspergillosis—Guidelines suggest some benefits from prolonged oral voriconazole (200 mg twice daily) or itraconazole (200 mg twice daily) therapy.

4. Life-threatening invasive aspergillosis—When severe invasive aspergillosis is considered clinically likely or is demonstrable by laboratory testing, rapid institution of voriconazole, high doses of liposomal amphotericin B (3–5 mg/kg/d), or caspofungin may be life-saving. Voriconazole (6 mg/kg intravenously twice on day 1, then 4 mg/kg/d thereafter) has been shown to be more effective, improve survival, and be associated with fewer severe side effects than conventional amphotericin B when used as initial therapy in invasive aspergillosis. Oral dosing of voriconazole at 4 mg/kg twice daily can be used for less serious infections or as a stepdown strategy after intravenous therapy.

Caspofungin (70 mg intravenously on day 1, then 50 mg/d thereafter) is approved for the treatment of invasive aspergillosis in patients who do not respond to or are intolerant of other treatments. Other options include micafungin (100–150 mg/d intravenously) and posaconazole (200 mg orally four times daily). In critically ill patients who are not responding to conventional antifungal treatment, there may be a role for the addition of caspofungin to liposomal amphotericin B or voriconazole therapy, although randomized trials are lacking. Surgical debridement is generally done for sinusitis, and there is increasing data regarding resection of focal pulmonary lesions, especially for treatment of life-threatening hemoptysis. The mortality rate of pulmonary or disseminated disease in the immunocompromised patient remains well above 50%, particularly in patients with refractory neutropenia.

Knutsen AP et al. Allergic bronchopulmonary aspergillosis in asthma and cystic fibrosis. Clin Dev Immunol. 2011;2011: 843763. [PMID: 21603163] Kousha M et al. Pulmonary aspergillosis: a clinical review. Eur Respir Rev. 2011 Sep 1;20(121):156–74. [PMID: 21881144] Traunmüller F et al. Efficacy and safety of current drug therapies for invasive aspergillosis. Pharmacology. 2011;88(3–4): 213–24. [PMID: 21986253]

Kontoyiannis DP et al. How I treat mucormycosis. Blood. 2011 Aug;118(5):1216–24. [PMID: 21622653] Spellberg B et al. The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial. J Antimicrob Chemother.

2012 Mar;67(3):715–22. [PMID: 21937481] Sun HY. Mucormycosis: its contemporary face and management strategies. Lancet Infect Dis. 2011 Apr;11(4):301–11. [PMID: 21453871]

BLASTOMYCOSIS Blastomycosis occurs most often in men infected during occupational or recreational activities out of doors and in a geographically limited area of the south central and midwestern United States and Canada. Disease usually occurs in immunocompetent individuals.

Chronic pulmonary infection is most common and may be asymptomatic. When dissemination takes place, lesions are most frequently seen in the skin, bones, and urogenital system.

Cough, moderate fever, dyspnea, and chest pain are common. These may resolve or progress, with purulent sputum production, pleurisy, fever, chills, loss of weight, and prostration. Radiologic studies, either chest radiographs or CT scans, usually reveal airspace consolidation or masses.

Mycotic Infections Raised, verrucous cutaneous lesions are commonly present in disseminated blastomycosis. Bones—often the ribs and vertebrae—are frequently involved. Epididymitis, prostatitis, and other involvement of the male urogenital system may occur. Although they do not appear to be at greater risk for acquisition of disease, infection in HIVinfected persons may progress rapidly, with dissemination common.

Laboratory findings usually include leukocytosis and anemia, though these are not specific. The organism is found in clinical specimens, such as expectorated sputum or tissue biopsies, as a thick-walled cell 5–20 mcm in diameter that may have a single broad-based bud. It grows readily on culture. Serologic tests are not well standardized. A urinary antigen test is available, but it has considerable cross reactivity with Histoplasma; consequently, its usefulness in diagnosis and in assessing response to therapy is unclear.

Itraconazole, 200–400 mg/d orally for at least 2–3 months, is the therapy of choice for nonmeningeal disease, with a response rate of over 80%. Amphotericin B, 0.7–1.0 mg/kg/d intravenously (or lipid formulation amphotericin B), is given for severe disease, treatment failures, or central nervous system involvement.

Clinical follow-up for relapse should be made regularly for several years so that therapy may be resumed or another drug instituted.

Bariola JR et al. Detection of Blastomyces dermatitidis antigen in patients with newly diagnosed blastomycosis. Diagn Microbiol Infect Dis. 2011 Feb;69(2):187–91. [PMID: 21251563] Saccente M et al. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010 Apr;23(2):367–81. [PMID: 20375357]

PARACOCCIDIOIDOMYCOSIS (South American Blastomycosis) Paracoccidioides brasiliensis infections have been found only in patients who have resided in South or Central America or Mexico. Long asymptomatic periods enable patients to travel far from the endemic areas before developing clinical problems. Weight loss, pulmonary complaints, or mucosal ulcerations are the most common symptoms. Cutaneous papules may ulcerate and enlarge both peripherally and deeper into the subcutaneous tissue.

Differential diagnosis includes mucocutaneous leishmaniasis and syphilis. Extensive coalescent ulcerations may eventually result in destruction of the epiglottis, vocal cords, and uvula. Extension to the lips and face may occur.

Eating and drinking are extremely painful. Skin lesions may occur, usually on the face. Variable in appearance, they may have a necrotic central crater with a hard hyperkeratotic border. Lymph node enlargement may follow mucocutaneous lesions, eventually ulcerating and forming draining sinuses; in some patients, it is the presenting symptom. Hepatosplenomegaly may be present as well.

HIV-infected patients with paracoccidioidomycosis are more likely to have extra-pulmonary dissemination and a more rapid clinical disease course.

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Laboratory findings are nonspecific. Serology by immunodiffusion is positive in 98% of cases. Complement fixation titers correlate with progressive disease and fall with effective therapy. The fungus is found in clinical specimens as a spherical cell that may have many buds arising from it.

If direct examination of secretions does not reveal the organism, biopsy with Gomori staining may be helpful.

Itraconazole, 100 mg twice daily orally, is the treatment of choice and generally results in a clinical response within 1 month and effective control after 2–6 months. Voriconazole, 200 mg twice daily orally, appears to be as effective as itraconazole. Amphotericin B intravenously is the drug of choice for severe and life-threatening infection.

Ameen M et al. Advances in paracoccidioidomycosis. Clin Exp Dermatol. 2010 Aug;35(6):576–80. [PMID: 19874328] Bellissimo-Rodrigues F et al. Paracoccidioidomycosis epidemiological features of a 1,000-cases series from a hyperendemic area on the southeast of Brazil. Am J Trop Med Hyg. 2011 Sep;85(3):546–50. [PMID: 21896820]

SPOROTRICHOSIS Sporotrichosis is a chronic fungal infection caused by Sporothrix schenckii. It is worldwide in distribution; most patients have had contact with soil, sphagnum moss, or decaying wood. Transmission from animals to humans has also been reported. Infection takes place when the organism is inoculated into the skin—usually on the hand, arm, or foot, especially during gardening.

The most common form of sporotrichosis begins with a hard, nontender subcutaneous nodule. This later becomes adherent to the overlying skin and ulcerates. Within a few days to weeks, similar nodules develop along the lymphatics draining this area, and these may ulcerate as well.

Disseminated sporotrichosis is rare in the immunocompetent person but may present with widespread cutaneous, lung, bone, joint, and central nervous system involvement in immunocompromised patients, especially those with AIDS and alcohol abuse.

Cultures are needed to establish diagnosis. Antibody tests may be useful for diagnosis of disseminated disease, especially meningitis.

Itraconazole, 200–400 mg orally daily for several months, is the treatment of choice for localized disease and some milder cases of disseminated disease. Terbinafine, 500 mg orally twice daily, also appears to have good efficacy in lymphocutaneous disease. Amphotericin B intravenously, 1–2 g, is used for severe systemic infection. Surgery is usually contraindicated except for simple aspiration of secondary nodules. Joint involvement may require arthrodesis.

The prognosis is good for lymphocutaneous sporotrichosis; pulmonary, joint, and disseminated disease respond less favorably. de Lima Barros MB et al. Sporothrix schenckii and sporotrichosis. Clin Microbiol Rev. 2011 Oct;24(4):633–54. [PMID: 21976602] de Lima Barros MB et al. Treatment of cutaneous sporotrichosis with itraconazole—study of 645 patients. Clin Infect Dis. 2011 Jun 15;52(12):e200–6. [PMID: 21628477]

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Penicillium Marneffei INFECTIONS Penicillium marneffei is a dimorphic fungus, endemic in southeast Asia, that causes systemic infection in both healthy and immunocompromised hosts. There have been reports of travelers with advanced AIDS returning from southeast Asia with disseminated infection. Clinical manifestations include fever, generalized umbilicated papular rash, lymphadenopathy, cough, and diarrhea. Central nervous system infection has been reported. Diagnosis is made by identification of the organism on smears or histopathologic specimens or by culture, where the fungus produces a characteristic red pigment. The best sites for isolation of the fungus include the skin, blood, bone marrow, respiratory tract, and lymph nodes. Antigen and antibody tests have been developed in endemic regions. Patients with mild to moderate infection can be treated with itraconazole, 400 mg divided into two doses daily by mouth for 8 weeks.

Amphotericin B, 0.5–0.7 mg/kg/d intravenously, is the drug of choice for severe disease and should be continued until patients have had a satisfactory clinical response, at which time they can be switched to itraconazole. Because the relapse rate after successful treatment is 30%, maintenance therapy with itraconazole, 200–400 mg daily orally, is indicated indefinitely, or until immune reconstitution occurs.

Wong SY et al. Penicillium marneffei infection in AIDS. Patholog Res Int. 2011 Feb 10;2011:764293. [PMID: 21331327]

CHROMOBLASTOMYCOSIS (Chromomycosis) Chromoblastomycosis is a chronic, principally tropical cutaneous infection usually affecting young men who are agricultural workers and caused by several species of closely related black molds; Cladophialophora carrionii and Fonsecaea pedrosoi are the most common etiologic agents.

Lesions usually follow puncture wounds and are slowly progressive, occurring most frequently on a lower extremity. The lesion begins as a papule or ulcer. Over months to years, papules enlarge to become vegetating, papillomatous, verrucous elevated nodules. Satellite lesions may appear along the lymphatics. There may be secondary bacterial infection. Elephantiasis may result.

The fungus is seen as brown, thick-walled, spherical, sometimes septate cells in potassium hydroxide preparations of pus or skin scrapings, which are quite sensitive for diagnosis. The type of reproduction found in culture determines the species.

Itraconazole, 200–400 mg/d orally for 6–18 months, achieves a response rate of 65%. Terbinafine at 500–1000 mg/d orally may have similar efficacy to itraconazole and may be useful in combination, especially in difficult to treat cases. Cryosurgery alone for smaller lesions or combined with itraconazole for larger lesions is beneficial.

Ameen M. Managing chromoblastomycosis. Trop Doct. 2010 Apr;40(2):65–7. [PMID: 20305094] Queiroz-Telles F et al. Chromoblastomycosis: an overview of clinical manifestations, diagnosis and treatment. Med Mycol.

2009 Feb;47(1):3–15. [PMID: 19085206]

MYCETOMA (Maduromycosis & Actinomycetoma) Mycetoma is a chronic local, slowly progressive destructive infection, usually involving the foot, that begins in subcutaneous tissues, frequently after localized trauma, and then spreads to contiguous structures. Maduromycosis (also known as eumycetoma) is the term used to describe mycetoma caused by the true fungi and by phylogenetically diverse organisms. Actinomycotic mycetoma is caused by Nocardia and Actinomadura species. The disease begins as a papule, nodule, or abscess that over months to years progresses slowly to form multiple abscesses and sinus tracts ramifying deep into the tissue. Secondary bacterial infection may result in large open ulcers. Radiographs may show destructive changes in the underlying bone. Tissue Gram stain reveals fine branching hyphae with actinomycotic mycetoma. Larger hyphae are seen with fungal mycetoma; the causative species can often be identified by the color of the characteristic grains within the infected tissues.

The prognosis is good for patients with actinomycetoma, since they usually respond well to sulfonamides and sulfones, especially if treated early. TMP-SMZ, 160/800 mg orally twice a day, or dapsone, 100 mg twice daily after meals, has been reported to be effective. Streptomycin, 14 mg/kg/d intramuscularly, may be useful during the first month of therapy. All oral medications must be taken for months and continued for several months after clinical cure to prevent relapse. Debridement assists healing.

The prognosis for maduromycosis is poor, though surgical debridement along with prolonged itraconazole therapy may result in a response rate of 70%. The various etiologic agents may respond differently to antifungal agents, so culture results are invaluable. Amputation is necessary in far advanced cases.

Garnica M et al. Difficult mycoses of the skin: advances in the epidemiology and management of eumycetoma, phaeohyphomycosis and chromoblastomycosis. Curr Opin Infect Dis. 2009 Dec;22(6):559–63. [PMID: 19773651]

OTHER OPPORTUNISTIC MOLD INFECTIONS Fungi previously considered to be harmless colonizers, including Pseudallescheria boydii (Scedosporium apiospermum), Scedosporium prolificans, Fusarium, Paecilomyces, Trichoderma longibrachiatium, and Trichosporon, are emerging as significant pathogens in immunocompromised patients. This occurs most often in patients being treated for hematopoietic malignancies and in those receiving broad-spectrum antifungal prophylaxis. Infection may be localized in the skin, lungs, or sinuses, or widespread disease may appear with lesions in multiple organs.

Fusariosis should be suspected in severely immunosuppressed persons in whom multiple, painful skin lesions develop; blood cultures are often positive. Sinus infection may cause bony erosion. Infection in subcutaneous tissues following traumatic implantation may develop as a wellcircumscribed cyst or as an ulcer.

Nonpigmented septate hyphae are seen in tissue and are indistinguishable from those of Aspergillus when infections

Mycotic Infections are due to S apiospermum or species of Fusarium, Paecilomyces, Penicillium, or other hyaline molds. Spores or mycetoma-like granules are rarely present in tissue. The differentiation of S apiospermum and Aspergillus is particularly important, since the former is uniformly resistant to amphotericin B but may be sensitive to azole antifungals (eg, voriconazole). Infection by any of a number of black molds is designated as phaeohyphomycosis. These black molds (eg, Exophiala, Bipolaris, Cladophialophora, Curvularia, Alternaria) are common in the environment, especially on decaying vegetation. Human disease due to these agents is rarely encountered but may result in soft tissue abscesses due to traumatic inoculation or may occur as a sequela of chronic sinusitis or profound immunosuppression. In tissues of patients with phaeohyphomycosis, the mold is seen as black or faintly brown hyphae, yeast cells, or both. Culture on appropriate medium is needed to identify the agent. Histologic demonstration of these organisms is definitive evidence of invasive infection; positive cultures must be interpreted cautiously and not

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assumed to be contaminants in immunocompromised hosts. Some isolates are sensitive to antifungal agents.

Ben-Ami R et al. Phaeohyphomycosis in a tertiary care center. Clin Infect Dis. 2009 Apr 15;48(8):1033–41. [PMID: 19267655] Campo M et al. Invasive fusariosis in patients with hematologic malignancies at a cancer center: 1998–2009. J Infect. 2010 May;60(5):331–7. [PMID: 20138081] Revankar SG et al. Melanized fungi in human disease. Clin Microbiol Rev. 2010 Oct;23(4):884–928. [PMID: 20930077]

ANTIFUNGAL THERAPY Table 36–1 summarizes the major properties of currently available antifungal agents. Two different lipid-based amphotericin B formulations are used to treat systemic candidiasis, invasive aspergillosis and other disseminated mold infections, disseminated histoplasmosis, and

Table 36–1. Agents for systemic mycoses.

Renal Clearance?

CSF Penetration?

Drug

Dosing

Toxicities

Spectrum of Activity

Amphotericin B

0.3–1.5 mg/kg/d intravenously

No

Poor

Rigors, fever, azotemia, hypokalemia, hypomagnesemia, renal tubular acidosis, anemia

All major pathogens except Scedosporium

Amphotericin B lipid complex

5 mg/kg/d intravenously

No

Poor

Fever, rigors, nausea, hypotension, anemia, azotemia, tachypnea

Same as amphotericin B, above

Amphotericin B, liposomal

3–6 mg/kg/d intravenously

No

Poor

Fever, rigors, nausea, hypotension, azotemia, anemia, tachypnea, chest tightness

Same as amphotericin B, above

Anidulafungin

100 mg intravenous loading dose, followed by 50 mg/d intravenously in one dose

< 1%

Poor

Diarrhea, hepatic enzyme elevations, histaminemediated reactions

Mucosal and invasive candidiasis

Caspofungin acetate

70 mg intravenous loading dose, followed by 50 mg/d intravenously in one dose

< 50%1

Poor

Transient neutropenia; hepatic enzyme elevations when used with cyclosporine

Aspergillosis, mucosal and invasive candidiasis, empiric antifungal therapy in febrile neutropenia

Fluconazole

100–800 mg/d in one or two doses intravenously or orally

Yes

Yes

Nausea, rash, alopecia, headache, hepatic enzyme elevations

Mucosal candidiasis (including urinary tract), cryptococcosis, histoplasmosis, coccidioidomycosis

Flucytosine (5-FC)

100–150 mg/kg/d orally in four divided doses

Yes

Yes

Leukopenia,2 rash, diarrhea, hepatitis, nausea, vomiting

Cryptococcosis,3 candidiasis,3 chromomycosis

Itraconazole

100–400 mg/d orally in one or two doses with a meal or carbonated beverage

No

Variable

Nausea, hypokalemia, edema, hypertension, peripheral neuropathy

Histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioidomycosis, mucosal candidiasis (except urinary), sporotrichosis, aspergillosis, chromomycosis (continued )

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Table 36–1. Agents for systemic mycoses. (continued) Drug

Dosing

Renal Clearance?

CSF Penetration?

Poor

Toxicities

Spectrum of Activity

Anorexia, nausea, suppression of Nonmeningeal histoplasmosis and coccidioidomycosis, testosterone and cortisol, blastomycosis, paracoccidio­ rash, headache, hepatic idomycosis, mucosal enzyme elevations, hepatic candidiasis (except urinary) failure Rash, rigors, headache, Mucosal and invasive candidiphlebitis asis, prophylaxis in hematopoietic stem cell transplantation

Ketoconazole

200–800 mg/d orally in one or two doses with a meal or carbonated beverage

No

Micafungin sodium

150 mg intravenously in one dose (treatment) 50 mg (prophylaxis)

No

Poor

Posaconazole

400–800 mg/d orally in one or two doses5

No

Yes

Nausea, vomiting, abdominal pain, diarrhea, and headache

Broad range of activity including zygomycosis

Terbinafine

250 mg/d orally in one dose

Yes

Poor

Nausea, abdominal pain, taste disturbance, rash, diarrhea, and hepatic enzyme elevations

Dermatophytes, sporotrichosis

Voriconazole

200–400 mg/d orally in two doses or 12 mg/kg intravenously as loading dose for 2 days followed by 6 mg/kg/d intravenously in two doses5

Yes

Yes

Transient visual disturbances, rash, photosensitivity, fluoride excess with periostitis, peripheral neuropathy, hepatic enzyme elevations4

All major pathogens except zygomycetes and sporotrichosis

1

No dosage adjustment required for chronic kidney disease; dosage adjustment necessary with moderate to severe hepatic dysfunction.

2 Use should be monitored with blood levels to prevent this or the dose adjusted according to creatinine clearance.

3 In combination with amphotericin B. 4 Administration with drugs that are metabolized by the cytochrome P450 system is contraindicated or requires careful monitoring.

5 Some authorities advocate therapeutic drug monitoring in patients who are not responding to therapy.

cryptococcal meningitis. Their principal advantage appears to be substantially reduced nephrotoxicity, allowing administration of much higher doses. Three agents of the echinocandin class, caspofungin acetate, anidulafungin, and micafungin sodium, are currently approved.

The echinocandins have relatively few adverse effects and are useful for the treatment of invasive Candida infections. Caspofungin acetate is also approved for use in refractory cases of invasive aspergillosis. Voriconazole has excellent activity against a broad range of fungal pathogens and has been FDA approved for use in invasive Aspergillus cases, Fusarium and Scedosporium infections, Candida esophagitis, deep Candida infections, and candidemia. Posaconazole has good activity against a broad range of filamentous fungi, including the zygomycetes.

Some experts now recommend therapeutic drug monitoring in individuals with severe invasive fungal infections receiving these newer azoles because of unreliable serum levels due to either metabolic alterations as a result of

genetic polymorphisms (voriconazole) or erratic absorption (posaconazole). As a result of their more frequent and sometimes extended use, newly recognized adverse drug effects are being recognized with the azoles, including peripheral neuropathy (itraconazole and voriconazole) and fluoride excess resulting in periostitis and alkaline phosphatase elevations (voriconazole).

Baxter CG et al. Peripheral neuropathy in patients on long-term triazole antifungal therapy. J Antimicrob Chemother. 2011 Sep;66(9):2136–9. [PMID: 21685202] Lass-Flörl C. Triazole antifungal agents in invasive fungal infections: a comparative review. Drugs. 2011 Dec 24;71(18): 2405–19. [PMID: 22141384] Lewis RE. Current concepts in antifungal pharmacology. Mayo Clin Proc. 2011 Aug;86(8):805–17. [PMID: 21803962] Wermers RA et al. Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy. Clin Infect Dis. 2011 Mar;52(5):604–11. [PMID: 21239842]