Current Medical Diagnosis & Treatment 2015

36

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, Pneu mocystis, 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.

CANDIDIASIS

 ESSENTIALS OF DIAGNOSIS

 Common normal flora but opportunistic pathogen.

 Gastrointestinal mucosal disease, particularly esophagitis, most common.

 Fungemia, arising from an intravenous catheter or the gastrointestinal tract occurs in patients who have sustained cutaneous or mucosal injury, undergone instrumentation, are receiving total parenteral nutrition, have kidney disease, or have received broad-spectrum antibiotics.

 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, kidney disease, and the presence of 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

  1. 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.

  1. 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.

  1. Disseminated Candidiasis

The clinical presentation of disseminated candidiasis varies from minimal fever to septic shock that can resemble a severe bacterial infection. Occasionally, patients with candidiasis will have skin lesions ranging from pustules to large nodules. Organs that may be involved in disseminated candidiasis include the liver, spleen, kidney, eyes, and heart. 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. The role of antigen tests, serologic tests (such as beta-D-glucan), and polymerase chain reaction (PCR) in diagnosing invasive candidiasis remains undefined.

Hepatosplenic candidiasis can occur following 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.

  1. Candidal Endocarditis

Candidal endocarditis is a rare infection that is most frequently associated with exposure to a health care 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

  1. 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).

  1. 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.

  1. 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 fluconazole-resistant 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, given until clinical and radiographic improvement occurs.

  1. Candidal Endocarditis

Best results are achieved with a combination of medical and surgical therapy. Amphotericin, either in a lipid or standard formulation, has long been considered the optimal therapy for candidal endocarditis, given in a dosage of 3–5 mg/kg/d (lipid formulation) or 0.6–1 mg/kg/d (deoxycholate) intravenously, and can be given along with 5-flucytosine (25 mg/kg four times daily). Echinocandins are considered an alternative. Step-down or long-term suppressive therapy for nonsurgical candidates may be done with fluconazole at 6–12 mg/kg/d for susceptible organisms.

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.

Ben-Ami R et al; Israeli Candidemia Study Group. Antibiotic exposure as a risk factor for fluconazole-resistant Candida bloodstream infection. Antimicrob Agents Chemother. 2012 May;56(5):2518–23. [PMID: 22314534]

Eschenauer GA et al. Fluconazole versus an echinocandin for Candida glabrata fungaemia: a retrospective cohort study. J Antimicrob Chemother. 2013 Apr;68(4):922–6. [PMID: 23212115]

Kullberg BJ et al. European expert opinion on the management of invasive candidiasis in adults. Clin Microbiol Infect. 2011 Sep;17(Suppl 5):1–12. [PMID: 21884296]

HISTOPLASMOSIS

 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.

 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

  1. 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 pulmonary histoplasmosis frequently occurs in epidemics, often when soil containing infected bird or bat droppings is disturbed. Clinical manifestations can vary from a mild influenza-like illness to severe 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 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) Chronic pulmonary histoplasmosis is usually seen in older patients who usually have underlying chronic lung disease. Chest radiographs show various lesions including apical cavities, infiltrates, and nodules. (4) 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.

  1. Laboratory Findings

Most patients with chronic 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 (LD) 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 first morning urine and serum antigen assays has an 83% sensitivity for the diagnosis of acute pulmonary histoplasmosis. Blood or bone marrow cultures from immunocompromised 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, 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.

Assi M et al. Histoplasmosis after solid organ transplant. Clin Infect Dis. 2013 Dec;57(11):1542–9. [PMID: 24046304]

McKinsey DS et al. Pulmonary histoplasmosis. Semin Respir Crit Care Med. 2011 Dec;32(6):735–44. [PMID: 22167401]

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.

 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 ofCoccidioides 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

  1. 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. HIV-infected persons with disseminated disease have a higher incidence of miliary infiltrates, lymphadenopathy, and meningitis, but skin lesions are uncommon.

  1. 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, immunodiffusion complement fixation titers can be used to assess the adequacy of therapy. Serum complement fixation titer may be 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.

  1. Imaging

Radiographic findings vary, but patchy, nodular and lobar upper lobe pulmonary infiltrates 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. 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. 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).

 Prognosis

The prognosis for patients with limited disease is good, but persistent pulmonary cavities may cause complications such as hemoptysis or rupture producing pyopneumothorax. 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 with stroke and hydrocephalitis that may require shunting. Disseminated and meningeal forms still have mortality rates exceeding 50% in the absence of therapy.

Nguyen C et al. Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis. Clin Microbiol Rev. 2013 Jul;26(3):505–25. [PMID: 23824371]

Thompson GR 3rd. Pulmonary coccidioidomycosis. Semin Respir Crit Care Med. 2011 Dec;32(6):754–63. [PMID: 22167403]

PNEUMOCYSTOSIS (Pneumocystis jirovecii 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 jirovecii in sputum, bronchoalveolar lavage fluid, or lung tissue.

 General Considerations

Pneumocystis jirovecii, the Pneumocystis species that affects humans, is distributed worldwide. Although symptomatic P jirovecii disease is rare in the general population, serologic evidence indicates that asymptomatic infections have occurred in most persons by a young age. 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. De novo infection and reactivation of latent disease likely contribute to the mechanism of acute disease in older children and adults.

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 commonly in patients with cancer or severe malnutrition and 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).

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

  1. 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 cell-mediated 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.

  1. 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 jirovecii 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 exercise before samples are drawn. Serologic tests are not helpful in diagnosis, but several studies have suggested that elevated (1→3)-beta-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 diagnose a granulomatous form of Pneumocystis pneumonia. PCR of bronchoalveolar lavage is overly sensitive in that the test is often positive in colonized, noninfected persons but quantitative values may help with identifying infected patients.

 Treatment

See Table 31–5. It is appropriate to start empiric therapy for P jirovecii 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 DHPS and DHFR genes that mediate TMP-SMZ 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 below). 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.

  1. 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.

  1. Primaquine/Clindamycin

Although there are strong data indicating that trimethoprim-sulfamethoxazole is optimal first-line therapy for Pneumocystis pneumonia, the data on alternative agents are 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.

  1. 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.

  1. 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.

  1. 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.

  1. 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.

 Prevention

Primary prophylaxis for Pneumocystis pneumonia in HIV-infected 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.

 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).

Sassi M et al. Outbreaks of Pneumocystis pneumonia in 2 renal transplant centers linked to a single strain of Pneumocystis: implications for transmission and virulence. Clin Infect Dis. 2012 May;54(10):1437–44. [PMID: 22431811]

Tanaka M et al. Pneumocystis jirovecii pneumonia associated with etanercept treatment in patients with rheumatoid arthritis: a retrospective review of 15 cases and analysis of risk factors. Mod Rheumatol. 2012 Nov;22(6):849–58. [PMID: 22354637]

CRYPTOCOCCOSIS

 ESSENTIALS OF DIAGNOSIS

 Most common cause of fungal meningitis.

 Predisposing factors: Hematologic cancer chemotherapy, Hodgkin lymphoma, 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.

 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 is 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. Progressive lung disease and dissemination most often occur in the setting of cellular immunodeficiency, including underlying hematologic cancer under treatment, Hodgkin lymphoma, long-term corticosteroid therapy, solid-organ transplant, TNF-inhibitor therapy, or HIV infection.

 Clinical Findings

  1. 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 HIV-infected patients. Communicating hydrocephalus may complicate the course. C gattii infection frequently presents with respiratory symptoms along 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 HIV-positive and transplant patients with cryptococcosis; this entity has been labeled the immune reconstitution inflammatory syndrome (IRIS).

  1. 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. Antigen testing by a new lateral flow assay appears to have improved sensitivity and specificity over the conventional latex agglutination test.

 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.

 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.

Antinori S. New insights into HIV/AIDS-Associated cryptococcosis. ISRN AIDS. 2013 Feb 25;2013:471363. [PMID: 24052889]

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]

McMullan BJ et al. Cryptococcus gattii infections: contemporary aspects of epidemiology, clinical manifestations and management of infection. Future Microbiol. 2013 Dec;8:1613–31. [PMID: 24266360]

ASPERGILLOSIS

 ESSENTIALS OF DIAGNOSIS

 Most common cause of non-candidal invasive fungal infection in stem cell or organ transplant recipients and in patients with hematologic malignancies.

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

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

 Detection of galactomannan by ELISA or PCR 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

  1. 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 IgGAspergillus precipitins in the blood. It also may complicate cystic fibrosis.

  1. Invasive Aspergillosis

Invasive manifestations may be seen in immunocompetent or only mildly immunocompromised adults. These include 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 withAspergillusspecies. 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. 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 PCR, or both, has been used for the early diagnosis of invasive disease, though multiple determinations should be done. Galactomannan levels and PCR can be tested in serum or in bronchoalveolar lavage fluid, which may be more sensitive compared to serum. Higher galactomannan levels are correlated with increased mortality, and failure of galactomannan levels to fall in response to therapy portends a worse outcome. False-positive galactomannan tests have been reported in patients receiving beta-lactam antibiotics. Isolation ofAspergillusfrom 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 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.

 Treatment

  1. Allergic Bronchopulmonary Aspergillosis

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.

  1. Invasive Aspergillosis
  2. Sinusitis—These patients may require protracted courses of antifungals (itraconazole, 200 mg twice daily, for weeks to months) in addition to the surgical debridement.
  3. Aspergilloma—The most effective therapy for symptomatic aspergilloma remains surgical resection.
  4. Chronic necrotizing aspergillosis—Guidelines suggest some benefits from prolonged oral voriconazole (200 mg twice daily) or itraconazole (200 mg twice daily) therapy.
  5. Life-threatening invasive aspergillosis—When severe invasive aspergillosis is considered clinically likely or is demonstrable by laboratory testing, rapid institution of voriconazole (6 mg/kg intravenously twice on day 1 and then 4 mg/kg every 12 hours thereafter) is considered optimal therapy. Alternatives include a lipid formulation of amphotericin B (3–5 mg/kg/d), caspofungin 70 mg intravenously on day 1 and then 50 mg/d thereafter), and posaconazole oral tablets (300 mg twice daily on day 1 and then 300 mg daily thereafter). Oral dosing of voriconazole at 4 mg/kg twice daily can be used for less serious infections or as a step-down strategy after intravenous therapy. Therapeutic drug monitoring should be considered for both voriconazole and posaconazole given variations in metabolism and absorption.

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.

Morrissey CO et al; Australasian Leukaemia Lymphoma Group and the Australia and New Zealand Mycology Interest Group. Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial. Lancet Infect Dis. 2013 Jun;13(6):519–28. [PMID: 23639612]

Park WB et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis. 2012 Oct;55(8):1080–7. [PMID: 22761409]

Schwarzinger M et al; PREVERT Investigators. Performance of serum biomarkers for the early detection of invasive aspergillosis in febrile, neutropenic patients: a multi-state model. PLoS One. 2013 Jun 14;8(6):e65776. [PMID: 2379904]

MUCORMYCOSIS

 ESSENTIALS OF DIAGNOSIS

 Most common cause of non-Aspergillus invasive mold infection.

 Predisposing factors: poorly controlled diabetes, leukemia, bone marrow or organ transplant, trauma with wound contamination by soil.

 Pulmonary, rhinocerebral, and skin are most common disease sites.

 Rapidly fatal without multidisciplinary interventions.

 General Considerations

The term “mucormycosis” is applied to opportunistic infections caused by members of the genera RhizopusMucor, Lichtheimia (formerly 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.

 Clinical Findings

Invasive disease of the sinuses, orbits, and the lungs may occur. Necrosis is common due to hyphal tissue invasion that may manifest as ulceration of the hard palate or nasal palate or hemoptysis. Widely disseminated disease is seen in patients who have received cytotoxic chemotherapy. No serologic or laboratory findings assist with diagnosis, and blood cultures are unhelpful. A reverse halo sign may be seen on chest CT. Biopsy of involved tissue remains the cornerstone of diagnosis, although cultures are frequently negative. The organisms appear in tissues as broad, branching nonseptate hyphae.

 Treatment

Optimal therapy of mucormycosis involves reversal of predisposing conditions (if possible), surgical debridement, and prompt antifungal therapy. A prolonged course of a lipid preparation of intravenous amphotericin B (5 mg/kg) should be started early. Based on in vitro susceptibility, posaconazole tablets 300 mg/d orally is generally used after disease has been stabilized. Combination therapy with amphotericin and posaconazole is not proven but is commonly used because of the poor response to monotherapy. 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 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 remains guarded. The historical 4-week mortality rate is 40%, although better response rates have been noted since 2000.

Katragkou A et al. Why is mucormycosis more difficult to cure than more common mycoses? Clin Microbiol Infect. 2013 Nov 27. [Epub ahead of print] [PMID: 24279587]

Neblett Fanfair R et al. Necrotizing cutaneous mucormycosis after a tornado in Joplin, Missouri, in 2011. N Engl J Med. 2012 Dec 6;367(23):2214–25. [PMID: 23215557]

Pagano L et al. Combined antifungal approach for the treatment of invasive mucormycosis in patients with hematologic diseases: a report from the SEIFEM and FUNGISCOPE registries. Haematologica. 2013 Oct;98(10):e127–30. [PMID: 23716556]

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.

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 HIV-infected 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. A serum enzyme immunoassay based on the surface protein BAD-1 appears sensitive and specific.

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.

Bush JW et al. Outcomes of persons with blastomycosis involving the central nervous system. Diagn Microbiol Infect Dis. 2013 Jun;76(2):175–81. [PMID: 23566338]

López-Martínez R et al. Blastomycosis. Clin Dermatol. 2012 Nov–Dec;30(6):565–72. [PMID: 23068144]

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. 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 extrapulmonary dissemination and a more rapid clinical disease course.

Laboratory findings are nonspecific. Serology by immunodiffusion is positive in > 80% 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. Trimethoprim-sulfamethoxazole (480/1200 mg) twice daily orally is equally effective and less costly but associated with more adverse effects. Amphotericin B intravenously is the drug of choice for severe and life-threatening infection.

Marques SA. Paracoccidioidomycosis: epidemiological, clinical, diagnostic and treatment up-dating. An Bras Dermatol. 2013 Sep–Oct;88(5):700-11. [PMID: 24173174]

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. 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, lymphocutaneous spread along the lymphatics draining this area occurs, which may result in ulceration. Cavitary pulmonary disease occurs in individuals with underlying chronic lung disease.

Disseminated sporotrichosis is rare in immunocompetent persons 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, or a lipid amphotericin B preparation, 3–5 mg/kg/d are used for severe systemic infection. Surgery may be indicated for complicated pulmonary cavitary disease, and joint involvement may require arthrodesis.

The prognosis is good for lymphocutaneous sporotrichosis; pulmonary, joint, and disseminated disease respond less favorably.

Aung AK et al. Pulmonary sporotrichosis: case series and systematic analysis of literature on clinico-radiological patterns and management outcomes. Med Mycol. 2013 Jul;51(5): 534–44. [PMID: 23286352]

de Lima Barros MB et al. Sporothrix schenckii and sporotrichosis. Clin Microbiol Rev. 2011 Oct;24(4):633–54. [PMID: 21976602]

PENICILLIUM MARNEFFEI INFECTIONS

Penicillium marneffei, which is endemic in southeast Asia, is a dimorphic fungus that causes systemic infection predominately in 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.

Hu Y et al. Penicillium marneffei infection: an emerging disease in mainland China. Mycopathologia. 2013 Feb;175(1–2):57–67. [PMID: 22983901]

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 (so-called Medlar bodies), which are quite sensitive for diagnosis.

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. Photodynamic therapy combined with antifungal drugs have been successfully used.

Queiroz-Telles F et al. Challenges in the therapy of chromoblastomycosis. Mycopathologia. 2013 Jun;175(5-6):477–88. [PMID: 23636730]

MYCETOMA (Eumycetoma & Actinomycetoma)

Mycetoma is a chronic local, slowly progressive destructive infection that usually involves the foot; it begins in subcutaneous tissues, frequently after localized trauma, and then spreads to contiguous structures. Eumycetoma (also known as maduromycosis) is the term used to describe mycetoma caused by the true fungi and by phylogenetically diverse organisms. Actinomycotic mycetoma is caused byActinomaduraStreptomyces, and Nocardia 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. 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 for eumycetoma is poor, though surgical debridement along with prolonged itraconazole therapy or combination therapy including itraconazole and terbinafine 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.

Estrada R et al. Eumycetoma. Clin Dermatol. 2012 Jul;30(4): 389–96. [PMID: 22682186]

OTHER OPPORTUNISTIC MOLD INFECTIONS

Fungi previously considered to be harmless colonizers, including Pseudallescheria boydii (Scedosporium apiospermum)Scedosporium prolificansFusarium, PaecilomycesTrichoderma 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 well-circumscribed cyst or as an ulcer.

Nonpigmented septate hyphae are seen in tissue and are indistinguishable from those of Aspergillus when infections are due to S apiospermum or species of FusariumPaecilomycesPenicillium, 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. Environmental molds are commonly implicated in asthma and other allergic disease but invasive disease due to these agents is rarely encountered except in persons with profound immunosuppression. Although the popular press has implicated some environmental molds, such as Stachybotrys chartarum, as causative agents of some toxin-induced disorders, specific toxicity from inhaled mold substances has not been scientifically established. 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 assumed to be contaminants in immunocompromised hosts. Some isolates are sensitive to antifungal agents.

A multistate outbreak of fungal infections was reported in 2012 among patients who had received contaminated preservative-free methylprednisolone acetate corticosteroid injections provided by one compounding pharmacy. Four clinical syndromes were recognized: (1) meningitis; (2) basilar stroke; (3) spinal epidural abscess/osteomyelitis; and (4) peripheral joint infections or septic arthritis. Over 751 cases have been reported by the end of 2013 and 64 patients have died; sporadic cases continue to be reported. Most of the infections were due to the dematiaceous fungus, Exserohilum rostratum, a normally rare cause of human disease. Diagnosis depended on a strong index of suspicion. Routine cultures of affected tissues or fluids were performed, although the diagnosis was often made by PCR on specimens sent to the Centers for Disease Control and Prevention. Management included provision of a combination of liposomal amphotericin B, 5–6 mg/kg/d intravenously along with high-dose voriconazole, 6 mg/kg every 12 hours intravenously or orally, for severely ill patients. Less ill patients were treated with voriconazole, 6 mg/kg every 12 hours for a prolonged period of time.

Chiller TM et al; Multistate Fungal Infection Clinical Investigation Team. Clinical findings for fungal infections caused by methylprednisolone injections. N Engl J Med. 2013 Oct 24; 369(17):1610–9. [PMID: 24152260]

Pappas PG. Lessons learned in the multistate fungal infection outbreak in the United States. Curr Opin Infect Dis. 2013 Dec;26(6):545–50. [PMID: 24152763]

Shoham S. Emerging fungal infections in solid organ transplant recipients. Infect Dis Clin North Am. 2013 Jun;27(2):305–16. [PMID: 23714342]

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 invasive fungal infections. 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, Fusariumand Scedosporium infections, Candida esophagitis, deep Candida infections, and candidemia. Posaconazole has good activity against a broad range of filamentous fungi, including the Mucorales. 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). A new delayed-release tablet preparation of posaconazole provides more reliable pharmacokinetics. Isavuconazole is an investigational azole that has recently been granted orphan drug status for the treatment of aspergillosis and mucormycosis.

Table 36–1. Agents for systemic mycoses.

Falci DR et al. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist. 2013 Oct 22;6:163–74. [PMID: 24187505]

Paiva JA et al. New antifungal antibiotics. Curr Opin Infect Dis. 2013 Apr;26(2):168–74. [PMID: 23411420]