Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.
Title: Current Medical Diagnosis & Treatment, 46th Edition
Copyright ©2007 McGraw-Hill
> Table of Contents > 36 - Infectious Diseases: Mycotic
Infectious Diseases: Mycotic
Samuel A. Shelburne MD
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 risen. 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.
Essentials of Diagnosis
Common normal flora but opportunistic pathogen.
Gastrointestinal mucosal disease, particularly esophagitis, most common; catheter-associated fungemia occurs in patients who have sustained mucosal injury or received broad-spectrum antibiotics.
Diagnosis of invasive systemic disease requires tissue biopsy or evidence of retinal disease.
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, renal failure, the presence of intravascular catheters (especially when providing total parenteral nutrition), and injection drug use. 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 & Treatment
A. Mucosal Candidiasis
Esophageal involvement is the most frequent type of significant mucosal disease. Individuals present with 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; the condition may be difficult to distinguish from esophagitis caused by infection with cytomegalovirus or herpes simplex virus when barium swallow alone is used for diagnosis. Therapy 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, 100 mg/d), for 10–14 days will usually suffice. 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; or intravenous caspofungin, 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.
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. Various topical azole preparations (eg, clotrimazole, 100 mg vaginal tablet for 7 days, or miconazole, 200 mg vaginal suppository for 3 days) are effective. 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 if renal function is normal. Bladder irrigation with amphotericin B (50–200 mg/mL) is rarely indicated, though it may transiently clear candiduria, especially if colonization is confined to the bladder. However, failure
to clear the candiduria in this way suggests the presence of upper urinary tract infection. Rare complications of candidal urinary tract infections are ureteral obstruction and dissemination.
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. Thus, the decision to treat for Candida when organisms are isolated from urine or sputum (or both) needs to be individualized for each patient. Disseminated candidiasis may represent a benign, self-limited process, but until proven otherwise it should be considered a sign of serious, complicated disease. If fungemia resolves with removal of intravascular catheters, there are often no further complications, but the incidence of endophthalmitis may be higher than previously recognized.
Important clinical findings in invasive candidiasis are fluffy white retinal infiltrates that extend into the vitreous and raised, erythematous skin lesions that may be painful. Though characteristic, these are seen in less than 50% of cases. Other organ system involvement in invasive disease may include the brain, meninges, and myocardium. Antifungal therapy for invasive candidiasis is rapidly evolving with the addition of new agents and the emergence of non-albicans species causing significant disease. Options for treatment include fluconazole, 400–800 mg daily; amphotericin B, 0.3–0.5 mg/kg/d; voriconazole, 200 mg twice a day; or caspofungin, 50 mg/d. Combination therapy with azoles and amphotericin B is an area being explored. Flucytosine, 150 mg/kg/d orally in four divided doses, is added if central nervous system involvement occurs. Therapy for disseminated candidiasis should be continued for 2 weeks after the last positive blood culture and resolution of symptoms and signs of infection. 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. Although debated, removal or exchange of intravascular catheters is generally recommended and substantially decreases the duration of candidemia and overall mortality, which approaches 30%.
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. CT scanning of the abdomen shows hepatosplenomegaly, most often with multiple low-density defects in the liver and spleen. Diagnosis is established by liver biopsy, histopathology, and culture. Fluconazole, 400 mg daily, or a lipid formulation of amphotericin B is given until clinical and radiographic improvement occurs.
D. Candidal Endocarditis
Candidal endocarditis rarely is a complication of transient fungemia. It usually results from direct inoculation at the time of valvular heart surgery or repeated inoculation with injection drug use. Candidal endocarditis occurs with increased frequency on prosthetic valves in the first few months following surgery. Splenomegaly and petechiae are common, and there is a predilection for large-vessel embolization. Non-albicans species such as Candida parapsilosis and Candida tropicalis are more often important etiologic agents in endocarditis than in fungemia, which is most often due to C albicans. The diagnosis is established definitively by culturing Candida from emboli or from vegetations at the time of valve replacement. Valve destruction (usually aortic or mitral) is common, and surgical therapy is necessary in addition to a prolonged course of amphotericin therapy, given in a dosage of 0.5–1 mg/kg/d intravenously, usually to a total dose of 1–1.5 g intravenously.
It is important to note that non-albicans species of Candida now account for over 50% of clinical bloodstream isolates and are often resistant to imidazole antibiotics such as fluconazole. The widespread use of these agents for prophylaxis in immunocompromised patients can lead to the emergence of pathogens such as Candida krusei. Dissemination of this organism has been reported in patients undergoing bone marrow transplantation for leukemia. Azole-resistant C albicans has increased in frequency in immunocompromised patients, particularly in patients with late-stage AIDS receiving long-term suppressive fluconazole.
In all forms of invasive candidiasis, an important element of therapy is reversal of the underlying predisposing factor when possible. 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.
Kulberg BJ et al: Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial. Lancet 2005;366:1435.
Pappas PG et al: Guidelines for the treatment of candidiasis. Clin Infect Dis 2004;38:161.
Raad I et al: Management of central venous catheters in patients with cancer and candidemia. Clin Infect Dis 2004;38:1119.
Sobel JD et al: Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med 2004;351:876.
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.
Rare patients with normal immune function develop dissemination, with hepatosplenomegaly, lymphadenopathy, and oral ulcers.
Widespread disease especially common in AIDS or other immunosuppressed states, with poor prognosis.
Skin test and serology seldom diagnostic; biopsy of affected organs with culture, or urinary polysaccharide antigen most useful in disseminated disease.
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 phagocytic cells in the lungs. The organism proliferates and is carried hematogenously to other organs.
A. Symptoms and Signs
Most cases of histoplasmosis are asymptomatic or mild and thus go unrecognized. Past infection is recognized by the development of a positive histoplasmin skin test and occasionally by pulmonary and splenic calcification noted on incidental radiographs. Symptoms and signs of pulmonary involvement are usually absent even in patients who subsequently show areas of calcification on chest 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 severe disease manifested by marked prostration, fever, and relatively few pulmonary complaints even when radiographs show diffuse pneumonia. The illness may last from 1 week to 6 months but is almost never fatal. (2) Progressive disseminated histoplasmosis is usually fatal within 6 weeks or less. 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 progressive pulmonary histoplasmosis is usually seen in older patients with chronic obstructive lung disease. The lungs show chronic progressive changes, often with apical cavities. (4) Disseminated disease in the profoundly immunocompromised host often represents reactivation of prior infectious foci or may reflect acute infection. This form is commonly seen in patients with underlying HIV infection—with CD4 cell counts usually < 100 cells/mcL—and 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.
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.
In pulmonary disease, sputum culture is rarely positive except in chronic disease; antigen testing of bronchoalveolar lavage fluid may be helpful in acute disease. 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. A urine antigen assay has a sensitivity of greater than 90% for disseminated disease in AIDS patients and can be used to follow response to therapy. The sensitivity of screening immunodiffusion is 70% in acute pulmonary histoplasmosis, and complement fixation titers are positive in about 80% of cases. A combination of these two methods yields a sensitivity of up to 80% in immunodeficient adults.
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. Duration of therapy ranges from weeks to several months depending on the severity of illness. Amphotericin B is reserved for individuals who cannot take oral medications; for
those who have not responded to itraconazole therapy; for those with meningitis; and for management of severe disseminated disease in an immunocompromised person. Up to 2.5 g total may need to be given in the latter two situations, though this course of treatment can be abbreviated and oral itraconazole instituted once clinical stabilization has occurred. (See Amphotericin B, Chapter 37.) Liposomal amphotericin B in a dosage of 3 mg/kg/d intravenously may be more effective and safer than conventional amphotericin B in seriously ill individuals. 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.
Couppie P et al: Histoplasmosis and acquired immunodeficiency syndrome: a study of prognostic factors. Clin Infect Dis 2004;38:134.
Kahi CJ et al: Gastrointestinal histoplasmosis. Am J Gastroenterol 2005;100:220.
Essentials of Diagnosis
Influenza-like illness with malaise, fever, backache, headache, and cough.
Arthralgia and periarticular swelling of knees and ankles.
Erythema nodosum common.
Dissemination may result in meningitis, bony lesions, or skin and soft tissue abscesses.
Chest radiograph findings vary widely from pneumonitis to cavitation.
Serologic tests useful; spherules containing endospores demonstrable in sputum or tissues.
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 Coccidioides 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.
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. Pleuritic pain is common. Nasopharyngitis may be followed by bronchitis accompanied by a dry or slightly productive cough.
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. Symptoms depend on the site of dissemination. 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.
Bone lesions most often occur at bony prominences. 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. Mediastinal and retroperitoneal abscesses are not uncommon. 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 tube precipitin test and an immunodiffusion test detect IgM antibodies and are useful for diagnosis early in the disease process. Historically, a persistent rising 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 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; though they are not infectious, they convert to the highly contagious arthroconidia when grown in culture media. Blood cultures in appropriate media are only rarely positive in disseminated disease.
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.
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 generally used although oral azoles may be used for mild cases (see Chapter 37). Therapy should be continued, with duration of therapy 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) 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 may be an alternative to intrathecal amphotericin B in patients who do not respond to fluconazole. Once the patient is clinically stable, oral therapy with an azole for an indefinite period is the recommended alternative to intrathecal amphotericin B therapy.
Fluconazole, 200–400 mg orally once daily, or itraconazole, 400 mg orally daily divided into two doses, may 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 progressive decrease in serum complement fixation titers.
Thoracic surgery is occasionally indicated for giant, infected, or ruptured cavities. Surgical drainage is necessary for management of soft tissue abscesses and bone disease. Amphotericin B, 1 mg/kg/d intravenously, is advisable following extensive surgical manipulation of infected tissue until the disease is inactive, whereupon therapy may be continued with an azole.
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. Disseminated and meningeal forms still have mortality rates exceeding 50% in the absence of therapy.
Galgiani JN et al: Coccidioidomycosis. Clin Infect Dis 2005;41:1217.
Johnson RH et al: Coccidioidal meningitis. Clin Infect Dis 2005;42:103.
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.
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 immune status. Cases occur generally 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 commonly, 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 infection in older children and adults results from de novo infection or from reactivation of latent infection is unknown.
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 below 200/mcL. Dissemination of the infection to tissues other than the lung is rare, except in those who have received prophylactic aerosolized pentamidine. In non-AIDS patients receiving immunosuppressive therapy, symptoms frequently begin after corticosteroids have been tapered or discontinued.
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 cell-mediated immunity, the onset is 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.
Typically, there is reduction in vital and total lung capacity, and the single-breath diffusing capacity for carbon monoxide shows impaired diffusion. 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. Lymphopenia with depleted CD4 lymphocytes is common. Serologic tests, including tests to detect antigenemia, are not helpful in diagnosis.
Specific diagnosis depends on morphologic demonstration of the organisms in clinical specimens using specific stains. The organism cannot be cultured. Although patients rarely spontaneously produce sufficient sputum for examination, 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. If diagnostic results cannot be achieved with induced sputum specimens and the diagnosis of P jiroveci pneumonia is strongly suspected, 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. Although conclusions are still preliminary, the polymerase chain reaction (PCR) test for the detection of P jiroveci appears to be sensitive but does not provide more rapid diagnosis.
See Table 31-4.
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 the toxicity of therapy and the possible coexistence of other infections. Both in AIDS patients and in non-AIDS patients with mild to moderately severe disease, oral trimethoprim-sulfamethoxazole (TMP-SMZ) is the preferred agent because of its low cost and excellent bioavailability. Patients suffering from nausea and vomiting or intractable diarrhea should be given intravenous TMP-SMZ until they can tolerate the oral formulation. Other options include clindamycin/primaquine, dapsone/trimethoprim, pentamidine, and atovaquone. 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.
The dosage is TMP 20 mg/kg (12–15 mg/kg may decrease side effects without decreasing efficacy) and SMZ 100 mg/kg given orally or intravenously daily in three or four divided doses for 14–21 days. Adverse reactions are generally those of the sulfonamide component. 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.
B. Pentamidine Isethionate
This drug is administered intravenously (preferred) or intramuscularly as a single dose of 3 mg (salt)/kg/d for 14–21 days. To avoid injection site pain or sterile abscesses, most clinicians administer the drug only intravenously by diluting it in 250 mL of 5% dextrose in water and giving it slowly over 1 hour. Pentamidine causes side effects in nearly 50% of patients. Occasional reactions include rash, neutropenia, abnormal liver function tests, serum folate depression, hyperkalemia, and hypocalcemia. 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.
Atovaquone has been 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. Because poor gastrointestinal absorption can lead to low serum concentrations and treatment failure, the drug should be taken with food, especially a fatty meal.
D. Other Drugs
Clindamycin, 600 mg three times daily, plus primaquine, 15 mg/d; and dapsone, 100 mg/d, plus trimethoprim 15 mg/kg/d, in three divided doses daily, are alternative oral regimens for mild to moderate disease or for continuation of therapy after intravenous therapy is no longer needed. Trimetrexate, 45 mg/m2/d intravenously, plus high-dose leucovorin has been approved for salvage use in patients not responding to other therapies, but the success rate is less than 25%.
In conjunction with antimicrobials, prednisone is given for moderate to severe pneumonia (when Pao2 on admission is < 70 mm Hg or oxygen saturation is < 90%); its use during the first 72 hours of therapy for severe Pneumocystis pneumonia prevents deterioration in oxygenation and improves survival. The dosage of prednisone is 40 mg twice daily for 5 days, then 40 mg daily for 5 days, and then 20 mg daily until therapy is completed.
F. Supportive Care
Oxygen therapy is indicated to maintain the oxygen saturation over 90% by pulse oximeter.
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. Development of P jiroveci pneumonia while on prophylaxis may be associated with development of resistance to TMP-SMZ. 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 > 250 cells/mcL.
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).
Crothers K et al: Severity and outcome of HIV-associated Pneumocystis pneumonia containing Pneumocystis jirovecii dihydropteroate synthase gene mutations. AIDS 2005;19:801.
Festic E et al: Acute respiratory failure due to pneumocystis pneumonia in patients without human immunodeficiency virus infection: outcome and associated features. Chest 2005;128:573.
Essentials of Diagnosis
Most common cause of fungal meningitis.
Predisposing factors: Hodgkin's disease, corticosteroid 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 diagnostic; 95% of HIV-infected patients also have a positive serum antigen.
Cryptococcosis is mainly caused by Cryptococcus neoformans var neoformans, an encapsulated budding yeast that has been found worldwide in soil and on dried pigeon
dung. Cryptococcus gattii is a closely related species that also causes disease in humans although C gattii appears to affect more immunocompetent persons, usually outside of North America.
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's disease, long-term corticosteroid therapy, or HIV infection.
A. Symptoms and Signs
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. Intracerebral mass lesions (cryptococcomas) are rarely seen. Communicating hydrocephalus may complicate the course. Primary C neoformans infection of the skin may mimic bacterial cellulitis, especially in immunocompromised persons.
B. Laboratory Findings
For suspected meningeal disease, lumbar puncture is the preferred diagnostic procedure. A substantial proportion of individuals who have systemic disease without clinical signs of meningitis will have meningeal involvement, mandating examination of the cerebrospinal fluid. 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. India ink smear or 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 a sensitive screening test for meningitis, being positive in over 95% of cases. CT or MRI scanning of the head should be performed if focal neurologic signs or papilledema are present to evaluate for mass lesions (eg, cryptococcoma) or hydrocephalus.
In AIDS-related cryptococcal meningitis, oral fluconazole, 400 mg/d for a minimum of 10 weeks, has reasonable efficacy as immediate therapy in patients with mild disease. Candidates for initial fluconazole therapy are patients with an intact level of consciousness and a spinal fluid cryptococcal antigen titer of less than 1:128. Higher-risk patients should receive amphotericin B initially.
There has been a trend away from regimens based on prolonged amphotericin B therapy, particularly in HIV-infected patients. However, this agent remains important, especially in severe disease. Amphotericin B, 0.7–1 mg/kg/d intravenously for 14 days, followed by an additional 8 weeks of fluconazole, 400 mg/d orally, has been quite effective, achieving clinical responses and cerebrospinal fluid sterilization in about 70% of patients. Adding flucytosine initially does prevent late relapses but does not substantially contribute to improved cure rates. 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. 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), declining cerebrospinal fluid cryptococcal antigen titer, 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. Because of serious underlying illnesses and generally greater age, this group of patients does not tolerate the higher doses of amphotericin B as well as patients with AIDS. Lipid amphotericin B preparations appear to have equivalent efficacy with reduced nephrotoxicity. Therapy is generally continued until cerebrospinal fluid cultures become negative and cerebrospinal fluid antigen titers are below 1:8.
Maintenance antifungal therapy is important after treatment of an acute episode in HIV-related cases, since otherwise the rate of relapse is greater than 50%. Fluconazole, 200 mg/d, 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 brief course (eg, 3 months) of fluconazole as maintenance therapy following successful therapy for acute illness; recently published guidelines suggest this as an option.
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.
Brouwer AE et al: Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomized trial. Lancet 2004;363:1764.
Kidd SE et al: A rare genotype of Cryptococcus gattii caused the cryptococcosis outbreak on Vancouver Island (British Columbia, Canada). Proc Natl Acad Sci U S A 2004;101:17258.
Mussini C et al: Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with highly active antiretroviral therapy: an international observational study. Clin Infect Dis 2004;38:565.
Aspergillus fumigatus is the usual cause of aspergillosis, though many species of Aspergillus may cause a wide spectrum of disease. Burn eschar and debris in the external ear canal are often colonized by these fungi. Clinical illness results either from an aberrant immunologic response or tissue invasion.
Allergic bronchopulmonary 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. The disease characteristically pursues a waxing and waning course with gradual improvement over time, but it may result in saccular bronchiectasis and end-stage fibrotic lung disease. 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.
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. Sinus involvement is usually diagnosed histologically after patients with chronic sinus disease undergo surgery. These patients may require protracted courses of antifungals (itraconazole, 200 mg twice daily, for weeks to months) in addition to the surgical debridement. Aspergillomas of the lung occur when preexisting lung lesions become secondarily colonized with Aspergillus species. These may be found by incidental radiographic studies but may also present with significant hemoptysis. Intracavitary instillation of amphotericin B and bronchoscopic removal have been tried with little success; several uncontrolled trials have suggested some benefit from oral itraconazole. The most effective therapy for symptomatic aspergilloma remains surgical resection.
Chronic necrotizing aspergillosis 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 and the response to antifungal therapy is not clear at present, although it would be reasonable to institute therapy targeting Aspergillus. Surgical intervention may be necessary but complications are common.
Life-threatening invasive aspergillosis most commonly occurs in profoundly immunodeficient patients, particularly those with prolonged, severe neutropenia. Patients with very advanced HIV disease may also be at risk for invasive aspergillosis, particularly if they have other risk factors for the disease. Pulmonary disease is most common, with patchy infiltration leading to a severe necrotizing pneumonia. 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. AIDS patients are also predisposed to a unique ulcerative tracheobronchitis that may coexist with parenchymal pulmonary disease. 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. In contrast to allergic aspergillosis, serologic tests have low sensitivities for invasive disease; detection of galactomannan by enzyme-linked immunosorbent assay (ELISA) has recently been demonstrated to have a sensitivity of 89% and a specificity of 98% for the diagnosis of invasive disease, though multiple determinations should be done. 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. Therefore, the mainstay of diagnosis is demonstration of Aspergillus in tissue. Biopsy specimens may show branched septate hyphae but will not invariably grow the organism. CT scan of the chest may show characteristics quite suggestive of invasive aspergillosis.
When severe invasive aspergillosis is considered clinically likely or is demonstrable by laboratory testing, rapid institution of voriconazole, high doses of amphotericin B, or caspofungin may be life-saving (see Chapter 37). Voriconazole 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. The dosage of voriconazole is 6 mg/kg intravenously twice on the first day, followed by 4 mg/kg twice daily given either intravenously or by mouth. Some experts believe that lipid preparations of amphotericin B should be used preferentially in this setting because they are better tolerated and can be given at higher doses. Caspofungin acetate, an echinocandin antifungal, has been approved for the treatment of invasive
aspergillosis in patients who are refractory to or intolerant of other treatments. The drug is given as a 70 mg intravenous loading dose followed by 50 mg intravenously daily. In critically ill patients who are not responding to conventional antifungal treatment, there may be a role for the addition of caspofungin to amphotericin B or voriconazole therapy, although randomized trials are lacking. Based on promising results in neutropenic patients with invasive pulmonary aspergillosis, surgical resection warrants further study. The mortality rate of pulmonary or disseminated disease in the immunocompromised patient remains well above 50%, particularly in patients with refractory neutropenia. This high mortality rate often leads clinicians to institute prophylactic therapy around the time of bone marrow transplantation with agents such as itraconazole.
Bart-Delabesse E et al: Detection of Aspergillus galactomannan antigenemia to determine biological and clinical implications of beta-lactam treatments. J Clin Microbiol 2005;43:5214.
Klont RR: Utility of Aspergillus antigen detection in specimens other than serum samples. Clin Infect Dis 2004;39:1467.
Marr KA et al: Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogenic stem cell transplants. Blood 2004;103:1527.
Singh N et al: Aspergillus infections in transplant recipients. Clin Micro Rev 2005;18:44.
The term mucormycosis (zygomycosis, phycomycosis) is applied to opportunistic infections caused by members of the genera Rhizopus, Mucor, Absidia, and Cunninghamella. Predisposing conditions include diabetic ketoacidosis, chronic renal failure, 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 has been more commonly seen recently in patients who have received aggressive chemotherapy and broad-spectrum antifungal prophylaxis. The diagnosis should be considered in immunocompromised patients with black necrotic lesions of the nose or sinuses or with new cranial nerve abnormalities. Without treatment, cerebral invasion may ensue. A prolonged course of high-dosage amphotericin B (1–1.5 mg/kg/d intravenously) or a lipid preparation of amphotericin B should be started early. Based on in vitro susceptibility, there may be a role for posaconazole in the treatment of these infections, but other azoles are likely to be ineffective. 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.
Kontoyiannis DP et al: Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy. A case-control observational study of 27 recent cases. J Infect Dis 2005;191:1350.
Prabhu RM et al: Mucormycosis and entomophthoramycocis: a review of the clinical manifestations, diagnosis, and treatment. Clin Microbiol Infect 2004;10(Suppl 1):31.
Spellberg B et al: Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Micro Rev 2005;18:556.
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. A few cases have been found in Mexico and Africa. Disease usually occurs in immunocompetent individuals.
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 bloody and purulent sputum production, pleurisy, fever, chills, loss of weight, and prostration. Radiologic studies, either chest radiographs or CT scans, usually reveal pulmonary infiltrates and enlarged regional lymph nodes, though less commonly than in histoplasmosis or coccidioidomycosis.
Raised, verrucous cutaneous lesions that have an abrupt downward sloping border are usually present in disseminated blastomycosis. The border extends slowly, leaving a central atrophic scar. If left untreated for long periods, they may mimic skin cancer. Bones—often the ribs and vertebrae—are frequently involved. Lesions appear to be both destructive and proliferative on radiography. Epididymitis, prostatitis, and other involvement of the male urogenital system may occur. Central nervous system involvement is uncommon. 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, 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.
Itraconazole, 100–200 mg/d orally for at least 2–3 months, is now the therapy of choice for nonmeningeal disease, with a response rate of over 80%. Amphotericin B, 0.3–0.6 mg/kg/d intravenously for a total dose of 1.5–2.5 g, is given for treatment failures or cases with central nervous system involvement.
Clinical follow-up for relapse should be regularly made for several years so that therapy may be resumed or another drug instituted.
Bradsher RW et al: Blastomycosis. Infect Dis Clin North Am 2003;17:21.
Martynowicz MA et al: Pulmonary blastomycosis. An appraisal of diagnostic techniques. Chest 2002;121:768.
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. Ulceration of the nasopharynx and oropharynx is usually the first symptom. Papules 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. Cough, sometimes with sputum, indicates pulmonary involvement, but the symptoms and signs are often mild, even though radiographic findings indicate severe parenchymatous changes in the lungs. The extensive ulceration of the upper gastrointestinal tract may prevent caloric intake and result in cachexia.
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 does not reveal the organism, biopsy with Gomori staining may be helpful.
Itraconazole, 100–200 mg orally daily, is the treatment of choice and generally results in a clinical response within 1 month and effective control after 2–6 months.
Tobon AM et al: Residual pulmonary abnormalities in adult patients with chronic paracoccidioidomycosis: prolonged follow-up after itraconazole therapy. Clin Infect Dis 2003;37:898.
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, similar nodules develop along the lymphatics draining this area, and these may ulcerate as well. The lymphatic vessels become indurated and are easily palpable.
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 now the treatment of choice for localized disease and some milder cases of disseminated disease. Terbinafine, 500 mg twice daily, also appears to have good efficacy in noninvasive disease. Amphotericin B intravenously, 1–2 g (see Chapter 37), 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.
Chapman SW et al: Comparative evaluation of the efficacy and safety of two doses of terbinafine (500 mg and 1000 mg/day) in the treatment of cutaneous and lymphocutaneous sporotrichosis. Mycoses 2004;47:62.
Lyon GM et al: Population-based surveillance and a case-control study of risk factors for endemic lymphocutaneous sporotrichosis in Peru. Clin Infect Dis 2003;36:34.
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. 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, 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, is indicated indefinitely.
Chariyalertsak S et al: A controlled trial of itraconazole as primary prophylaxis for systemic fungal infections in patients with advanced human immunodeficiency virus infection in Thailand. Clin Infect Dis 2002;34:277.
Wong SS et al: Differences in clinical and laboratory diagnostic characteristics of Penicillium marneffei in human immunodeficiency virus (HIV)- and non-HIV-infected patients. J Clin Microbiol 2001;39:4535.
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%. Response rates may be improved by the addition to itraconazole of flucytosine, 100–150 mg/kg/d by mouth divided into four doses. Terbinafine at 500 mg/d may have similar efficacy to itraconazole. Cryosurgery alone for smaller lesions or combined with itraconazole for larger lesions is beneficial.
Andrade TS et al: Susceptibility of sequential Fonsecaea pedrosoi isolates from chromoblastomycosis patients to anti-fungal agents. Mycoses 2004;47:216.
Queiroz-Telles F et al: Subcutaneous mycoses. Infect Dis Clin North Am 2003;17:59.
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 terbinafine or 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.
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. Infection may be localized in the skin, lungs, or sinuses, or widespread disease may appear with lesions in multiple organs. Colonization of old cavitary disease may cause minimal symptoms or may precede dissemination with meningitis or brain abscesses. Endocarditis occurs more commonly in injection drug users. 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 Fusarium, Paecilomyces, Penicillium, or other hyaline molds. Spores or mycetoma-like granules are rarely present in tissue.
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 assumed to be contaminants in immunocompromised hosts. Some isolates are sensitive to antifungal agents. 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).
Table 36-1. Agents for systemic mycoses.
Husain S et al: Infections due to Scedosporium apiospermum and Scedosporium prolificans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome. Clin Infect Dis 2005;40:89.
Revankar SG et al: Primary central nervous system phaeohyphomycosis: a review of 101 cases. Clin Infect Dis 2004;38:206.
Walsh TJ et al: Infections due to emerging and uncommon medically important fungal pathogens. Clin Microbiol Infect 2004;10(Suppl 1):48.
Table 36-1 summarizes the major properties of currently available or soon to be available antifungal agents. A number of lipid-based amphotericin B formulations are available. These agents are used to treat systemic candidiasis, invasive aspergillosis and other disseminated mold infections, disseminated histoplasmosis, and cryptococcal meningitis. Their principal advantage appears to be substantially reduced nephrotoxicity, allowing administration of much higher doses. Because of their expense, use of these agents should be reserved for individuals in whom significant nephrotoxicity develops during amphotericin B therapy. Two agents of the echinocandin class, caspofungin acetate and micafungin sodium, are currently approved and a third, anidulafungin should be available soon. The echinocandins have relatively few adverse effects. Caspofungin acetate is approved for use in esophageal and invasive candidiasis, as empiric therapy in patients with neutropenic fever, and 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, a new azole, is currently used on a compassionate basis in zygomycetes infections and likely will be widely available soon. Cytokine therapy (such as with interferon-γ) and use of growth factors such as granulocyte macrophage-colony-stimulating factor (GM-CSF) (sargramostim or molgramostim) have been shown in animal models to increase clearance of fungi and result in better clinical outcomes and are being evaluated in human disease.
Higashiyama Y et al: Micafungin: a therapeutic review. Expert Rev Anti Infect Ther 2004;2:345.
Torres HA et al: Posaconazole: a broad-spectrum triazole antifungal. Lancet Infect Dis 2005;5:775.
Vazquez JA: Anidulafungin: a new echinocandin with a novel profile. Clin Ther 2005;27:657.