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| General Diagnostic Principles |
Several considerations are important in the diagnosis of the systemic mycoses.
1. Many of the causative fungi are opportunists and are not usually pathogenic unless they enter a compromised host. Opportunistic fungal infections are particularly likely to occur and should be anticipated in patients after ionizing (x-) radiation and during therapy with corticosteroids, immunosuppressants, or antimetabolites; such infections also tend to occur in patients with AIDS, azotemia, diabetes mellitus, bronchiectasis, emphysema, TB, Hodgkin's disease or other lymphoma, leukemia, or burns. Candidiasis, aspergillosis, phycomycosis, nocardiosis, and cryptococcosis are typical opportunistic infections.
2. Fungal diseases occurring as primary infections may have a typical geographic distribution. For example, in the USA, coccidioidomycosis is virtually confined to the Southwest, while histoplasmosis occurs in the East and Midwest, especially in the Ohio and Mississippi river valleys. Blastomycosis is restricted to North America and Africa; paracoccidioidomycosis, often called South American blastomycosis, is confined to that continent. However, travelers can develop disease some time after becoming infected and returning from such endemic areas.
3. The major characteristic of virtually every systemic mycosis is its chronic course. Septicemia or acute pneumonia is rare. Lung lesions develop slowly. Months or years may elapse before medical attention is sought or a diagnosis is made.
4. Symptoms are rarely intense, but fever, chills, night sweats, anorexia, weight loss, malaise, and depression all may be present.
5. When a fungus disseminates from a primary focus in the lung, the manifestations may be characteristic. For example, cryptococcosis usually appears as meningitis, progressive disseminated histoplasmosis as hepatic disease, and blastomycosis as a skin lesion.
6. Delayed cutaneous hypersensitivity and serologic tests are available for only 3 or 4 of the infections discussed in this chapter. Even in these, the tests may become positive either so late (eg, coccidioidomycosis) or so infrequently (eg, blastomycosis) that they are of no diagnostic value in the acutely ill patient.
7. The diagnosis is usually confirmed by isolating the causative fungus from sputum, bone marrow, urine, blood, or CSF, or from lymph node, liver, or lung biopsy. When the fungus is a commensal of humans or is prevalent in their environment (eg, Candida or Aspergillus spp), interpretation of culture from such specimens as sputum is difficult, and confirmation of tissue invasion is necessary to attribute an etiologic role to it.
8. In contrast to viral and bacterial diseases, fungal infections can be diagnosed histopathologically with a high degree of reliability. The distinctive fungal morphologic characteristics, not the tissue reaction, permit specific causative identification.
9. Even when the fungus has been demonstrated histopathologically in tissues, the activity of the disease must be established before treatment is begun. Culture of the causative fungus or such clinical and laboratory findings as fever, leukocytosis, elevated ESR, abnormal liver function, worsening of chest film findings, increasing antigen titers, or elevated serum globulins are helpful as indications for therapy.
General Therapeutic Principles
General medical care, surgery, and chemotherapy constitute modes of treatment. Some new antifungal agents offer promise for therapeutic advancements. Ketoconazole, an imidazole derivative, appears to have major advantages in oral dosage and broad antifungal activity. However, testosterone and cortisol synthesis may be blocked, usually transiently, and serious hepatotoxicity may occur. From 200 to 400 mg orally may be given once a day with a meal for prolonged periods to establish and maintain remission or to prevent reinfection. The drug is not absorbed in the absence of gastric acidity.
Flucytosine, a fluorine-containing analog of cytosine, is incorporated into the fungal cell, is converted to 5-fluorouracil, and acts as an inhibitor of thymidylate synthetase. It is absorbed in the GI tract, and serum concentrations of 30 to 40 µg/mL are achieved with 150 mg/kg orally in 4 equally divided doses daily. CSF levels are 75% and urine levels are 300 to 700% of serum levels. The drug is active in vitro and in vivo against a number of fungi, but its use in humans is currently limited to selected patients with cryptococcosis, candidiasis, and chromomycosis. It is the sole agent only in chromomycosis. In cryptococcosis, flucytosine given with amphotericin B is successful in about 85% of patients (excluding those with AIDS). Patients with AIDS do not tolerate flucytosine well, and only about 50% survive a 6-wk course. Reduced renal function, specifically decreased creatinine clearance, resulting from amphotericin B may raise flucytosine serum levels, which in turn may depress the bone marrow and produce, notably, thrombocytopenia.
Fluconazole, a water-soluble triazole that is almost completely absorbed from the GI tract, produces excellent serum levels. CSF levels are approximately 70% of serum levels. This drug has been used chiefly as suppressive therapy for cryptococcosis in patients with AIDS; 200 mg/day have been given orally after primary treatment with amphotericin B (with or without flucytosine, preferably with). In contrast to ketoconazole, fluconazole does not inhibit testosterone and cortisol synthesis. Azotemia increases serum levels, and nomograms for dose adjustment should be consulted.
Itraconazole resembles ketoconazole, but peak serum levels are lower, tissue levels are higher, and no inhibition of testosterone or cortisol synthesis has been reported. Indications for therapy are the same as for ketoconazole, although itraconazole may also be used to treat systemic sporotrichosis. Like ketoconazole, itraconazole produces negligible levels in CSF and urine. Dose-related (>200 mg/day) nausea is the most frequently reported side effect; hepatotoxicity occurs less frequently than with ketoconazole. Itraconazole is not yet commercially available in the USA.
Amphotericin B, a fungicidal and fungistatic antibiotic, is useful in many systemic mycoses. Indications and directions for complementary therapeutic measures are given below in the discussions of specific mycoses. An initial IV dose of 0.1 mg/kg is increased by 0.05 to 0.10 mg/kg daily until 1.0 mg/kg (but not exceeding 50 mg/dose) is given daily or every other day; 10 mL of 5% D/W is injected into the vial, further diluting the antibiotic in the same diluent, to a final optimal concentration of 0.1 mg/mL. (CAUTION: Saline solution precipitates the drug and should not be used. Follow the manufacturer's instructions in preparing and storing solutions.)
The drug should be given over a 2- to 6-h period. Reactions are usually mild, but some patients may experience chills, fever, headache, anorexia, nausea, and occasionally vomiting, particularly with the initial infusions. The severity of reactions may be reduced by giving aspirin or an antihistamine (eg, diphenhydramine 50 mg) before, after 3 h, and at the end of treatment. If this therapy is ineffective, hydrocortisone 25 to 50 mg may be injected into the tubing at the beginning of each infusion.
Chemical thrombophlebitis may occur; adding heparin (300 u.) to the infusion (or into the tubing just before starting the injection) may lessen the frequency.
The BUN or serum creatinine level should be determined before and periodically during treatment. A slight increase can be ignored. A moderate rise, up to 50 mg/dL in the BUN or 3.5 mg/dL in the serum creatinine, may be reversed by giving the drug on alternate days; if the rise is not reversed, treatment should be discontinued until the levels approach normal. If this requires only a few days, treatment can be resumed with the previous dose, but if a longer period is necessary, therapy should be restarted with a smaller dose. Sodium supplementation may prevent or correct some degree of nephrotoxicity. Serum potassium concentration should be determined regularly, since hypokalemia is common and occasionally dramatic and dangerous. Oral liquid supplements are usually sufficient; rarely, potassium IV (not added to the amphotericin B infusion) may be necessary .
Intrathecal injection may be indicated in meningitis, but great care must be taken to ensure proper dose and volume: 50 mg of amphotericin B should be painstakingly dissolved in 10 mL of sterile water. The total volume should then be diluted in a 250-mL bottle of 5% D/W from which 10 mL has been removed. Next, from 0.5 mL (0.1 mg) to 5.0 mL (1.0 mg) should be drawn into a 10-mL syringe, further diluted at the time of spinal tap with 10 mL of CSF, and injected slowly (over at least 2 min). A lumbar, cisternal, or ventricular (by an Ommaya reservoir) site may be used.
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