SYSTEMIC FUNGAL INFECTIONS

SYSTEMIC MYCOSIS

General

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 in patients during therapy with corticosteroids, immunosuppressants or antimetabolites; such infections also tend to occur in patients with AIDS, azotemia, diabetes mellitus, bronchiectasis, emphysema, TB, lymphoma, leukemia, or burns. Typical opportunistic infections are: Candidiasis, aspergillosis, mucormycosis (phycomycosis), nocardiosis and cryptococcosis. 

Systemic mycoses affecting severely immunocompromised patients often have acute or subacute presentations with rapidly progressive pneumonia, fungemia or manifestations of extrapulmonary dissemination.

Fungal diseases occurring as primary infections may have a typical geographic distribution. For example:  Paracoccidioidomycosis, sometimes called South American blastomycosis, is confined to the South American continent. In Africa: Blastomycosis. In the USA, coccidioidomycosis is virtually confined to the Southwest; histoplasmosis occurs primarily in the East and Midwest; and blastomycosis. However, travelers can develop disease some time after becoming infected and returning from such endemic areas.

In immunocompetent patients, systemic mycoses typically have a chronic course. Months or even years may elapse before medical attention is sought or a diagnosis is made. Symptoms are rarely intense in such chronic mycoses but fever, chills, night sweats, anorexia, weight loss, malaise and depression may occur.

When a fungus disseminates from a primary focus in the lung, the manifestations may be characteristic. For example, cryptococcosis usually presents as a chronic meningitis; progressive disseminated histoplasmosis as generalized involvement of the reticuloendothelial system (liver, spleen, bone marrow); and blastomycosis as single or multiple skin lesions.

Immunoserologic tests are available for many systemic mycoses, but few provide definitive diagnoses by themselves. Among the most useful assays are those that measure specific antigenic products of organisms, most notably Cryptococcus neoformans and, more recently, Histoplasma capsulatum. Some tests, such as complement fixation assays for anti-coccidioidal antibodies, are specific and do not require proof of rising levels and thus can provide invaluable confirmatory evidence for diagnosis as well as an indication of the relative risk of extrapulmonary dissemination. In chronic meningitis, a positive complement fixation for anti-coccidioidal antibodies in CSF often provides the only definite diagnostic indication of the need for aggressive antifungal therapy. Most tests for antifungal antibodies, however, are of limited usefulness. Many have low sensitivity and/or specificity, and because measurement of high or rising antibody titers takes a long time, it is unhelpful in guiding initial therapy.

Diagnoses are usually confirmed by isolating causative fungi from sputum, urine, blood, bone marrow, or specimens from infected tissues. The clinical significance of positive sputum cultures may be difficult to interpret for commensal organisms (eg, Candida albicans) or for those that are prevalent in the environment (eg, Aspergillus sp). Therefore, an etiologic role can be established with certainty only by confirmation of tissue invasion.

In contrast to viral and bacterial diseases, fungal infections often can be diagnosed histopathologically with a high degree of reliability based on distinctive morphologic characteristics of invading fungi rather than assay of specific antibody products. However, definitive identification may be difficult, especially if few organisms are visible, so that histopathologic diagnoses should be confirmed by cultures whenever possible. Assessment of the activity of the infection is based on cultures from many different sites, fever, leukocyte counts, clinical and laboratory parameters related to specific involved organs (eg, liver function tests), and immunoserologic tests in certain mycoses.

Therapeutic Principles

In addition to antifungal chemotherapy and general medical care, surgery may be needed to clear certain localized infections. 

Drugs for systemic antifungal treatment include: amphotericin B, the antifungal azoles and flucytosine. 

• Amphotericin B: Despite its high toxicity, amphotericin B remains the standard therapy for most life-threatening systemic mycoses. 

Renal functional impairment is the major toxic risk of amphotericin B therapy: Serum creatinine and BUN should be monitored before and at regular intervals during treatment. Amphotericin B is unique among nephrotoxic antimicrobial drugs in that it is not eliminated appreciably via the kidneys. Thus, amphotericin B does not accumulate in increasing amounts as renal failure worsens, and the dose should not be reduced with moderate abnormalities in renal function. However, in patients who begin therapy with normal renal function, amphotericin B dosages should be reduced if serum creatinine rises to more than 3.0 to 3.5 mg/dL (265 to 309 µmol/L) or BUN to more than 50 mg/dL (18 mmol Urea/L). 

• Antifungal azoles: These drugs are not nephrotoxic and can be administered orally. They have made treatment of chronic mycoses in an outpatient setting easier. The first such oral drug, ketoconazole, has largely been supplanted by newer, more effective, less toxic triazole derivatives such as fluconazole and itraconazole.

Fluconazole is water-soluble and is absorbed almost completely after an oral dose. It is excreted largely unchanged in urine and has a half-life > 24 h, facilitating use in single daily doses. 

Candida cruzii is typically fluconazole-resistant, and Candida (Torulopsis) glabrata is generally less sensitive than C. albicans. Other fluconazole-resistant Candida sp have been increasingly emerging recently in relation to repeated widespread use for the treatment and prevention of candidiasis and other mycoses. So far, most resistant Candida isolates appear sensitive to itraconazole, but some are not. Of special concern are reports of fluconazole-resistant Candida in non-AIDS patients never previously treated with azoles. Restraint is strongly recommended to avoid indiscriminate fluconazole use when other therapy would be effective for mucocutaneous candidiasis.

GI discomfort and skin rash are the most common side effects. More severe toxicity is unusual, but fluconazole use has been associated with hepatic necrosis, Stevens-Johnson syndrome, anaphylaxis, alopecia, and congenital anomalies after use beyond the 1st trimester of pregnancy. Interactions with other drugs occur less often with fluconazole than with ketoconazole or itraconazole. However, fluconazole sometimes causes elevated serum levels of cyclosporine, rifabutin, phenytoin, warfarin-type oral anticoagulants, sulfonylurea drugs such as tolbutamide, or zidovudine. Rifampin may lower fluconazole blood levels.

Itraconazole has become the standard treatment for lymphocutaneous sporotrichosis as well as mild or moderately severe histoplasmosis, blastomycosis, or paracoccidioidomycosis. It also has proven effective in mild cases of invasive aspergillosis, some cases of coccidioidomycosis, and certain types of chromomycosis. Because of its high lipid solubility and protein binding, itraconazole blood levels tend to be low, but tissue levels are generally high. Drug levels are negligible in urine or CSF. Itraconazole has been used successfully to clear some types of fungal meningitis, although it is not the drug of choice.

Itraconazole, like ketoconazole, requires an acid pH for absorption, so that blood levels may vary after oral administration. Acidic drinks (eg, cola, acidic fruit juices) or food may improve absorption. However, absorption may be lowered if itraconazole is taken with any prescription or OTC drugs used to lower gastric acidity. Several drugs may decrease serum itraconazole concentrations, including rifampin, rifabutin, didanosine, phenytoin, and carbamazepine. Itraconazole also inhibits metabolic degradation of other drugs, causing blood level elevations with potentially serious consequences. Serious, even fatal cardiac arrhythmias may occur if itraconazole is used with cisapride or some antihistamines, such as terfenadine, astemizole, and perhaps loratadine. Rhabdomyolysis has been associated with itraconazole-induced elevations in blood levels of cyclosporine or cholesterol-reducing drugs such as lovastatin or simvastatin. Blood level elevations of digoxin, tacrolimus, oral anticoagulants, or oral hypoglycemic drugs also may occur when these drugs are used with itraconazole.

In doses of up to 400 mg/day, the main side effects are GI-related, but a few men have reported impotence, and higher doses may cause hypokalemia, hypertension, and edema. Other reported side effects include allergic rash, hepatitis, and hallucinations.

• Flucytosine: Flucytosine, a nucleic acid analog, is water-soluble and well absorbed after oral administration. Preexisting or emerging resistance to the drug is common, so that it is almost always used with another antifungal drug, usually amphotericin B. Flucytosine combined with amphotericin B is primarily used to treat cryptococcosis but has also proven valuable for some cases of disseminated candidiasis, other yeast infections, and severe invasive aspergillosis. Occasionally, flucytosine alone has improved (but probably not completely cured) some cases of chromomycosis. Flucytosine has also been used in combination with antifungal azoles in recent trials. This latter combination has yielded promising preliminary results in cryptococcosis and some cases of other mycoses but remains experimental.

Source: Merck