TERMINOLOGY AND MICROBIOLOGY
Traditionally, fungal infections have been classified into specific categories based on both anatomic location and epidemiology. The most common general anatomic categories are mucocutaneous and deep organ infection; the most common general epidemiologic categories are endemic and opportunistic. Although mucocutaneous infections can cause serious morbidity, they are rarely fatal. Deep organ infections also cause severe illness in many cases but, in contrast to mucocutaneous infections, are often fatal.The endemic mycoses (e.g., coccidioidomycosis) are infections caused by fungal organisms that are not part of the normal human microbial flora and are acquired from environmental sources. In contrast, opportunistic mycoses are caused by organisms (e.g., Candida and Aspergillus) that frequently are components of the normal human flora and whose ubiquity in nature renders them easily acquired by the immunocompromised host.
Opportunistic fungi cause serious infections when the immunologic response of the host becomes ineffective, allowing the organisms to transition from harmless commensals to invasive pathogens. Frequently, the diminished effectiveness of the immune system is a result of advanced modern therapies that coincidentally either unbalance the host’s microflora or directly interfere with immunologic responses. Endemic mycoses cause more severe illness in immunocompromised patients than in immunocompetent individuals. Patients acquire infection with endemic fungi almost exclusively by inhalation.The soil is the natural reservoir for the vast majority of endemic mycoses.The dermatophytic fungi may be acquired by human-to-human transmission, but the majority of infections result from environmental contact. In contrast, the opportunistic fungus Candida invades the host from normal sites of colonization, usually the mucous membranes of the gastrointestinal tract. In general, innate immunity is the primary defense mechanism against fungi. Although antibodies are formed during many fungal infections (and even during commensalism), they generally do not constitute the primary mode of defense.
Nevertheless, in selected infections, as discussed below, measurement of antibody titers may be a useful diagnostic test. Three other terms frequently used in clinical discussions of fungal infections are yeast, mold, and dimorphic fungus. Yeasts are seen as rounded single cells or as budding organisms. Candida and Cryptococcus are traditionally classified as yeasts. Molds grow as filamentous forms called hyphae both at room temperature and when they invade tissue. Aspergillus, Rhizopus [the species that causes mucormycosis (zygomycosis)], and fungi commonly infecting the skin to cause ringworm and related cutaneous conditions are classified as molds.Variations occur within this classification of yeasts and molds. For instance, when Candida infects tissue, both yeasts and filamentous forms may occur (except with C. glabrata, which forms only yeasts in tissue); in contrast, Cryptococcus exists only in yeast form. Dimorphic is the term used to describe fungi that grow as yeasts or large spherical structures in tissue but as filamentous forms at room temperature in the environment. Classified in this group are the organisms causing blastomycosis, paracoccidioidomycosis, coccidioidomycosis, histoplasmosis, blastomycosis, and sporotrichosis. The incidence of fungal infections has risen substantially over the past several decades. Opportunistic infections have increased in frequency as a consequence of intentional immunosuppression in organ and stem cell transplantation and many other diseases, the administration of cytotoxic chemotherapy for cancers, and the liberal use of antibacterial agents.The incidence of endemic mycoses has increased in geographic locations where there has been substantial population growth.
The definitive diagnosis of any fungal infection requires histopathologic identification of the fungus invading tissue, accompanied by evidence of an inflammatory response.The identification of an inflammatory response has been especially important with regard to Aspergillus infection. Aspergillus is ubiquitous and can float from the air onto biopsy material. Therefore, in rare but important instances, this fungus is an ex vivo contaminant during processing of a specimen for microscopy, with a consequent incorrect diagnosis. The stains most commonly used to identify fungi are periodic acid–Schiff and Gomori methenamine silver. Candida, unlike other fungi, is visible on gram-stained tissue smears. Hematoxylin and eosin stain is not sufficient to identify Candida in tissue specimens. When positive, an India ink preparation of cerebrospinal fluid (CSF) is diagnostic for cryptococcosis. Most laboratories now use calcofluor white staining coupled with fluorescent microscopy to identify fungi in fluid specimens. Extensive investigations of the diagnosis of deep organ fungal infections have yielded a variety of tests with different degrees of specificity and sensitivity.The most reliable tests are the detection of antibody to Coccidioides immitis and Histoplasma capsulatum in serum and CSF, the detection of cryptococcal polysaccharide antigen in serum and CSF, and the detection of Histoplasma antigen in urine or serum. The test for galactomannan has been used extensively in Europe and is now approved in the United States for diagnosis of aspergillosis.
This test requires additional validation before its true usefulness can be determined. Sources of concern are the incidence of false-negative results and the need for multiple serial tests to reduce this incidence.The â-glucan test for Candida is also under evaluation but, like the galactomannan test, requires additional validation. Numerous polymerase chain reaction assays to detect antigens are in the developmental stages, as are nucleic acid hybridization techniques; however, these methods are not currently used on a widespread basis in major medical centers. Of the fungal organisms, Candida is by far most frequently recovered from blood. Although Candida species can be detected with any of the automated blood culture systems widely used at present, the lysis-centrifugation technique increases the sensitivity of blood cultures for less common organisms (e.g., H. capsulatum) and should be used when disseminated fungal infection is suspected. Except in the cases of coccidioidomycosis, cryptococcosis, and histoplasmosis, there are no fully validated and widely used tests for serodiagnosis of disseminated fungal infection. Skin tests for the endemic mycoses are no longer available. CHAPTER 102
This discussion is intended as a brief overview of general strategies for the use of antifungal agents in the treatment of fungal infections. Details on regimens, schedules, and strategies are discussed in the chapters on specific mycoses that follow in this section. Since fungal organisms are eukaryotic cells that contain most of the same organelles (with many of the same physiologic functions) as human cells, the identification of drugs that selectively kill or inhibit fungi but are not toxic to human cells has been highly problematic. Far fewer antifungal than antibacterial agents have been introduced into clinical medicine.
AMPHOTERICIN B (AmB)
The introduction of AmB in the late 1950s revolutionized the treatment of fungal infections in deep organs. Before AmB became available, cryptococcal meningitis and other disseminated fungal infections were nearly always fatal. For nearly a decade after AmB was introduced, it was the only effective agent for the treatment of life-threatening fungal infections. AmB remains the broadest-spectrum antifungal agent but carries several disadvantages, including significant nephrotoxicity, lack of an oral preparation, and unpleasant side effects (fever, chills, and nausea) during treatment. To circumvent nephrotoxicity and infusion side effects, lipid formulations of AmB were developed and have virtually replaced the original colloidal deoxycholate formulation in clinical use (although the older formulation is still available). The lipid formulations include liposomal AmB (L-AB; 435 mg/kg per day) and AmB lipid complex (ABLC; 5 mg/kg per day).
A third preparation, AmB colloidal dispersion (ABCD; 3–4 mg/kg per day), is rarely used because of the high incidence of side effects associated with infusion. (The doses listed are standard doses for adults with invasive infection.) The lipid formulations of AmB have the disadvantage of being considerably more expensive than the deoxycholate formulation. Experience is still accumulating on the comparative efficacy, toxicity, and advantages of the different formulations for specific clinical fungal infections [e.g., central nervous system (CNS) infection]. Whether there is a clinically significant difference in these drugs with respect to CNS penetration or nephrotoxicity remains controversial. Despite these issues and despite the expense, the lipid formulations are now much more commonly used than AmB deoxycholate in the United States.
This class of antifungal drugs offers important advantages over AmB: the azoles cause little or no nephrotoxicity and are available in oral preparations. Early azoles included ketoconazole and miconazole, which have been replaced by newer agents for the treatment of deep organ fungal infections. The azoles’ mechanism of action is inhibition of ergosterol synthesis in the fungal cell wall. Unlike AmB, these drugs are considered fungistatic, not cidal. Fluconazole Since its introduction, fluconazole has played an extremely important role in the treatment of a wide variety of serious fungal infections. Its major advantages are the availability of both oral and IV formulations, a long half-life, satisfactory penetration of most body fluids (including ocular fluid and CSF), and minimal toxicity (especially relative to AmB). Its disadvantages include (usually reversible) hepatotoxicity and—at high doses—alopecia, muscle weakness, and dry mouth with a metallic taste.
Fluconazole is not effective for the treatment of aspergillosis, mucormycosis, or Scedosporium apiospermum infections. It is less effective than the newer azoles against C. glabrata and C. krusei. Fluconazole has become the agent of choice for the treatment of coccidioidal meningitis, although relapses have followed therapy with this drug. In addition, fluconazole is useful for both consolidation and maintenance therapy for cryptococcal meningitis. This agent has been shown to be as efficacious as AmB in the treatment of candidemia. The effectiveness of fluconazole in candidemia and the drug’s relatively minimal toxicity, in conjunction with the inadequacy of diagnostic tests for widespread hematogenously disseminated candidiasis, have led to a change in the paradigm for candidemia management. The standard of care is now to treat all candidemic patients with an antifungal agent and to change all their intravascular lines, if feasible, rather than merely to remove a singular suspect intravascular line and then observe the patient.The usual fluconazole regimen for treatment of candidemia is 400 mg/d given until 2 weeks after the last positive blood culture. Fluconazole is considered effective as fungal prophylaxis in bone marrow transplant recipients and high-risk liver transplant patients. Its use for prophylaxis in patients with leukemia, in AIDS patients with low CD4+ T-cell counts, and in patients on surgical intensive care units remains controversial.
Voriconazole Like fluconazole, voriconazole is available in both oral and IV formulations. Voriconazole has a broader spectrum than fluconazole against Candida species (including C. glabrata and C. krusei) and is active against Aspergillus, Scedosporium, and Fusarium. It is generally considered the first-line drug of choice for treatment of aspergillosis. A few case reports have shown voriconazole to be effective in individual patients with coccidioidomycosis, blastomycosis, and histoplasmosis, but (because of limited data) this agent is not recommended for treatment of the endemic mycoses. Among the disadvantages of voriconazole (compared with fluconazole) are its more numerous interactions with many of the drugs used in patients predisposed to fungal infections. Hepatotoxicity, skin rashes (including photosensitivity), and visual disturbances are relatively common. Voriconazole is also considerably more expensive than fluconazole. Moreover, it is advisable to monitor voriconazole levels in certain patients since (1) this drug is completely metabolized in the liver by CYP2C9, CYP3A4, and CYP2C19; and (2) human genetic variability in CYP2C19 activity exists. Dosages should be reduced accordingly in those patients with liver failure. Dose adjustments for renal insufficiency are not necessary; however, because the IV formulation is prepared in cyclodextrin, it should not be given to patients with severe renal insufficiency. Itraconazole Itraconazole is available in IV and oral (capsule and suspension) formulations.
Varying blood levels among patients taking oral itraconazole reflect a disadvantage compared with the other azoles. Itraconazole is the drug of choice for mild to moderate histoplasmosis and blastomycosis and has often been used for chronic mucocutaneous candidiasis. It has been approved by the U.S. Food and Drug Administration (FDA) for use in febrile neutropenic patients. Itraconazole has also proven useful for the treatment of chronic coccidioidomycosis, sporotrichosis, and S. apiospermum infection. The mucocutaneous and cutaneous fungal infections that have been treated successfully with itraconazole include oropharyngeal candidiasis (especially in AIDS patients), tinea versicolor, tinea capitis, and onychomycosis. Disadvantages of itraconazole include its poor penetration into the CSF, the use of cyclodextrin in both the oral suspension and the IV preparation, the variable absorption of the capsules, and the need for monitoring of blood levels in patients taking capsules for disseminated mycoses. In recent years, reported cases of severe congestive heart failure in patients taking itraconazole have been a source of concern.
Like the other azoles, itraconazole can cause hepatic toxicity. Posaconazole Posaconazole is approved by the FDA for prophylaxis of aspergillosis and candidiasis in patients at high risk for developing these infections because of severe immunocompromise. This drug has also been evaluated for the treatment of zygomycosis, fusariosis, aspergillosis, and oropharyngeal candidiasis. The relevant studies of posaconazole in zygomycosis, fusariosis, and aspergillosis have examined salvage therapy. A study of >90 patients whose zygomycosis was refractory to other therapy yielded encouraging results. No trials of posaconazole for the treatment of candidemia have yet been reported. Case reports have described the drug’s efficacy in coccidioidomycosis and histoplasmosis. Controlled trials have shown its effectiveness as a prophylactic agent in patients with acute leukemia and in bone marrow transplant recipients. In addition, posaconazole has been found to be effective against fluconazole-resistant Candida species. The results of a large-scale study of the use of posaconazole as salvage therapy for aspergillosis have been promising but, as of this writing, have not been published in a peer-reviewed format.
The echinocandins, including the approved drugs caspofungin, anidulafungin, and micafungin, have added considerably to the antifungal armamentarium. All three of these agents inhibit â-1,3- glucan synthase, which is necessary for cell wall synthesis in fungi and is not a component of human cells. None of these agents is available in an oral formulation. The echinocandins are considered fungicidal for Candida and fungistatic for Aspergillus. Their greatest use to date is against candidal infections. They offer two advantages: broad-spectrum activity against all Candida species and relatively low toxicity. The minimum inhibitory concentrations (MICs) of all the echinocandins are highest against C. parapsilosis; it is not clear whether these higher MIC values represent less clinical effectiveness against this species. The echinocandins are among the safest antifungal agents. In controlled trials, caspofungin has been at least as efficacious as AmB for the treatment of candidemia and invasive candidiasis and as efficacious as fluconazole for the treatment of candidal esophagitis. In addition, caspofungin has been efficacious as salvage therapy for aspergillosis.
At present, it is used most extensively for the treatment of candidemic patients, especially before the infecting species is precisely identified. Anidulafungin has been approved by the FDA as therapy for candidemia in nonneutropenic patients and for Candida esophagitis, intraabdominal infection, and peritonitis. In controlled trials, anidulafungin has been more efficacious than fluconazole against candidemia and invasive candidiasis and as efficacious as fluconazole against candidal esophagitis. When anidulafungin is used with cyclosporine, tacrolimus, or voriconazole, no dosage 1003 adjustment is required for either drug in the combination. Micafungin has been approved for the treatment of esophageal candidiasis and for prophylaxis in patients receiving stem cell transplants. Studies thus far have shown that coadministration of micafungin and cyclosporine does not require dose adjustments for either drug. When micafungin is given with sirolimus, the AUC rises for sirolimus, usually necessitating a reduction in its dose. In open-label trials, favorable results have been obtained with micafungin for the treatment of deepseated Aspergillus and Candida infections.
The use of flucytosine has diminished in recent years as newer antifungal drugs have been developed. Flucytosine has a unique mechanism of action based on intrafungal conversion to 5-fluorouracil, which is toxic to the cell. Development of resistance to the compound has limited its use as a single agent. Flucytosine is nearly always used in combination with AmB. Its good penetration into the CSF makes it attractive for use with AmB for treatment of cryptococcal meningitis. Flucytosine has also been recommended for the treatment of candidal meningitis in combination with AmB; comparative trials with AmB alone have not been done. Significant and frequent bone marrow depression is seen with flucytosine when this drug is used with AmB.
GRISEOFULVIN AND TERBINAFINE
Historically, griseofulvin has been useful primarily for ringworm infection. This agent is usually given for relatively long periods. Terbinafine has been used primarily for onychomycosis but also for ringworm. In comparative studies, terbinafine has been as effective as itraconazole and more effective than griseofulvin for both conditions.
TOPICAL ANTIFUNGAL AGENTS
A detailed discussion of the agents used for the treatment of cutaneous fungal infections and onychomycosis is beyond the scope of this chapter; the reader is referred to the dermatology literature.Many classes of compounds have been used to treat the common fungal infections of the skin. Among the azoles used are clotrimazole, econazole, miconazole, oxiconazole, sulconazole, ketoconazole, tioconazole, butoconazole, and terconazole. In general, topical treatment of vaginal candidiasis has been successful. Since there is considered to be little difference in the efficacy of the various vaginal preparations, the choice of agent is made by the physician and/or the patient on the basis of preference and availability. Fluconazole given orally at 150 mg has the advantage of not requiring repeated intravaginal application. Nystatin is a polyene that has been used for both oropharyngeal thrush and vaginal candidiasis. Useful agents in other classes include ciclopirox olamine, haloprogin, terbinafine, naftifine, tolnaftate, and undecylenic acid.