Peggy L. Carver
Systemic mycoses can be caused by pathogenic fungi and include histoplasmosis, coccidioidomycosis, cryptococcosis, blastomycosis, paracoccidioidomycosis, and sporotrichosis, or infections by opportunistic fungi such as Candida albicans, Aspergillus species, Trichosporon, Candida glabrata, Fusarium, Alternaria, and Mucor.
The diagnosis of fungal infection generally is accomplished by careful evaluation of clinical symptoms, results of serologic tests, and histopathologic examination and culture of clinical specimens.
Histoplasmosis is caused by Histoplasma capsulatum and is endemic in parts of the central United States along the Ohio and Mississippi River valleys. Although most patients experience asymptomatic infection, some can experience chronic, disseminated disease.
Asymptomatic patients with histoplasmosis are not treated, although patients who do not have acquired immune deficiency syndrome (AIDS) patients with evident disease are treated with either oral ketoconazole or IV amphotericin B; AIDS patients are treated with amphotericin B and then receive lifelong suppression.
Blastomycosis is caused by Blastomyces dermatitidis. In the immunocompetent host, acute pulmonary blastomycosis can be mild and self-limited and may not require treatment. However, consideration should be given to treating all infected individuals to prevent extrapulmonary dissemination. All persons with moderate to severe pneumonia, disseminated infection, or those who are immunocompromised require antifungal therapy.
Coccidioidomycosis is caused by Coccidioides immitis and is endemic in some parts of the southwestern United States. It can cause nonspecific symptoms, acute pneumonia, or chronic pulmonary or disseminated disease. Primary pulmonary disease (unless severe) frequently is not treated, whereas extrapulmonary disease is treated with amphotericin B, and meningitis is treated with fluconazole.
Cryptococcosis is caused by Cryptococcus neoformans, which occurs primarily in immunocompromised patients, and Cryptococcus gattii, which occurs primarily in nonimmunocompromised patients. Patients with acute meningitis are treated with amphotericin B with flucytosine. Patients infected with human immunodeficiency virus (HIV) often require long-term suppressive therapy with fluconazole or itraconazole.
A variety of Candida species (including C. albicans, C. glabrata, Candida tropicalis, Candida parapsilosis, and Candida krusei) can cause diseases such as mucocutaneous, oral, esophageal, vaginal, and hematogenous candidiasis, as well as candiduria. Candidemia can be treated with a variety of antifungal agents; the optimal choice depends on previous patient exposure to antifungal agents, potential drug interactions and toxicities of each agent, and local epidemiology of intensive care unit (ICU) or hematology–oncology centers.
Aspergillosis can be caused by a variety of Aspergillus species that can cause superficial infections, pneumonia, allergic bronchopulmonary aspergillosis (BPA), or invasive infection. Voriconazole has emerged as the drug of choice of most clinicians for primary therapy of most patients with invasive aspergillosis (IA). Combination therapy, while widely used, lacks clinical trial data to support its use.
For many years, fungal infections were classified as either superficial “nuisance diseases,” such as athlete’s foot or vulvovaginal candidiasis, or as relatively rare infections confined primarily to endemic areas of the country. When invasive fungal infections were encountered, amphotericin B was the only consistently effective, systemically active agent available for the treatment of systemic mycoses. Advances in medical technology including organ and bone marrow transplantation, cytotoxic chemotherapy, the widespread use of indwelling IV catheters, and the increased use of potent broad-spectrum antimicrobial agents all have contributed to the dramatic increase in the incidence of fungal infections worldwide.
Fungal infections have emerged as a major cause of death among cancer patients and transplant recipients.1–3 In addition, patients with acquired immune deficiency syndrome (AIDS) experience substantially more frequent and severe forms of cryptococcosis, histoplasmosis, coccidioidomycosis, and mucocutaneous (esophageal, oral, and vulvovaginal) candidiasis.
Problems remain in the diagnosis, prevention, and treatment of fungal infections. Unlike the available diagnostic techniques for most bacterial pathogens, there remains a host of unresolved issues regarding standardization of susceptibility testing methods, in vitro and in vivo models of infection, the usefulness of monitoring antifungal plasma concentrations, and the development and identification of resistant pathogens.1,4–6 The Infectious Diseases Society of America (IDSA) publishes guidelines for the treatment of many commonly encountered fungal infections.7–12 These guidelines provide summaries of the literature and a consensus of expert opinions regarding the treatment of these difficult infections.
Fungi are eukaryotic organisms with a defined nucleus enclosed by a nuclear membrane; a cytoplasmic membrane containing lipids, glycoproteins, and sterols, mitochondria, Golgi apparatus, and ribosomes bound to endoplasmic reticulum; and a cytoskeleton with microtubules, microfilaments, and intermediate filaments. Fungi have rigid cell walls composed of chitin, cellulose, or both that stain with Gomori methenamine silver or periodic acid–Schiff reagent. Most fungi, except Candida species, are too weakly gram-positive to be seen well on Gram stain. Cryptococcus neoformans has a polysaccharide capsule surrounding the cell wall.1
Morphologically, pathogenic fungi can be grouped as either filamentous molds or unicellular yeasts (Fig. 99–1). Molds grow as multicellular branching, threadlike filaments (hyphae) that are either septate (divided by transverse walls) or coenocytic (multinucleate without cross walls). On agar media, molds grow outward from the point of inoculation by extension of the tips of filaments and then branch repeatedly, interweaving to form fuzzy, matted growths called mycelia. Yeasts are oval or spherically shaped unicellular forms that generally produce pasty or mucoid colonies on agar medium similar to those observed with bacterial cultures. Yeasts have rigid cell walls and reproduce by budding, a process in which daughter cells arise from pinching off a portion of the parent cell.
FIGURE 99-1 Morphologically, pathogenic fungi can be grouped as either filamentous molds or unicellular yeasts. Molds grow as multicellular branching, thread-like filaments (hyphae) that are either septate (divided by transverse walls) or coenocytic (multinucleate without cross walls).
Many pathogenic fungi, termed dimorphic fungi, exist as either a yeast or a mold, depending on pathogen, site of growth (in the host or in the laboratory setting), and temperature. Usually yeasts are the parasitic form that invades human or animal host tissue, whereas molds are the free-living form found in the environment. For example, Histoplasma capsulatum exists as a yeast in humans and as a mold in the laboratory.1
Susceptibility Testing of Antifungal Agents
Most laboratories do not routinely perform susceptibility tests on fungal isolates, but standardized methods for performing these tests are being developed and are now available for testing selected yeasts.
The Clinical and Laboratory Standards Institute (CLSI) defined clinical breakpoints (CBPs) for fluconazole, itraconazole, voriconazole, and flucytosine for all Candida species. Breakpoints are antimicrobial concentrations (MICs) obtained from susceptibility testing, which are used to define isolates as susceptible, intermediate, or resistant. No CBPs have been established for posaconazole or amphotericin B versus Candida.6 (Tables 99–1 and 99-2). Reliable and convincing interpretive breakpoints are not yet available for amphotericin B since available methodology does not reliably identify amphotericin B-resistant isolates.5–7 The breakpoints should be used following testing with the standardized, reproducible laboratory methodology used to develop the test and they should be interpreted in the context of the delivered dose of the antifungal agent.
TABLE 99-1 General Patterns of Susceptibility and Interpretive Breakpoints of Candida Speciesa
TABLE 99-2 General Patterns of In Vitro Susceptibility of Non-Candida Fungal Pathogensa
Host factors contribute greatly to clinical outcome. A patient may respond clinically to treatment with an antifungal agent despite resistance to that agent in vitro because the patient’s own immune system may eradicate the infection, or the agent may reach the site of infection in high concentrations.13 Thus, in vitro susceptibility does not necessarily equate with in vivo clinical success, and in vitro resistance might not always correlate with treatment failure.
CBPs are based primarily on pharmacokinetic–pharmacodynamic relationships but do take into account other factors, such as differences in dosing regimens, toxicology, resistance mechanisms, intended or approved indications for use, clinical outcome data, and wild type (WT; i.e., the typical strain as it occurs in nature) MIC distributions. CBPs can be used to differentiate strains for which there is a high likelihood of treatment success (organisms which are clinically susceptible, or [S]), from those for which treatment is more likely to fail (clinically resistant [R]). A clinically intermediate (I) or susceptible dose-dependent (SDD) category can be assigned to pathogens for which the level of antimicrobial agent activity is associated with uncertain therapeutic effect, implying that infections due to the isolate may be appropriately treated in body sites where the drugs are physically concentrated or when a high dosage of drug can be used. Although CBPs are designed to guide therapy, they do not distinguish between fungal isolates with or without resistance mechanisms, nor do they always allow for early detection of resistant isolates.
Susceptibility testing occasionally is indicated, for example, in a patient with prolonged fungemia with a presumed susceptible isolate. Because of wide interlaboratory variability in test results, isolates should be tested at specialty laboratories that routinely perform these specialized tests. Susceptibility testing is most helpful in dealing with infections caused by non-albicans species of Candida.5–7
Resistance to Antifungal Agents
It is important to distinguish between clinical resistance and microbial resistance. Clinical resistance refers to failure of an antifungal agent in the treatment of a fungal infection that arises from factors other than microbial resistance, such as failure of the antifungal agent to reach the site of infection or inability of a patient’s immune system to eradicate a fungus whose growth is retarded by an antifungal agent.13
Microbial resistance can refer to primary or secondary resistance, as determined by in vitro susceptibility testing using standardized methodology. Primary or intrinsic resistance refers to resistance recorded prior to drug exposure in vitro or in vivo. Secondary or acquired resistance develops on exposure to an antifungal agent and can be either reversible, owing to transient adaptation, or acquired as a result of one or more genetic alterations. The clinical consequences of antifungal resistance can be observed in treatment failures and in changes in the prevalences of Candida species causing disease.13
The most exhaustive and definitive accounts of antifungal resistance have been described in Candida species, in particular Candida albicans and, to a lesser extent, Candida glabrata, Candida tropicalis, and Candida krusei, as well as in a few C. neoformans isolates.14 There are four different mechanisms that result in azole resistance: (a) mutations or upregulation of ERG11 (an enzyme involved in the ergosterol biosynthesis pathway), (b) expression of multidrug efflux transport pumps that decrease antifungal drug accumulation within the fungal cell, (c) alteration of the structure or concentration of antifungal drug target proteins, and (d) alteration of membrane sterol proteins (Fig. 99–2). It is beyond the scope of this chapter to provide a complete discussion of the biochemical mechanisms of fungal resistance. Interested readers are referred to several excellent reviews concerning this topic.13,14
FIGURE 99-2 Mechanisms of azole resistance. Four different mechanisms result in azole resistance: (a) mutations or upregulation of ERG11, the target enzyme of azoles, (b) expression of multidrug efflux transport pumps that decrease antifungal drug accumulation within the fungal cell, (c) alteration of the structure or concentration of antifungal drug target proteins, and (d) alteration of membrane sterol proteins.
Among hospitalized patients, there is increasing evidence for a shift toward isolation of other resistant species, such as C. glabrata and C. krusei, that have moderate or high-level resistance to fluconazole. This phenomenon has been especially common among patients in whom fluconazole has been used extensively.3
The most commonly reported mechanisms of azole resistance among C. albicans isolates include reduced permeability of the fungal cell membrane to azoles, alteration in the target fungal enzymes (cytochrome P450, CYP) resulting in decreased binding of the azole to the target site, and overproduction of the fungal CYP enzymes. Studies also suggest the presence of efflux pumps capable of actively pumping azoles from the target pathogen, thereby conferring multidrug resistance to azole antifungals.13,14 C. glabrata isolates are increasingly resistant to both azole and echinocandin antifungal agents.
Although rare, in vitro intrinsic resistance to amphotericin B is described, primarily in Candida lusitaniae, Candida guilliermondii, and some molds (Fusarium spp. and Pseudallescheria boydii).6 Although the rate of apparent resistance to amphotericin B appears to be quite low, breakthrough bacteremias in patients treated with amphotericin B have been observed. C. glabrata, C. guilliermondii, C. krusei, and C. lusitaniae appear to have a higher propensity than other Candida species to develop resistance to amphotericin B; this point should be kept in mind when treating patients with infections caused by one of these pathogens.6,13 Acquired resistance of Aspergillus species to azoles or echinocandins is relatively uncommon.
Resistant isolates of C. neoformans have been reported to have a mutation in the C8 isomerization step of ergosterol synthesis.6 Current guidelines for the management of cryptococcal infections recommend susceptibility testing only for patients in whom primary treatment has failed, patients with relapse, and for those with recent exposure to antifungals.6 Acquired resistance of Candida species to echinocandins is typically mediated via one of several mechanisms: acquisition of, or intrinsic possession of point mutations in the FKS genes encoding the major subunit of its target enzyme.6
PATHOGENESIS AND EPIDEMIOLOGY
Systemic mycoses caused by primary or pathogenic fungi include histoplasmosis, coccidioidomycosis, cryptococcosis, blastomycosis, paracoccidioidomycosis, and sporotrichosis. Primary pathogens can cause disease in both healthy and immunocompromised individuals, although disease generally is more severe or disseminated in the immunocompromised host. In contrast, mycoses caused by opportunistic fungi such as C. albicans, Aspergillus species, Trichosporon, Torulopsis (Candida) glabrata, Fusarium, Alternaria, and Mucor generally are found only in the immunocompromised host.1
Most fungal infections are acquired as a result of accidental inhalation of airborne conidia. For example, H. capsulatum is found in soil contaminated by bat, chicken, or starling excreta, and C. neoformans is associated with pigeon droppings. Although some fungi, including C. albicans, C. neoformans, and Aspergillus species, are ubiquitous pathogens with worldwide distribution, other fungi have regional distributions associated with specific geographic environments.1
Systemic fungal infections are a major cause of morbidity and mortality in the immunocompromised patient. Fungal infections account for 20% to 30% of fatal infections in patients with acute leukemia, 10% to 15% of fatal infections in patients with lymphoma, and 5% of fatal infections in patients with solid tumors. The frequency of fungal infections among transplant recipients ranges from 0% to 20% for kidney and bone marrow transplant recipients, to 10% to 35% for heart transplant recipients, and 30% to 40% for liver transplant recipients.15,16
Approximately 2% to 4% of all hospitalized patients develop a nosocomial infection. Of these, bacteria comprise the most common etiologic agent.1 Fungi, however, are becoming increasingly significant nosocomial pathogens. Fungi account for 10% of all bloodstream isolates. Candida species (primarily C. albicans) are the fourth most commonly isolated bloodstream isolate and account for 78% of all nosocomial fungal infections.17
Nosocomially acquired fungal infections can arise from either exogenous or endogenous flora. Endogenous flora can include normal commensal organisms of the skin, GI, genitourinary, or respiratory tract. C. albicans is found as a normal commensal of the GI tract in 20% to 30% of humans.
A complex interplay of host and pathogen factors influences the acquisition and development of fungal infections. Intact skin or mucosal surfaces serve as primary barriers to infection. Desiccation, epithelial cell turnover, fatty acid content, and low pH of the skin are believed to be important factors in host resistance. Bacterial flora of the skin and mucous membranes compete with fungi for growth. Alterations in the balance of normal flora caused by the use of antibiotics or alterations in nutritional status can allow the proliferation of fungi such as Candida, increasing the likelihood of systemic invasion and infection.1
Tissue reaction in the presence of fungi varies with fungal species, site of proliferation, and duration of infection. Phagocytosis by neutrophils and macrophages is the earliest mechanism that prevents the establishment of fungi. Consequently, patients with decreased neutrophil counts or decreased neutrophil function are at higher risk of infections, particularly infections caused by Candida and Aspergillusspecies. Some mycoses are characterized by a low-grade inflammatory response that does not eliminate the fungi. Fungal cells sometimes can persist within macrophages without being killed, perhaps because of resistance to the effects of lysosomal enzymes.1
The diagnosis of invasive fungal infections generally is accomplished by careful evaluation of clinical symptoms, results of serologic tests, and histopathologic examination and culture of clinical specimens. Skin tests generally are not useful diagnostically because they do not distinguish between active and past infection. They remain useful as screening tools and in epidemiologic studies to determine endemic areas. It is beyond the scope of this chapter to discuss the relative merits of each of the immunologic tests used in the diagnosis of invasive fungal infections. Interested readers, however, are referred to several excellent reviews concerning this topic.18,19
Strategies for the prevention or treatment of invasive mycoses can be classified broadly as prophylaxis, early empirical therapy, empirical therapy, and secondary prophylaxis or suppression.1 In patients undergoing cytotoxic chemotherapy, antifungal therapy is directed primarily at the prevention or treatment of infections caused by Candida and Aspergillus species. Prophylactic therapy with topical, oral, or IV antifungal agents is administered prior to and throughout periods of granulocytopenia (absolute neutrophil count <1,000 cells/L). The potential benefits of prophylactic therapy must be weighed against the potential risks inherent in each regimen, including safety, efficacy, cost, the prevalence of infection, and the potential consequences (e.g., resistance) of widespread use.
Early empirical therapy is the administration of systemic antifungal agents at the onset of fever and neutropenia. Empirical therapy with systemic antifungal agents is administered to granulocytopenic patients with persistent or recurrent fever despite the administration of appropriate antimicrobial therapy.
Secondary prophylaxis (or suppressive therapy) is the administration of systemic antifungal agents (generally prior to and throughout the period of granulocytopenia) to prevent relapse of a documented invasive fungal infection that was treated during a previous episode of granulocytopenia.
Although these treatment classifications also have been applied to the treatment of fungal infections in AIDS, patients with AIDS rarely acquire systemic infections caused by Candida or Aspergillus species, unless they become granulocytopenic because of disease or drugs. The use of antifungal prophylaxis is much less widely studied in this population, although studies suggest that early antifungal prophylaxis with fluconazole or itraconazole decreases the incidence of invasive cryptococcal disease among adult patients who have advanced human immunodeficiency virus (HIV) disease and severe immune suppression (CD4 count <50 cells/mm3 [<50 × 106/L]). However, neither of these interventions showed a clear effect on mortality.9 Suppressive therapy generally is necessary following acute therapy for histoplasmosis, coccidioidomycosis, and cryptococcosis because of the high rates of relapse when antifungal therapy is discontinued.
In humans, histoplasmosis is caused by inhalation of dust-borne microconidia of the dimorphic fungus H. capsulatum. Although there exist two dimorphic varieties of H. capsulatum, the small-celled (2 to 5 microns) form (var. capsulatum) occurs globally, whereas the large-celled (8 to 15 microns) form (var. duboisii) is confined to the African continent and Madagascar. In tissues stained by conventional techniques, H. capsulatum appears as an oval or round, narrow-pore, budding, unencapsulated yeast.20
Although histoplasmosis is found worldwide, certain areas of North and Central America are recognized as endemic areas. In the United States, most disease is localized along the Ohio and Mississippi River valleys, where more than 90% of residents may be affected. Precise reasons for this endemic distribution pattern are unknown but are thought to include moderate climate, humidity, and soil characteristics. H. capsulatum is found in nitrogen-enriched soils, particularly those heavily contaminated by avian or bat guano, which accelerates sporulation. Blackbird or pigeon roosts, chicken coops, and sites frequented by bats, such as caves, attics, or old buildings, serve as “microfoci” of infections; once contaminated, soils yield Histoplasma for many years. Although birds are not infected because of their high body temperature, bats (mammals) may be infected and can pass yeast forms in their feces, allowing the spread of H. capsulatum to new habitats. Air currents carry the spores for great distances, exposing individuals who were unaware of contact with the contaminated site.20
At ambient temperatures, H. capsulatum grows as a mold. The mycelial phase consists of septate branching hyphae with terminal micro- and macroconidia that range in size from 2 to 14 microns in diameter. When soil is disturbed, these conidia become aerosolized and reach the bronchioles or alveoli.20
Animal studies demonstrate that within 2 to 3 days after reaching lung tissue, the conidia germinate, releasing yeast forms that begin multiplying by binary fission. During the next 9 to 15 days, organisms are ingested but not destroyed by large numbers of macrophages that are recruited to the infected site, resulting in small infiltrates. Infected macrophages migrate to the mediastinal lymph nodes and other sites within the mononuclear phagocyte system, particularly the spleen and liver. At this time, the onset of specific T-cell immunity in the nonimmune host activates the macrophages, rendering them capable of fungicidal activity. Tissue granulomas form, many of which develop central caseation and necrosis over the next 2 to 4 months. Over a period of several years, these foci become encapsulated and calcified, often with viable yeast trapped within the necrotic tissue.20,21
Cellular immunity, as measured by histoplasmin skin-test reactivity, wanes in the absence of occasional reexposure. Although exposure to heavy inocula can overcome these immune mechanisms, resulting in severe disease, reinfection occurs frequently in endemic areas. In the immune individual, the reactions of acquired immunity begin 24 to 48 hours after the appearance of yeast forms, resulting in milder forms of illness and little proliferation of organisms. Although viable organisms can be found within granulomas years after initial infection, the organisms appear to have little ability to proliferate within the fibrous capsules, except in immunocompromised patients.20,21
The outcome of infection with H. capsulatum depends on a complex interplay of host, pathogen, and environmental factors.10,20,21 Host factors include the degree of immunosuppression and the presence of immunity (from prior infection). Environmental factors include inoculum size, exposure within an enclosed area, and duration of exposure. Hematogenous dissemination from the lungs to other tissues probably occurs in all infected individuals during the first 2 weeks of infection before specific immunity has developed but is nonprogressive in most cases, which leads to the development of calcified granulomas of the liver and/or spleen. Progressive pulmonary infection is common in patients with underlying centrilobular emphysema.
Acute and chronic manifestations of histoplasmosis appear to result from unusual inflammatory or fibrotic responses to the pathogen, including pericarditis and rheumatologic syndromes during the first year after exposure, with chronic mediastinal inflammation or fibrosis, broncholithiasis, and enlarging parenchymal granulomas later in the course of disease.
Acute Pulmonary Histoplasmosis
In the vast majority of patients, low-inoculum exposure to H. capsulatum results in mild or asymptomatic pulmonary histoplasmosis. The course of disease generally is benign, and symptoms usually abate within a few weeks of onset. Patients exposed to a higher inoculum during an acute primary infection or reinfection can experience an acute, self-limited illness with flu-like pulmonary symptoms, including fever, chills, headache, myalgia, and a nonproductive cough. Patients with diffuse pulmonary histoplasmosis can have diffuse radiographic involvement, become hypoxic, and require ventilatory support. A low percentage of patients present with arthritis, erythema nodosum, pericarditis, or mediastinal granuloma.
Chronic Pulmonary Histoplasmosis
Chronic pulmonary histoplasmosis generally presents as an opportunistic infection imposed on a preexisting structural abnormality, such as lesions resulting from emphysema. Patients demonstrate chronic pulmonary symptoms and apical lung lesions that progress with inflammation, calcified granulomas, and fibrosis. Patients with early, noncavitary disease often recover without treatment. Progression of disease over a period of years, seen in 25% to 30% of patients, is associated with cavitation, bronchopleural fistulas, extension to the other lung, pulmonary insufficiency, and often death.
In patients exposed to a large inoculum and in immunocompromised hosts, successful containment of the organism within macrophages may not occur, resulting in a progressive illness characterized by yeast-filled phagocytic cells and an inability to produce granulomas. This disease, termed disseminated histoplasmosis, is characterized by persistent parasitization of macrophages. The clinical severity of the diverse forms of disseminated histoplasmosis (Table 99–3) generally parallels the degree of macrophage parasitization observed.
TABLE 99-3 Clinical Manifestations and Therapy of Histoplasmosis
Acute (infantile) disseminated histoplasmosis is characterized by massive involvement of the mononuclear phagocyte system by yeast-engorged macrophages. Classically, this severe type of infection is seen in infants and young children and (rarely) in adults with Hodgkin’s disease or other lymphoproliferative disorders. In infants or children, acute disseminated histoplasmosis is characterized by unrelenting fever, anemia, leukopenia or thrombocytopenia, enlargement of the liver, spleen, and visceral lymph nodes, and GI symptoms, particularly nausea, vomiting, and diarrhea. The chest roentgenogram often demonstrates remnants of the initiating acute pulmonary lesion. Untreated disease is uniformly fatal in 1 to 2 months. A less severe “subacute” form of the disease, which occurs in both infants and immunocompetent adults, is characterized by focal destructive lesions in various organs, weight loss, weakness, fever, and malaise. Untreated disease generally is fatal in approximately 10 months.
Most adults with disseminated histoplasmosis demonstrate a mild, chronic form of the disease. Untreated patients often are ill for 10 to 20 years, demonstrating long asymptomatic periods interrupted by relapses of clinical illness characterized primarily by weight loss, weakness, and fatigue. Chronic disseminated histoplasmosis can be seen in patients with lymphoreticular neoplasms (Hodgkin’s disease) and patients undergoing immunosuppressant chemotherapy for organ transplantation or for rheumatic diseases. Although CNS involvement occurs in 10% to 20% of patients with severe underlying immunosuppressive conditions, focal organ involvement is uncommon. The disease is characterized by the development of focal granulomatous lesions, often with bone marrow involvement resulting in thrombocytopenia, anemia, and leukemia. Fever, hepatosplenomegaly, and GI ulceration are common.
Histoplasmosis in HIV-Infected Patients
Adult patients with AIDS demonstrate an acute form of disseminated disease that resembles the syndrome seen in infants and children. Progressive disseminated histoplasmosis (PDH), which is defined as a clinical illness that does not improve after at least 3 weeks of observation and that is associated with physical or radiographic findings and/or laboratory evidence of involvement of extrapulmonary tissues, can occur as the direct result of initial infection or because of the reactivation of dormant foci. In endemic areas, 50% of AIDS patients demonstrate PDH as the first manifestation of their disease. PDH is characterized by fever (75% of patients), weight loss, chills, night sweats, enlargement of the spleen, liver, or lymph nodes, and anemia. Pulmonary symptoms occur in only one third of patients and do not always correlate with the presence of infiltrates on chest roentgenogram. A clinical syndrome resembling septicemia is seen in approximately 25% to 50% of patients.21
Detection of single, yeastlike cells 2 to 5 microns in diameter with narrow-based budding by direct examination or by histologic study of blood smears or tissues should raise strong suspicion of infection with H. capsulatum because colonization does not occur as with Aspergillus or Candida infection. Identification of mycelial isolates from clinical cultures can be made by conversion of the mycelium to the yeast form (requires 3 to 6 weeks) or through a rapid (2 hours) and 100% sensitive chemiluminescent DNA probe that recognizes ribosomal DNA. In patients with suspected disseminated or chronic cavitary histoplasmosis, 2 to 3 blood, sputum, and bone marrow cultures and stains should be obtained using the lysis centrifugation (Isolator tube) technique, and the cultures should be held for 14 to 21 days for optimal yield of H. capsulatum. In patients with acute self-limited histoplasmosis, extensive testing to verify the diagnosis may not be necessary.
In most patients, serologic evidence remains the primary method in the diagnosis of histoplasmosis. Results obtained from commercially available complement fixation (CF), immunodiffusion (ID), and latex agglutination (LA) antibody tests are used alone or in combination. In general, the use of histoplasmin skin tests is of little value except in epidemiologic studies because histoplasmin reactivity waxes in the absence of occasional reexposure. In addition, histoplasmin skin testing can result in a false increase in the CF titer for mycelial antigen (CF-M) to H. capsulatum. A fourfold rise in the CF titer is usually indicative of recent infection, although some patients with severe disease or profound immunosuppression can demonstrate a weaker antibody response. CF titers remain positive for many years, since CF antibodies persist after infection. Because the ID test is more specific but less sensitive than CF, it should be used to assess the importance of weakly reactive results obtained by CF rather than as a screening procedure.
In the AIDS patient with PDH, the diagnosis is best established by bone marrow biopsy and culture, which yield positive cultures in more than 90% of patients, although blood cultures and histopathologic examination and culture of pulmonary tissue, sputum, skin, and lymph nodes also can be helpful. Detection of H. capsulatum polysaccharide antigen (HPA) in urine, blood, or cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay (ELISA) or by modified radioimmunoassay (RIA) offer promising new techniques for the rapid diagnosis of histoplasmosis. The HPA (by RIA) levels also have been used successfully to monitor the course of therapy and to detect relapses in patients with AIDS, and the clearance of antigen from serum and urine correlates with clinical efficacy during maintenance therapy with itraconazole.21
Table 99–3 summarizes the recommended therapy for the treatment of histoplasmosis. In general, asymptomatic or mildly ill patients and patients with sarcoid-like disease do not benefit from antifungal therapy. In the vast majority of patients, low-inoculum exposure to H. capsulatum results in mild or asymptomatic pulmonary histoplasmosis. The course of disease generally is benign, and symptoms usually abate within a few weeks of onset. Therapy can be helpful in symptomatic patients whose conditions have not improved during the first month of infection. Fever persisting more than 3 weeks can indicate that the patient is developing progressive disseminated disease, which can be aborted by antifungal therapy. Whether antifungal therapy hastens recovery or prevents complications is unknown because it has never been studied in prospective trials.
Fluconazole remains a second-line agent for the treatment of histoplasmosis. Clinical data regarding the use of newer azoles such as voriconazole and posaconazole are limited. While both have activity against Histoplasma, posaconazole appears to be more active than itraconazole in the immune compromised and nonimmune compromised mouse model of infection, while voriconazole has not been tested in animal models. Both agents have been used successfully in a few patients. Of note, the echinocandins have no activity against Histoplasma.
Patients with mild, self-limited disease, chronic disseminated disease, or chronic pulmonary histoplasmosis who have no underlying immunosuppression usually can be treated with either oral itraconazole or IV amphotericin B. The goals of therapy are resolution of clinical abnormalities, prevention of relapse, and eradication of infection whenever possible, although chronic suppression of infection can be adequate in immunosuppressed patients, including those with HIV disease.10,21
In AIDS patients, intensive 12-week primary antifungal therapy (induction and consolidation therapy) is followed by lifelong suppressive (maintenance) therapy with itraconazole. Amphotericin B dosages of 50 mg/day (up to 1 mg/kg per day) should be administered IV to a cumulative dose of 15 to 35 mg/kg (1 to 2 g) in patients who require hospitalization. Amphotericin B can be replaced with itraconazole 200 mg orally twice daily when the patient no longer requires hospitalization or IV therapy to complete a 12-week total course of induction therapy. In patients who do not require hospitalization, itraconazole therapy for 12 weeks can be used.
Fluconazole 800 mg/day orally as induction, followed by 400 mg/day, was effective in 88% of patients, but relapses occurred in approximately one third of patients, and in vitro resistance developed in approximately 50% of patients who relapsed.
In regions experiencing high rates of histoplasmosis (>5 cases/100 patient-years), itraconazole 200 mg/day is recommended as prophylactic therapy in HIV-infected patients. Fluconazole is not an acceptable alternative because of its inferior activity against H. capsulatum and its lower efficacy for the treatment of histoplasmosis.10
Although patients receiving secondary prophylaxis (chronic maintenance therapy) might be at low risk for recurrence of systemic mycosis when their CD4+ T lymphocyte counts increase to >100 cells/μL (>100 × 106/L) in response to highly active antiretroviral therapy (HAART), the number of patients who have been evaluated is insufficient to warrant a recommendation to discontinue prophylaxis.
Evaluation of Therapeutic Outcomes
Response to therapy should be measured by resolution of radiologic, serologic, and microbiologic parameters and by improvement in signs and symptoms of infection. Although investigators are limited by the lack of standardized criteria to quantify the extent of infection, degree of immunosuppression, or treatment response, response rates (based on resolution or improvement in presenting signs and symptoms) of greater than 80% have been reported in case series in AIDS patients receiving varied dosages of amphotericin B. Rapid responses are reported, with the resolution of symptoms in 25% and 75% of patients by days 3 and 7 of therapy, respectively.
After the initial course of therapy for histoplasmosis is complete, lifelong suppressive therapy with oral azoles or amphotericin B (1 to 1.5 mg/kg weekly or biweekly) is recommended because of the frequent recurrence of infection. Relapse rates in AIDS patients not receiving maintenance therapy range from 50% to 90%.10
Antigen testing can be useful for monitoring therapy in patients with disseminated histoplasmosis. Antigen concentrations decrease with therapy and increase with relapse.
North American blastomycosis is a systemic fungal infection caused by Blastomyces dermatitidis, a dimorphic fungus that infects primarily the lungs. Patients, however, can present with a variety of pulmonary and extrapulmonary clinical manifestations. Pulmonary disease can be acute or chronic and can mimic infection with tuberculosis, pyogenic bacteria, other fungi, or malignancy. Blastomycosis can disseminate to virtually every other body organ, and approximately 40% of patients with blastomycosis present with skin, bone and joint, or genitourinary tract involvement without any evidence of pulmonary disease.8,22
Pulmonary infection probably occurs by inhalation of conidia, which convert to the yeast form in the lung. A vigorous inflammatory response ensues, with neutrophilic recruitment to the lungs followed by the development of cell-mediated immunity and the formation of noncaseating granulomas.
Blastomycosis was renamed North American blastomycosis in 1942, when Conant and Howell named a similar fungus endemic to South America, Blastomyces braziliensis, and the disease it caused South American blastomycosis. Although the disease is now recognized to be endemic to the southeastern and south central states of the United States (especially those bordering on the Mississippi and Ohio River basins) and the midwestern states and Canadian provinces bordering the Great Lakes, numerous cases of North American blastomycosis have been diagnosed in Africa, northern parts of South America, India, and Europe. Endemic areas have been defined primarily by analysis of sporadic cases and epidemics or clusters of disease because the lack of a dependable skin or laboratory test makes wide-scale epidemiologic testing to determine the incidence of infection unfeasible at present.8,19,22 Although initial review of sporadic cases suggested that males with outdoor occupations that exposed them to soil were at greatest risk for blastomycosis, there is no sex, age, or occupational predilection for blastomycosis.8,19,22
Although B. dermatitidis generally is considered to be a soil inhabitant, attempts to isolate the organism in nature frequently have been unsuccessful. B. dermatitidis has been isolated from soil containing decayed vegetation, decomposed wood, and pigeon manure, frequently in association with warm, moist soil of wooded areas that is rich in organic debris.8,19,22
Pathophysiology and Clinical Presentation
Colonization does not occur with Blastomyces.8,19,22 Acute pulmonary blastomycosis generally is an asymptomatic or self-limited disease characterized by fever, shaking chills, and productive, purulent cough, with or without hemoptysis, in immunocompetent individuals. The clinical presentation can be difficult to differentiate from other respiratory infections, including bacterial pneumonia, on the basis of clinical symptoms alone.
Sporadic (nonepidemic) pulmonary blastomycosis can present as a more chronic or subacute disease, with low-grade fever, night sweats, weight loss, and productive cough that resembles tuberculosis rather than bacterial pneumonia. Chronic pulmonary blastomycosis is characterized by fever, malaise, weight loss, night sweats, chest pain, and productive cough. Patients often are thought to have tuberculosis and frequently have evidence of disseminated disease that can appear 1 to 3 years after the primary pneumonia has resolved. Reactivation of disease can occur in the lungs or as the focus of new infection in other organs.
In approximately 40% of patients, dissemination is not accompanied by reactivation of pulmonary disease. The most common sites for disseminated disease include the skin and bony skeleton, although less commonly the prostate, oropharyngeal mucosa, and abdominal viscera are involved. CNS disease, while exceedingly uncommon, is associated with the highest mortality rate.
Laboratory and Diagnostic Tests
The simplest and most successful method of diagnosing blastomycosis is by direct microscopic visualization of the large, multinucleated yeast with single, broad-based buds in sputum or other respiratory specimens following digestion of cells and debris with 10% potassium hydroxide.8,19 Histopathologic examination of tissue biopsies and culture of secretions also should be used to identify B. dermatitidis, although it can require up to 30 days to isolate and identify a small inoculum.
No reliable skin test exists to determine the incidence and prevalence of disease in endemic populations, and reliable serologic diagnosis of blastomycosis has long been hampered by the lack of specific and standardized reagents. Serologic response does not always correlate with clinical improvement, although some investigators have noted that a decline in the number of precipitins or CF titers can offer evidence of a favorable prognosis in patients with established disease.
Acute pulmonary blastomycosis generally is an asymptomatic or self-limited disease characterized by fever, shaking chills, and productive, purulent cough, with or without hemoptysis, in immunocompetent individuals. The clinical presentation can be difficult to differentiate from other respiratory infections, including bacterial pneumonia, on the basis of clinical symptoms alone. Sporadic (nonepidemic) cases of pulmonary blastomycosis can present as a more chronic or subacute disease with low-grade fever, night sweats, weight loss, and productive cough that resembles tuberculosis rather than bacterial pneumonia.
In the immunocompetent host, acute pulmonary blastomycosis can be mild and self-limited and may not require treatment. However, consideration should be given to treating all infected individuals to prevent extrapulmonary dissemination. All individuals with moderate to severe pneumonia, disseminated infection, or those who are immunocompromised require antifungal therapy.
In patients with mild to moderate pulmonary blastomycosis, itraconazole is effective; however, in patients with moderately severe to severe pulmonary disease, the clinical presentation of the patient, the immune competence of the patient, and the toxicity of the antifungal agents are the main determinants of the choice of antifungal therapy. All immunocompromised patients and patients with progressive pulmonary disease or with extrapulmonary disease should be treated (Table 99–4). In the case of disease limited to the lungs, cure might have occurred without treatment before the diagnosis is made. Regardless of whether or not the patient receives treatment, however, he or she must be followed carefully for many years for evidence of reactivation or progressive disease.8,19,22
TABLE 99-4 Therapy of Blastomycosis
Some authors recommend azole therapy for the treatment of self-limited pulmonary disease, with the hope of preventing late extrapulmonary disease; however, data supporting the efficacy of these regimens are lacking.8,22Itraconazole 200 to 400 mg/day demonstrated 90% efficacy as a first-line agent in the treatment of non–life-threatening non-CNS blastomycosis, and for compliant patients who completed at least 2 months of therapy, a success rate of 95% was noted. No therapeutic advantage was noted with the higher (400 mg) dosage as compared with patients treated with 200 mg.
All patients with disseminated blastomycosis, as well as those with extrapulmonary disease, require therapy. Due to its adverse effects, variable oral absorption, and lack of CNS penetration, ketoconazole is now reserved as an alternative therapy for mild to moderate pulmonary and non-CNS disease. However, older studies demonstrate that ketoconazole 400 mg/day orally for 6 months cures more than 80% of patients with chronic pulmonary and nonmeningeal disseminated blastomycosis. Amphotericin B is more efficacious but more toxic and therefore is reserved for noncompliant patients and patients with overwhelming or life-threatening disease, CNS infection, and treatment failures.8,22 Lipid preparations of amphotericin B have largely replaced conventional amphotericin B for treatment of blastomycosis, despite their higher cost, due to their decreased renal toxicity. Surgery has only a limited role in the treatment of blastomycosis.
For unclear reasons, blastomycosis is an uncommon opportunistic disease among immunocompromised individuals, including AIDS patients; however, blastomycosis can occur as a late (CD4 lymphocytes <200 cells/mm3 [<200 × 106/L]) and frequently fatal complication of HIV infection. In this population, overwhelming disseminated disease with frequent involvement of the CNS is common.8,22 Following induction therapy with amphotericin B (total cumulative dose of 1 g), HIV-infected patients should receive chronic suppressive therapy with an oral azole antifungal.8,22
Coccidioidomycosis is caused by infection with Coccidioides immitis, a dimorphic fungus found in the southwestern and western United States, as well as in parts of Mexico and South America. In North America, the endemic regions encompass the semiarid areas of the southwestern United States from California to Texas known as the Lower Sonoran Zone, where there is scant annual rainfall, hot summers, and sandy, alkaline soil. C. immitis grows in the soil as a mold, and mycelia proliferate during the rainy season. During the dry season, resistant arthroconidia form and become airborne when the soil is disturbed.
Although generally considered to be a regional disease, coccidioidomycosis has increased in importance in recent years because of the increased tourism and population in endemic areas, the increased use of immunosuppressive therapy in transplantation and oncology, and the AIDS epidemic. Although there is no racial, hormonal, or immunologic predisposition for acquiring primary disease, these factors affect the risk of subsequent dissemination of disease (Table 99–5).11
TABLE 99-5 Factors for Severe, Disseminated Infection with Coccidioidomycosis
When individuals come in contact with contaminated soil during ranching, dust storms, or proximity to construction sites or archaeologic excavations, arthroconidia are inhaled into the respiratory tree, where they transform into spherules, which reproduce by cleavage of the cytoplasm to produce endospores. The endospores are released when the spherules reach maturity. Similar to histoplasmosis, an acute inflammatory response in the tissue leads to infiltration of mononuclear cells, ultimately resulting in granuloma formation.11
Clinical Presentation of Coccidioidomycosis
Coccidioidomycosis encompasses a spectrum of illnesses ranging from primary uncomplicated respiratory tract infection that resolves spontaneously to progressive pulmonary or disseminated infection.11,19,23Initial or primary infection with C. immitis almost always involves the lungs. Although approximately one third of the population in endemic areas is infected, the average incidence of symptomatic disease is only approximately 0.43%.
Signs and Symptoms
Primary Coccidioidomycosis (“Valley Fever”) Approximately 60% of infected patients have an asymptomatic, self-limited infection without clinical or radiological manifestations. The remaining 40% of patients exhibit nonspecific symptoms that are often indistinguishable from ordinary upper respiratory infections, including fever, cough, headache, sore throat, myalgias, and fatigue that occur 1 to 3 weeks after exposure to the pathogen. More commonly, a diffuse, mild erythroderma or maculopapular rash is observed. Patients can have pleuritic chest pain and peripheral eosinophilia.
A fine, diffuse rash can appear during the first few days of the illness. Primary pneumonia can be the first manifestation of disease, characterized by a productive cough that can be blood-streaked, as well as single or multiple soft or dense homogeneous hilar or basal infiltrates on chest roentgenogram. Chronic, persistent pneumonia or persistent pulmonary coccidioidomycosis (primary disease lasting more than 6 weeks) is complicated by hemoptysis, pulmonary scarring, and the formation of cavities or bronchopleural fistulas.
Necrosis of pulmonary tissue with drainage and cavity formation occurs commonly. Most parenchymal cavities close spontaneously or form dense nodular scar tissue that can become superinfected with bacteria or spherules of C. immitis. These patients often have persistent cough, fevers, and weight loss.
Disseminated disease occurs in less than 1% of infected patients. The most common sites for dissemination are the skin, lymph nodes, bone, and meninges, although the spleen, liver, kidney, and adrenal gland also can be involved. Occasionally, miliary coccidioidomycosis occurs, with rapid, widespread dissemination, often in concert with positive blood cultures for C. immitis. Patients with AIDS frequently present with miliary disease. Coccidioidomycosis in AIDS patients appears to be caused by reactivation of disease in most patients. Dissemination also is more likely if infection occurs during pregnancy, especially during the third trimester or in the immediate postpartum period.23
CNS infection occurs in approximately 16% of patients with disseminated coccidioidomycosis. Patients can present with meningeal disease without previous symptoms of primary pulmonary infection, although disease usually occurs within 6 months of the primary infection. The signs and symptoms are often subtle and nonspecific, including headache, weakness, changes in mental status (lethargy and confusion), neck stiffness, low-grade fever, weight loss, and occasionally, hydrocephalus. Space-occupying lesions are rare, and the main areas of involvement are the basilar meninges.
The diagnoses of coccidioidomycosis generally utilizes identification or recovery of Coccidioides spp. from clinical specimens and detection of specific anticoccidioidal antibodies in serum or other body fluids.19
Therapy for coccidioidomycosis is difficult, and the results are unpredictable. Guidelines11 are available for treatment of this disease; however, optimal treatment for many forms of this disease still generates debate. The efficacy of antifungal therapy for coccidioidomycosis often is less certain than that for other fungal etiologies, such as blastomycosis, histoplasmosis, or cryptococcus, even when in vitro susceptibilities and the sites of infections are similar. The refractoriness of coccidioidomycosis can relate to the ability of C. immitis spherules to release hundreds of endospores, maximally challenging host defenses.11,23 Fortunately, only approximately 5% of infected patients require therapy.23
Goals of Therapy
Desired outcomes of treatment are resolution of signs and symptoms of infection, reduction of serum concentrations of anticoccidioidal antibodies, and return of function of involved organs. It would also be desirable to prevent relapse of illness on discontinuation of therapy, although current therapy is often unable to achieve this goal.
Specific Agents Used for the Treatment of Coccidioidomycosis
Azole antifungals, primarily fluconazole and itraconazole, have replaced amphotericin B as initial therapy for most chronic pulmonary or disseminated infections. Amphotericin B is now usually reserved for patients with respiratory failure because of infection with Coccidioides species, those with rapidly progressive coccidioidal infections, or women during pregnancy. Therapy often ranges from many months to years in duration, and in some patients, lifelong suppressive therapy is needed to prevent relapses. Specific antifungals (and their usual dosages) for the treatment of coccidioidomycosis include IV amphotericin B (0.5 to 1.5 mg/kg per day), ketoconazole (400 mg/day orally), IV or oral fluconazole (usually 400 to 800 mg/day, although dosages as high as 1,200 mg/day have been used without complications), and itraconazole (200 to 300 mg orally twice daily or three times daily, as either capsules or solution).11,23 If itraconazole is used, measurement of serum concentrations can be helpful to ascertain whether oral bioavailability is adequate.
Amphotericin B generally is preferred as initial therapy in patients with rapidly progressive disease, whereas azoles generally are preferred in patients with subacute or chronic presentations. The lipid formulations of amphotericin B have not been studied extensively in coccidioidal infection but can offer a means of giving more drug with less toxicity. Fluconazole probably is the most frequently used medicine given its tolerability, although high relapse rates have been reported in some studies. Relapse rates with itraconazole therapy can be lower than those with fluconazole.11,23
The usefulness of newly available antifungal agents of possible benefit for the treatment of refractory coccidioidal infections has not been adequately assessed and they are not yet FDA approved for use in this population. Case reports have suggested that voriconazole can be effective in selected patients. Caspofungin has been effective in treating experimental murine coccidioidomycosis, but in vitro susceptibility of isolates varies widely, and there is only one report regarding its value. Posaconazole was shown to be an effective treatment in a small clinical trial and in patients with refractory infections. Its efficacy relative to other triazole antifungals is unknown.
Because of the lack of prospective, controlled trials, there is continued disagreement among experts in endemic areas whether patients with coccidioidomycosis should be treated, and if so, which ones and for how long. The excellent tolerability of oral azoles has lowered the threshold for deciding to treat primary infection, and some clinicians treat all primary infections. Rationales for treating a primary self-limiting infection include the ability to lessen the morbidity associated with the acute infection and the possible ability to reduce the development of more serious complications. However, there is currently no evidence that treatment of the primary infection accomplishes either of these goals.25
Combination therapy with members of different classes of antifungal agents has not been evaluated in patients, and there is a hypothetical risk of antagonism. However, some clinicians feel that outcome in severe cases is improved when amphotericin B is combined with an azole antifungal. If the patient improves, the dosage of amphotericin B can be slowly decreased while the dosage of azole is maintained.11,23
Primary Respiratory Infection
Although most patients with symptomatic primary pulmonary disease recover without therapy, management should include followup visits for 1 to 2 years to document resolution of disease or to identify as early as possible evidence of pulmonary or extrapulmonary complications.
Patients with a large inoculum, severe infection, or concurrent risk factors (e.g., HIV infection, organ transplant, pregnancy, or high doses of corticosteroids) probably should be treated, particularly those with high CF titers, in whom incipient or occult dissemination is likely. Because some racial or ethnic populations have a higher risk of dissemination, some clinicians advocate their inclusion in the high-risk group. Common indicators used to judge the severity of infection include weight loss (>10%), intense night sweats persisting more than 3 weeks, infiltrates involving more than one half of one lung or portions of both lungs, prominent or persistent hilar adenopathy, CF antibody titers of greater than 1:16, failure to develop dermal sensitivity to coccidial antigens, inability to work, or symptoms that persist for more than 2 months.11,23
Commonly prescribed therapies include currently available oral azole antifungals at their recommended doses for courses of therapy ranging from 3 to 6 months.11,23 In patients with diffuse pneumonia with bilateral reticulonodular or miliary infiltrates, therapy usually is initiated with amphotericin B; several weeks of therapy generally are required to produce clear evidence of improvement. Consolidation therapy with oral azoles can be considered at that time. The total duration of therapy should be at least 1 year, and in patients with underlying immunodeficiency, oral azole therapy should be continued as secondary prophylaxis. Although HIV-infected patients receiving secondary prophylaxis might be at low risk for recurrence of systemic mycosis when their CD4+ T-lymphocyte counts increase to >100 cells/μL (>100 × 106/L) in response to HAART, the number of patients who have been evaluated is insufficient to warrant a recommendation to discontinue prophylaxis.
Infections of the Pulmonary Cavity
Many pulmonary infections that are caused by C. immitis are benign in their course and do not require intervention. In the absence of controlled clinical trials, evidence of the benefit of antifungal therapy is lacking, and asymptomatic infections generally are left untreated. Symptomatic patients can benefit from oral azole therapy, although recurrence of symptoms can be seen in some patients once therapy is discontinued. Surgical resection of localized cavities provides resolution of the problem in patients in whom the risks of surgery are not too high.11,23
Extrapulmonary (Disseminated) Disease
Almost all patients with disease located outside the lungs should receive antifungal therapy; therapy usually is initiated with 400 mg/day of an oral azole. Amphotericin B is an alternative therapy and can be necessary in patients with worsening lesions or with disease in particularly critical locations such as the vertebral column. Approximately 50% to 75% of patients treated with amphotericin B for nonmeningeal disease achieve a sustained remission, and therapy usually is curative in patients with infections localized strictly to skin and soft tissues without extensive abscess formation or tissue damage. The efficacy of local injection into joints or the peritoneum, as well as intraarticular or intradermal administration, remains poorly studied. Amphotericin B appears to be most efficacious when cell-mediated immunity is intact (as evidenced by a positive coccidioidin or spherulin skin test or low CF antibody titer). Controlled trials that document these clinical impressions are lacking, however.11,23
Fluconazole has become the drug of choice for the treatment of coccidioidal meningitis. A minimum dose of 400 mg/day orally leads to a clinical response in most patients and obviates the need for intrathecal amphotericin B. Some clinicians will initiate therapy with 800 or 1,000 mg/day, and itraconazole dosages of 400 to 600 mg/day are comparably effective. It is also clear, however, that fluconazole only leads to remission rather than cure of the infections; thus suppressive therapy must be continued for life. Ketoconazole cannot be recommended routinely for the treatment of coccidioidal meningitis because of its poor CNS penetration following oral administration. Patients who do not respond to fluconazole or itraconazole therapy are candidates for intrathecal amphotericin B therapy with or without continuation of azole therapy. The intrathecal dose of amphotericin B ranges from 0.01 to 1.5 mg given at intervals ranging from daily to weekly. Therapy is initiated with a low dosage and is titrated upward as patient tolerance develops.11,23
Cryptococcosis is a noncontagious, systemic mycotic infection caused by the ubiquitous encapsulated soil yeast Cryptococcus, which is found in soil, particularly in pigeon droppings, although disease occurs throughout the world, even in areas where pigeons are absent. Infections caused by C. neoformans var. grubii (serotype A) are seen worldwide among immunocompromised hosts, followed by C. neoformansvar. neoformans (serotype D). On the other hand, Cryptococcus gattii (serotypes B and C) is geographically more restricted and in contrast to C. neoformans, rarely infects immunosuppressed patients, is not associated with HIV infection, and the infections are more difficult to treat. C. gattii is not associated with birds; its main reservoir was thought to be limited to certain species of eucalyptus tree. Until recently, it was most common in tropical and subtropical areas, such as Australia, South America, Southeast Asia, and central Africa, with the highest incidence in Papua New Guinea and Northern Australia, although infections occur in nontropical areas such as North America and Europe. C. gattii emerged on Vancouver Island, British Columbia, Canada, in 1999, and subsequently spread to the Vancouver lower mainland, Washington state, and Oregon.24
Infection is acquired by inhalation of the organism. The incidence of cryptococcosis has risen dramatically in recent years, reflecting the increased numbers of immunocompromised patients, including those with malignancies, diabetes mellitus, chronic renal failure, and organ transplants and those receiving immunosuppressive agents. The AIDS epidemic also has contributed to the increased numbers of patients; cryptococcosis is the fourth most common infectious complication of AIDS and the second most common fungal pathogen. In most developed countries, widespread use of HAART has significantly decreased the incidence of cryptococcosis; however, the incidence and mortality of this infection are still extremely high in areas with limited access to HAART and a high incidence of HIV.25
Cell-mediated immunity appears to play a major role in host defense against infection with C. neoformans; 29% to 55% of patients with cryptococcal meningitis have a predisposing condition. Many patients with disseminated cryptococcosis demonstrate defects in cell-mediated immunity. The predilection of C. neoformans for the CNS appears to be caused by the lack of immunoglobulins and complement and the excellent growth medium afforded by CSF.25
Disease can remain localized in the lungs or can disseminate to other tissues, particularly the CNS, although the skin also can be affected. Hematogenous spread generally occurs in the immunocompromised host, although it also has been seen in individuals with intact immune systems.
Clinical Presentation of Cryptococcosis
Primary cryptococcosis in humans almost always occurs in the lungs, although the pulmonary focus usually produces a subclinical infection.23–28 Symptomatic infections usually are manifested by cough, rales, and shortness of breath that generally resolve spontaneously. Cryptococcus can present as part of an immune reconstitution inflammatory syndrome (IRIS), a paradoxical worsening of preexisting infectious processes following the initiation of HAART in HIV-infected individuals. In non-AIDS patients, the symptoms of cryptococcal meningitis are nonspecific. Headache, fever, nausea, vomiting, mental status changes, and neck stiffness generally are observed. Less common symptoms include visual disturbances (photophobia and blurred vision), papilledema, seizures, and aphasia. In AIDS patients, fever and headache are common, but meningismus and photophobia are much less common than in non-AIDS patients. Approximately 10% to 12% of AIDS patients have asymptomatic disease, similar to the rate observed in non-AIDS patients.25,27,28 Intracerebral mass lesions (cryptococcomas) are more common in C. gattiithan in C. neoformans, presumably due to their different host immune responses.24
With cryptococcal meningitis, the CSF opening pressure generally is elevated. There is a CSF pleocytosis (usually lymphocytes), leukocytosis, a decreased glucose concentration, and an elevated CSF protein concentration. There is also a positive cryptococcal antigen (detected by LA). The test is rapid, specific, and extremely sensitive, but false-negative results can occur. False-positive tests can result from cross-reactivity with rheumatoid factor and Trichosporon beigelii. C. neoformans can be detected in approximately 60% of patients by India ink smear of CSF, and it can be cultured in more than 96% of patients. Occasionally, large volumes of CSF are required to confirm the diagnosis.
The CSF parameters in patients with AIDS are similar to those seen in non-AIDS patients, with the exception of a decreased inflammatory response to the pathogen, resulting in a strikingly low number of leukocytes in CSF and extraordinarily high cryptococcal antigen titers.
The choice of treatment for disease caused by C. neoformans depends on both the anatomic sites of involvement and the host’s immune status, and thus, treatment recommendations are divided into three specific risk groups: (a) HIV-infected individuals, (b) transplant recipients, and (c) non–HIV-infected and nontransplant hosts (Table 99–6).9 The management of cryptococcosis includes systemic antifungal therapy, control of elevated ICP, and supportive care. When possible, immune defects should be addressed. Despite the lack of randomized clinical trials, outcomes of treatment for CNS cryptococcosis (without mass lesions or hydrocephalus) appear to be similar for disease due to either C. neoformans or C. gattii, although no randomized clinical trials have been performed to address this.24
TABLE 99-6 Therapy of Cryptococcosisa,b
Prior to the introduction of amphotericin B, cryptococcal meningitis was an almost uniformly fatal disease; approximately 86% of patients died within 1 year. The use of large (1 to 1.5 mg/kg) daily doses of amphotericin B resulted in cure rates of approximately 64%. When amphotericin B is combined with flucytosine, a smaller dose of amphotericin B can be employed because of the in vitro and in vivo synergy between the two antifungal agents. Resistance develops to flucytosine in up to 30% of patients treated with flucytosine alone, limiting its usefulness as monotherapy.26,27 Combination therapy with amphotericin B and flucytosine will sterilize the CSF within 2 weeks of treatment in 60% to 90% of patients, and most immunocompetent patients will be treated successfully with 6 weeks of combination therapy.25 However, because of the need for prolonged IV therapy and the potential for renal and hematologic toxicity with this regimen, alternative regimens utilizing lipid formulations of amphotericin B and the use of shorter (2 weeks) courses of amphotericin B followed by consolidation therapy with fluconazole for 8 weeks, then maintenance therapy with a lower dosage of fluconazole for 6 to 12 months has been advocated.9,27–29
For asymptomatic, immunocompetent hosts with isolated mild to moderate pulmonary disease and no evidence of CNS disease, careful observation can be warranted; in the case of symptomatic infection, fluconazole for 6 to 12 months is warranted. In individuals with non-CNS cryptococcemia, a positive serum cryptococcal antigen titer (>1:8), cutaneous infection, a positive urine culture, or prostatic disease, the clinician must decide whether to follow the regimen for isolated pulmonary disease or the more aggressive regimen for patients with CNS (disseminated) disease.9
Pilot studies evaluating combination therapy with fluconazole plus flucytosine as initial therapy yielded unsatisfactory results, and this approach is discouraged even in “low-risk” patients. Ketoconazole has been used successfully in the treatment of cutaneous cryptococcosis, but it is not useful in the treatment of CNS disease, probably because of its poor penetration into the CNS.9
Despite low CSF concentrations of amphotericin B (2% to 3% of those observed in plasma), the use of intrathecal amphotericin B is not recommended for the treatment of cryptococcal meningitis except in very ill patients or in patients with recurrent or progressive disease despite aggressive therapy with IV amphotericin B. The dosage of amphotericin B employed is usually 0.5 mg administered through the lumbar, cisternal, or intraventricular (through an Ommaya reservoir) route two or three times weekly. Side effects of intrathecal amphotericin B include arachnoiditis and paresthesias. Intrathecal amphotericin B therapy should be administered in combination with IV amphotericin B.29
The recommended management of raised intracranial pressure (ICP) in cryptococcal meningitis (without hydrocephalus, a mass lesion, or a shift on computed tomography [CT] scan) has been repeated CSF removal by spinal tap. Those who do not respond and have ongoing raised ICP should have ophthalmologic monitoring for possible vision loss, and should be considered for ventriculoperitoneal shunt surgery. Neither corticosteroids (in the absence of IRIS) nor acetazolamide is recommended for management of raised ICP. Symptomatic, medically refractory mass lesions that may be compressing vital structures should be considered for surgical therapy.24
Immunocompromised hosts with isolated severe pulmonary and extrapulmonary disease (including cryptococcemia) without CNS disease should be treated similarly to nonimmunocompromised patients with CNS disease. Immunocompromised patients with CNS infection require more prolonged therapy; treatment regimens are based on those used in the HIV-infected population and follow induction therapy with amphotericin B and consolidation therapy with 6 to 12 months of suppressive therapy with fluconazole.9
Organ Transplant Recipients
Cryptococcosis has been documented in an average of 2.8% of solid-organ transplant recipients, with ~25% to 54% having pulmonary infection (of whom 6% to 33% have disease that is limited to the lungs), ~25% of patients having fungemia, and 52% to 61% having CNS involvement and disseminated (involvement of ≥2 sites) infections.9 The median time to disease onset is 21 months after transplantation; 68.5% of the cases occur >1 year after transplantation.
Fluconazole maintenance therapy should be continued for at least 6 to 12 months. Immunosuppressive management should include sequential or stepwise reduction of immunosuppressants, with consideration of lowering the corticosteroid dose first.20 Amphotericin B should be used with caution in transplant recipients and is not recommended as first-line therapy in this patient population due to the risk of nephrotoxicity in this population that frequently has reduced renal function. If used, the tolerated dosage of amphotericin B is uncertain, but 0.7 mg/kg daily is suggested with frequent renal function monitoring. Regardless of the agent utilized, all antifungal dosages need to be carefully monitored.11
Primary antifungal prophylaxis for cryptococcosis is not routinely recommended in HIV-infected patients in the United States and Europe. However, in areas with limited HAART availability, high levels of antiretroviral drug resistance, and a high burden of disease, clinicians may wish to consider the use of either prophylactic therapy or a preemptive strategy with serum cryptococcal antigen testing for asymptomatic antigenemia.9
Fluconazole is beneficial for both acute and chronic maintenance therapy for cryptococcal meningitis. Amphotericin B 0.4 to 0.5 mg/kg IV daily was compared with oral fluconazole 200 mg/day. Although the overall 10-week mortality was the same in both groups, the time until the CSF culture became negative was longer, and there were more deaths in the first 2 weeks of therapy in the fluconazole group.28 In later trials,29 amphotericin B 0.7 mg/kg IV daily for 2 weeks (with or without oral flucytosine 100 mg/kg per day), followed by consolidation therapy with either itraconazole 400 mg/day orally or fluconazole 400 mg/day orally, led to markedly improved outcomes in comparison with earlier regimens. This study confirmed the benefit of early high-dose (0.7 mg/kg per day) amphotericin B use, the usefulness of flucytosine added to amphotericin B for induction therapy, and the slight superiority of fluconazole over itraconazole for consolidation therapy.
Amphotericin B combined with flucytosine is the initial treatment of choice.9 In patients who cannot tolerate flucytosine, amphotericin B alone is an acceptable alternative. After the initially successful 2-week induction period, consolidation therapy with fluconazole can be administered for 8 weeks or until CSF cultures are negative. In patients in whom fluconazole cannot be given, itraconazole is an acceptable, albeit less effective, alternative. Combination therapy with fluconazole plus flucytosine is effective; however, it is recommended as an alternative to the preceding therapies because of its potential for toxicity. Lipid formulations of amphotericin B are effective, but the optimal dosage is unknown.9
In HIV-infected patients, mortality is highly associated with elevated ICP (CSF opening pressure >250 mm H2O [>2.5 kPa]). At the initiation of antifungal therapy, lumbar drainage should remove enough CSF to reduce the opening pressure by 50%. Patients initially should undergo daily lumbar punctures to maintain CSF opening pressure in the normal range. When the CSF pressure is normal for several days, the procedure can be suspended. Adjunctive steroid treatment is not recommended because therapy has resulted in mixed results and its impact on outcome is unclear. Similarly, neither mannitol nor acetazolamide therapy provides any clear benefit in the management of elevated ICP.9
Suppressive (Maintenance) Therapy for Cryptococcal Meningitis in the HIV-Infected Patient
Relapse of C. neoformans meningitis occurs in approximately 50% of AIDS patients after completion of primary therapy. Persistence of asymptomatic urinary C. neoformans has been documented in a high percentage of AIDS patients despite seemingly adequate courses of therapy for primary meningeal disease. The prostate appears to act as a sequestered reservoir of infection in these patients, resulting in systemic relapse.
Patients appear to be at low risk for recurrence of cryptococcosis when they have successfully completed a course of initial therapy for cryptococcosis, remain asymptomatic with regard to signs and symptoms of cryptococcosis, have received antifungal therapy for >3 of the previous 6 months, have a serum cryptococcal antigen titer <1:512, or have a sustained increase (e.g., >6 months) in their CD4+ T-lymphocyte counts to >100 to 200 cells/μL (>100 × 106 to 200 × 106/L) and an HIV viral load of fewer than 50 copies/mL (50 × 103/L).9,27–29
In HIV-infected patients requiring chronic suppressive therapy of cryptococcal meningitis, oral fluconazole 200 mg/day is superior to IV administration of amphotericin B 1 mg/kg weekly in preventing relapse, results in a lower incidence of adverse drug reactions and bacterial infections, and is superior to itraconazole as maintenance therapy.29
Until recently, lifelong maintenance therapy to prevent disease relapse was recommended for all patients with AIDS after successful completion of primary induction therapy for cryptococcal meningoencephalitis. However, several studies indicate that the risk of relapse is low and that discontinuation of maintenance therapy is reasonable, provided patients have successfully completed primary therapy, are free of symptoms and signs of active cryptococcosis, and have been receiving HAART with a sustained CD4 cell count >100 cells/mL (>100 × 103/L) and an undetectable viral load.9
Evaluation of Therapeutic Outcomes
Once the CNS is involved, the usual course is weeks to months of progressive deterioration, with 80% of untreated patients dying within the first year. The prognosis of cryptococcal meningitis depends largely on the underlying predisposing factors of the host. Although cryptococcal antigen is positive in 90% of patients with cryptococcal meningitis, fewer than one half of the patients with cryptococcal meningitis develop antibody to capsular polysaccharide. Those who produce antibody have a slightly improved prognosis. In contrast, the presence of headache is a favorable symptom, presumably because it leads to an earlier diagnosis. A favorable outcome is also associated with a normal mental status on diagnosis and a CSF white blood cell (WBC) count of less than 20 cells/mm3 (20 × 106/L). A poor outcome is predicted, however, by the presence of one or more underlying diseases (including hematopoietic disorders and AIDS), corticosteroid or immunosuppressive therapy, pretreatment serum cryptococcal antigen titers of 1:32, and posttherapy serum antigen titers of 1:8. In non-AIDS patients, the cryptococcal antigen titer can be followed during therapy to assess response to antifungal therapy. In AIDS patients, decreasing titers are not necessarily predictive of success, and titers rarely become negative at the completion of therapy.
Candida species are yeasts that exist primarily as small (4 to 6 microns), unicellular, thin-walled, ovoid cells that reproduce by budding. On agar medium, they form smooth, white, creamy colonies resembling staphylococci. Although there are more than 150 species of Candida, eight species—C. albicans, C. tropicalis, Candida parapsilosis, C. krusei, Candida stellatoidea, C. guilliermondii, C. lusitaniae, and C. glabrata—are regarded as clinically important pathogens in human disease.17 Yeast forms, hyphae, and pseudohyphae can be found in clinical specimens.
C. albicans is a normal commensal of the skin, female genital tract, and entire GI tract of humans. Therefore, the mere presence of hyphae or pseudohyphae in a clinical specimen is insufficient for the diagnosis of invasive disease. The majority of infections with C. albicans are acquired endogenously, although human-to-human transmission also can occur. Oral candidiasis in the newborn probably is acquired during passage through the birth canal, and balanitis in the uncircumcised male can be acquired through contact with a female with vaginal candidiasis. Although the term fungemia refers to the presence of fungi in the blood, the most commonly isolated organism is C. albicans. Candidiasis can cause mucocutaneous or systemic infection, including endocarditis, peritonitis, arthritis, and infection of the CNS. (Mucocutaneous infections caused by Candida are discussed in further detail in Chap. 98.)
The role of an intact integument is crucial in the prevention of mucocutaneous or hematogenous candidiasis. After Candida invades the dermis or enters the bloodstream, polymorphonuclear (PMN) leukocytes play a major role in the defense of the patient because PMN leukocytes are capable of damaging pseudohyphae and can phagocytize and kill blastoconidia. In addition to neutrophils, lymphocytes, monocytes, macrophages, complement, and eosinophils play a role in the prevention of infection. Adherence of C. albicans is important in the pathogenesis of oral candidiasis and subsequent colonization of the GI tract. Because evidence suggests that the GI tract is often the portal of entry for Candida in disseminated disease, factors that alter the adherence of Candida are crucial in the development of local and systemic infection. C. tropicalis adheres to intravascular catheters at a higher rate than C. albicans, a factor that may help to account for the increased incidence of systemic infections caused by this pathogen.
The incidence of fungal infections caused by Candida species has increased substantially in the past three decades, and Candida infections currently constitute a significant cause of morbidity and mortality among severely ill patients. Candida species now constitute the fourth most common cause of bloodstream infections (BSIs) for patients hospitalized in ICUs in the United States, following coagulase-negative staphylococci, Staphylococcus aureus, and enterococci. The Centers for Disease Control and Prevention’s (CDC) National Nosocomial Infection Survey implicated fungi as the cause of 8% of nosocomial infections. Although C. albicans accounted for approximately 50% of Candida species, non-albicans species of Candida, including C. glabrata, C. tropicalis, C. krusei, and C. parapsilosis, are increasingly frequent causes of invasive candidal infections.30,31 C. lusitaniae infections are a cause of breakthrough fungemia in cancer patients; C. parapsilosis has emerged as the second most common pathogen, following C. albicans, in neonatal ICU patients, where it is often associated with central lines and parenteral nutrition (PN), and fungemias in patients outside the United States, in particular in South America. Fungemia caused by C. glabrata is observed more commonly in adults older than 65 years of age.32 The change in species is of concern clinically because certain pathogens such as C. krusei and C. glabrataare intrinsically more resistant to commonly used triazole drugs (see Table 99–1).
Candida generally is acquired via the GI tract, although organisms also can enter the bloodstream via indwelling IV catheters. Immunosuppressed patients, including those with lymphoreticular or hematologic malignancies, diabetes, and immunodeficiency diseases and those receiving immunosuppressive therapy with high-dose corticosteroids, immunosuppressants, antineoplastic agents, or broad-spectrum antimicrobial agents, are at high risk for invasive fungal infections. However, a number of prospective, randomized, controlled trials have validated the efficacy of antifungal prophylaxis and the use of antifungal agents for the treatment of persistently febrile patients with neutropenia who do not respond to antibiotics, and in the prophylaxis of patients undergoing hematopoietic stem cell transplantation (HSCT), in particular in HSCT patients with graft-versus-host disease (GVHD).33 These efforts have resulted in a reduction in the frequency of BSIs caused by Candida species and systemic candidiasis in patients with neutropenia. Retrospective studies have identified a number of risk factors for candidal BSIs in ICU patients, most of which have been verified in multiple studies, although some remain controversial34 (Table 99–7). Major risk factors include the use of central venous catheters (CVCs), total PN, receipt of multiple antibiotics, extensive surgery and burns, renal failure and hemodialysis, mechanical ventilation, and prior fungal colonization. Patients who have undergone surgery (particularly surgery of the GI tract) are increasingly susceptible to disseminated candidal infections.15,34
TABLE 99-7 Risk Factors for Invasive Candidiasis
Clinical Presentation of Hematogenous Candidiasis
Dissemination of C. albicans can result in infection in single or multiple organs, particularly the kidney, brain, myocardium, skin, eye, bone, and joints.17 In most patients, multiple micro- and macroabscesses are formed. Infection of the liver and spleen is becoming recognized as a particularly common and difficult-to-treat site of infection that characteristically occurs in patients undergoing chemotherapy for acute leukemia or lymphoma.
Although a variety of serologic tests have been proposed for the detection of Candida protein antigens, serum antibodies to Candida, and antibodies to cell wall components such as mannan, no test has demonstrated reliable accuracy in the clinical setting for the diagnosis of disseminated infection with Candida. Only 25% to 45% of neutropenic patients with disseminated candidiasis at autopsy had a positive blood culture with C. albicans prior to death. The interpretation of positive surveillance cultures of the skin, mouth, sputum, feces, or urine is hampered by their occurrence as commensal pathogens and in distinguishing colonization from invasive disease.
Until recently, a rapid presumptive identification of C. albicans could be made by incubation of the organism in serum; formation of a germ tube (the beginning of hyphae, which arise as perpendicular extensions from the yeast cell, with no constriction at their point of origin) within 1 to 2 hours offered a positive identification of C. albicans. Unfortunately, C. dubliniensis, a new species of Candida that was identified recently as an important cause of mucosal colonization and infection in HIV-infected individuals, also can produce a germ tube. A negative germ tube test does not rule out the possibility of C. albicans, but further biochemical tests must be performed to differentiate between other non-albicans species.35
In patients with hepatosplenic candidiasis, as the WBC count increases to >1,000 cells/mm3 (>1 × 109/L), imaging studies can detect the presence of abscess or microabscesses in the liver and spleen, often found with acute suppurative and granulomatous reactions.
The peptide nucleic acid (PNA) fluorescence in situ hybridization (FISH) method uses fluorescein-labeled PNA probes that target C. albicans 26S rRNA for the identification of C. albicans. The test has excellent sensitivity (99% to 100%) and specificity (100%) in the direct identification of C. albicans from blood cultures.18
Matrix-assisted laser desorption/ionization time-of-flight intact cell mass spectrometry (MALDI-TOF-ICMS) is a promising tool for the rapid detection and identification of pathogenic Candida species.
The list of risk factors for invasive candidiasis in critically ill patients is extensive, and trying to decipher which patients may benefit from antifungal prophylaxis or empirical therapy based on risk factors in an ICU is exceedingly difficult. In addition, the number of risk factors present in ICU patients changes over time, and the majority of ICU patients will have more than one risk factor. Thus, recent studies have focused on combining risk factors to devise clinically useful, practical predictive algorithms and “scoring systems” that can identify high-risk patients early during their ICU admission. To maximize its clinical utility as a decision-making tool, the ideal algorithm would identify high-risk populations (ones with a rate of invasive candidiasis of 10% to 15%), providing clinicians with a means of administering prophylaxis to a minimal number of patients, while preventing the maximal number of invasive candidiasis cases. However, a scoring system is not yet available for use in clinical practice.34
There is a high rate of mortality in nonneutropenic patients with fungal blood cultures.36 Mortality was highest in patients with sustained positive blood cultures, those who did not receive antifungal therapy, and those infected with non-albicans strains of Candida. This study clearly documented the importance of early recognition and treatment of positive fungal blood cultures. Prompt initiation of therapy is important. Delays in empiric antifungal treatment greater than 12 hours after obtaining a positive blood sample are associated with greater hospital mortality.37–39 Despite increased awareness of the importance of treating patients with positive blood cultures, mortality associated with candidemia remains high.40
Current guidelines recommend that the treatment of candidiasis should be guided by knowledge of the infecting species; the clinical status of the patient; when available, the antifungal susceptibility of the infecting isolate; and whether the patient has received antifungal therapy previously (Table 99–8). Therapy should be continued for 2 weeks after the last positive blood culture and resolution of signs and symptoms of infection. All patients should undergo an ophthalmologic examination to exclude the possibility of candidal endophthalmitis.7 Amphotericin B can be switched to fluconazole (IV or oral) for the completion of therapy. Susceptibility testing of the infecting isolate is a useful adjunct to species identification during selection of a therapeutic approach because it can be used to identify isolates that are unlikely to respond to fluconazole or amphotericin B. However, this is not currently available at many institutions.6
TABLE 99-8 Antifungal Therapy of Invasive Candidiasis7,34
A meta-analysis of individual patient-level data of 1,915 patients, compiled from seven randomized clinical trials, compared a variety of antifungal therapies for the treatment of candidemia and reported improved survival and greater clinical success with the use of an echinocandin and removal of CVCs.41,42 Overall, 30-day all-cause mortality was 31.4%; however, mortality was 27% for echinocandins versus 36% for other regimens (P < 0.0001). By comparison, mortality was 36% for triazoles versus 30% for other drugs (P < 0.006), and 35% for polyenes versus 30% for other drugs (P = 0.04). In addition, they reported that mortality for CVC removal 28% versus 41% for patients in whom CVCs were retained (P < 0.0001). Based on their findings, echinocandins should be considered as initial therapy not only for critically ill patients, those with prior triazole exposure, and those infected with less susceptible Candida spp. such as C. glabrata or C. krusei, but for most patients with candidemia, and that CVC removal should be performed. Limitations of this study include the exclusion of patients who fall into extremes, and that these studies undertaken during a 15-year period, during which time treatment practices have changed. There was a lack of information regarding the timing of CVC removal, and that only three of the seven randomized clinical trials compared the use of an echinocandin with other antifungals, and in those studies, the mortality rate of patients receiving an echinocandin was similar to that of patients receiving other antifungal therapy.
In ICUs, the use of fluconazole for prophylaxis or empirical therapy has increased exponentially in the past decade. However, studies that demonstrated benefit in the prevention of invasive candidal BSIs did so either by using highly selective criteria or by studying patients in an unusually high-risk ICU setting, and the role of antifungal prophylaxis in the surgical ICU remains extremely controversial. For a study to demonstrate efficacy in clinical trials, the baseline rate of invasive candidiasis must be >10%, and that prophylaxis must result in > fourfold reduction of disease.7 Although ICU-specific, a >10% rate of invasive candidiasis is generally found only in the setting of high-risk transplant patients (e.g., patients undergoing liver transplantation), or in patients with one or more of the following risk factors by day 3 of their ICU stay: new-onset dialysis, receipt of broad-spectrum antibiotics, the presence of diabetes, and in patients receiving PN.42,43 Prophylactic antifungals are indicated in patients with recurrent intestinal perforations and/or anastomotic leak as these patients are at extremely high risk for invasive candidiasis (35%) and the use of empiric fluconazole has been shown to significantly decrease the incidence of infection to 4%.34
“Empirical” Therapy (Also Known as Preemptive Therapy)
The term “preemptive” antifungal therapy is often used to describe early antifungal therapy given to high-risk patients with persistent signs and symptoms and clinical, laboratory, or radiologic surrogate markers of infection but without mycological evidence of infection, or those heavily colonized with Candida. Few data are available for assessing the role of antifungals as empirical therapy for suspectedfungemia in patients who do not yet exhibit a positive blood culture, or for isolates other than C. albicans.
In a double-blind randomized placebo controlled trial, the empiric use of fluconazole 800 mg daily in 270 high-risk patients with a baseline rate of IC of 9% decreased the incidence of invasive candidiasis only to 5% (P = 0.24). The authors concluded that the use of empiric fluconazole cannot be recommended for ICU populations with similar risk factors as those included in the trial.
Initial Antifungal Therapy in Patients with Documented Candidemia
Several large randomized studies in nonneutropenic patients have demonstrated that azoles (fluconazole or voriconazole) and deoxycholate amphotericin B are similarly effective for the therapy of documented candidemia; however, fewer adverse effects are observed with azole therapy (Tables 99–8 and 99-9). Similarly, echinocandins are at least as effective as amphotericin B or fluconazole in (primarily nonneutropenic) adult patients with candidemia with fewer drug-related adverse events. Although the use of combination therapy (high-dose fluconazole plus amphotericin B) was demonstrated recently to be superior to treatment with fluconazole alone, it was associated with a higher rate of nephrotoxicity, and the routine use of combination therapy in this patient population is not yet recommended. Alternatives to fluconazole should be considered when patients have a history of recent exposure to fluconazole or other azoles, when a broader spectrum is desirable (e.g., persistently neutropenic patient), when non-albicans species are isolated during or immediately following azole therapy, and in unstable or severely immunocompromised patients.44–51
TABLE 99-9 Initial Antifungal Therapy of Candidemia in the Nonneutropenic Host
Neonates with disseminated candidiasis usually are treated with amphotericin B because of its low toxicity in this patient population and because of the lack of experience with other agents in this population; however, micafungin or caspofungin may offer safe, effective alternatives.7,40,52 Treatment should continue until 2 weeks following the last positive blood culture and resolution of signs and symptoms of infection.
Among the lipid-associated formulations of amphotericin B, only liposomal amphotericin B (AmBisome) and amphotericin B lipid complex (ABLC; Abelcet) have been approved for use in proven cases of candidiasis; however, patients with invasive candidiasis also have been treated successfully with amphotericin B colloid dispersion (ABCD, Amphotec or Amphocil). The lipid-associated formulations are less toxic but as effective as amphotericin B deoxycholate.
Antifungal Therapy for Specific Candida Species
C. krusei infections should be treated with large doses of amphotericin B (≥1 mg/kg per day) or with caspofungin (70-mg IV loading dose, followed by 50 mg/day IV) (Table 99–8).7 C. tropicalis, and C. parapsilosis can be treated with either amphotericin B at 0.6 mg/kg per day or fluconazole at 6 mg/kg per day. Amphotericin B resistance remains relatively rare despite more than 45 years of clinical use, although it has been reported in C. lusitaniae (now Clavispora lusitaniae) and C. guilliermondii. Candida rugosa often is considered to be “polyene tolerant,” and these isolates are believed to be selected owing to the wide use of amphotericin B.
In immunocompromised patients, the presence of candidemia is associated with evidence of disseminated disease in more than 70% of patients and with a 70% to 80% fatality rate. Therapy should include removal of the catheter and administration of systemic antifungal therapy.7 The optimal agent, dose, and duration of therapy are unclear, and patients must be monitored carefully with serial blood cultures and careful physical examinations, particularly of the retina. Patients who are neutropenic at the time of developing candidemia should receive a recombinant cytokine (granulocyte colony-stimulating factor or granulocyte-monocyte colony-stimulating factor) that accelerates recovery from neutropenia.7
Recognition of the role of the GI tract in invasive Candida infections has led to efforts to decrease infections by prophylactic administration of topical or systemically absorbed antifungal agents in immunocompromised patients. The use of systemically absorbable agents such as azole antifungal agents appears to decrease the risk of invasive fungal infections.7,53,54
Fluconazole (400 mg/day), posaconazole (200 mg three times daily), or micafungin (50 mg daily) from the start of the conditioning regimen until day 75 can reduce the frequency of invasive Candidainfections and decrease mortality at day 110 in patients undergoing allogeneic bone marrow transplantation.7,16,54,55 IV caspofungin (50 mg daily) was compared with IV itraconazole (200 mg twice daily for 2 days, then 200 mg once daily). Mortality was similar in both groups. Micafungin 50 mg daily was compared to IV fluconazole 400 mg daily in patients undergoing HSCT. Significantly fewer patients in the micafungin arm versus the fluconazole arm required empiric antifungal therapy, and mortality was decreased, although not significantly, in the micafungin arm. Based on this limited data, micafungin and caspofungin may provide options for prophylaxis in patients undergoing HSCT. However, more compelling data have been demonstrated with posaconazole. In a double-blinded, multi-center clinical trial of the prophylaxis of invasive fungal infections in patients who had undergone HSCT with GVHD, posaconazole (200 mg every 8 hours) was superior to fluconazole (400 mg daily) in preventing aspergillosis and comparable to fluconazole in preventing other breakthrough invasive fungal infections.16,56
In less risk-selected patients with hematologic malignancies who are undergoing remission-induction chemotherapy, fluconazole (400 mg/day), posaconazole (200 mg three times daily), or caspofungin (50 mg daily), during induction chemotherapy for the duration of neutropenia, are effective in preventing systemic infection and death caused by Candida species.7,57,58 Itraconazole cyclodextrin (2.5 mg/kg orally twice daily) is an option for less risk-selected patients, but it offers little advantage over other agents and is less well tolerated.16
For solid-organ transplant recipients, fluconazole (200 to 400 mg [3 to 6 mg/kg] daily) or liposomal amphotericin B (1 to 2 mg/kg daily for 7 to 14 days) is recommended as postoperative antifungal prophylaxis for liver, pancreas, and small bowel transplant recipients at high risk of candidiasis.7,15
The use of prophylactic fluconazole (400 mg [6 mg/kg] daily) can decrease the incidence of fungal infections in select high-risk groups of patients. However, despite decreases in the rate of invasive candidiasis, to date, no mortality benefit has been demonstrated in any clinical trial. Widespread use of prophylactic fluconazole in all ICU patients is not warranted and may lead to an increase in resistance and adverse events. If utilized, prophylactic fluconazole should target high-risk patients with a presumed risk of invasive candidiasis of 10% to 15%.7,34
Empirical Therapy for Febrile Neutropenic Patients
Many clinicians advocate early institution of empirical IV amphotericin B in patients with neutropenia and persistent (>5 to 7 days) fever.16 However, the potential toxicities (particularly nephrotoxicity) of this agent preclude its routine use in all patients. Suggested criteria for the empirical use of amphotericin B include: (a) fever of 5 to 7 days’ duration that is unresponsive to antibacterial agents, (b) neutropenia of more than 7 days’ duration, (c) no other obvious cause for fever, (d) progressive debilitation, (e) chronic adrenal corticosteroid therapy, and (f) indwelling intravascular catheters. In patients who fail therapy with amphotericin B, lipid formulations of amphotericin B can be used (3 to 5 mg/kg per day). Comparative trials have indicated that lipid formulations of amphotericin B can be used as alternatives to amphotericin B deoxycholate for empirical therapy. Although they do not appear to be substantially more effective, there is less drug-related toxicity (Table 99–10).16
TABLE 99-10 Comparative Trials for Initial Antifungal Therapy in the Febrile Neutropenic Host
Itraconazole and ubiquitous mold that grows well on a variety of substrates, including fluconazole have demonstrated efficacy equivalent to that of deoxycholate amphotericin B in patients with hematologic malignancy (not treated with allogeneic HSCT).59,60 However, as fluconazole is not active against filamentous fungi, its use in patients at high risk for these pathogens should be avoided. If itraconazole is used, the IV formulation should be used because the bioavailability of the oral formulations (including the solution) is unreliable; however, it is no longer available. Voriconazole and caspofungin were compared with liposomal amphotericin B in large randomized, multicenter trials of empirical antifungal therapy in febrile neutropenic patients. Voriconazole did not fulfill the protocol-defined criteria for noninferiority (a difference in success rates between voriconazole and amphotericin B of no more than 10 percentage points) to liposomal amphotericin; however, it was superior in reducing documented breakthrough infections, infusion-related toxicity, and nephrotoxicity. Patients who received voriconazole had more frequent episodes of transient visual disturbances and hallucinations. Caspofungin demonstrated equivalent efficacy but was superior in the successful treatment of baseline invasive fungal infections.52,61
Amphotericin B, the azoles, and the echinocandins have roles in the treatment of hematogenous candidiasis, and the choice of therapy is guided by weighing the greater activity of amphotericin B for some non-albicans species (e.g., C. krusei) against the lower toxicity and ease of administration of fluconazole and the echinocandins.7
Most clinicians recommend amphotericin B in total dosages of 0.5 to 1 g administered over approximately 1 to 2 weeks in patients with Candida endophthalmitis and in all neutropenic patients with candidemia. Longer courses of therapy can be needed in some patients.17 Fluconazole and amphotericin B appear similarly effective for the treatment of C. albicans BSIs in the neutropenic patient; controlled data, however, are lacking. In patients with uncomplicated C. albicans fungemia who have not received systemic prophylaxis with antifungal azoles, therapy with fluconazole 400 to 800 mg/day IV can be considered.62 However, in patients who have undergone allogeneic HSCT, the role of fluconazole is becoming more limited because of its widespread use for antifungal prophylaxis. In this setting, particularly if the patient has been treated previously with an azole antifungal agent, the possibility of microbiologic resistance must be considered.7 Infections with fluconazole-resistant Candida species, including C. glabrata, C. krusei, and fluconazole-resistant C. albicans, or with Aspergillus species are more likely.
Because C. glabrata demonstrates reduced susceptibility in vitro to both fluconazole and amphotericin B, optimal therapy is unclear. Larger doses of fluconazole (800 mg/day in a 70-kg patient) have been used in less critically ill patients or amphotericin B (≥0.7 mg/kg per day). However, observational studies demonstrated no difference in mortality in nonneutropenic patients administered fluconazole versus amphotericin B for BSIs caused by C. glabrata.40In vitro, echinocandin antifungal agents appear very active against C. glabrata. Current guidelines recommend the use of echinocandins, instead of fluconazole, for the treatment of fungemia caused by C. glabrata; however, their usefulness in vivo has not been adequately assessed in controlled trials.7,40
In patients intolerant to amphotericin B or fluconazole, one of the lipid formulations can be used. In a randomized trial, ABLC was found to be equivalent to 0.6 to 1 mg/kg per day of amphotericin B, and open-label therapy with ABCD has been successful.
Within the urinary tract, most common lesions are either Candida cystitis or hematogenously disseminated renal abscesses. Candida cystitis often follows catheterization or therapy with broad-spectrum antimicrobial agents. The diagnosis of Candida cystitis can be problematic because of the frequent presence of Candida pseudohyphae and yeast cells in urine specimens secondary to urethral colonization. The usefulness of urine colony counts or antibody coating techniques is questionable. The recovery of 10,000 organisms or visualization of both yeast and pseudohyphae from fresh midstream urine or from bladder urine obtained by single catheterization (not indwelling) is suggestive of genitourinary candidiasis. In most patients, the infection is asymptomatic and clears spontaneously without specific antifungal therapy.
Initial therapy of candidal cystitis should focus on removal of urinary catheters whenever possible. Changing the catheter will eliminate candiduria in only 20% of patients, whereas discontinuation will eradicate Candida in 40% of patients. Asymptomatic candiduria rarely requires therapy. Therapy should be used in symptomatic patients and in neutropenic patients, as well as in patients with renal allografts and those who will undergo urologic manipulation, because of the risk of dissemination.63,64
Fluconazole 200 mg/day for 14 days hastens the time to a negative urine culture as compared with placebo treatment, but 2 weeks after the end of therapy, the frequency of a negative urine culture remains the same with both treatments.64 Short courses of therapy are not recommended; treatment should include removal of catheters and stents whenever possible plus 7 to 14 days of therapy. Bladder irrigation with amphotericin B (50 mg in 500 mL sterile water instilled twice daily into the bladder via a three-way catheter) is only transiently effective. Minimal quantities (<3%) of amphotericin B are absorbed systemically from the bladder.64,65
Role of Catheter Removal
Although it is common practice in today’s standard of care to place indwelling catheters in patients for the administration of medications and PN, catheter-related infections are a common complication. These foreign bodies (especially triple-lumen catheters) double as entry ports for normal skin flora or other nosocomial pathogens, and they provide a readily available site for the binding of pathogens through microbiotic biofilms. Their subsequent role as a source of BSIs is facilitated by frequent use, PN, and the potential for contamination of catheters by medical staff who are colonized with Candida species.
Most consensus recommendations urge that, if feasible, initial nonmedical management should include removal of all existing tunneled CVCs and implantable devices, particularly in patients with fungemia caused by C. parapsilosis, which is very frequently associated with catheters.7 Arguments against the removal of all catheters in patients with candidemia include the prominent role of the gut as a source for disseminated candidiasis, the significant cost and potential for complications, and the problems that can be encountered in patients with difficult vascular access.66 However, in an individual patient it is often difficult to determine the relative contribution of gut versus catheter as the primary source of fungemia. The evidence for this recommendation is weakest in cancer patients with severe neutropenia and mucositis (e.g., acute leukemia, stem cell transplant), in whom candidemia is almost always primarily of gut origin, and removal of the catheter is least likely to have an impact on mortality. Nucci and Anaissie62,66 have proposed that CVCs be removed in nonneutropenic patients without a short life expectancy who have one of the following criteria: (a) otherwise unexplained hemodynamic instability, (b) lack of clinical improvement or resolution of candidemia after more than 72 hours of an optimal dose of an appropriate antifungal agent, (c) established or at high risk for endocarditis or septic thrombophlebitis, or (d) a pocket infection or cellulitis. In patients with more than one CVC, they recommend removal if one tunneled or implanted catheter is the likely source of infection and the patient meets the preceding criteria.62
Aspergillus is a ubiquitous mold that grows well on a variety of substrates, including soil, water, decaying vegetation, moldy hay or straw, and organic debris. Although more than 300 species of Aspergillushave been characterized, three species are most commonly pathogenic: Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger. The varying degrees of pathogenicity of each species depend on their relative geographic prevalence, conidial size and shape, thermotolerance, and production of mycotoxins. For example, transport of A. fumigatus conidia into the lungs is facilitated by their smaller diameter in comparison with A. flavus and A. niger.
The term aspergillosis may be broadly defined as a spectrum of diseases attributed to allergy, colonization, or tissue invasion caused by members of the fungal genus Aspergillus. A single satisfactory classification system for these disease entities is difficult because different populations of patients can develop the same type of infection. For example, osteomyelitis can result from local trauma or hematogenous dissemination in an immunocompromised host. Colonization in normal hosts can lead to allergic diseases ranging from asthma to allergic BPA or, rarely, invasive disease.67
Aspergillosis generally is acquired by inhalation of airborne conidia that are small enough (2.5 to 3 microns) to reach alveoli or the paranasal sinuses. Each conidiophore releases 104 conidia that remain suspended for long periods and are viable for months in dry locations. Although some authors advocate monitoring of hospital air for Aspergillus conidia, guidelines for interpreting results do not exist. The use of high-efficiency particulate air (HEPA) filters in operating rooms and laminar flow rooms and removal of immunocompromised patients from hospital renovation sites can be helpful in preventing infection in this population. Although the fate of Aspergillus conidia in the GI tract has not been closely studied, limited evidence suggests that this route may provide an important portal of entry for disseminated infections in humans.68
Superficial or locally invasive infections of the ear, skin, or appendages often can be managed with topical antifungal therapy. Skin infections in patients with burn wounds, although uncommon, can progress to deep-tissue invasion despite the use of topical or parenteral antifungal agents. Risk factors for deep infection include extensive thermal injuries, malnutrition, cirrhosis, and previous infection with Pseudomonas aeruginosa.68
Allergic Bronchopulmonary Aspergillosis
Allergic manifestations of Aspergillus range in severity from mild asthma to allergic BPA. BPA, which is almost always caused by A. fumigatus, is characterized by severe asthma with wheezing, fever, malaise, weight loss, chest pain, and a cough productive of blood-streaked sputum. Following recurrent episodes of severe asthma, the disease usually progresses to fibrosis and bronchiectasis with granuloma formation. When Aspergillus conidia become trapped in the viscous mucus of asthmatic patients, BPA develops. The fungus grows, releasing toxins and antigens. The resulting host sensitization results in a variety of immune reactions. Early in the course of disease, an immunoglobulin E (IgE)-mediated (type I) immune reaction results in bronchospasm, eosinophilia, and immediate skin reactivity. The ensuing fibrosis and pulmonary infiltrates appear to be mediated by circulating or precipitating antibody complexes of IgG antibody, followed by granuloma formation and mononuclear infiltration because of a type IV delayed hypersensitivity reaction. Therapy is aimed at minimizing the quantity of antigenic material released in the tracheobronchial tree. Management of acute asthma attacks minimizes trapping of Aspergillus by bronchial secretions, and administration of parenteral corticosteroids clears lung infiltrates.68 Antifungal therapy generally is not indicated in the management of allergic manifestations of aspergillosis, although some patients have demonstrated a decrease in their corticosteroid dose following therapy with itraconazole. A double-blind, randomized, placebo-controlled trial showed that itraconazole 200 mg orally twice daily for 16 weeks resulted in significant differences in the amelioration of disease, as measured by the reduction in corticosteroid dose and improvement in exercise tolerance and pulmonary function.67
In the nonimmunocompromised host, Aspergillus infections of the sinuses most commonly occur as saprophytic colonization (aspergillomas or “fungus balls”) of previously abnormal sinus tissue. An aspergilloma is composed of intertwined Aspergillus hyphae matted together with fibrin, mucus, and cellular debris. Infection usually is localized in the maxillary sinus and rarely is associated with local invasion of adjacent bone or brain tissue. Sinus aspergillosis also can present as allergic sinusitis with nasal drainage of brownish mucous plugs. Therapy with corticosteroids and surgery generally is successful. In the immunocompromised host, subacute, chronic, or fulminant invasive disease can be seen, and a combination of antifungal and surgical therapy generally is required.12,68
Pulmonary aspergillomas are fungus balls arising in preexisting cavities because of tuberculosis, histoplasmosis, lung tumors, or radiation fibrosis, although occasionally no previous pulmonary disease is present. The diagnosis of aspergilloma generally is made on the basis of chest radiographs, on which aspergillomas appear as a solid rounded mass, sometimes mobile, of water density within a spherical or ovoid cavity and separated from the wall of the cavity by an airspace of variable size and shape. Patients generally experience chest pain, dyspnea, and sputum production. Hemoptysis is observed in 50% to 80% of patients, probably because of ulceration of the epithelial lining of the cavity with formation of granulation tissue, and hemoptysis is the cause of death in up to 26% of patients with aspergilloma. A poor prognosis is associated with increasing size or number of aspergillomas, immunosuppression (including corticosteroids), increasing Aspergillus-specific titers, underlying sarcoidosis, and HIV infection. Although Aspergillus can be cultured in only 50% to 60% of patients, precipitating antibodies are positive in virtually 100% of patients.
Invasive disease occurs rarely, and therapy therefore is controversial. There are no controlled clinical trials with which to guide therapy, and recommendations for treatment have been generated from uncontrolled trials and case reports.12 Concern regarding the risk of severe hemorrhage has led some clinicians to use aggressive surgical excision of aspergillomas or pulmonary resection in patients with hemoptysis. Complications, including bronchopulmonary fistulas, hemorrhage, empyema, and persistent airspace problems, have led to the recommendation that surgical intervention be reserved for patients with severe (>500 mL/24 h) hemoptysis, however. Bronchial artery embolization has been used to occlude the vessel that supplies the bleeding site in patients experiencing hemoptysis. Unfortunately, bronchial artery embolization generally is unsuccessful or only temporarily effective. Collateral circulation eventually develops, supplying blood flow to the affected area, and hemoptysis often recurs; consequently, reembolization is often unsuccessful. Bronchial artery embolization should be used as a temporizing procedure in a patient with life-threatening disease who might respond to more definitive therapy if hemoptysis is stabilized. Mild to moderate hemoptysis should be managed conservatively. Although IV amphotericin B generally is not useful in eradicating aspergillomas, inhaled or intracavitary instillation of amphotericin B has been employed successfully in a limited number of patients. Itraconazole has been efficacious in uncontrolled studies; however, the dose and duration of therapy have not been standardized. Hemoptysis generally ceases when the aspergilloma is eradicated.12,68
Although exposure to Aspergillus conidia is nearly universal, impaired host defenses are required for the development of invasive disease. Phagocytes (neutrophils, monocytes, and macrophages) rather than antibodies or lymphocytes constitute the primary host defense system against invasive disease with aspergillosis. Macrophages prevent germination of conidia and also eradicate conidia, providing the first line of defense against invasive disease. Administration of corticosteroids appears to impair the killing of conidia by macrophages and to impair mobilization of neutrophils. Neutrophils halt hyphal growth and dissemination and kill mycelia, constituting a second line of defense. Prolonged neutropenia appears to be the most important predisposing factor to the development of IA, accounting for the high frequency of disease in patients with acute leukemia. Complement provides a source of chemotactic factor and facilitates neutrophil damage to hyphae and monocyte killing of conidia. Complement is not necessary for the attachment or ingestion of conidia by human alveolar macrophages.68,69
Aspergillosis is an uncommon fungal infection in patients with AIDS. AIDS patients may be at less risk for aspergillosis than other fungal infections because the primary cellular defect in AIDS patients is in the T-lymphocytes, whereas neutrophils and macrophages constitute the primary lines of defense to infection with aspergillosis. Aspergillosis was reported as a late complication of disease in AIDS patients with additional risk factors for aspergillosis, such as corticosteroid use, neutropenia, previous Pneumocystis carinii or cytomegalovirus pneumonia, marijuana smoking, or the use of broad-spectrum antibiotics. However, approximately 50% of patients with aspergillosis have no classic risk factors. The majority of these patients had CD4 counts <50 cells/mm3 (<50 × 106/L). Although some patients diagnosed early in their infection responded to treatment, most patients do not respond to therapy with amphotericin B 0.5 mg/kg per day or itraconazole 200 to 600 mg/day.70
Invasive disease with Aspergillus can arise de novo or from any of the allergic or colonizing forms of aspergillosis. Predisposing factors to the development of IA include glucocorticoid therapy, particularly following chronic administration or with higher dosages (30 to 200 mg/day of prednisone), cytotoxic agents, and recent or concurrent therapy with broad-spectrum antimicrobial agents. Patients with chronic hepatitis, alcoholism, diabetes mellitus, chronic granulomatous disease, leukopenia (<1,000 cells/mm3 [<1 × 109/L]), leukemia (particularly acute lymphocytic or myelogenous leukemia), lymphoma, and acute rejection of an organ transplant are also at a higher risk of invasive disease. Although rare, IA has been reported in apparently normal hosts.68
The lung is the most common site of invasive disease.12,68 In the immunocompromised host, aspergillosis is characterized by vascular invasion leading to thrombosis, infarction, necrosis of tissue, and dissemination to other tissues and organs in the body. Survival beyond 2 or 3 weeks is uncommon. If bone marrow function returns, cavitation of the pulmonary lesion generally occurs, and the spread of infection can be halted. The progressive nature of the disease and its refractoriness to therapy are, in part, caused by the organism’s rapid growth and its tendency to invade blood vessels.
Signs and Symptoms
Patients often present with classic signs and symptoms of acute pulmonary embolus: pleuritic chest pain, fever, hemoptysis, and friction rubs. The CNS, liver, spleen, heart, GI tract, pericardium, and other body sites are involved in a substantial minority of cases. In neutropenic patients with Aspergillus pneumonia, hyphae invade the walls of bronchi and surrounding parenchyma, resulting in an acute necrotizing, pyogenic pneumonitis. As a result, patients often present with classic signs and symptoms of acute pulmonary embolus: pleuritic chest pain, fever, hemoptysis, and friction rubs.
The diagnosis of aspergillosis is complicated by the presence of Aspergillus as a normal commensal in the human GI tract and respiratory secretions, and establishment of a definitive diagnosis of disease is difficult. Although suggestive of infection, the presence of hyphae in a smear or biopsy specimen is not diagnostic. Demonstration of Aspergillus by repeated culture and microscopic examination of tissue provides the most firm diagnosis. The appearance of Aspergillus in tissues varies with increasing host resistance from the normal vegetative hyphae found with necrotic tissue and exudate in the alveoli of immunocompromised hosts to the compact, tangled filaments (granules) observed in fungal balls. Identification of Aspergillus generally is based on the appearance of 2- to 4-micron-wide septate hyphae that are dichotomously branched at 45° angles. Sporulation is observed rarely in tissue. Although growth on Sabouraud dextrose or brain-heart infusion agar can be used for primary culture, bronchoscopy or bronchoalveolar lavage cultures are positive in only 40% of histopathologically identified specimens. Blood, CSF, and bone marrow cultures are rarely positive for Aspergillus.
Many clinicians treat positive respiratory cultures of Aspergillus as a common contaminant and argue that a minimum of two to three positive cultures is necessary before antifungal therapy is indicated. Any positive culture, however, can be indicative of true infection in the immunocompromised host, and the positive predictive value can be as high as 80% to 90% in patients with leukemia or bone marrow transplants.
Diagnostic Tests Galactomannan is a cell-wall polysaccharide specific to Aspergillus species that is detectable in serum and other body fluids during IA. Galactomannan levels, reported as optical density values, can be measured in body fluids by means of a double-sandwich enzyme immunosorbent assay (EIA).
The Platelia Aspergillus EIA test (Bio-Rad Laboratories) is FDA-approved for use in the diagnosis of IA in HSCT recipients and in patients with leukemia; its usefulness in solid-organ transplant and pediatric populations needs to be established. The use of mold-active antifungals can decrease the sensitivity of the test. In most patients, circulating antigen can be detected at a mean of 8 days before diagnosis by other means. However, false-positive galactomannan assay results have been reported for patients receiving piperacillin–tazobactam and amoxicillin–clavulanate, those with bifidobacteria infections, and in neonates.18,19,57
The BG test (Fungitell; Associates of Cape Cod) detects (1,3)-β-D-glucan (BG) in the serum of patients with symptoms of or medical conditions predisposing to invasive fungal infections and aids in the diagnosis of deep-seated mycoses and fungemia. BG is a cell-wall constituent of many pathogenic fungi, including Aspergillus and Candida species, and is detectable in patients’ serum during invasive disease due to these organisms. In addition to patients with IA and candidiasis, BG is also detectable in patients with infections caused by species of Fusarium, Trichosporon, Saccharomyces, and Acremonium, which are less common but very important fungal pathogens, especially in immunocompromised hosts. Detection of BG in serum uses a chromogenic variant of the limulus amoebocyte lysate assay. Although a positive test result for the presence of BG does not identify the infecting fungus, the practical application of this test includes its use as a screening assay (presumptive marker) for invasive fungal infection to allow the earlier initiation of antifungal therapy. Other tests are necessary for the confirmation and identification of the fungal pathogen.18
Late findings on radiographic studies include wedge-shaped pleural-based infiltrates or cavities on chest radiographs. Findings on CT scans include the halo sign (an area of low attenuation surrounding a nodular lung lesion) initially (caused by edema or bleeding surrounding an ischemic area) and, later, the crescent sign (an air crescent near the periphery of a lung nodule caused by contraction of infarcted tissue). CT abnormalities are best documented in neutropenic marrow transplant recipients and commonly precede plain chest radiograph abnormalities.57
Therapy for IA is far from optimal at this time in part because of the difficulties in establishing a diagnosis and in part because of a lack of truly effective antifungal agents. Administration of amphotericin B appears to decrease mortality from more than 90% to approximately 45%. These data, however, are difficult to interpret because many patients were diagnosed postmortem, or amphotericin B therapy was not administered until the patient had very advanced disease. Mortality from pulmonary aspergillosis in bone marrow transplant recipients exceeds 94% regardless of therapy.68 Although early diagnosis and administration of antifungal therapy can result in higher response rates, correction of underlying immune deficits (in particular, return of neutrophil counts) is of paramount importance in eradication of infection.12
Until the diagnosis of aspergillosis can be determined more rapidly and definitively, empirical therapy must be instituted when invasive disease is suspected. In patients at highest risk for invasive disease (acute leukemia and bone marrow transplant recipients), the most important predisposing factors include prolonged severe neutropenia (<100 cell/μL [<100 × 106/L] for more than 1 week), graft rejection, chronic administration of corticosteroids, and tissue damage from preexisting infection. In these patients, antifungal therapy should be instituted in any of these conditions: (a) persistent fever or progressive sinusitis unresponsive to antimicrobial therapy, (b) an eschar over the nose, sinuses, or palate, (c) the presence of characteristic radiographic findings, including wedge-shaped infarcts, nodular densities, and new cavitary lesions, or (d) any clinical manifestation suggestive of orbital or cavernous sinus disease or an acute vascular event associated with fever. Isolation of Aspergillus species from nasal or respiratory tract secretions should be considered confirmatory evidence in any of the previously mentioned clinical settings.68
Unfortunately, effective chemoprophylaxis against infections by Aspergillus species has not been demonstrated thus far.7 As noted above in the discussion of prophylaxis for Candida infections in immunocompromised hosts, prophylaxis with azoles or echinocandins can reduce the incidence of fungal infections in select high-risk populations.
Even though older azole antifungal agents (miconazole and ketoconazole) possess poor in vitro activity against Aspergillus species, newer triazoles demonstrate improved activity both in vitro and in animal models of infection.71Voriconazole has emerged as the drug of choice of most clinicians for primary therapy of most patients with IA.72 A randomized trial, which compared voriconazole with amphotericin B (followed by other licensed antifungal therapy) for primary therapy of aspergillosis, noted better responses, improved survival, and fewer severe side effects with voriconazole.73
In patients who are unable to tolerate voriconazole, amphotericin B can be used. Because Aspergillus is only moderately susceptible to amphotericin B, full doses (1 to 1.5 mg/kg/day) are generally recommended, with response measured by defervescence and radiographic clearing. To treat microfoci, therapy should be continued after resolution of clinical and radiographic abnormalities until cultures (if they can be obtained) are negative, and reversible underlying predispositions have abated. Clinical response rather than any arbitrary total dose should guide duration of therapy. The optimal dosage or duration of amphotericin B therapy for the treatment of invasive disease is unknown and dependent on the extent of disease, the response to therapy, and the patient’s underlying disease(s) and immune status. Unfortunately, the response rate averages only 37% (range, 14% to 83%), and the response to therapy is largely related to the extent of aspergillosis at the time of diagnosis, and host factors, such as resolution of neutropenia and the return of neutrophil function, lessening immunosuppression, and the return of graft function from a bone marrow or organ transplant.
Lipid formulations of amphotericin B can be indicated in patients with impaired renal function, and in those patients who develop nephrotoxicity while receiving deoxycholate amphotericin B. The lipid-based formulations may be preferred as initial therapy in patients with marginal renal function or in patients receiving other nephrotoxic drugs. Although these preparations appear less toxic than standard preparations, only limited data regarding their relative efficacy for IA are available at this time, as the studies with the lipid preparations have been open-label or with historical conventional amphotericin B controls.70,74
Caspofungin was approved by the FDA for use as salvage therapy in patients who are intolerant or who fail therapy with one of the amphotericin B formulations.52 Caspofungin has in vitro activity against Aspergillus species and is indicated for the treatment of IA in patients who are refractory to or intolerant of other therapies such as conventional amphotericin B, lipid formulations of amphotericin B, and/or itraconazole. Caspofungin has not yet been studied as first-line therapy for patients with aspergillosis. Because of the high risk of mortality from IA even following treatment with standard therapy such as amphotericin B or itraconazole, caspofungin can offer a new mechanism for salvage therapy for patients with this disease.
The use of adjuvant therapies, such as granulocyte transfusions or recombinant colony-stimulating factors, remains controversial, and controlled trials are lacking at this time. Although some authors advocate combination therapy with azoles, flucytosine, or rifampin plus amphotericin B, controlled clinical studies verifying the efficacy of these combination therapies are lacking.
The use of prophylactic antifungal therapy to prevent primary infection or reactivation of aspergillosis during subsequent courses of chemotherapy is controversial.12 Studies assessing the utility of IV administration of amphotericin B in low doses (0.1 mg/kg per day) as prophylactic therapy or with higher dosages (0.5 to 0.6 mg/kg per day) as empirical therapy for invasive fungal infections in patients with granulocytopenia have not included sufficient numbers of patients to enable detection of differences in the number of Aspergillus infections.
In granulocytopenic patients who recover from an episode of IA, the risk of relapse of aspergillosis during subsequent courses of chemotherapy is greater than 50%. Secondary prophylaxis of aspergillosis with empirical administration of high-dose amphotericin B decreases the risk of relapse. Amphotericin B 1 mg/kg per day is started 24 to 48 hours prior to the start of chemotherapy and continued throughout the period of granulocytopenia.
The increased frequency of fungal pathogens that were once rare is gaining attention from the medical community. Mucormycosis, previously known Zygomycosis, is a term describing infections caused by fungi belonging to the order Mucorales. Permissive environmental conditions, selective antifungal pressure, and increased numbers of immunosuppressed patients have led to increased numbers of infections caused by the Mucorales (e.g., Mucor, Rhizopusspp., or Absidia) or filamentous fungi such as Scedosporium or Fusarium species. Posaconazole appears promising for the treatment of Mucorales infections. Breakthrough mucormycosis has been increasingly observed in patients with leukemia and recipients of HSCT receiving Aspergillus-active drugs, such as voriconazole or an echinocandin, as neither agent has activity against Mucorales. Of currently available systemic antifungals, only amphotericin B (including the lipid formulations) and posaconazole exhibit good in vitro activity against Mucorales. Echinocandins, which demonstrate modest in vivo activity against some Mucorales, demonstrate enhanced activity when coadministered with lipid amphotericin B formulations. Prompt initiation of antifungal therapy is crucial, as treatment delays are associated with increased mortality.75
Unfortunately, the early presentation of Fusarium and Scedosporium infections often mimics that of aspergillosis. On histopathology, Scedosporium species resembles Aspergillus species with dichotomously branching, septate hyphae and has a tendency for invasion of vascular structures.76 These pathogens often demonstrate intrinsic resistance to amphotericin B and are associated with high mortality rates.73 For example, mortality caused by Scedosporium prolificans, previously known as Scedosporium inflatum, exceeds 85%; Scedosporium apiospermum (the asexual state of P. boydii) was uniformly fatal in 23 solid-organ transplant recipients with disseminated disease.76 However, in vitro data suggest that S. prolificans is more sensitive to voriconazole than to amphotericin B or itraconazole.76,77 Voriconazole recently received FDA approval for the treatment of serious fungal infections caused by S. apiospermum and Fusarium species, including Fusarium solani, in patients intolerant of or refractory to other therapy.78
The antifungal armamentarium for the treatment of invasive fungal infections includes: (a) inhibitors of the fungal cell membrane such as polyenes (e.g., amphotericin B) and azole antifungals, (b) inhibitors of DNA (5-flucytosine), and more recently, (c) inhibitors of cell wall biosynthesis (echinocandins).78
Antifungal therapy generally uses one or more of these agents, depending on the severity of infection and the patients’ immune status. Rarely are the agents used in combination. Often therapy is initiated with an IV agent such as amphotericin B, and therapy is changed to an oral (azole) regimen as the patient’s clinical status improves and oral therapy is tolerated. The most widely used combination therapy consists of flucytosine plus amphotericin B. The role of combination therapy is unclear at this time; controlled trials are lacking and the possibility of therapeutic antagonism when using azoles in combination with amphotericin B remains debated. Controlled trials are needed to define the role of azoles plus amphotericin B and azoles or amphotericin B plus an echinocandin.79
Amphotericin B remains the therapy of choice for many systemic fungal infections despite a lack of controlled clinical trials documenting the optimal dosage, duration of therapy, or relative efficacy of this agent in comparison with newer azole antifungal agents. During pregnancy, amphotericin B remains the treatment of choice for most fungal infections because azole antifungals are teratogenic.65,80
The side effects of amphotericin B generally are categorized as acute (infusion-related) or long term. Gallis et al.65 recently reviewed the side effects and clinical uses of amphotericin B.
Lipid Formulations of Amphotericin B
The use of deoxycholate amphotericin B frequently is associated with the development of induced nephrotoxicity. In an attempt to decrease the incidence of nephrotoxicity, three lipid formulations of amphotericin B have been developed and approved for use in humans: ABLC (Abelcet; Enzon Pharmaceuticals), ABCD (Amphotec; Intermune Pharmaceuticals), and liposomal amphotericin B (AmBisome; Gilead Pharmaceuticals). In these preparations, amphotericin B is incorporated into the phospholipid bilayer membrane rather than in the enclosed aqueous phase.
The various lipid formulations of amphotericin B exhibit markedly different pharmacokinetics; however, the clinical implications of these differences remain unclear. Although larger doses of these preparations are required to achieve similar pharmacologic effects as the deoxycholate form of amphotericin B, the toxicity appears to be much lower.80 Although the FDA-approved dosages of these agents are 5 mg/kg per day (ABLC), 3 to 6 mg/kg per day (ABCD), and 3 to 5 mg/kg per day (liposomal amphotericin B), the agents appear generally equipotent. The optimal dose of these compounds for serious Candida infections is unknown; however, dosages of 3 to 5 mg/kg per day appear reasonable. Liposomal amphotericin B administered at 3 mg/kg per day was equally as effective but less toxic than a dosage of 10 mg/kg per day as initial therapy for invasive mold infections.81 The relative efficacy of these agents is unknown; whether differences in pharmacokinetic features result in different outcomes in the treatment of specific types of infections (e.g., CNS infections) is unclear.7
Lipid formulations of amphotericin B are indicated for patients intolerant of, refractory to, or at high risk of being intolerant to conventional antifungal therapy.7,82 Intolerance generally is defined as initial renal insufficiency (creatinine >2.5 mg/dL [>221 μmol/L] or creatinine clearance <25 mL/min [<0.42 mL/s]), a significant increase in creatinine (to 2.5 mg/dL [221 μmol/L] for adults or 1.5 mg/dL [133 μmol/L] for children), or severe acute administration-related toxicity, whereas refractory infections are defined as therapeutic failure of more than 500 mg amphotericin B.
Owing to the higher cost and paucity of randomized trials showing the efficacy of lipid-associated formulations of amphotericin B against proven invasive candidiasis, many clinicians limit their first-line use for the treatment of these infections to individuals who are intolerant to, at high risk of intolerance to, or refractory to amphotericin B deoxycholate. However, the data demonstrating up to a 6.6-fold increase in mortality in patients with amphotericin B-induced nephrotoxicity have convinced other clinicians that high-risk patients (e.g., residence in an ICU care or intermediate care unit at the time of initiation of amphotericin B therapy) warrant first-line therapy with these agents.
Only ABLC and liposomal amphotericin B have been approved for use in proven candidiasis. Both in vivo and clinical studies indicate that these compounds are less toxic but as effective as amphotericin B when used in appropriate dosages. Nevertheless, their higher cost and the paucity of randomized trials in proven invasive candidiasis limit their front-line use in these infections.82
Flucytosine (also known as 5-flucytosine) is a fluorinated pyrimidine analog that is highly water-soluble. Patients with creatinine clearances of less than 40 mL/min (0.67 mL/s) should receive 100 to 150 mg/kg daily in four divided doses. The dosage should be reduced by 50% in patients with a creatinine clearance of 25 to 50 mL/min (0.42 to 0.83 mL/s) and by 75% in patients with a clearance of 13 to 25 mL/min (0.21 to 0.42 mL/s). Peak serum concentrations (2 hours after an oral dose) should be monitored in all patients (particularly those with a creatinine clearance of less than 10 mL/min [0.17 mL/s]) to maintain peak serum concentrations of more than 100 mg/L (775 μmol/L).26
Flucytosine generally is associated with few side effects in patients with normal renal, GI, and hematologic function, although rash, GI discomfort, diarrhea (5% to 10%), and reversible elevations in hepatic enzymes are observed occasionally. In patients with renal dysfunction or concomitant amphotericin B therapy, leukopenia, thrombocytopenia, and (rarely) enterocolitis can occur. Although studies have suggested that little or no conversion of flucytosine to fluorouracil occurs in vitro, serum concentrations of greater than 1,000 ng/mL (~7.7 μmol/L) (therapeutic for the treatment of malignancies) have been documented in some patients. Investigators have theorized that flucytosine may be secreted into the GI tract, deaminated by intestinal bacteria, and reabsorbed as 5-fluorouracil.26
Flucytosine is used in combination with amphotericin B or fluconazole in the treatment of cryptococcosis or (less commonly) candidiasis. The rapid development of resistance to flucytosine, however, precludes its use as single-agent therapy. Mechanisms for drug resistance can include loss of deaminase and decreased permeability to the drug.26
The echinocandins (caspofungin, micafungin, and anidulafungin) are a new class of antifungal agents that act as concentration-dependent, noncompetitive inhibitors of BG synthase, an essential component of the cell wall of susceptible filamentous fungi that is absent in mammalian cells.52
All echinocandins display linear pharmacokinetics following administration of IV dosages, and are degraded primarily by the liver (also in the adrenals and spleen) by hydrolysis and N-acetylation. Following initial distribution, echinocandins are taken up by red blood cells (micafungin) and the liver (caspofungin and micafungin) where they undergo slow degradation to mainly inactive metabolites, although two uncommon metabolites of micafungin possess antifungal activity. Degradation products are excreted slowly over many days, primarily through the bile. Among the echinocandins, anidulafungin is unique in being eliminated almost exclusively by slow chemical degradation rather than undergoing hepatic metabolism.52
Echinocandins are available only as parenteral formulations, are not dialyzable, and do not require dosage adjustment in patients with renal insufficiency. They have minimal CSF penetration, largely because of their high protein binding and large molecular weights, although the clinical relevance of these findings can be disputed, given that several other antifungal agents (amphotericin B and itraconazole) are effective for the treatment of fungal meningitis despite low CSF concentrations.
Adverse effects of echinocandins include histamine release resulting in rash, facial swelling, and itchiness. Limited experience suggests that caspofungin and micafungin are safe to use in pediatric patients; the safety and effectiveness of anidulafungin in pediatric patients has not been established. At the time of FDA approval, there were concerns regarding the safety of caspofungin when combined with cyclosporine. However, three retrospective analyses of the use of caspofungin and cyclosporine in patients do not support a risk of clinically relevant hepatotoxicity.52
Azole Antifungal Agents
The introduction of the azole antifungal agents has rapidly expanded the armamentarium of agents useful in the treatment of systemic fungal infections.9 Adverse effects of azoles include GI disturbances (primarily nausea, vomiting, epigastric pain, and diarrhea), which appear to be more common in patients receiving ketoconazole and the solution formulation of itraconazole. Although cyclodextrin is not absorbed following oral administration, use of the IV formulations of itraconazole and voriconazole is limited to 2 weeks because of concerns for potential nephrotoxicity secondary to accumulation of the cyclodextrin vehicle.83 Fluconazole is well tolerated; intestinal complaints are the most frequently reported, followed by headaches and rash. Unlike ketoconazole, fluconazole does not inhibit testicular or adrenal steroidogenesis in healthy volunteers or hospitalized patients. Reversible alopecia occurs not infrequently and usually appears after several months of treatment with higher doses of fluconazole. Azoles are potentially teratogenic and should be avoided in pregnant women.78,80
Itraconazole is triazole antifungal with a broad spectrum of antifungal activity. Despite its marked structural similarity to ketoconazole, itraconazole differs in several important respects. Itraconazole appears to have greater specificity against fungal versus mammalian CYP, resulting in greater potency and a decrease in CYP-mediated side effects. In addition, itraconazole possesses excellent in vitro activity against Aspergillus and Sporothrix species.4
Like ketoconazole, the capsule formulation of itraconazole depends on the availability of low gastric pH for dissolution and absorption. Administration with food appears to enhance significantly the bioavailability of itraconazole capsules, whereas it decreases the bioavailability of the oral solution. Because itraconazole exhibits pH-dependent dissolution and absorption, absorption of the capsule formulation is impaired in patients receiving antacids or H2-receptor antagonists and in patients with achlorhydria.83 Plasma concentrations of itraconazole following a single oral dose (capsules) in HIV-infected patients are approximately 50% lower than concentrations observed in healthy volunteers. The capsule formulation of itraconazole exhibits unpredictable oral bioavailability, particularly in subjects with hypochlorhydria and in patients with enteropathy caused by mucositis or graft-versus-host gut disease. An oral suspension formulation of itraconazole is available; that uses cyclodextrin as a solubilizing vehicle to increase the solubility of the drug. The oral bioavailability of the solution is unaffected by alterations in gastric pH or in patients with enteropathy.7,83
Fluconazole is a triazole antifungal agent with markedly different pharmacologic features than other marketed azole antifungals. The small molecular weight, low protein binding, and increased water solubility of fluconazole result in rapid, essentially complete absorption of drug following oral administration. Because fluconazole is excreted primarily (>80%) as unchanged drug in the urine, dosage adjustments are necessary in patients with renal dysfunction.71
The hepatic biotransformation of voriconazole is fairly complex and involves CYP2C19, CYP3A4, and CYP2C9, with most metabolism mediated through CYP2C19. Two of the CYPs involved in voriconazole metabolism (CYP2C19 and CYP2C9) exhibit genetic polymorphism; variability in the CYP2C19 genotype accounts for approximately 30% of the overall between-subject variability in voriconazole pharmacokinetics. About 3% to 5% of white and African human populations are poor metabolizers, while 15% to 20% of Asian populations are poor metabolizers. Drug levels can be as much as fourfold greater in poor metabolizers than in individuals who are homozygous extensive metabolizers. Coadministration of voriconazole with drugs that are potent CYP450 enzyme inducers can significantly reduce voriconazole levels. Voriconazole drug interactions are dose-dependent, as they exhibit unpredictable nonlinear pharmacokinetics; thus, drug interactions are more difficult to predict and manage.
The most common side effect of voriconazole is a reversible disturbance of vision (photopsia), which occurs in approximately 30% of patients but rarely leads to discontinuation of the drug. Symptoms tend to occur during the first week of therapy and decrease or disappear despite continued therapy. Patients experience altered color discrimination, blurred vision, the appearance of bright spots and wavy lines, and photophobia. Patients should be cautioned that driving can be hazardous because of the risk of visual disturbances. The visual effects are associated with changes in electroretinogram tracings, which revert to normal when treatment with the drug is stopped; no permanent damage to the retina has been demonstrated.71
Controversy has arisen about whether single-drug therapy or combination therapy (e.g., voriconazole plus an echinocandin or voriconazole plus a lipid formulation of amphotericin B) is optimum therapy. At present, the highest interest concerns combination therapy in the treatment of aspergillosis, given the continued high mortality of these infections.83 However, in vitro and animal data have produced conflicting results. Several retrospective studies have suggested an improvement in mortality with combination therapy with two or three antifungal agents; however, prospective, controlled human studies are lacking. Thus, there are as yet no firm recommendations regarding the use of such combinations in humans.12
Posaconazole has a broad spectrum of antifungal activity, including Aspergillus and Candida species and zygomycetes. In vitro studies demonstrate that posaconazole is an inhibitor but not a substrate of hepatic (but not total) CYP3A4, and both a substrate and an inhibitor of P-glycoprotein (Pgp), suggesting that it may exhibit a drug interaction profile similar to other azoles. In addition, posaconazole undergoes glucuronidation by uridine diphosphate (UDP)-glucuronosyltransferase enzymes.71
Drug Interactions with Antifungal Agents
Drug interactions with azole antifungals generally can be placed into three broad categories: (a) decreases in azole bioavailability because of chelation or secondary to increases in gastric pH, (b) interactions with other CYP-metabolized drugs, and (c) interactions caused by inhibition of Pgp. Drug interactions in the latter two categories can result in increases or decreases in the azole antifungal, in the interacting drug, or in both drugs.
The interaction of azole antifungal agents with other CYP-metabolized drugs is well recognized. The azoles appear to be metabolized almost entirely via the CYP3A4 subfamily. As expected, they interact with other drugs metabolized partly or wholly through this enzyme pathway. In addition, fluconazole and voriconazole use the CYP2C19 pathway. Numerous clinically significant interactions have been documented with azole antifungals and a variety of other drugs. In most cases, the azole interferes with the metabolism of the other CYP-metabolized drug.71
The interaction between ketoconazole and cyclosporine has been exploited to reduce drug costs associated with administration of cyclosporine following organ transplantation. Relative to ketoconazole and itraconazole, fluconazole appears to be intermediate in its ability to inhibit human cytochromes P450. The magnitude of fluconazole-induced inhibition of cyclosporine metabolism appears, however, to depend on the dosage of fluconazole.
Predictably, drugs such as rifampin, rifabutin, isoniazid, phenytoin, and carbamazepine, which are known to induce the activity of cytochromes P450, result in increased metabolism of the azole antifungals and can result in therapeutic failures. Increased dosages of azole antifungals can be required in patients receiving these combinations of drugs.
Itraconazole is an inhibitor of intestinal Pgp. Significant increases in digoxin (a Pgp substrate) have been observed in patients receiving both agents concurrently. Interactions with other substrates of Pgp would be expected to occur.
Echinocandins are not inducers of CYP enzymes, nor do they interact with Pgp, and are considered poor substrates of CYP3A4. Nevertheless, cyclosporine increases the area under the plasma-concentration versus time curve (AUC) of caspofungin by ~35%, and tacrolimus AUC, peak, and 12-hour concentrations are decreased by approximately 20% during concomitant administration with caspofungin. Additionally, when caspofungin was administered concurrently with tacrolimus, tacrolimus levels were reduced by 20% compared to administration with tacrolimus alone. The mechanism for these interactions is not yet known. Rifampin both inhibits (acutely) and induces (after chronic administration) caspofungin metabolism. A dosage increase is recommended in patients receiving other enzyme inducers, such as efavirenz, nevirapine, phenytoin, dexamethasone, and carbamazepine. Although micafungin does not significantly affect the clearance (or AUC) of tacrolimus, it increases the AUC of sirolimus by 21%, and of nifedipine by 18%, and decreases the clearance of cyclosporine by 16%. Monitoring of cyclosporine levels during combination therapy with micafungin is recommended.52
Plasma Concentration Monitoring of Antifungal Agents
Routine therapeutic plasma drug concentration monitoring (TDM) of plasma concentrations of antifungal agents to assess efficacy or toxicity of these agents generally is not available. Correlations between plasma concentrations of antifungal agents and therapeutic outcomes have been poorly studied. However, the available, good-quality, prospectively obtained data in the prophylactic or therapeutic setting are insufficient to justify the routine use of therapeutic drug monitoring. In addition, logistics, cost, and incorporation of therapeutic drug monitoring have yet to be worked out in modern prophylactic algorithms.84,85
Under certain circumstances, serum or plasma concentration monitoring is warranted. Given the tremendous interpatient and intrapatient variability in voriconazole metabolism, and poor oral bioavailability of posaconazole, monitoring is often warranted, particularly in patients with GVHD of the gut, mucositis, or diarrhea, or poor oral intake or those receiving concomitant therapy with proton-pump inhibitors. Additional settings include patients susceptible to flucytosine toxicity, to document adequate oral absorption of poorly bioavailable azoles in cases of suspected treatment failure or concern about compliance or absorption, solubility and finally, when drug interactions that might reduce or accelerate the metabolism of azoles is suspected (Table 99–11).17,84,85
TABLE 99-11 Plasma Concentration Monitoring of Antifungal Agents78,84,85
Combination Antifungal Therapy for Invasive Fungal Infections
Based on extensive experience in the management of bacterial, and more recently, retroviral infections, the use of combination agents for synergistic or additive effects is now common practice, particularly for the treatment of IA.79High-dose fluconazole, alone or in combination with amphotericin B, in nonimmunocompromised patients with candidemia demonstrated no antagonism and a trend toward improved success and more rapid clearance of Candidafrom the bloodstream.48
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