Pharmacotherapy - A Pathophysiologic Approach. Third Edition, 1997, Chapter 113, pp 2251-2279 or Second Edition, Chapter 108, pp 1763-1787.
By the end of this lecture the student should be able to:
1. Identify a "classic" microbiologic characteristic for identifying of Candida albicans, Cryptococcus neoformans, and the dimorphic fungi.
2. Describe epidemiologic factors important in the acquisition of fungal infections due to Candida, Cryptococcus, Aspergillus, and the dimorphic fungi.
3. Design appropriate treatment regimens for the various clinical manifestations of fungal infections due to Candida, Cryptococcus, Aspergillus, and the dimorphic fungi.
4. List adverse effects and appropriate monitoring parameters for amphotericin B, flucytosine, and the azoles.
The incidence of fungal infections has markedly increased in recent years. Several factors have contributed to this increase. These include greater use of immunosuppressive drugs; prolonged use of broad-spectrum antibiotics; widespread use of indwelling catheters; and the acquired immunodeficiency syndrome (AIDS). Fungal infections have emerged as a major cause of death among cancer patients and transplant recipients. In addition, immunocompromised patients (AIDS) often experience more frequent and severe fungal infection.
Fungal infections are not as easy to diagnose and treat as most bacterial infections. Both diagnostic and susceptibility testing methods for fungi have not progressed as quickly as those for bacteria. Fungi, especially molds, can be very slow growing and difficult to identify. While tentative guidelines for antifungal susceptibility testing of yeasts have been published, methods for filamentous fungi are just beginning to be studied. Serum concentrations of most antifungal agents are not routinely monitored. The relationship between clinical efficacy, susceptibility results, and plasma concentrations for fungi is not known. The emergence of new fungal pathogens and the development of resistance is also a major concern.
Candida species
MICROBIOLOGY:
Candida species are yeasts. They are small (4-6 um), unicellular, thin-walled, ovoid cells that reproduce by budding. They grow well on commonly used bacterial culture media and do not require special fungal media for cultivation. In clinical specimens, a KOH prep (10% potassium hydroxide) is performed to identify yeast, pseudohyphae, and hyphae; identification of the fungal forms is facilitated with the KOH which clears the epithelial cells and other debris.
There are more than 150 species of Candida. Of these approximately 10 are considered important pathogens for humans. They are C. albicans, C. guilliermondii, C. krusei, C. parapsilosis, C. stellatoidea, C. tropicalis, C. pseudotropicalis, C. lusitaniae, C. rugosa, and Torulopis (formerly Candida) glabrata. Because of differences in pathogenicity and resistance, speciation is desirable. A rapid, presumptive diagnosis of C. albicans can be made using the germ tube test. This test is performed by placing the yeast in serum and observing the formation of germ tubes, which are small projections from the cell surface that appear within 1-2 hours. Presence of chlamydospores is also used to identify C. albicans. Various biochemical tests or kits (API Strips) can be used to identify yeasts within 2 days.
EPIDEMIOLOGY:
Candida species are part of the normal flora in humans. They are commonly found on skin and throughout the gastrointestinal (GI) tract. These sites are believed to be the most likely ports of entry into the blood stream. Candida species are also commonly found in expectorated sputum, the female genital tract, and in urine of patients with indwelling Foley catheters.
PATHOGENESIS:
Intact skin and mucus membranes are the most important defense mechanisms in maintaining resistance to mucocutaneous or systemic candidiasis; any process causing skin maceration leaves the site susceptible to Candida invasion, even in healthy individuals. Polymorphonuclear leukocytes (PMNs) play a major role in fighting Candida infections. PMNs damage pseudohyphae and phagocytosize and kill blastospores.
Interruption of normal defense mechanisms is necessary for Candida to become a pathogen. The factors responsible for immunocompromise fall into two categories: naturally occurring and iatrogenic. Naturally occurring includes diabetes mellitus, which predisposes to cutaneous candidiasis. Iatrogenic factors are thought to be the most important predisposing factors to Candida infections, especially disseminated infections. The most common iatrogenic factors involve the use of antibiotics and intravenous catheters. Antibiotics suppress normal bacterial flora which then allows yeast to proliferate, especially in the GI tract. Factors that provide a route for Candida to enter the blood include IV drug abuse, parenteral nutrition, chemotherapy, cardiac catheters and prosthetic valves and other implanted prosthetic material. In general, any immune suppression (steroids, AIDS, organ transplantation) can potentially lead to cutaneous or disseminated candidiasis.
CLINICAL MANIFESTATIONS:
(1) Thrush: The term thrush is used to identify oral candidiasis characterized by creamy white, curdlike patches on the tongue and other oral mucosal surfaces, which, when removed by scraping, leave a raw, bleeding, and painful surface. The patches are a pseudomembrane made up of Candida, epithelial cells, leukocytes, bacteria, keratin, necrotic tissue, and food debris. The diagnosis is made by the clinical appearance of the lesion and by KOH prep. Thrush is commonly seen in patients with cancer, AIDS, and asthma treated with inhaled steroids. Patients with thrush for no obvious reason should be evaluated for AIDS. Treatment usually consists of topical antifungals: nystatin 5 ml (100,000 units/ml) "swish and swallow" QID or clotrimazole trouches (10 mg) five times daily, for 10-14 days. Patients should be treated for 48 hours after becoming asymptomatic. In AIDS and oncology patients, both ketaconazole (200-400 mg/day po) and fluconazole (50-100 mg/day po) have been used for treatment and prophylaxis. A major concern is the emergence of resistance in HIV infected patients receiving fluconazole for long-term prophylactic therapy. Larger doses of fluconazole, change in therapy to itraconazole, and the use of amphotericin suspensions (1 ml [100 mg/ml] QID swish & swallow) have all been used as treatment options. Specific regimens for HIV infected patients are covered in separate lectures.
(2) Candida Esophagitis: This form of fungal infection is most commonly seen in patients undergoing treatment for cancer and in AIDS patients. Esophageal disease was thought to occur by direct spread from oral disease, but has also been reported to occur without thrush. The most common symptoms include painful swallowing, a feeling of obstruction on swallowing, and substernal chest pain. Nausea and vomiting may also occur. The diagnosis is made by biopsy during endoscopy. Treatment generally consists of a minimum of 14 days with either ketoconazole (200-400 mg/day) or fluconazole (100-200 mg/day) or itraconazole (200 mg/BID). Fluconazole has demonstrated greater efficacy than ketoconazole in some AIDS patients, possibly due to achlorhydria, resulting in decreased absorption of the ketoconazole. For patients that do not respond to the azoles, low-dose (10-20 mg/day) intravenous amphotericin B should be effective.
(3) Candida Vaginitis: This common infection is most frequent in a setting of diabetes melitis, antibiotic therapy, and pregnancy. Candida vaginitis is usually accompanied by a thick, curdlike discharge and intense pruritus. Recommended treatment has been 7-day topical treatment with miconazole or clotrimazole. Recently 1- and 3-day topical regimens have been shown to be effective. Several of the topical antifungal agents are now available as over-the-counter (OTC) preparations. Oral therapy with fluconazole (150 mg/day x 3 days) and ketoconazole (200-400 mg/daily x 3 days) has also be used.
(4) Urinary Tract Candidiasis: The presence of Candida in the urine is common and does not necessarily indicate infection. Candiduria is often seen in association with antibiotics and Foley catheters. In the absence of bladder instrumentation, Candida cystitis has been associated most often with diabetes mellitus. Symptoms may be absent or identical to bacterial cystitis. Initial therapy of candidal cystitis consists of removal of urinary catheters whenever possible. Postcatheterization persistent candiduria usually resolves without specific antifungal therapy. If it persists but is asymptomatic, there are 2 populations in which it should be treated: renal transplant patients and neutropenic patients. Treatment generally consists of local irrigation with amphotericin B (50 mg in 1 liter sterile water infused at 40 ml/hr) for 5-7 days. Oral therapy with fluconazole (50-100 mg/day for 7-10 days) may also be effective, as this drug is excreted in high concentrations in the urine.
(5) Candidemia and Disseminated Candidiasis: Problems with management of candidemia and detection of underlying disseminated candidiasis present major enigmas for clinicians dealing with patients who are predisposed to disseminated disease. The diagnosis of disseminated candidiasis is a clinical one. Definitive diagnosis is made by histopathologic demonstration of the organism invading tissues. Diagnosis is difficult because many patients with disseminated disease do not have positive blood cultures. Interpretation of the significance of increased numbers of Candida from sites such as sputum, urine, feces, and skin is difficult, because the organism is frequently cultured from these sites, without causing infection.
Management of candidemia poses particularly difficult problems. Some patients with competent immune status, have spontaneous resolution of candidemia with removal of an indwelling catheter. Among severely immunocompromised patients, almost all with candidemia have disseminated disease. Assuming a positive blood culture for Candida represents "contamination" may be dangerous; an extensive evaluation of the patient should be conducted to rule out disseminated disease. This evaluation should consist of repeated blood cultures and careful physical exam to look for cutaneous manifestations and ocular involvement. In the immunocompetent patient the catheter, if present, should be removed, and repeat blood cultures performed. Interpretation of repeat cultures should be done with the recognition that 50% of patients with disseminated candidiasis do not have positive blood cultures. Removal of an indwelling intravenous catheter is very important in the management of candidemia and a new catheter should not be inserted over a wire in the site of the old one.
Until more comparative data on the efficacy of the azoles is available, Amphotericin B remains the gold standard of therapy for candidemia and disseminated Candida infection. There are an increasing number of reports of serious Candida infections being successfully treated with fluconazole. Although these reports are encouraging, they either lack comparison with amphotericin B or have problems in study design. Fluconazole has emerged as an alternative to amphotericin B because of several factors: ease of administration, availability of both oral and intravenous forms, and low adverse effect profile. In patients who are neutropenic or unstable (or rapidly worsening), amphotericin B (0.5-1 mg/kg/day) should be selected for initial therapy. Depending on the severity of the infection, 5-fluorocytosine (5-FC, flucytosine) may be added to the regimen (100-150 mg/kd/day). However, the addition of 5-FC may result in bone marrow suppression, therefore serum levels of 5-FC should be monitored. Treatment with amphotericin B or combination therapy is continued until obvious clinical improvement is seen. Unfortunately, there are no controlled studies giving guidelines for the total dose of amphotericin B or 5-FC needed. Most therapies are continued for weeks to months, with total dosages of 0.5-1 gram or more generally recommended. In patients who are clinically stable and patients without neutropenia, the use of fluconazole (400 mg/day IV) or other azoles may be considered.
Cryptococcus neoformans
MICROBIOLOGY:
Cryptococcus neoformans is an encapsulated yeast that reproduces by budding. The cell is round or oval and generally 4-6 um in diameter. The surrounding capsule may vary greatly in size depending on growth conditions of the environment.
EPIDEMIOLOGY:
C. neoformans is found in the soil and other sources in nature. It has a worldwide distribution. Infection occurs after the organism is aerosolized and inhaled.
PATHOGENESIS:
Because the organism is ubiquitous, it is assumed that exposure is common. There appears to be high natural resistance to infection. Patients with cell-mediated immune defects appear to be at increased risk for infection. Currently AIDS is the predisposing factor in the vast majority of cryptococcal infections. After AIDS, transplantation is the next most frequent risk factor. The major virulence factor for this pathogen is the polysaccharide capsule which allows the organism to resist phagocytosis by the host.
CLINICAL MANIFESTATIONS:
(1) Meningitis: The onset of CNS cryptococcoses may be acute or insidious. Acute manifestations are more common in immunosuppressed patients. Those with more chronic courses may have waxing and waning manifestations over weeks to months, often with completely asymptomatic periods. Complaints may be referable to the CNS, although they may be mild and nonspecific. Commonly reported symptoms include headache, fever, nausea, vomiting, mental status changes, and stiff neck. Like the history, physical findings do not provide specific clues to the diagnosis. Patients are often afebrile or have only a mildly elevated temperature. Routine laboratory tests are often normal. Except for infections in severely immunosuppressed patients, CNS involvement is almost always indicated by abnormalities in the CSF (elevated opening pressure, glucose decreased, protein increased, elevated WBC with more lymphocytes than neutrophils). Detection of the organism by culture is necessary for diagnosis. India ink smears can be used to presumptively identify the organism. Latex agglutination tests rapidly identify antigens in CSF (and serum) from 90% or more of patients with cryptococcal meningitis.
Effective treatment of CNS cryptococcoses in non-AIDS patients has been demonstrated with either amphotericin B (0.5-0.7 mg/kg/day for 10 weeks) or combination therapy with amphotericin B (0.3 mg/kg/day) and 5-FC (150 mg/kg/day in 4 divided doses) for 6 weeks. In patients with AIDS, efficacy has been demonstrated with amphotericin alone, and in combination with 5-FC, and with fluconazole (200-400 mg/day for 6-10 weeks). Because cryptococcoses is seldom cured in HIV-positive patients, lifelong suppressive treatment is used. Many authorities recommend an initial aggressive treatment course with amphotericin B (with or without 5-FC) for 6-10 weeks, followed by lifelong maintenance therapy with fluconazole (200 mg/day or higher if necessary).
Histoplasma capsulatum
MICROBIOLOGY:
Histoplasma capsulatum is dimorphic, meaning it can grow as a mycelial form at ambient temperatures and as a yeast form at body temperature. The macroconidia (8-15 um) of the mycelial form are spherical and thick-walled. They appear tuberculated due to fingerlike protrusions from the outermost layer of the cell wall. The organism was originally named H. capsulatum because it appeared to have a capsule; however, the pseudo-encapsulated appearance turned out to be an artifact caused by cytoplasmic shrinkage from the rigid cell wall during tissue fixation. The yeast cells are small (3-4 um), round to oval, and have thin walls. The yeast reproduce by polar budding with a narrow neck between the mother and daughter cell.
EPIDEMIOLOGY:
H. capsulatum is present in temperate zones around the world. It is highly endemic in the midwestern and south central U.S. (Ohio and Mississippi river valleys). The natural habitat of the mycelium form is soil. Infections are acquired by inhalation and deposition of conidia in pulmonary alveoli.
PATHOGENESIS:
Following deposition of conidia in the alveolar spaces, conversion to the yeast form is necessary for pathogenesis. Conversion is believed to occur in 2-3 days. Macrophages are a major component of the earliest inflammatory response to H. capsulatum and may play a significant role in limiting infection. CD4+ T-lymphocytes are crucial to host defense, as indicated by the marked susceptibility to disseminated histoplasmosis of people with AIDS
CLINICAL MANIFESTATIONS:
(1) Acute Pulmonary Histoplasmosis: Approximately 99% of primary pulmonary infections are asymptomatic or an acute, self-limiting illness with flu-like pulmonary symptoms. Most clinically apparent infections are mild to moderate in severity with nonspecific symptoms. Two important factors that determine the degree of symptomology are the quantity of inoculum inhaled and the immune status of the host. The incubation period after exposure ranges from 3-21 days, with peak onset of symptoms at 3-14 days. Fever, chills, headache, myalgia, and nonproductive cough are common. Weight loss secondary to anorexia, marked fatigue, and myalgia also are frequent complaints. Five to 6% of patients experience rheumatologic manifestations in the form of arthralgias, frank arthritis, erythema multiforme, and/or erythema nodosum. Occasionally, people with severe infections with present with a clinical picture that resembles adult respiratory distress syndrome (ARDS). Most patients become asymptomatic within 2 weeks after onset of symptoms. Weakness and fatigability may persist for several months in more severe infections. Routine lab studies are not distinctive. Pulmonary function tests may be abnormal and CXR typically shows one or more patchy pneumonic infiltrates.
Both asymptomatic and symptomatic infections require no specific treatment. Patients with severe infections may be treated with ketoconazole (400 mg/day) or itraconazole (200 mg/BID) for 3-6 months. If azole therapy is contraindicated or not tolerated, a brief 2-4 week course of amphotericin B (0.3-0.7 mg/kg/day) may be given.
(2) Chronic Pulmonary Histoplasmosis: CPH usually presents as an opportunistic infection imposed on a pre-existing structural abnormality. The majority of patients are males over the age of 50 who have COPD. The most common complaints are persistent cough, weight loss, malaise, and low-grade fever. Night sweats and pleuritic chest pain are also reported. Routine lab tests are not helpful in the diagnosis. Patients exhibit chronic pulmonary symptoms and apical lung lesions which progress with inflammation, calcified granulomas, and fibrosis. Patients with early, noncavitory disease generally recover without treatment. Progression of disease occurs over a period of years (in approximately 25% of patients), with cavitation, bronchopleural fistulas, extension to the other lung, pulmonary insufficiency, and frequently death. Immunosuppressed patients with persistent radiographic abnormalities should be treated, as well as those who are symptomatic or who present with thick-walled cavities (>2 mm). Amphotericin B is effective when given to a total dosage of 35 mg/kg. Treatment with ketoconazole (400-800 mg/day) and itraconazole (200 mg/BID) for 6-12 months is also effective.
(3) Disseminated Histoplasmosis: Disseminated infection can develop by extension from primary pulmonary infection, by exogenous reinfection, or by reactivation of an endogenous focus of latent infection. The clinical spectrum of disseminated histoplasmosis is broad. Most adults exhibit a mild, chronic form of the disease. Untreated patients are often ill for years, with long asymptomatic periods interrupted by relapses of clinical illness characterized by weight loss, weakness, and fatigue. Treatment for chronic disseminated histoplasmosis is the same as for CPH.
Blastomyces dermatitidis
MICROBIOLOGY:
B. dermatitidis is dimorphic fungus, growing as a mycelial form at room temperature and as a yeast form at 37C. Conversion of the mycelial form to the yeast form is necessary for definitive identification. The yeast cells are 8-15 um in diameter, with a thick cell wall that is highly refractile. The yeast reproduce by single buds, with a broad base between parent and bud. The daughter cell is often nearly as large as the mother cell before detachment. These characteristics are also seen in tissue samples and are used to distinguish B. dermatitidis from other fungi.
EPIDEMIOLOGY:
The fungus is endemic in the U.S. in the southeastern and south central states, especially those bordering the Mississippi and Ohio river basins, and in the midwestern states that border the Great Lakes. B. dermatitidis is considered to be an inhabitant of soil, although attempts to isolate the organism in nature have been difficult and the results inconsistent.
PATHOGENESIS:
Blastomycosis results from inhalation of spores from the soil, with disease at other sites a result of dissemination from a primary pulmonary infection. Immunocompetent people are fairly resistant to infection by B. dermatitidis. When conidia are inhaled, natural resistance is likely mediated by neutrophils, monocytes, and macrophages, which can phagocytize and kill the conidia. Alveolar macrophages inhibit the transformation of conidia to the pathogenic yeast forms. However, once converted in tissue, the yeast forms are relatively resistant to phagocytosis and killing.
CLINICAL MANIFESTATIONS:
Blastomycosis is a systemic disease with a wide variety of pulmonary and extrapulmonary manifestations. Pulmonary disease may be acute or chronic and is difficult to differentiate from infections with bacteria, tuberculosis, other fungi, or malignancy. Acute pulmonary blastomycosis is generally asymptomatic or a self-limiting disease characterized by fever, shaking chills, and a productive cough. Chronic disease is characterized by fever, malaise, weight loss, night sweats, and cough. B. dermititidis may involve almost every organ of the body, resulting in the diversity of clinical manifestation. Skin, bone, and genitourinary sites of infection are common. As no clinical syndrome is characteristic of blastomycosis, the definitive diagnosis requires growth of the organism from clinical specimens. A presumptive diagnosis can be made by visualization of the fungus in specimens. Ketoconazole (400 mg/day) or itraconazole (200 mg BID) [treat for 6 months] can be used to treat mild to moderate disease. Amphotericin B (0.5-1 mg/kg/day) is the drug of choice for patients who are severely immunocompromised and for patients with life-threatening disease, central nervous system disease, or have progression of disease on azoles, or are not able to tolerate azole therapy. Although the exact dose and optimal duration of therapy are unknown, relapse appears to be more common if the total dose is less than 1.5 g. Most recommend a total dose of 1.5-2.5 g of amphotericin B. Relapse is more common in immunocompromised patients, especially AIDS. Chronic suppressive therapy with an azole is recommended for immunocompromised patients.
Coccidioides immitis
MICROBIOLOGY:
This dimorphic fungus exists in the soil in the mycelial phase. As it matures, alternate cells (arthroconidia) in the hyphae become barrel shaped. The hyphae is easily fragmented, and the arthroconidia become airborne, where they may be inhaled by an animal host. In the host, the spores swell, become spherical, and develop a thick wall. This new structure, the spherule, reproduces by formation of internal spores (endospores). A single spherule may develop as many as 800 endospores. When the spherule ruptures, the endospores are released and each in turn can develop into a new spherule.
EPIDEMIOLOGY:
Coccidioidomycosis is endemic in certain areas of the Americas. Almost all infections in the U.S. occur in 7 southwestern states. The incidence of infections will likely rise over time, since the endemic areas are in the sunbelt states and Latin America, which has a rapidly growing population and because of the increase in travel to these areas.
PATHOGENESIS:
Coccidioidomycosis resembles tuberculosis in its pathologic manifestations. The predominant tissue reaction is granulomatous. After the arthrospore first impacts in the lower airways, the initial host response consists of macrophages and neutrophils. Neutrophils are prominent again when spherules rupture. Arthroconidia, endospores, and particularly spherules are quite resistant to killing by neutrophils. Studies in animals suggest that T-lymphocytes play a critical role in immune response.
CLINICAL MANIFESTATIONS:
Approximately 60% of those infected have asymptomatic infections or mild non-specific symptoms. The remainder develop symptoms of a primary infection 1-3 weeks after exposure. These infections resemble a lower respiratory tract infection and/or systemic illness with the following symptoms: cough, sputum production, chest pain, malaise, fever, chills, night sweats, anorexia, weakness, and arthralgias. Erythema nodosum or erythema multiforme involving the upper trunk and extremities may occur. CXR show minimal changes, infiltrates, or pleural effusion. In most cases, these manifestations resolve spontaneously. Some develop acute progressive pneumonia, often with a fatal outcome; others progress to chronic pulmonary disease. Usually, cavitary lesions are part of the chronic disease. About 0.5% of infected patients develop disseminated disease. The most common sites of disseminated infection are musculoskeletal (muscles, tendons, bones, joints), cutaneous, and the meninges. Disseminated coccidioidomycosis became an AIDS-defining event in HIV- positive people in 1987. Definitive diagnosis of C. immitis infection is by culture and identification of the spherule. Most patients improve without therapy; however patients with severe primary infection should be treated. Once the disease has disseminated, antibiotic therapy is mandatory. Initial doses of 1-1.5 mg/kg/day of amphotericin B , with total doses of 1-2.5 g are generally used. Prolonged courses are necessary if remission is not achieved. Studies with the azoles (ketoconazole, fluconazole, itraconazole) are encouraging and may be used for treatment of some infections.
Aspergillus species
MICROBIOLOGY:
Aspergillus is an ubiquitous mold. The three most common species involved in human infections are A. fumigatus, A. flavus and A. niger. Aspergillus species are identified by appearance of the colony and by microscopic examination of the spore-bearing structures and spores. Hyphae of Aspergillus are 2-4 um wide, septate, and dichotomously branched. In the absence of sporulation, the hyphae cannot be readily differentiated from a large number of other molds.
EPIDEMIOLOGY:
Aspergillus are ubiquitous in the environment of most countries of the world. Aspergillus reaches the patient by airborne conidia that are small enough (2.5-3 um) to reach the alveoli upon inhalation and hardy enough to survive for prolonged periods in fomites. Besides the lung, Aspergillus can invade the nose and paranasal sinuses, external ear, or traumatized skin. The most important determinant of infection is the immune status of the patient, not the intensity of exposure. In acute leukemia and bone marrow transplantation, prolonged and intense neutropenia is probably the most important predisposing factor, just as return of marrow function is vital to therapeutic response. High-dose corticosteroid therapy is the only predisposing factor in some patients. In previously normal children, invasive aspergillosis should suggest the possibility of granulomatous disease.
PATHOGENESIS:
Aspergillus can invade the lung through the alveoli or the tracheobronchial tree. Complement activation recruits monocytes and neutrophils to the infected site. Killing by these cells is poor until the conidia swell and germinate into hyphae. Then, these cells as well as activated macrophages, can attach and damage the fungus. Wherever the initial lesion is, growth of hyphae into and extension along blood vessels is universal in the markedly neutropenic patient, leading to hemorrhagic infarction and necrosis. Infection extends directly across tissue planes as well as hematogenously. Aspergillus can colonize bronchi and preexisting pulmonary cavities, growing as balls of hyphae. The fungal ball is composed entirely of hyphae that are originally viable. With time, central areas of the ball degenerate and soften. Intermittent obstruction of the bronchial communication may cause the cavity to fill with fluid in which bacteria may grow and increase the inflammation of the cavity wall.
CLINICAL MANIFESTATIONS:
The term "aspergillosis" is broadly defined as a spectrum of diseases attributed to allergy, colonization, or tissue invasion by Aspergillus species. Allergic manifestation range in severity from mild asthma to allergic bronchopulmonary aspergillosis (BPA). BPA is caused by A. fumigatus, and is characterized by severe asthma with wheezing, fever, malaise, weight loss, chest pain, and a cough productive of blood-streaked sputum. BPA develops when spores become trapped in the viscous mucus of asthmatic patients. The fungus grows, releasing toxins and antigens. Therapy is aimed at minimizing the amount of antigenic material released in the tracheobronchial tree. Antifungal therapy is generally not indicated, with treatment consisting of parenteral corticosteroids. Superficial infections of the ear and skin can often be managed with topical antifungals. Aspergillus infections of the sinuses occurs following colonization in abnormal sinus tissue, resulting in aspergillomas or fungus balls. Infection is generally localized in the maxillary sinus; treatment consists of removal of the aspergilloma. In immunocompromised patients, invasive disease ranging from chronic to subacute to fulminant infection can be seen. A combination of surgical and antifungal therapy is generally required. Pulmonary aspergillomas are fungal balls arising in pre-existing cavities due to tuberculosis, histoplasmosis, or other pulmonary condition. Patients commonly experience chest pain, dyspnea, and sputum production. Hemoptysis is observed in 50-80% of patients, with approximately 10% having hemorrhage severe enough to cause death. Invasive disease rarely occurs, and therapy for aspergillomas is controversial. Surgical excision is generally performed. Intravenous amphotericin B is generally not useful in eradicating aspergillomas. Invasive aspergillosis is rare in immunocompetent hosts. The lung is the most common site of invasive disease. Neutropenic patients with Aspergillus pneumonia can develop an acute necrotizing, pyogenic pneumonitis, caused by hyphae invading the walls of bronchi and surrounding parenchyma. These patients present with classic signs and symptoms of acute pulmonary embolism: pleuritic chest pain, fever, hemoptysis, a friction rub, and a wedge-shaped infiltrate on CXR. Thrombosis with resultant infarction, necrosis, and dissemination to other tissues and organs in the body is caused when hyphae invade blood vessels. Neutropenic patients with invasive aspergillosis do not generally survive beyond 2-3 weeks, unless bone marrow function is restored. Treatment for invasive aspergillosis is with amphotericin B. The optimal dose or duration of therapy has not been determined. Therapy is usually started with 1-1.5 mg/kg/day of amphotericin B, and continued until clinical improvement is apparent, bone marrow has recovered, or the drug can no longer be tolerated. Itraconazole has been useful in some of the more indolent, nonmeningeal cases.
Amphotericin B
Mechanism of Action: Amphotericin B is a lipophilic polyene that binds ergosterol in the cell walls of susceptible fungi; the resultant alteration of membrane permeability allows leakage of the cellular contents and thus causes cell death.
Pharmacokinetics: Amphotericin B has poor oral absorption. It is almost always given intravenously, the main exceptions being for bladder irrigation and topical treatment of thrush. The drug is highly protein bound. It is distributed to many tissues, including lung, spleen, and kidney. Penetration into the CSF is poor; intrathecal administration may be necessary for some infections of the CNS. After an initial half-life of 24-48 hours, a terminal half-life of 15 days reflects slow release from a peripheral compartment. The drug has a large volume of distribution (4 L/kg). A dose of 0.5 mg/kg achieves a serum concentration of approximately 2-3 ug/ml; however, the relationship of serum concentrations and clinical efficacy is unknown. The metabolism of amphotericin B is not clearly understood. Some of the drug is eliminated through renal and biliary routes. Metabolic pathoways for a considerable portion of the drug is unknown. Hepatic or renal dysfunction has minor effects on serum levels, and hemodialysis does not alter blood levels of the drug.
Administration: Solutions should be prepared in 5% dextrose; saline solutions should be avoided because of precipitation of the drug. It is stable in normal light for usual durations and does not need to be covered. Traditionally, patients have received a "test dose" of amphotericin B to observe for adverse effects while vital signs are monitored. This is accomplished by adding 1 mg in 25-50 ml of 5% dextrose and administering over 30-60 minutes. Alternatively, a portion of the first regular dose may be given, with the remainder administered later or the full dose then administered on the second day. However, anaphylaxis is extremely rare and a test dose is not necessary. In the past patients were slowly escalated to full dose regimens. However, it is now standard practice to initiate therapy at target doses, especially in patients with severe infection or worsening condition. While doses of 0.5-0.75 mg/kg/day are commonly used, doses of 1.0-1.5 mg/kg/day are recommended for some serious infections. While the duration of infusion has traditionally been 4-6 hours, administration over 1-2 hours shows no significant increase in the incidence of adverse reactions.
Spectrum of Activity: Most species of fungi that cause human infection are susceptible to amphotericin B. It is considered the treatment of choice for most serious, systemic fungal infections. It is used to treat candidiasis, cryptococcoses, aspergillosis, histoplasmosis, blastomycosis, coccidioidomycosis, as well as most other fungi.
Adverse Effects: While amphotericin B is very efficacious, it is the adverse effects associated with this agent that complicate therapy. These adverse effects are usually categorized as acute (infusion-related) or chronic (non-infusion related). The most common infusion related side effects are shaking chills, fever, myalgias, arthralgias, and headache. The fever and chills are thought to be due to induction of tumor necrosis factor or production of prostaglandin E by macrophages. Premedication with acetaminophen (650 mg po), aspirin, or ibuprofen may blunt this response. If unsuccessful, other measures include premedication with diphenhydramine (25-50 mg po/IV), meperidine (25-50 mg), or hydrocortisone (25 mg) or symptomatic treatment with meperidine (25-50 mg IV/IM). Thrombophlebitis at the site of infusion may occur, but is less likely with rapid infusion or central venous administration. Heparin (1000 units/L) may be added to each infusion as a prophylactic measure.
Chronic adverse effects commonly seen with amphotericin B include anemia, renal dysfunction, and potassium/magnesium wasting. Reversible normochromic, normocytic anemia is a frequent complication that is probably due to suppression of erythropoietin. The most significant adverse effect of amphotericin B administration is nephrotoxicity. Renal dysfunction is generally reversible upon discontinuation of the drug; however persistent impairment is common in those patients who receive large cumulative doses. Renal dysfunction may be manifested by loss of urinary concentrating ability, sodium and potassium wasting, and renal tubular acidosis, in addition to azotemia. Nephrotoxicity is potentiated by depletion of sodium, such as with the use of a diuretic, poor oral intake, or vomiting. Coadministration of other nephrotoxic agents should be avoided when possible. Administration of 0.5 liter of 0.9% NaCl before and after the infusion of amphotericin B has been suggested to reduce nephrotoxicity. The serum creatinine increases in the majority of patients. Mild to moderate increases in serum creatinine concentrations (less than 3 mg/dl) are common and should not prompt discontinuation of therapy. Hypokalemia and hypomagnesemia generally occur in association with decreased renal function; replacement of these elements should be provided as indicated.
Monitoring Parameters: Regular monitoring of complete blood count, creatinine, potassium, magnesium, and other pertinent labs is essential for all patients. A flow sheet should be used to record daily and cumulative doses.
Lipid Preparations of Amphotericin B: In recent years, novel approaches have been developed to improve the delivery and decrease the toxicity of amphotericin B. This products include:
(1) ABLC (Abelcet) - amphotericin B lipid complex
(2) ABCD (Amphocil or Amphotec) - amphotericin B colloidal dispersion
(3) liposomal amphotericin B (AmBisome) - simple unilamellar vesicle around amphotericin B
These lipid formulations allow much larger doses of amphotericin B to be administered. While nephrotoxicity appears to be significantly reduced, the acute infusion-related adverse effects are still seen. These products are very expensive (i.e., ABLC approximately $400 vs $20 per day for standard therapy). In addition, clinical trials comparing the lipid formulations with amphotericin B are lacking. Attempts have been made to prepare a cheap lipid formulations using lipid emulsions, such as Intralipid. These admixtures have been shown to be unstable and should not be used until further data are available on their stability and efficacy.
Flucytosine
Mechanism of Action: Flucytosine, or 5-fluorocytosine (5FC), is a fluorinated pyrimidine. Susceptible fungi contain cytosine deaminase, which converts flucytosine to 5-fluorouracil, which in turn inhibits synthesis of DNA and RNA. When used in combination with amphotericin B, the altered permeability of the fungal cell membrane allows enhanced uptake of flucytosine by strains that are usually resistant.
Pharmacokinetics: Flucytosine is well absorbed after oral administration. The drug demonstrates little protein binding and good penetration into most body sites and fluids, including the CSF. Peak serum concentrations of 70-80 ug/ml occur 1-2 hours after oral administration of 37.5 mg/kg. The half-life is approximately 3 hours in patients with normal renal function and 85 hours in those with anuria. The drug is excreted in the urine. Renal dysfunction considerably prolongs excretion and necessitates major modifications in dosage. Flucytosine is removed by hemodialysis and peritoneal dialysis.
Administration: Flucytosine is only administered orally. The usual dose is 150 mg/kg/day, divided into 4 doses of 37.5 mg/kg. Studies are currently being conducted to evaluate lower dosages of 50-75 mg/kg/day.
Spectrum of Activity: Flucytosine has a narrow spectrum of activity and is used primarily for Candida and Cryptococcus neoformans. It is rarely used as a single agent due to the rapid development of resistance which can occur during therapy, especially cryptococcal infections. Adverse Effects: Suppression of the bone marrow is the main serious complication of flucytosine therapy. The suppression is usually reversible. Target peak serum concentrations (obtain 2 hours post dose) should range from 50-100 ug/ml; toxicity is related to the dose and occurs frequently when levels exceed 100 ug/ml. GI intolerance is also reported with flucytosine. Because of possible teratogenicity, flucytosine is contraindicated in pregnancy.
Monitoring Parameters: Complete blood count, renal function, and serum concentrations.
Imidazoles and Triazoles
Mechanism of Action: All azoles interfere with the synthesis and permeability of fungal cell membranes. The mechanism involves inhibition of the cytochrome P-450 enzyme responsible for conversion of lanosterol to ergosterol, the major sterol of most fungal cell membranes. These agents are generally considered to be fungistatic.
Monitoring Parameters: All azoles inhibit the cytochrome P450 enzyme system resulting in potential drug interactions with other agents metabolized in the liver. Medications must be carefully watched to prevent toxicities or subtherapeutic levels due to these drug interactions. Patients on ketoconazole and itraconazole should have liver function monitored, while those receiving fluconazole should have renal function routinely monitored.
Ketoconazole: (imidazole)
Pharmacokinetics: Gastric acidity must be normal for absorption of the drug. Patients with achlorhydria do not adequately absorb the drug. Ketoconazole is highly protein bound. It adequately penetrates most areas; however, CSF levels are undetectable at the usual recommended doses (200-400 mg/day). Ketoconazole is extensively metabolized in the liver and excreted in inactive form in the bile. Because only a minimal amount of drug enters the urinary tract, the dose need not be altered in patients with renal insufficiency. Although adjustment of the dose is not necessary for mild to moderate hepatic insufficiency, the dose should be decreased or the drug avoided entirely in patients with severe liver failure. The drug is not removed by hemodialysis or peritoneal dialysis.
Administration: Ketoconazole is soluble only at a pH of less than 3 and is therefore not available in parenteral form.
Spectrum of Activity: Ketoconazole has in vitro activity against most Candida species, C. neoformans, and the dimorphic fungi. It does not have good activity against Aspergillus.
Adverse Effects: The most common adverse effects of ketoconazole involve the gastrointestinal tract. Anorexia, nausea, vomiting, or some combination of these factors occurs frequently. Symptoms may be minimized by dividing the daily dose or taking the drug with food. Rash and pruritus occur in a small percentage of patients, as does asymptomatic increases in serum transaminases. Hepatitis has been reported, but is rare. Ketoconazole can cause problems with steroidogenesis (decreased cortisol production) resulting in various endocrine-related problems. Other adverse effects include impotence, decreased libido, gynecomastia, or some combination of these findings in men. These effects are due to the transient dose-dependent inhibition of synthesis of testosterone.
Drug Interactions: Many drug interactions have been reported with ketoconazole. Most occur by 1 of 2 basic mechanisms; inhibition of absorption leading to decreased bioavailability or interference with the activity of hepatic microsomal enzymes (cytochrome P450) which alters the metabolism and plasma concentration of the azole, the interacting drug, or both. Drugs which decrease the concentration of ketoconazole include antacids, H-2 blockers, phenytoin, rifampin, and ddI. Ketoconazole can increase the concentration of the following drugs: cyclosporin, terfenadine, astemizole, and saquinavir.
Fluconazole: (triazole)
Pharmacokinetics: Absorption is essentially complete, with 85-90% bioavailability. Food does hinder absorption. High levels of fluconazole can be found in most body fluids and tissues; it enters the CSF extremely well. Unlike ketoconazole, fluconazole is about 80% excreted unchanged in the urine. The dose must be adjusted in patients with severe renal dysfunction. Hemodialysis removes about 50% of the drug.
Administration: Both PO and IV. Unlike ketoconazole, fluconazole is highly water soluble and can be administered intravenously in patients who are too ill to take medication orally.
Spectrum of Activity: Fluconazole has in vitro activity against fungi that is similar to ketoconazole. The main advantages of this azole are penetration into the CSF to provide coverage of meningeal infections and high urine concentrations for Candida UTIs.
Adverse Effects: Fluconazole appears to have less adverse effects that ketoconazole. The most common side effects are gastrointestinal, especially nausea. Abdominal pain, vomiting, and diarrhea may also occur. Headache and skin rashes have also been reported. Mild transient increases in liver function tests have been reported also. In contrast to ketoconazole, fluconazole does not interfere with synthesis of testosterone or with adrenocortical function.
Drug Interactions: Fluconazole inhibits the metabolism and thereby increases plasma concentrations and potentiates the effects of phenytoin, orally administered hypoglycemic agents, and warfarin. Cyclosporine levels have been increased in some patients. Concurrent administration of rifampin decreases the serum concentration of fluconazole.
Itraconazole:
Pharmacokinetics: Itraconazole is well absorbed, with absorption enhanced by the presence of food in the stomach. Approximately 99% of the drug in serum is bound to protein. Itraconazole is metabolized entirely by the liver and excreted in the feces. Only a minimal amount of drug is measurable in urine and CSF. No adjustment of dosage is necessary in patients with renal failure; whether adjustment is necessary in hepatic dysfunction is unclear and therefore should be monitored. Neither hemodialysis nor peritoneal dialysis alters serum concentrations of itraconazole.
Administration: Currently itraconazole is only available in oral dosage forms.
Spectrum of Activity: The spectrum of activity of itraconazole is similar to the other azoles. The major advantage over ketoconazole and fluconazole is good activity against Aspergillus.
Adverse Effects: The most common side effects of itraconazole also include the gastrointestinal system: nausea, abdominal discomfort, and diarrhea. Headache, pruritis, and dizziness have been reported occasionally. Mild reversible increases in liver enzymes have been noted, but no reports of serous hepatotoxicity. Unlike ketoconazole, itraconazole has a minimal inhibitory effect on the synthesis of testosterone or cortisol; however, reports have described a possible syndrome of mineralocorticoid excess manifested by hypokalemia, hypertension, and edema. Impotence has developed in a few patients, but serum testosterone levels were found to be normal.
Drug Interactions: Coadministration of rifampin or phenytoin may lower the plasma concentrations of itraconazole. Itraconazole has been reported to increase cyclosporine levels in some but not all patients receiving both drugs.