Definition and causes
The incidence of superficial and deep fungal infections has increased in the era of increasing immunosuppression due to underlying disease states such as HIV/AIDS in addition to immunomodulatory therapy for the prevention of rejection in solid organ and hematopoietic cell transplantation. The spectrum of fungal infections ranges from localized skin and soft tissue infections to fungemia with disseminated disease to almost any organ system.
Mycoses can be further defined into fungi that are yeasts or molds. The terms yeast form and yeastlike describe fungi that reproduce by budding. Yeasts include the Candida spp., Cryptococcus spp., and Pneumocystis jiroveci. Candida species grow by forming pseudohyphae. The pathogenic species of Candida include C. albicans, C. krusei, C. parapsilosis, C. tropicalis, C. lusitaniae, C. glabrata (Torulopsis glabrata), C. guilliermondii, C. pseudotropicalis, and C. dubliniensis.
Molds are filamentous fungi composed of hyphae. Molds include Aspergillus spp. and the agents of mucormycosis. Aspergillus fumigatus is the most pathogenic of the molds and the most common of that species to cause invasive disease. Other species of aspergillus include A. flavus, A. terreus, and A. niger. These pathogens grow as molds in the environment and as hyphal forms in tissue.
The dimorphic fungi are capable of producing both hyphal and yeastlike forms depending on temperature. They typically grow as yeasts at body temperature and as molds at room temperature. The dimorphic fungi include the agents of histoplasmosis, blastomycosis, sporotrichosis, coccidiomycosis, paracoccidioidomycosis, and chromoblastomycosis.
A definitive review of mycoses is beyond the scope of this chapter. Therefore, this discussion will be limited to and focus on the more common fungal infections caused by Candida, Aspergillus, and the endemic fungi, histoplasmosis, blastomycosis, and coccidiomycosis.
Prevalence and risk factors
Fungi are ubiquitous in nature and are found in the air, soil, and decaying matter. The scope of fungal infections can manifest from asymptomatic colonization to invasive disease. Candida spp. are commensals of human mucocutaneous surfaces and of the gastrointestinal, respiratory, and female genital tracts. Colonization with Aspergillus appears most commonly in the respiratory tracts of those with underlying chronic pulmonary disease. Colonization does not occur with coccidioidomycosis and blastomycoses.
The major risk factor for invasive, disseminated fungal disease is an immunocompromised state. This includes patients with HIV/AIDS, who are neutropenic from an underlying hematologic malignancy or from cytotoxic therapy, as well as patients treated with prolonged corticosteroids.
The most common human pathogenic fungi are the Candida species. Candida is now recognized as the fourth most common organism recovered from blood culture isolates in the United States,1 accounting for 8% to 10% of all nosocomial bloodstream infections. Invasive candidiasis is associated with an attributable mortality rate of up to 49%.2,3 C. albicans is the most commonly recovered species, followed by C. glabrata, C. tropicalis, and C. parapsilosis. The risk factors that have been identified for invasive candidal infections include intensive care unit stay, presence of indwelling vascular catheters, treatment with broad-spectrum antibiotics, colonization with Candida, renal failure, and having undergone abdominal, gastrointestinal, or cardiac surgical procedures.
Aspergillus is the most common invasive mold. Invasive aspergillosis has become the major cause of morbidity and mortality in immunocompromised patients, with mortality rates as high as 88%. Almost two thirds (61%) of patients with invasive aspergillosis have an underlying hematologic disease, or have undergone bone marrow transplantation (BMT). Risk factors for the development of invasive aspergillosis include prolonged or repeated episodes of profound neutropenia, solid organ or hematopoietic stem cell transplantation, grade III or IV graft-versus-host disease, and steroid therapy.
The endemic mycoses have specific geographic distributions. Histoplasma capsulatum is endemic in the midwestern and southeastern United States, notably highly prevalent in the Ohio and Mississippi River valleys. Blastomyces dermatitidis is endemic in southeastern and south central states that border the Mississippi and Ohio Rivers, the midwestern states, and Canadian provinces bordering the Great Lakes and the St. Lawrence River. Most cases of blastomycosis are reported in Mississippi, Arkansas, Kentucky, Tennessee, and Wisconsin. In the United States, the endemic regions for Coccidioides immitis and C. posadasii, the agents of coccidiomycoses, include southern Arizona, central and southern California, southern New Mexico, and west Texas.
Residence in or travel to these endemic areas is a risk factor. Sporadic and epidemic cases of the endemic mycoses have been associated with disruption and exposure to infected soil. Histoplasmosis has a strong association with bird and bat guano and persons at high risk include spelunkers who explore caves where bats reside. Persons at highest risk for exposure to and infection by histoplasmosis and coccidioidomycosis also include workers in agriculture, outdoor construction, and excavation. Blastomycosis is isolated from soil containing decayed vegetation or decomposed wood.
Pathophysiology and natural history
Mycoses that are pathogenic to humans are rarely transmissible from person to person and are usually acquired via inhalation or ingestion of spores and, in some cases, direct inoculation. Severity of illness is dependent on the intensity of exposure and the immune status of the patient. Inhalation allows initial infection in the lungs, which can result in subsequent dissemination to other body sites. Most acute infections go unrecognized with asymptomatic or mild illness.
Intact human defense mechanisms are needed to prevent and contain fungal disease. The cell-mediated arm of the immune system is important in producing granulomatous inflammation and in cytokine and chemokine production for the recruitment of macrophages and neutrophils. The hallmark of tissue response is the development of caseating or noncaseating granulomas. Granulomas consist of an admixture of mononuclear phagocytes and lymphocytes, principally T cells. The function of the granuloma is to contain fungal growth.
Signs and symptoms
Candidal infection manifests as superficial mucocutaneous disease to invasive disease with dissemination. Oral candidiasis (thrush) and esophageal candidiasis are characterized by white patches (pseudomembranes) on the tongue or mucosal surfaces, which can be removed by scraping. Vulvovaginitis is seen in the settings of oral contraceptive use, diabetes mellitus, pregnancy, and antibiotic therapy; it manifests with vaginal discharge and vulvar edema and pruritis. Chronic mucocutaneous candidiasis (CMC) is associated with failure of T cells to respond to candidal antigen stimulation, resulting in onset in childhood of persistent candidal infections of the mucous membranes, nails, hair, and skin. There is an association of CMC with the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome.
Candiduria is common and usually asymptomatic. Most cases represent colonization of the bladder, perineum, or indwelling urinary catheter. However, it can represent upper and lower urinary tract involvement or candidemia, and this should be considered in patients with recurrent or relapsing infection. Risk factors for candiduria include increased age, female gender, antibiotic use, urinary drainage devices, prior surgical procedures, and diabetes mellitus. Of note, discontinuation of urinary catheter use alone results in eradication of candiduria in almost 40% of patients.4
Candidal pneumonia exists in two forms, primary pneumonia from an aspiration event and pulmonary lesions from hematogenous dissemination. More common, however, is benign colonization of the airways or contamination by oropharyngeal material. Therefore, identifying yeast forms from cultured sputum or endotracheal aspirates is unreliable and definitive diagnosis requires histopathologic evidence of fungal invasion of pulmonary tissue.
Invasive candidiasis manifests as candidemia, infective endocarditis, joint and bone infection, and endophthalmitis. Clinical signs of disseminated disease may include skin lesions described as painless, erythematous, pustular to macronodular lesions. Notable features of candidal infective endocarditis are larger vegetations and the propensity of embolization to major vessels. Candidal endophthalmitis occurs from hematogenous seeding in as many as 28% of patients. It is manifested by symptoms of blurry vision, floaters, and pain. Prompt recognition and diagnosis are necessary, because permanent blindness may ensue. Hepatosplenic or chronic disseminated candidiasis is a distinct entity in patients with hematologic malignancies in the setting of recovering neutropenia. Patients classically present with persistent fever, right upper quadrant pain, nausea, and vomiting.
Candidal brain abscess and meningitis occur in the setting of disseminated infection, local trauma or surgery, or ventricular shunt. Symptoms are similar to those of bacterial meningitis. A notable frequent complication is hydrocephalus.
The clinical spectrum of aspergillosis ranges from allergic reaction and colonization to invasive disease. The three main diseases caused by Aspergillus species include allergic bronchopulmonary aspergillosis (ABPA), invasive aspergillosis, and aspergilloma.
Allergic bronchopulmonary aspergillosis (ABPA) is diagnosed by the following criteria5: asthma; central bronchiectasis on chest computed tomography (CT) scan; immediate cutaneous reactivity to Aspergillus species; total serum immunoglobulin E (IgE) concentration higher than 417 IU/ml; elevated serum IgE and/or IgG antibody to A. fumigatus; fleeting infiltrates on the chest radiograph; serum precipitating antibodies to A. fumigatus; and peripheral blood eosinophilia. The usual course of disease is one of remissions and exacerbations, which can eventually lead to pulmonary fibrosis.
Invasive disease occurs most commonly in the lungs and sinuses. Invasive pulmonary aspergillosis (IPA) occurs in the setting of profound neutropenia. Patients present with fever, progressive dry cough, dyspnea, fever, and pleuritic chest pain, as well as hemoptysis. In IPA, vascular invasion and pulmonary infarction are classic and can lead to fatal pulmonary hemorrhage. Distinctive radiographic findings include pleura-based, wedge-shaped densities or cavitary lesions on chest radiographs. On CT scan early IPA has a halo sign, which is an area of low attenuation surrounding a nodular lesion, representing edema or bleeding surrounding an ischemic area. Later in the course of disease, the classic air crescent sign is seen near the periphery of a lung nodule, caused by contraction of infarcted tissue and signifying cavitation of the nodular lesions. This finding is seen in association with neutrophil recovery.
Cerebral aspergillosis is the second most common site of invasive disease. It occurs in the setting of sinonasal disease causing acute or chronic indolent invasion in the immunocompromised host and presents with epistaxis and naso-orbital pain.
Chronic invasive pulmonary aspergillosis manifests as an aspergilloma or fungus ball. An aspergilloma is a solid mass of hyphae growing in a previously existing pulmonary cavity or ectatic bronchus and typically develops in patients with chronic lung disease. Patients present with hemoptysis and chest radiograph findings of an apical solid, rounded mass within a spherical or ovoid cavity, and positive Aspergillus-specific serum precipitins.
Histoplasmosis, Blastomycosis, and Coccidiomycosis
Histoplasmosis can manifest as asymptomatic infection to progressive pulmonary and disseminated disease. Pulmonary histoplasmosis can be subdivided into acute, subacute, and chronic forms. Acute disease manifests with diffuse interstitial or reticulonodular infiltrates associated with fever, sweats, and weight loss. The subacute form occurs over weeks to months and is characterized by hilar or mediastinal lymphadenopathy and focal or patchy infiltrates. Chronic pulmonary disease may show calcifications and consolidation with upper lobe thin- or thick-walled cavitary lesions. A histoplasmoma is a mass lesion that resembles a fibroma and, on chest radiograph, has either a central core of calcium or rings of calcium, which are useful to exclude malignancy.
Five percent to 10% of patients with histoplasmosis suffer from acute pericarditis and other rheumatologic syndromes. Rheumatologic manifestations of arthralgias, erythema nodosum, and erythema multiforme may be present in cases of acute pulmonary histoplasmosis, and can also be seen in cases of coccidiomycosis.
Mediastinal lympadenopathy is common in acute and subacute cases. A late complication that may develop is fibrosing mediastinitis. This can lead to subsequent impingement of mediastinal structures, with a progressive fatal course.
In disseminated histoplasmosis, patients present with fever, sweats, weight loss, fatigue, and respiratory symptoms. Physical findings include hepatosplenomegaly (in almost all patients), lymphadenopathy of the cervical chain, oropharyngeal ulcer (tongue, buccal mucosa, larynx, gums, and lips), and cutaneous lesions (maculopapular eruption, petechiae, or ecchymosis). Central nervous system involvement occurs in 5% to 20% of cases of acute disseminated histoplasmosis, presenting as chronic meningitis—usually lymphocytic—or focal brain lesions. Disseminated disease can be self limited or progressive. Laboratory findings include bone marrow suppression and elevated alkaline phosphatase and lactic acid dehydrogenase levels.
Blastomycosis can manifest as nonspecific febrile illness to acute or chronic pulmonary disease mimicking community-acquired pneumonia and malignancy, and ultimately to disseminated disease involving cutaneous, genitourinary, and bony lesions. Pulmonary infection can have alveolar or reticulonodular infiltrates or mass lesion. Cutaneous blastomycosis is reported in 40% to 80% of cases and is the marker for multiorgan involvement. Skin or naso-oropharyngeal mucosal lesions may be seen. Superficial skin lesions can be verrucous or ulcerative and deep lesions can be noted as subcutaneous nodules or cold abscesses. Skeletal blastomycosis most commonly involves the long bones, vertebrae, and ribs and is typically a well-circumscribed osteolytic lesion manifesting as a soft tissue abscess, chronic draining sinus, or septic arthritis. Ten percent to 30% of cases in men with blastomycosis have involvement of the genitourinary tract, primarily of the prostate and epididymis.
Primary coccidioidomycosis manifests with pulmonary involvement and in most cases is asymptomatic. Symptomatic coccidioidomycosis usually presents with fever, cough, and chest pain and may mimic community-acquired pneumonia. Laboratory findings include an increased erythrocyte sedimentation rate and peripheral eosinophilia. Chest radiographs may show infiltrates, nodules, or peripheral, solitary thin-walled cavities and parapneumonic effusion. More than 95% of patients recover spontaneously from the acute illness. Chronic pulmonary disease occurs in 5% of those with symptomatic primary pulmonary infection. This results in nodular lesions that may cavitate and subsequently rupture, causing pneumothorax or hemorrhage and then may become secondarily infected. Disseminated disease can occur locally with pleural or pericardial invasion or hematogenously to involve any organ of the body, most commonly the lungs, skin and soft tissue, bones, joints, and meninges. Central nervous system involvement manifests as meningitis and obstructive or communicating hydrocephalus. More severe and disseminated disease is seen in immunosuppressed women in the third trimester of pregnancy, and in those of Filipino and African American descent.
A prompt and accurate diagnosis of fungal infections is the key to affecting mortality. A comprehensive history, including a detailed travel history, and physical examination are needed for initial evaluation.
Chest x-ray and CT scanning of the chest, abdomen, and brain are useful in finding characteristic features of disease. Isolation of the organism with histopathology or culture is the gold standard to confirm fungal infections; however, this can be time consuming and delay prompt diagnosis. Therefore, various laboratory tests have been developed that may provide early clues to the diagnosis.
Preliminary identification of a fungal infection by direct microscopy can be done using several different stains of clinical specimens:
- Fungal specific stains include the Gomori methenamine-silver (GMS), periodic acid–Schiff reagent (PAS), and calcofour white. GMS stains target the fungal cell wall in all fungi, whereas PAS will identify the polysaccharide component in the cell wall in viable fungi. Calcofour will stain all fungi white or green under the fluorescent microscope.
- Routine Gram staining is useful only for Candida and stains gram positive.
A rapid presumptive diagnosis of C. albicans can be done using the germ tube test. This involves placing the organism in serum and observing germ tube formation, which are small projections from the cell surface that reflect initiation of hyphal growth.
Currently used automated blood culture methods have improved the isolation of fungal organisms, but blood culture isolation of fungi may be negative, even in disseminated fungal disease. The most common fungi recovered from blood cultures include Candida spp. and Histoplasma spp. Blood cultures and bone marrow are usually positive in up to 50% of disseminated histoplasmosis cases.
Tissue culture technique can take weeks for definitive results and most fungi require special fungal media for growth. Histopathologic diagnosis can yield faster presumptive diagnosis, as well as help distinguish between truly invasive tissue disease versus contamination or colonization. Distinctive histopathologic characteristics include the following:
- Candida spp.: oval, budding yeast with hyphae and pseudohyphae; microabscesses
- Aspergillus spp.: septate, acute-angle branching, nonpigmented hyphae
- Histoplasma: small ovoid, intracellular yeast forms with narrow-based budding, granulomas
- Blastomyces dermatitidis: large, thick-walled budding yeast with broad-based budding, daughter cell, often as large as mother cell before detachment
- Coccidiomycosis immitis: thick-walled spherules with endospores
The laboratory should be alerted and notified of a presumptive diagnosis of coccidiomycosis because of the potential of secondary infection when plates are examined.
Other diagnostic tests include serologic studies with antigen and antibody assays. Important limitations include lack of antibody response due to the immunocompromised state of the patient and cross-reactions resulting in false positivity.
Galactomannan is an immunoassay for the diagnosis of invasive Aspergillus infections. Galactomannan is a polysaccharide specific to Aspergillus that is detectable in serum, urine, cerebrospinal (CSF), and bronchoalveloar lavage (BAL) specimens by enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), and immunoblot testing. These assays have reported positive predictive values of 54% and negative predictive values of 95% in bone marrow transplant recipients.6 There have been conflicting and varying results and further studies need to be performed to test the validity of these assays. No antigen tests are currently approved for use in the United States.
Histoplasma antigen detection of fungal cell elements in urine, serum, and CSF by ELISA has proven to be important in the diagnosis, monitoring, and prognosis of acute disseminated histoplasmosis. The sensitivity of Histoplasma antigen is higher in urine (92%) than in serum (60%-80%). Antigen concentrations in both urine and serum decline with effective treatment. Therefore, failure of the antigen concentration to fall during therapy may suggest treatment failure or relapse and should prompt further investigation.
Serologic testing is the most frequent means of diagnosing primary coccidioidal infections. Early infection can be detected by tube precipitin antibodies as IgM and by complement-fixing antibodies as IgG. A titer of 1 : 16 or higher has been associated with extrathoracic dissemination and is especially important in the diagnosis of coccidioidal meningitis because CSF cultures are usually negative. More recently, ELISA for coccidioidal IgG and IgM antibodies has been used with 100% sensitivity and 99% specificity and positive predictive value (PPV) of 82% and negative predictive value (NPV) of 100%.7
Other nonculture diagnostic techniques include molecular techniques using nucleic acid (DNA and RNA) probes via polymerase chain reaction (PCR) technology and fluorescent in situ hybridization (FISH). PCR modalities allow rapid and definitive identification and are promising, but to date lack sufficient validity and standardization to be used clinically.
- The spectrum of fungal infection can range from asymptomatic infection to disseminated disease.
- The major risk factor for invasive fungal disease is immunosuppression.
- Diagnosis requires a thorough history, including travel history, and physical examination.
- A rapid presumptive diagnosis can be made by the use of staining, histopathologic characteristics, and serologic testing results.
Early diagnosis, efforts to improve immune function, and prompt administration of appropriate antifungal therapy are key to favorable outcomes.
A detailed review of the available antifungal agents and guidelines for treatment are beyond the scope of this chapter; therefore, a brief overview is presented here. Referral to medication package inserts, the Infectious Diseases Society of America practice guidelines, and management of cases in consultation with an infectious disease specialist are strongly recommended.
Classes of Antifungal Agents
Four classes of antifungal agents are approved for the treatment of fungal infections.
Amphotericin B deoxycholate (Fungizone) is the mainstay of antifungal therapy, with the broadest spectrum of activity. It is rapidly fungicidal by binding to ergosterol on the fungal cell membrane, causing disruption of the membrane and ultimately cell death. The few pathogens that are resistant to amphotericin include Candida lusitaniae and C. guilliermondii, A. terreus, and Fusarium, Rhizopus, Mucor, and Scedosporium spp.
Limiting factors in the use of amphotericin are associated toxicities, most importantly nephrotoxicity (elevation of serum creatinine level, hypokalemia, hypomagnesemia, and renal tubular acidosis), and infusion-related adverse affects, such as fever, chills, rigors, and hypotension. Amphotericin B–associated nephrotoxicity can be ameliorated or prevented by maintaining intravascular volume by with 500 to 1000 mL of normal saline before infusion and also by avoiding concurrent potentially nephrotoxic agents, such as radiocontrast dyes, nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and immunosuppressive agents, such as cyclosporine and tacrolimus. Infusion-related symptoms can be minimized by premedication with acetaminophen, diphenhydramine, and meperidine. Importantly, most patients develop tolerance over time to the acute infusion-related toxicities.
Lipid formulations (liposomal amphotericin B [L-AmB; AmBisome]) and amphotericin B lipid complex [ABLC, Abelcet]) and amphotericin B colloidal dispersion (ABCD; Amphotec) have a reduced toxicity profile but are more expensive. All are indicated for patients with systemic mycoses who are intolerant of or refractory to conventional amphotericin B, defined as follows: development of renal dysfunction (serum creatinine level higher than 2.5 mg/dL) during antifungal therapy; severe or persistent adverse events, despite premedication or comedication regimens; and disease progression after a 50-g total dose of amphotericin B. A triad of infusional toxicity has been characterized with the liposomal preparation, manifested as pulmonary toxicity (chest pain, dyspnea, hypoxia), abdominal, flank, or leg pain, or flushing and urticaria.
Dosages are as follows:
- Amphotericin B 0.1 to 1.5 mg/kg/day
- Liposomal amphotericin B 1 to 5 mg/kg/day
- ABLC and ABCD 3 to 5 mg/kg/day
The only approved drug in this class is flucytosine (5-fluorocytosine). It is a pyrimidine analogue that inhibits DNA and protein synthesis. Its limited spectrum of activity includes Candida spp., Cryptococcus neoformans, and some molds. Significant potential for toxic effects such as rash, nausea, vomiting, diarrhea, liver dysfunction, and bone marrow suppression limits its use. Because of emergence of resistance, it is used primarily in combination with amphotericin B as therapy for select life-threatening and disseminated fungal infections. Its dosage regimen is 50 to 150 mg/kg/day, divided into four doses.
Azoles also target the fungal cell membrane by inhibiting ergosterol synthesis through inhibition of cytochrome P-450–dependent 14a-lanosterol demethylation. The agents available are fluconazole (Diflucan), itraconazole (Sporanox), and ketoconazole (Nizoral). The second-generation azoles voriconazole (Vfend) and posaconazole (Noxafil) are synthetic triazole derivatives of fluconazole.
In general, azoles demonstrate fungistatic activity against Candida spp., but they have varying potency against endemic fungi such as C. immitis, B. dermatitidis, and H. capsulatum. Itraconazole, voriconazole, and posaconazole have increased spectrum of activity against molds such as Aspergillus.
Fluconazole, itraconazole, and voriconazole are available in oral and IV formulations. Itraconazole has unreliable oral absorption and requires an acidic gastric environment for the capsules and an empty stomach for the solution for optimal absorption. Both fluconazole and voriconazole achieve good CSF levels as well.
The azoles overall as a class are well tolerated. Side effects include gastrointestinal (GI) upset and elevated liver enzyme levels. Therefore, it is recommended to monitor liver functions every 2 to 4 weeks and to discontinue the medication if elevations of more than five times the normal are noted. The most common adverse effect with voriconazole is a transient and reversible visual disturbance in 30% of cases. This is manifested as bright spots and wavy lines, altered color discrimination, blurred vision, and photophobia; it usually appears during the first week of therapy and abates in most patients on continued therapy.
Both itraconazole and voriconazole are limited because of significant drug-drug interactions with other drugs metabolized by cytochrome P-450. Refer to Table 1 and medication package insert for details. IV intraconazole and IV voriconazole are contraindicated in patents with renal insufficiency (creatinine clearance <50 mL/min) because of concerns of accumulation of the cyclodextrin component in these formulations.
Table 1: Antifungal Agents
|Drug||Route of Administration||Dosage||Side Effects||Comments|
|Amphotericin B (Fungizone)||IV||0.5-1.0 mg/kg/day||Infusion-related: fever, chills, rigors, hypotension; thrombophlebitis, azotemia, renal tubular acidosis (RTA), K+, Mg2+, HCO3, wasting||Toxicities ameliorated or prevented by normal saline; avoid concurrent nephrotoxic agents, premedication with acetaminophen, diphenhydramine, meperidine|
|liposomal amphotericin B (AmBisome); amphotericin B lipid complex (ABLC, Abelcet); amphotericin B colloidal dispersion (ABCD, Amphotec)||IV||Liposomal amphotericin B, 1-5 mg/kg/day; ABLC and ABCD, 3-5 mg/kg/day||Infusion-related: chest pain, dyspnea, hypoxia, flushing, urticaria|
|Flucytosine||PO||50-150 mg/kg/day, qid||Rash, gastrointestinal (GI) upset, bone marrow suppression||Used primarily in combination therapy|
|Fluconazole (Diflucan)||PO, IV||100-800 mg/day||GI upset, elevated liver function tests (LFTs); drug-drug interactions: contraindicated with cisapride||Monitor liver enzyme levels, renal function|
|Ketoconazole (Nizoral)||PO, topical||200-400 mg/day||Significant drug-drug interactions: contraindicated with cisapride, midazolam, triazolam, ergot alkaloids, lovastatin, simvastatin, pimozide; hepatoxicity||Monitor liver enzyme levels|
|Itraconazole (Sporanox)||PO (capsule, 100 mg; solution, 100 mg/10 mL), IV||100-400 mg/day||Significant drug-drug interactions: contraindicated with cisapride, dofetilide, ergot derivatives, levomethadyl, lovastatin, midazolam, pimozide, quinidine, simvastatin, triazolam; rash; elevated LFTs; congestive heart failure||Bioavailability of capsule increased with food in acidic gastric environment: coadminister with cola beverage and avoid use with H2 blockers; bioavailability of suspension increased with empty stomach; monitor liver enzyme levels; avoid in patients with active liver disease; avoid IV formulation in renal insufficiency|
|Voriconazole (Vfend)||PO, IV||200 mg q12h; loading, 6 mg/kg q12h bid; maintenance, 4 mg/kg q12h||Significant drug-drug interactions: contraindicated with cisapride, pimozide, quinidine, long-acting barbiturates, carbamazepine, efavirenz, ergot alkaloids, rifampin, rifabutin, ritonavir, sirolimus; reversible photopsia in ~30%; rash; elevated LFTs||Bioavailability of PO form increased when given 1 hr before or after meal, decreased with fatty foods; dose adjustment for liver dysfunction; avoid IV formulation in renal insufficiency|
|Posaconazole (Noxafil)||PO||600-800 mg/day (two to four divided doses)||Drug-drug interactions: contraindicated with cisapride, pimozide, quinidine, ergot alkaloids; GI upset; rash||Requires high-fat meals for absorption; monitor liver enzyme levels|
|Caspofungin (Cancidas)||IV||Loading, 70 mg × one dose; maintenance, 50 mg/day||Histamine-like infusion reaction; elevated LFTs; thrombophlebitis||Monitor liver enzyme levels; dose adjustment in liver dysfunction|
|Micafungin (Mycamine)||IV||150 mg daily||Thrombophlebitis; elevated LFTs; leukopenia||Monitor liver enzyme levels|
|Anidulafungin (Eraxis)||IV||Loading, 100-200 mg × one dose; maintenance, 50-100 mg/day||Histamine-like infusion reaction; elevated LFTs||Monitor liver enzyme levels|
Adapted from Cisneros Herreros JM, Cordero Matia E: Therapeutic armamentarium against systemic fungal infections. Clin Microbiol Infect 2006;12(Suppl 7):53-64; Dimukes WE: Introduction to antifungal drugs. Clin Infect Dis 2000;30:653-657; Kauffman CA: Clinical efficacy of new antifungal agents. Curr Opin Microbiol. 2006;9:483-488; Vazquez JA, Sobel JD: Anidulafungin: A novel echinocandin. Clin Infect Dis 2006;43:215-222; and Wong-Beringer A, Kriengkauykiat J: Systemic antifungal therapy: New options, new challenges. Pharmacotherapy 2003;23:1441-1462.
Recommended dosages are as follows:
- Fluconazole 100 to 400 mg/day
- Ketoconazole 200 to 400 mg/day
- Itraconazole 200 to 400 mg/day
- Voriconazole: PO 200 mg every 12 hours; IV 6 mg/kg every 12 hours on first day, then 4 mg/kg/day
- Posaconazole 600 to 800 mg/day (in two to four divided doses)
The echinocandins are the newest class of antifungal agents. This class targets cell wall synthesis by inhibiting β-1,3-
The echinocandins have fungicidal activity against most Candida species, including azole-resistant strains, and have been shown to be as efficacious as amphotericin and fluconazole in cases of candidemia or invasive candidiasis. The echinocandins are fungistatic against Aspergillus spp. Caspofungin is currently U.S. Food and Drug Administration (FDA)-approved for the treatment of invasive aspergillosis as a salvage or secondary agent in patients with an initial response to voriconazole or amphotericin B, or in combination therapy with these agents. The echinocandins have no activity against the endemic mycoses.
The side effect profile of the echinocandins is relatively safe. The most common adverse reactions include headache, nausea, vomiting, flushing and infusion-related pruritis, erythema, and pain. Approximately 10% of patients will have elevations of liver enzyme levels.
Caspofungin distributes well into tissues but has little penetration into the brain and CSF. It does not inhibit or induce cytochrome P-450 (CYP450) but inducers of CYP450, such as rifampin, phenytoin, and carbamazepine reduce serum concentrations of caspofungin so that a higher daily dosage is needed. It is not recommended to be given with cyclosporine because it can result in an increased serum concentration of caspofungin and transient elevations of serum transaminase levels.
Recommended dosages are as follows:
- Caspofungin: 70-mg load, then 50 mg/day
- Anidulafungin: initial dose of 100 to 200 mg, followed by 50 to 100 mg/day
- Micafungin: 150 mg/day
Combination Antifungal Therapy
Combination therapy for invasive mold infections with different classes of antifungal drugs has shown to be promising according to their different mechanisms of action. For example, triazoles and echinocandins or echinocandins with amphotericin B have been used for the treatment of invasive aspergillosis (IA). However, further well-designed, randomized trials need to be done to establish their usefulness. The routine use of antifungal combinations as primary therapy is currently not recommended.
Guidelines for Treatment
- Susceptibility patterns of note: C. lusitaniae isolates are often resistant to amphotericin B. C. guilliermondii and C. parapsilosis may be less susceptible to echinocandins. C. glabrata and C. krusei are less susceptible to azoles.
- Esophageal candidiasis: fluconazole is used as primary therapy. Refractory cases can be treated with voriconazole, caspofungin, or intraconazole solution or amphotericin B formulations.
- Invasive candidal infections: amphotericin B preparations or caspofungin can be used for critically ill patients, given the increasing incidence of fluconazole-resistant non–C. albicans strains. Once the candidal isolate and susceptibility are known, the triazoles, fluconazole, itraconazole, and voriconazole (for salvage therapy) can be used.
- Other interventions: removal of indwelling catheters, ophthalmology examination to rule out endophthalmitis.
- Susceptibility patterns of note: itraconazole, voriconazole, and posaconazole have fungicidal activity against Aspergillus spp. Echinocandins are fungistatic against Aspergillus spp.
- APBA: the use of corticosteroids (prednisone 10 mg/day) is indicated for patients with increasing IgE levels, new or worsening infiltrate on chest radiograph, or worsening spirometry, with gradual dose reduction dependent on individual response. Itraconazole (200 mg twice daily) may be useful as a corticosteroid sparing agent.
- Invasive aspergillosis (IA): voriconazole has become the drug of choice for IA based on a large randomized trial that showed higher response rates and significantly improved survival rates in patients receiving voriconazole versus amphotericin B.8 Amphotericin B preparations (amphotericin B, 1 to 1.5 mg/kg/day or 5 mg/kg/day of lipid formulations of amphotericin, up to 400 mg/day) should be used in life-threatening cases. Itraconazole can be used as a second-line agent and for those with non–life-threatening infection. Caspofungin is the only echinocandin FDA-approved for salvage therapy in IA. Posaconazole is also an alternative for salvage therapy for those refractory or intolerant of previous therapy.9 The length of therapy is unknown; it should be dependent on the patient's response to therapy based on resolution of clinical and radiographic abnormalities and improvement of the patient's underlying condition or immune status.
- Aspergilloma: surgical removal is definitive therapy but is associated with high morbidity and mortality; it is usually reserved for those with life-threatening hemoptysis, the immunocompromised, and those with increasing Aspergillum-specific IgG titers. Bronchial artery embolization should be considered as a temporizing procedure until more definitive therapy can be done. Additional therapies that need further study and validation include radiation, intracavitary or endobronchial instillation of amphotericin B, and systemic antifungals (itraconazole).
Endemic Mycoses (Histoplasmosis, Blastomycosis, Coccidioidomycosis)
- Susceptibility patterns of note: voriconazole and posaconazole have in vitro activity but no trials have been done. The echinocandins are not active in vitro and should not be used.
- Asymptomatic patients do not require treatment.
- Acute pulmonary histoplasmosis: Amphotericin B should be used for severe cases and itraconazole can be used for milder cases. The optimal duration has not been determined but should be at least 3 months if there is no evidence of disseminated disease.
- Subacute pulmonary histoplasmosis: Most cases do not require treatment, however, it should be considered in immunosuppressed patients or those with underlying lung disease with 6 to 12 weeks of therapy.
- Chronic pulmonary histoplasmosis: This entity becomes progressive without therapy, so severe cases should be treated with amphotericin B. Milder cases can be treated with itraconazole. Duration of therapy should be continued for at least 1 year because of the high relapse rate (10%-25%), until radiographic abnormalities stabilize.
- Mediastinal lympadenopathy: For patients who do not show spontaneous improvement after 1 month of illness, a trial of itraconazole for 3 to 6 months can be used if there is response to therapy.
- Mediastinal fibrosis: There is no role for or effect of antifungal therapy or anti-inflammatory medications. Stents or surgery can be considered but this is high risk.
- Progressive disseminated histoplasmosis: This can be treated with liposomal amphotericin B (3-5 mg/kg/day), changing to intraconazole (200 mg three times daily × 3 days and then twice daily) if there is initial response. Therapy should be continued for at least 6 to 12 months, and until clinical findings and antigen levels resolve.
- Central nervous system involvement: Treat with liposomal amphotericin B (105-175 mg/kg over the total course), followed by itraconazole or posaconazole for at least 1 year of therapy.
- Uncomplicated: No treatment is required but close monitoring should be done every 3 to 6 months for up to 2 years with serologic testing, because a rise in antibody titers may be associated with progressive disease.
- Acute, diffuse pneumonia: Treat with amphotericin B for 3 to 6 months and then consider oral azole for at least 1 year.
- Chronic cavitary pneumonia: If asymptomatic, only close monitoring is needed, with consideration of resection if there are complications, enlargement, or persistence of the lesion after 2 years. If there is symptomatic disease, treat with fluconazole or itraconazole for at least 1 year. Voriconazole and posaconazole are other options for therapy. Surgical resection may need to be considered for refractory lesions.
- Disseminated coccidioidomycosis: Treat with fluconazole (400 or 800 mg/day) or intraconazole (200 mg twice daily) or amphotericin B for 6 to 12 months followed by close observation for years, given the risk of relapse in more than one third of cases.
- Central nervous system, meningitis: Treat with fluconazole (800 mg/day) or itraconazole (400-600 mg/day). Consider intrathecal amphotericin (0.01-1.5 mg) for those who do not respond to azoles. Azole therapy is continued for life. Other measures include ventriculoperitoneal (VP) shunting in cases with obstructive hydrocephalus.
- Uncomplicated/immunocompetent: Close monitoring is needed.
- Pulmonary (mild to moderate disease): Treat with itraconazole (200-400 mg/day) or ketoconazole (400-800 mg/day) or fluconazole (400-800 mg/day).
- All immunocompromised patients and those with progressive pulmonary and disseminated disease should be treated, because spontaneous resolution is uncommon and untreated cases are associated with mortality rates as high as 60%. Treatment options include amphotericin B (0.7-1.0 mg/kg/dose, with 1.5- to 2.5-g total dosage) for life-threatening infections, which can be changed to itraconazole (200-400 mg/day) if stabilized. Those patients with less severe infection can be treated with ketoconazole (400 mg/day, increased to maximum 800 mg/day for those who do not respond), itraconazole, or fluconazole. Treatment duration is at least 6 months.
- CNS infection: Treat with amphotericin B, with the total dosage at least 2 g.
- Amphotericin B should be the first-line agent in life-threatening fungal infections.
- There are significant drug-drug interactions with azoles that need close review when using this class of antifungals.
- Voriconazole is now considered the drug of choice for invasive aspergillosis.
- The echinocandins are well tolerated and are treatment options for infections with Candida and Aspergillus spp.
- Consultation with an infectious disease specialist is recommended.
Prevention and screening
Local measures including hygienic means to decrease colonization, careful attention to intravascular catheter use and care, judicious use of antibiotics, and strict infection control measures, can decrease the risk of fungal infections. High-risk patients should avoid environmental exposure or wear approved respiratory devices during recreation or if working at construction sites where soil or building disruption may cause high numbers of yeasts to be aerosolized.
For pathogenic molds, the use of high-efficiency particulate air (HEPA) filters, frequent air exchanges, and positive pressure ventilation are recommended to limit nosocomial exposure.
Considerations in special populations
Amphotericin B is the tratment of choice for pregnant women. Echinocandins and azoles (fluconazole and itraconazole) are designated category C (risk to fetus cannot be ruled out) and voriconazole as category D (positive evidence of human fetal risk).
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