US Pharm. 2011;36(7):HS-17-HS-24.
Invasive fungal infections occur in both immunocompetent and immunocompromised patients. An increase in the number of patients with malignancy, HIV, hematologic disease, and conditions requiring immunosuppressive medications has contributed to an escalation of respiratory fungal infections.1 Luckily, enhancements in diagnostic measures and treatment modalities have expanded early detection of infection and available treatment choices. This article will discuss endemic and opportunistic respiratory fungal infections encountered, as well as currently available treatment options.
Endemic Fungal Infections
Endemic fungal infections can affect both healthy and immunocompromised patients and are seen in specific geographic locations around the world. Four common endemic infections are described below.
Histoplasmosis: The fungus Histoplasma capsulatum is endemic to the Ohio and Mississippi River valleys, Central American and Southeast Asian rivers, and the Mediterranean.2 H capsulatum grows optimally in caves and bird roosting areas with rich nitrogen soil.3 Pulmonary disease occurs when the fungus is inhaled and phagocytized by neutrophils and macrophages in the alveoli.1,3 Itraconazole is used as monotherapy for mild and chronic pulmonary disease. Amphotericin B (AmB) with itraconazole is recommended for moderate-to-severe histoplasmosis.1
Blastomycosis: Blastomyces dermatitidis is endemic to the Great Lakes, the Mississippi and Ohio River valleys, the southeastern United States, and the African Mediterranean.3,4 The fungus grows in dead or decaying wood and acidic soil in close proximity to bodies of water. Blastomycosis occurs with mold inhalation into the alveoli, where further dissemination may ensue.1,3 Extrapulmonary dissemination involving the skin occurs in up to 40% of cases.4 Treatment includes itraconazole for mild-to-moderate disease and liposomal AmB (L-AmB) followed by itraconazole for life-threatening pulmonary infections.1
Sporotrichosis: Sporothrix schenckii is globally located and not isolated to certain regions.5 This fungus may be found in soil, decaying material, moss, hay, and infected animals. Infection results primarily from cutaneous contact with sporotrichosis.3,5 Pulmonary sporotrichosis and nodular lesions result from inhaling S schenckii. Mild-to-moderate pulmonary disease requires itraconazole, whereas AmB followed by itraconazole is recommended for severe disease.1
Coccidioidomycosis: Coccidioides immitis and Coccidioides posadasii are indistinguishable fungi, with C immitis being more common. Endemic to South America, Central America, northern Mexico, and the western U.S., fungal growth occurs in nitrogen-enriched soil from rodent and bat droppings.1,6 Inhalation of a few inocula may cause pulmonary disease, with presentation as community-acquired pneumonia in endemic areas. Immunocompetent infected hosts may not require treatment.1,6 Immunocompromised patients are treated with fluconazole or itraconazole. In serious pulmonary disease, treatment with AmB is initiated, followed by an azole.1
Opportunistic Fungal Infections
Opportunistic fungal infections primarily cause infections in patients who tend to be immunocompromised through a congenital or acquired disease process. Five common opportunistic infections are discussed below.
Aspergillosis: Aspergilli—fungi isolated from soil, plant debris, and indoor environments—are the most common cause of mortality due to invasive fungal infections.1,7 Inhalation of airborne spores can lead to invasive pulmonary aspergillosis (IPA) in severely immunocompromised patients, and to chronic necrotizing aspergillosis in patients with chronic lung diseases. Aspergilloma (occurring in patients with cavitary lung disease) and allergic bronchopulmonary aspergillosis (identified in patients with a hypersensitivity to aspergillus antigens) are noninvasive manifestations.8 Once the cause is identified, the primary treatment for IPA is voriconazole. Alternatives include lipid-based AmB formulations, echinocandins, and posaconazole. Data to support combination therapy are currently lacking; therefore, combination therapy is not recommended.1,8
Cryptococcosis: Cryptococcosis is an opportunistic infection seen in immunocompromised individuals, including HIV or AIDS patients and organ-transplant recipients; immunocompetent patients are typically asymptomatic, which results in a dormant infection.1,9,10 Found in soil contaminated with pigeon droppings, cryptococcosis commonly presents as cryptococcal meningoencephalitis; it also occurs as an isolated primary infection in the lungs after spore inhalation.11 Because cryptococcosis is associated with a high risk of mortality secondary to dissemination, immediate identification and treatment are necessary to avoid dissemination to the central nervous system. An AmB formulation with or without flucytosine, followed by oral fluconazole, is the primary recommendation for severe symptomatic pulmonary cryptococcosis. For immunosuppressed or immunocompetent patients exhibiting mild-to-moderate symptoms, fluconazole therapy is recommended.1,9
Candidiasis: Pulmonary pneumonia infection due to Candida species is rare and diagnosis can be difficult. Primary Candida pneumonia refers to an invasive infection in the lungs, while secondary pneumonia refers to dissemination of invasive candidiasis.1,12 Colonization of the lung parenchyma with Candida species is common; in critically ill patients, however, defense mechanisms are rendered ineffective, thus enabling penetration of lung tissue. Many critically ill patients are empirically treated with broad-spectrum antibiotics. Further clinical deterioration and lack of improvement in these cases suggest the initiation of empiric antifungal therapy. Because triazole antifungals and echinocandins exhibit excellent lung penetration, they—in addition to AmB formulations—are effective for treating pulmonary candidiasis, despite the lack of specific studies regarding the treatment of Candida pneumonia.12,13
Mucormycosis: Mucormycosis, while uncommon, occurs in patients with diabetes mellitus, organ or hematopoietic stem cell transplant, neutropenia, or malignancy.14 Pulmonary mucormycosis is primarily observed in patients with a predisposing condition of neutropenia or corticosteroid use.15 Owing to fungal adherence to and damage of endothelial cells, fungal angioinvasion, vessel thrombosis, and successive tissue necrosis can lead to disseminated mucormycosis infections. These complications make for poor penetration of antifungal agents. Treatment should include control of the predisposing problem, débridement of necrotic tissue, and antifungal therapy. Current recommendations for efficacious treatment of mucormycosis include AmB formulations, posaconazole, and iron chelation therapy. Although echinocandins as monotherapy do not act against mucormycosis, a few studies have found improved outcomes when AmB and an echinocandin are used.1,14 Because of the lack of literature regarding combination therapy, its use in mucormycosis is not recommended.
Pneumocystis jirovecii Pneumonia (PCP): Originally considered a parasite, PCP is currently categorized as a fungus based on molecular similarities to fungal RNA. PCP occurs in patients with HIV/AIDS, hematologic and solid malignancies, organ transplant, and diseases requiring immunosuppressive agents. Infection occurs through the inhalation of airborne spores, with further maturation occurring in the lungs.16 Evidence suggests that PCP has become transmissible between humans; therefore, immunocompromised patients should be diagnosed promptly and receive adequate prophylactic treatment.1 PCP is extremely resistant to common antifungal therapy, including AmB formulations and triazole antifungals. Trimethoprim/sulfamethoxazole remains the mainstay for PCP treatment and prophylaxis. If clinical improvement is not noted, failure of the first-line treatment should be considered and a second-line agent should be initiated. Second-line agents indicated for the treatment of PCP include primaquine plus clindamycin, atovaquone, or IV pentamidine. In addition, dapsone is an alternative for prophylactic therapy.1
The following are therapeutic treatment options for fungal lung infections (TABLES 1 and 2).
Triazole Antifungals: Available for several decades, triazole antifungals are well documented in the treatment of fungal infections. An interference with CYP450 leading to inhibition of lanosterol causes a decrease in ergosterol synthesis and inhibition of cell-membrane development.17 Classified as first-generation (fluconazole, itraconazole) or newer second-generation (voriconazole, posaconazole) antifungals, triazoles have activity against most Candida species (excluding Candida glabrata and Candida krusei), as well as Cryptococcus, Blastomyces, Histoplasma, and Coccidioides. The second-generation triazoles have broadened the spectrum of activity to include Aspergillus and Mucor (specific to posaconazole). Because of hepatic metabolism, caution must be taken to avoid potential drug–drug interactions through the CYP450 system. Characteristic side effects include gastrointestinal disturbances, hepatotoxicity, headache, and rash. All of these agents are available orally, and IV formulations of fluconazole and voriconazole are available.1,18
Echinocandins: Further expanding the arsenal of antifungal agents, the echinocandins have emerged during the past decade. These agents exhibit their effects through inhibition of the synthesis of beta-(1,3) glucan synthase, an important component of fungal cell walls, resulting in osmotic instability and cell death.17 Echinocandins, including caspofungin, micafungin, and anidulafungin, are active against Candida and Aspergillus species and PCP. Common side effects are infusion-related reactions such as rash, headache, fever, and chills. Hematologic events, such as a decrease in white blood cell and hemoglobin/hematocrit counts, have a 12% to 21% likelihood of occurrence. All of the echinocandins are available IV only, and all have analogous spectrums of activity.17,18
AmB Formulations: AmB is a macrocyclic polyene antifungal originally synthesized from Streptomyces. AmB exerts its antifungal activity on the cell membrane. Polyenes bind to the ergosterols on the fungal cell membrane, creating channels, or pores, where potassium and other cellular components are released, leading to fungal death.19,20 As a result of chemical changes in the parent drug and new delivery systems, the harmful effects of AmB have been reduced.
AmB is given IV for systemic fungal infections, including the respiratory tract. As previously mentioned, toxicity is a concern, the most prominent one being nephrotoxicity. The clinician should monitor serum creatinine, blood urea nitrogen, CBC, liver function, and serum electrolytes at least weekly, and more often in renal insufficiency.1 Infusion-related reactions may be associated with AmB administration, yet premedicating with antipyretics, antihistamines, and antiemetics can reduce fever, chills, and nausea.1,21 Finally, life-threatening hyperkalemia is associated with rapid infusion. AmB must be infused over several hours to prevent hyperkalemia-induced arrhythmias. Additional side effects of AmB are hypokalemia, weight loss, headache, fatigue, and phlebitis.20
As noted above, newer AmB delivery systems have greatly reduced infusion-related reactions and nephrotoxicity. AmB deoxycholate, commonly known as conventional AmB (C-AmB), is associated with a high incidence of toxicities. Because of the high toxicity rate of C-AmB, AmB colloidal dispersion (ABCD) was formulated to reduce nephrotoxicity. In a study comparing these two agents, the incidence of nephrotoxicity was 25% for ABCD versus 49% for C-AmB.22 Further toxicity reduction has occurred since the introduction of lipid formulations of AmB (AmB lipid complex [ABLC] and L-AmB).20 In one study, L-AmB infusion–related reactions of rigors and chills were significantly less prevalent than with ABLC (23.5% and 79.5%, respectively; P <.001). Nephrotoxicity, defined as an increase of three times baseline serum creatinine, occurred approximately 20% less often with L-AmB versus ABLC (P <.001).21
Current guidelines from the American Thoracic Society recommend that C-AmB be used because of its established efficacy. However, if a patient has underlying renal impairment, a lipid-based formulation (ABLC or L-AmB) is warranted. The use of a lipid-based formulation should be strongly considered when the C-AmB dose is greater than 1 mg/kg/day.1
Flucytosine: Flucytosine (5-FC) is one of the oldest antifungal agents still used today. Discovered in the 1950s, 5-FC was originally developed for the treatment of solid tumors, with antifungal usage beginning in the late 1960s.23 Chemically, 5-FC is a fluorinated cytosine similar to fluorouracil (5-FU) and has a relatively narrow spectrum of activity.23,24
The mechanism of action of 5-FC relies solely on conversion to 5-FU. Inactive 5-FC is enzymatically transported into the fungal cell, where cytosine deaminase converts 5-FC to 5-FU. 5-FU appears to exert two mechanisms of action, the first one being the conversion of 5-FU to fluorouridine monophosphate to fluorouridine diphosphate into active fluorouridine triphosphate (FUTP). FUTP inhibits protein synthesis by replacing uridylic acid in RNA. Incorporation into the RNA sequence ultimately disrupts transfer RNA and protein synthesis. The second mechanism pertains to 5-FU conversion to fluorodeoxyuridine monophosphate, which inhibits DNA synthesis by thymidylate.23,24
5-FC is considered to be a toxic antifungal. Hepatotoxicity and bone marrow suppression—characterized as leukopenia, thrombocytopenia, and/or pancytopenia—are generally considered dose-dependent toxicities.23,24 Serum flucytosine levels should be monitored, with target peaks of 50 mg/dL to 100 mg/dL and troughs of 25 mg/dL to 50 mg/dL.24
While the incidence of pulmonary fungal infections has increased over the years, advances in diagnostic techniques and treatments have improved. Despite these advances, patient outcomes remain poor owing to a lack of early infection identification. Therefore, treatment should begin as soon as a diagnosis is made. With the expansion of antifungal treatment options, pharmacists should be aware of specific recommended doses, available drug formulations, drug–drug interactions, and potential side effects when assisting with the prescribing of antifungal agents.
Acknowledgment: The authors would like to thank Edgar Gonzalez, PharmD, for his editorial recommendations.
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