In persons with endemic mycoses, spontaneous recovery usually occurs without treatment, especially in patients who are mildly affected and immunocompetent without dissemination; otherwise, administer treatment as outlined in the table below.
In cases in which aspergillosis, mucormycosis, and candidiasis occur in an immunocompromised host, reversing the factors affecting the patient's immune status is linked to successful recovery from the infection. Attempt ancillary interventions that may help to promote recovery from the opportunistic infection. These include (1) ensuring, with the use of growth factors, neutropenia recovery in patients receiving chemotherapy and bone marrow transplants; (2) withdrawing or tapering immunosuppressive drugs and steroids; and (3) removing infected or highly colonized catheters in patients with candidiasis.
Table. Medical and Surgical Fungal Therapy (Open Table in a new window)
Fungal Pathogen | Indication for Antifungal Therapy | Surgical Care and Other Treatments | Antifungal Drugs Used |
Histoplasmosis | Acute pulmonary histoplasmosis with hypoxia; prolonged moderate symptoms for more than 1 month; disseminated disease; immunosuppressed host Mortality rate for untreated disseminated disease at 80%; reduced to 25% with treatment | Significant hemoptysis; recurrent pneumonia; repair of bronchopleural fistula Corticosteroids in severe hypoxia or ARDS Anti-inflammatory agents to treat rheumatologic syndromes | Amphotericin B induces rapid response in patients who are severely ill or immunocompromised Azoles/triazoles in patients with milder illness |
Coccidioidomycosis | Disseminated disease; chronic pulmonary disease; acute pulmonary infection with hypoxia or protracted morbidity (>1-2 mo); immunosuppressed host (worst outcome, 70% mortality) | Surgical debridement or resection of infective tissue often necessary adjunct to antifungal treatment Anti-inflammatory agents for rheumatologic syndromes | Amphotericin B effective in more than 90% of cases; first choice in severe cases or immunocompromised Fluconazole/itraconazole first choice in mild to moderate infection (or after improvement) Treatment less effective than in other endemic mycoses |
Blastomycosis | Persistent or recurrent symptoms of acute or chronic pulmonary disease or with pleural involvement; disseminated disease | Steroids for ARDS | Amphotericin B response rates of 77-90% of cases; for severe infection or immunocompromised Itraconazole successful in 90% of cases; for mild to moderate infection Ketoconazole response of 80%; poor outcome in patients who are immunosuppressed Fluconazole less effective, 65% response rate Chronic maintenance treatment essential for all patients with AIDS or meningitis |
Cryptococcosis | Patients who are immunosuppressed and symptomatic; patients who are immunocompetent with disease progression; any patients with meningitis or disseminated disease | N/A | Amphotericin B in patients who are severely ill Fluconazole in milder cases or after clinical response to amphotericin B Lifelong maintenance therapy in AIDS patients may not be necessary as long as the patient's CD4 count is maintained above 100 cells/µL with HAART [37] Flucytosine may be of benefit when combined with amphotericin B in patients with severe or disseminated disease. [5] |
Aspergillosis | All patients with invasive disease; in patients who are immunosuppressed, early diagnosis and empiric treatment for persistent fever not responding to broad-spectrum antibiotics; high mortality once infiltrates and symptoms appear; prognosis ultimately linked to severity and outcome of underlying disease Mortality rate of 50-60% in patients with AIDS | Rapid tapering of immunosuppressive agents and corticosteroids and reversal of neutropenia (if possible) | Voriconazole is the new standard of care for invasive aspergillosis based on superiority over amphotericin B in primary therapy Lipid formulations of amphotericin B have at least equal efficacy but less toxicity compared with amphotericin B desoxycholate Oral voriconazole can be used to complete treatment with initial response to IV voriconazole or amphotericin B Posaconazole is second line agent Echinocandins second line agent when voriconazole is not tolerated or in combination with voriconazole in an attempt to enhance antifungal activity Isavuconazole has been shown to be not inferior to voriconazole for aspergillosis [38] |
Mucormycosis | Mortality rates as high as 70% in patients with invasive pulmonary mucormycosis | Aggressive surgical debridement of necrotic tissue important in mucormycosis, especially if confined to lungs | Lipid amphotericin B is the mainstay of therapy; posaconazol is poorly absorbed, considered second line Mucor species generally resistant to azoles (voriconazole has no activity against them) Echinocandins (Caspofungin) useful as salvage therapy Isavuconazole has been shown to be comparable to amphotericin B and posaconazole for mucormycosis [38] |
Candidiasis | All patients with invasive disease or dissemination; important to reverse factors affecting immune status Expert recommendations and clinical practice guidelines do not recommend antifungal treatment facing isolation in respiratory samples regardless the number of positive samples [15] | Rapid tapering of immunosuppressive agents and corticosteroids; important to remove indwelling infected intravenous lines or urinary catheters in setting of hematogenous spread | Amphotericin B is mainstay Flucytosine may be of benefit when added to amphotericin B Fluconazole use in pulmonary disease not studied but is effective in hepatosplenic candidiasis and candidemia Echinocandins may be useful alternatives |
Sporotrichosis | Management should be based in clinico-radiological manifestations; two presentations of pulmonary sporotrichosis: non-cavitary disease (multifocal) and cavitary disease (primary) [16] | Surgical interventions when presence of cavitations and initial medical therapies have failed; used as adjunctive therapy | Itraconazole as first line agent in mild to moderate cases Amphotericin B first line in life threatening conditions |
Scedosporiosis | Emerging opportunistic pathogen in similar scenario as aspergillosis but highly resistant to amphotericin B and echinocandins; mortality rate is 54-78% in transplant recipients In near-drowning victims, close surveillance for clinical and radiographic findings with low threshold for empiric treatment | Aggressive surgical debridement for disseminated disease in the form of subcutaneous abscesses, brain abscess, and others Granulocyte transfusions or growth factors to enhance neutrophil recovery | Resistant to amphotericin B and echinocandins Voriconazole as single agent or in combination with other agents such as terbinafine [39] |
When treatment is indicated, initiate antifungal agents as appropriate. Amphotericin B is the mainstay of initial therapy in many cases, especially for patients who are acutely ill. More expensive liposomal preparations of amphotericin B offer equal efficacy with less toxicity. In patients with invasive aspergillosis, including pulmonary aspergillosis, voriconazole is the new standard of care, based on its superiority over amphotericin B as primary therapy. [5, 12, 40, 41, 42] Vary the dose and treatment duration depending on the underlying pathogen causing the pneumonia.
Care should be taken regarding patients on long-term voriconazole treatment. Bone pain with radiologic evidence of periostitis and 10-fold increased fluoride levels have been reported in allogeneic stem cell transplant patients taking the drug for at least 3 months. Symptoms and findings were reversed with discontinuation of voriconazole. [43]
There is a possible association between the use of voriconazole in markedly immunosuppressed patients as prophylactic agent and the development of mucormycosis, but this matter is still controversial. [5]
Amphotericin B is available in a variety of formulations. Conventional amphotericin B injection contains amphotericin B and sodium deoxycholate as the solvent vehicle.
Amphotericin B cholesteryl sulfate complex (ABCD, Amphotec) consists of a 1:1 molar ratio of amphotericin B to cholesteryl sulfate in a colloidal dispersion, forming a bilayer in microscopic, disk-shaped particles that have a diameter of approximately 115 nm and a thickness of 4 nm.
Amphotericin B lipid complex (ABLC, Abelcet) is composed of amphotericin B and phospholipid complex, with a microscopic, ribbonlike structure having a diameter of approximately 2-11 µm.
Liposomal amphotericin B (L-AmB, AmBisome) contains amphotericin B intercalated in a unilamellar bilayer liposomal membrane; has a liposomal membrane diameter of less than 100 nm; and consists of hydrogenated soy phosphatidylcholine, cholesterol, distearoyl phosphatidylglycerol, and alpha tocopherol.
Some clinicians offer empiric therapy with conventional amphotericin B or liposomal amphotericin B for presumed fungal infections in patients who are febrile and neutropenic (eg, cancer, bone marrow transplantation, solid organ transplantation) and whose febrile state persists after receiving broad-spectrum antibiotics for a few days. Other agents that could be used in this setting are itraconazole and an echinocandin, namely, caspofungin. [44] The therapy is continued until the neutropenia resolves and the patient does not show a documented fungal infection or radiographic infiltrate.
Prophylactic therapy (suppressive therapy) with amphotericin B is used against recurrence or relapse of coccidioidomycosis, cryptococcosis, or histoplasmosis in individuals infected with the human immunodeficiency virus (HIV) who have received adequate treatment for the infection.
Other formulations, however, are starting to replace amphotericin B because of their ease of use (oral formulations) and lower toxicity for more long-term suppression. Posaconazole is used in the prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients receiving hematopoietic stem cell transplants who have graft versus host disease and in patients with hematologic malignancies who have chemotherapy-induced neutropenia. [45] While it used to be available only as an oral suspension given thrice daily, a delayed-release tablet formulation of posaconazole for once-daily administration allows for better bioavailability without being affected by food. The intravenous formulation is also administered once daily, but it has to be through a central line because of the presence of a solubilizing excipient SBECD (sulfobutylether-β-cyclodextrin), which can be potentially renal toxic and can accumulate in patients with moderate-to-severe renal failure. [46] Because of the large interindividual and intraindividual variations in bioavailability and drug-to-drug-interactions, therapeutic drug monitoring is recommended for posaconazole, especially if used in the therapeutic setting to treat invasive aspergillosis or zygomycosis.
Other antifungal agents used in the treatment of fungal pneumonia are fluconazole (Diflucan), itraconazole (Sporanox), flucytosine (Ancobon), and ketoconazole (Nizoral). Newer antifungal agents, such as the third-generation triazoles or the echinocandins, are more tolerable than amphotericin B or its liposomal preparations are and may even be more effective in first- or second-line treatment.
Isavuconazole has been approved by the FDA and the European Medicines Agency for the treatment of invasive aspergillosis and mucormycosis. Studies have shown it to be not inferior to voriconazole for aspergillosis and comparable to amphotericin B and posaconazole for mucormycosis. [38]
There have been increasing reports of azole resistance in Aspergillus species. This might be the result of the increasing use of these agents for prophylaxis and treatment of fungal infections; also there are associations with exposure to azole-like compounds used in the agricultural industry in some countries. In addition, some species have intrinsic resistance to various azoles. [5]
Caspofungin is approved for the treatment of invasive Aspergillus infections in patients unresponsive to or unable to receive amphotericin B. Combinations of a triazole with an echinocandin with or without amphotericin B have been anecdotally reported to be effective in some cases of resistant organisms, such as Mucor or Zygomycetes species. [44]
Echinocandins such as caspofungin, micafungin, and anidulafungin [47, 48, 49] offer a broad spectrum of activity for the many Candida species, including fluconazole-resistant strains. They also show effectiveness in Aspergillus infections alone or in combination with an azole.
Because of the introduction of these safer and (possibly) more potent agents, and owing to the ability to combine them together, the outlook for patients with invasive pulmonary infections, especially immunocompromised hosts, may be improving.
The role of combination therapy has been studied only in small retrospective studies with very unclear results. Combination therapy is usually not indicated in first-line treatment. In rare cases, it might be offered with a great deal of caution as second-line or salvage treatment. [39]
The establishment of neutrophil recovery or engraftment and the reduction of immunosuppression in certain patients who are at risk for fungal infections are likely to improve the chances of a successful treatment outcome. Granulocyte-macrophage colony-stimulating factor can theoretically augment pulmonary host defenses against A fumigatus infection.
Surgery may be indicated in invasive aspergillosis. [50] Surgery is indicated in patients with documented invasive aspergillosis who have been treated with antifungal agents but who have residual lesions. The surgery is performed to prevent disease relapse when additional immunosuppression is required. Surgery is also indicated as a means to prevent or treat massive bleeding, especially when the lung lesion is contiguous with a large blood vessel.
In cavitary pulmonary sporotrichosis, surgical management should be considered in the course of the disease, even for bilateral presentation, providing that the patient has adequate predicted respiratory reserves post-surgery, as delayed surgery may result in complications and poorer outcomes. [16]