AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Fungal pneumonia is an infectious process in the lungs caused by any one or a combination of endemic or opportunistic fungi. Endemic fungal pathogens (eg, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides brasiliensis) cause infection in both healthy and immunocompromised hosts in defined geographic locations of the Americas and around the world. Opportunistic fungal organisms (eg, Candida species, Aspergillus species, Mucor species, Cryptococcus neoformans) tend to cause pneumonia in patients with congenital or acquired defects in their host defenses.

Pathophysiology

Infection occurs following the inhalation of spores, after the inhalation of conidia, or by the reactivation of a latent infection. Hematogenous dissemination frequently occurs, especially in an immunocompromised host.

Frequency

United States

The endemic fungi are prevalent in the Mississippi River Valley and the Ohio River Valley (eg, H capsulatum, B dermatitidis), the southwestern United States, and northwestern Mexico (eg, C immitis).

International

These fungi have caused several pneumonia outbreaks in Argentina and other areas of Central and South America. P brasiliensis is restricted to Central and South America. African histoplasmosis, which is caused by Histoplasma capsulatum duboisii, is limited to equatorial Africa between 20° N and 10° S, which includes Gabon, Uganda, and Kenya.

The other opportunistic organisms are ubiquitous, are usually found worldwide, and tend to cause disease in hosts with abnormal immune defenses. For instance, C neoformans can affect people with intact immune systems at a rate of 0.2 cases per million population per year. Approximately 80-90% of patients with AIDS develop cryptococcosis.

Mortality/Morbidity

The endemic fungal pneumonias are generally self-limited in healthy hosts. C immitis is the most virulent; yet, 90% of patients recover without treatment. Patients with fungal pneumonias may develop chronic pulmonary (eg, cavitation, pleural effusions, bronchopleural fistulas) or extrapulmonary complications. However, in patients with AIDS, the mortality rate is as high as 70%.

Aspergillosis in patients who are neutropenic (from either leukemia chemotherapy or bone marrow transplantation) has a mortality rate of 50-85%. More often, the cause of mortality in patients who are immunocompromised is disseminated disease in the case of aspergillosis and candidal infections or meningoencephalitis in the case of cryptococcosis.

Race

No racial predilection is described, although C immitis causes more severe disease in patients of African American or Philippine descent.

Sex

Endemic fungal disease affects men (75-95%) more often than women; estrogen-mediated inhibition of mycelium-to-yeast transformation may be responsible for the male predominance. Estrogen seems to have a protective effect against cryptococcal infection. Cryptococcosis has a male-to-female ratio of 2-3:1.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Fever: In individuals who are neutropenic or immunocompromised, persistent fever (even before pulmonary findings) may be an early sign of infection, especially if the fever is unresponsive to broad-spectrum antibiotics.
• Cough, usually nonproductive
• Pleuritic chest pain or dull discomfort
• Dyspnea leading to respiratory failure
• Obstructive symptoms from enlarged mediastinal adenopathy in the endemic mycoses
• Hemoptysis in invasive aspergillosis or mucormycosis
• History of travel to or exposure in areas containing endemic mycoses
• Symptoms from involvement of extrapulmonary systems (may suggest disease)
• Rheumatologic syndromes (common among endemic mycoses)
• • Arthritis and arthralgia
  • Erythema nodosum
  • Erythema multiforme
  • Pericarditis
• Endemic mycoses  with associated dissemination
• • Skin (eg, papules, pustules, plaques, ulcers, abscesses, proliferative lesions) - May mimic skin cancer as in B dermatitidis infection
  • Bone and joints
  • Brain and meninges - Meningitis with poor prognosis (10-20%)
  • Septicemia or sepsis syndrome
• Hypersensitivity or allergic reactions
• • Allergic bronchial asthma (Aspergillus species, Candida species)
  • Allergic bronchopulmonary mycoses (Aspergillus species, Candida species)
  • Bronchocentric granulomatosis (necrotizing granulomatous replacement and eosinophilic infiltration of bronchial mucosa in infection with Aspergillus species)
  • Extrinsic allergic alveolitis (malt worker's lung, farmer's lung)
• Extrapulmonary sites in individuals who are immunocompromised
• Meningoencephalitis in patients with AIDS and cryptococcosis
• Skin (often a good site for biopsy)
• CNS (brain abscess in infection with Aspergillus and Mucor species)
• Kidneys
• Liver and spleen (hepatosplenic candidiasis)
• Muscle (Candida species)
• Eye (endophthalmitis) in Candida species infection
• Nasal passages and sinuses (Aspergillus and Mucor species)
• Bloodstream and bone marrow (sepsis syndrome)

Physical

• Temperature elevation and tachycardia
• Respiratory distress, rales, signs of pulmonary consolidation, and pleural rub
• Important possible extrapulmonary findings
• • Meningitis (neck stiffness, headaches, mental status change)
  • Skin lesions (pustules, papules, plaques, nodules, ulcers, abscesses, hemorrhagic lesions)
  • Nasal passage and sinuses (Mucor and Aspergillus species)
  • Rheumatologic and allergic findings

Causes

• Workers or farmers with heavy exposure to bird, bat, or rodent droppings and other animal excreta in endemic areas are predisposed to acquire any of the endemic fungal pneumonias.
• C immitis, because of its virulence, is also a threat among laboratory personnel working with this fungus.
• Conditions that predispose patients to any of the opportunistic fungal pathogens are as follows:
• • Acute leukemia or lymphoma during myeloablative chemotherapy
  • Bone marrow transplantation
  • Solid organ transplantation on immunosuppressive treatment
  • Prolonged corticosteroid therapy
  • Acquired immunodeficiency syndrome
  • Prolonged neutropenia from various causes
  • Congenital immune deficiency syndromes
  • Postsplenectomy state

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• CBC count with differential
• • The total WBC count may be elevated in normal hosts with endemic mycoses.
  • Eosinophilia can be observed in the differentials, particularly in persons with coccidioidomycosis.
  • If the patient presents with neutropenia or leukopenia, the possibility of an opportunistic infection with Candida or Aspergillus organisms is increased.
• Sputum examination and potassium hydroxide stain
• • This study may show fungal hyphae or yeasts, but the results must correlate with the clinical situation because saprophytic colonization occurs in the oropharyngeal or respiratory tract of some patients and may not necessarily indicate invasive infection.
  • Carefully transport, process, and culture specimens that may be contaminated by bacteria, may be saprophytic yeasts endogenous to the oral cavity, and may be airborne Conidia of saprophytic fungi.
• Blood culture: Obtain this culture to identify Candida species (lysis centrifugation) or B dermatitidis if the patient has disseminated disease.
• Culture of other fluids: Obtain a urine fungal culture in men after a prostatic massage to identify Cryptococcus species.
• Nonculture methods for detecting fungal infections: These provide a more rapid and sensitive test when compared with culture methodology. Various antigen detection assays, such as galactomannan enzyme immunoassay for detection of Aspergillus invasive infections, are now in clinical use. Polymerase chain reaction (PCR)–based assays are also available for detecting various pathogens, including Aspergillus, Histoplasma, and Candida species.
• • Comparison of these assays (antigen detection using enzyme-linked immunosorbent assay [ELISA] or latex agglutination and molecular detection with PCR) show equal specificities for all 3 assays (>97%) in the detection of Candida species. PCR-based assays are most sensitive compared with ELISA and latex agglutination (95%, 75%, and 25%, respectively).
  • For Aspergillus species antigen, galactomannan ELISA assay findings may be positive in the blood very early prior to clinical suspicion of invasive fungal infection and may be of use in monitoring and preemptive treatment in high-risk populations. Care, however, should be taken because false-positive results have been reported in patients taking piperacillin-tazobactam antibiotic.
  • Aspergillus PCR is most sensitive (100%) when performed on the bronchial lavage fluid of patients with invasive pulmonary aspergillosis, but it is only 40-66% sensitive when performed on the blood.
  • ELISA or latex agglutination is 70-80% sensitive for identifying H capsulatum and C immitis. PCR for H capsulatum from the bronchoalveolar lavage fluid aids in the rapid detection within 24 hours in a patient with AIDS, and this has been confirmed 10 days later based on the growth and culture isolation of the organism from various tissues.
• Serology: Utility depends on the individual fungal infectious agent. Antibody detection against C immitis is highly useful, but these tests are of less utility if the pulmonary infection is due to other fungi. Serology testing for blastomycosis provides little clinical diagnostic help because of the insensitivity of testing for this fungus and the antibody cross-reactivity that occurs with other fungal infections.

Imaging Studies

• Chest radiography
• • Patchy infiltrate, nodules, consolidation, cavitation, or pleural effusion may be observed.
  • Mediastinal adenopathy is common in patients with endemic fungal pneumonias. The adenopathy may be either unilateral or bilateral.
  • Miliary infiltration occurs in patients with disseminated disease.
• Chest CT scanning
• • This imaging study plays a role in the early diagnosis of nonspecific infiltrates in patients who are immunocompromised.
  • Chest CT scanning allows observation of the halo sign in patients with aspergillosis.
  • Obtaining a CT scan of the abdomen and brain may reveal sites of dissemination.
• MRI of lung lesions: This study may reveal the hemorrhagic content of Aspergillus lesions.

Procedures

• Fiberoptic bronchoscopy (procedure of choice) is used to obtain bronchial lavage specimens for staining and culture techniques and transbronchial biopsy specimens for identification of fungal tissue invasion. This procedure reveals positive results in 75-90% of endemic mycoses, shows a 50-90% yield in cryptococcal disease, and shows varying yields in Aspergillus and Candida infections, for which clinical correlation is still important.
• Perform transthoracic fine-needle aspiration of nodules to access lesions that are short of an open lung biopsy.
• Occasionally, performing an open lung biopsy is the only way to prove invasive disease for Aspergillus or Candida organisms; however, this procedure may be difficult to perform in patients with severe neutropenia and thrombocytopenia who are in respiratory failure.
• Perform a lumbar spinal puncture in patients with suspected cryptococcosis or disseminated disease with CNS symptomatology.
• Conduct a bone marrow aspiration and biopsy if the patient has persistent fever or suspected disseminated disease or if the patient has hematologic findings such as thrombocytopenia or neutropenia.

Histologic Findings

Biopsy specimens show the following:

• Caseating or necrotizing granulomas with intracellular organisms inside macrophages (eg, H capsulatum, C immitis)
• Fungal hyphae in infection with Aspergillus and Mucor species
• Intracellular yeast organisms in Candida species infections

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

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. 

If aspergillosis, mucormycosis, and candidiasis occur in an immunocompromised host, reverse the factors affecting the patient's immune status, which is linked to successful recovery from the infection. Attempt the following ancillary events, which may help to promote recovery from the opportunistic infection: 

• With the use of growth factors, ensure neutropenia recovery in patients receiving chemotherapy and bone marrow transplants.
• Withdraw or taper immunosuppressive drugs and steroids.
• Remove infected or highly colonized catheters in patients with candidiasis.

Medical treatment

Consultations

• A pulmonologist may perform diagnostic procedures (eg, bronchoscopy, lavage).
• Interventional radiologists can perform needle aspirations, when necessary, for diagnosis.
• Patients who are severely ill and progressively hypoxic may require intensive care, ventilatory support, and pressor support in the ICU under the care of a critical care intensivist.
• Consultations with surgeons are required as indicated the Table in Medical Care.
• Rheumatologists can assist with the rheumatologic syndromes manifesting with the endemic mycoses.
• Infectious disease consultants may assist with the intricacies of antifungal treatment, especially with respect to the exact drugs, dose, duration, therapy length, maintenance treatment, and even follow-up studies.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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 superiority over amphotericin B as primary therapy. Vary the dose and treatment duration depending on the underlying pathogen causing the pneumonia.

Amphotericin B is available in the following 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 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. 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 HIV who have received adequate treatment of the infection. Other formulations, however, are starting to replace amphotericin B because of their ease of use (oral formulations) and less 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 with graft versus host disease or those with hematologic malignancies with chemotherapy-induced neutropenia.

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 and may even be more effective in first- or second-line treatment.

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. Echinocandins such as caspofungin, micafungin, and anidulafungin 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 these new safer and possibly more potent agents and the ability to combine them together, the outlook for patients with invasive pulmonary infections, especially immunocompromised hosts, may be improving.

Drug Category: Antifungal Agent, Systemic

The mainstay of therapy for fungal pneumonias must include antifungal agents. The type of antifungal drug to be used must be tailored based on the particular pathogen isolated or clinically suspected. Many classes of antifungal agents are now available, including the classic antibiotics; first-, second-, and third-generation triazoles; and the echinocandins. 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 Aspergillus fumigatus infection.

Drug Name	Amphotericin B, conventional (Amphocin, Fungizone)
Description	Antifungal antibiotic produced by Streptomyces nodosus. Has a broad spectrum of activity against pathogenic fungi, including yeasts, except Fusarium species. Exerts antifungal activity, principally by binding to sterols in fungal cell membrane.
Adult Dose	0.25-1.5 mg/kg/d IV; not to exceed 1.5 mg/kg/d Test dose: 1 mg in 20 mL of D5W infused IV over 20-30 min; monitor pulse, respiration rate, temperature, and blood pressure q30min for 2 h Invasive aspergillosis: 0.5-0.6 mg/kg/d IV (1-1.5 mg/kg/d in patients who are neutropenic for rapidly progressing, potentially fatal infections); duration uncertain; cumulative dose of 1.5-4 g has been administered over 11 mo Zygomycosis or mucormycosis: 1-1.5 mg/kg/d IV for 2-3 mo; cumulative dose of 3-4 g Invasive candidiasis: 0.4-0.6 mg/kg/d IV (1-1.5 mg/kg/d for candidemia or rapidly progressing potentially fatal infections); treat for 7-14 d in low-risk patients (6 wk or longer in high-risk patients) Blastomycosis: 0.5-1 mg/kg/d IV; cumulative dose of 1.5 g for patients who are very ill Coccidioidomycosis: 0.5-1 mg/kg/d IV (1.5 mg/kg/d in rapidly progressing, potentially fatal infections); treat for 4-12 wk; treat for at least 8 wk in patients with HIV Histoplasmosis: 0.5-1 mg/kg/d IV for 7 d; then, 0.8 mg/kg IV qod; total dose of 10-15 mg/kg in patients with HIV Paracoccidioidomycosis: 0.4-0.5 mg/kg/d IV; total dose of 1.5-2.5 g Cryptococcosis: 0.3-1 mg/kg/d IV (with or without flucytosine) until response, usually 2-4 wk to several mo; then, change to fluconazole 400 mg PO/IV for 8-10 wk; in patients with HIV infection, follow with indefinite suppressive treatment with fluconazole at 200 mg/d Amphotericin B cholesteryl sulfate complex: 3-4 mg/kg/d IV for invasive aspergillosis; 3-6 mg/kg/d IV for invasive Candida species or cryptococcal infections in patients unresponsive to or intolerant of conventional IV amphotericin B; dosages of as high as 7.5 mg/kg are used in BMT patients Amphotericin B lipid complex: 5 mg/kg/d for aspergillosis at median duration of 25 d; as long as 6 wk for cryptococcosis in patients with HIV infection; then, 12 wk of fluconazole PO Liposomal amphotericin B: 3-5 mg/kg/d IV for systemic fungal infections (eg, Aspergillus, Candida, and Cryptococcus species)
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; renal toxicity risk increases with cyclosporine
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Monitor renal function, serum electrolyte values (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients who are neutropenic and receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion)

Drug Name	Amphotericin B, liposomal (AmBisome)
Description	Novel lipid formulations of amphotericin B that deliver higher concentrations of the drug, with a theoretical increase in therapeutic potential and decreased nephrotoxicity. Produced from a strain of S nodosus. Antifungal activity of amphotericin B results from its ability to insert itself into fungal cytoplasmic membrane at sites containing ergosterol or other sterols. Aggregates of amphotericin B accumulate at sterol sites, resulting in an increase in cytoplasmic membrane permeability to monovalent ions (eg, potassium, sodium). At low concentrations, main effect is increased intracellular loss of potassium, resulting in reversible fungistatic activity; however, at higher concentrations, pores of 40-105 nm in cytoplasmic membrane are produced, leading to large losses of ions and other molecules. A second effect of amphotericin B is its ability to cause auto-oxidation of the cytoplasmic membrane and release of lethal free radicals. Main fungicidal activity of amphotericin B may reside in ability to cause auto-oxidation of cell membranes.
Adult Dose	3-5 mg/kg/d IV for systemic fungal infections (eg, Aspergillus, Candida, and Cryptococcus species)
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity increased with cyclosporine
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Monitor renal function, serum electrolyte levels (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in neutropenic patients receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations of drug; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock

Drug Name	Amphotericin B lipid complex (Abelcet)
Description	Amphotericin B in phospholipid complexed form. Produced from a strain of S nodosus; can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death. Has a broad spectrum of activity against pathogenic fungi, including yeasts, except Fusarium species. Exerts antifungal activity, principally by binding to sterols in fungal cell membrane. Drug of third choice when conventional amphotericin B therapy is failing and renal function is not impaired.
Adult Dose	5 mg/kg/d IV for aspergillosis at median duration of 25 d; as long as 6 wk for cryptococcosis in patients with HIV infection; then, 12 wk of fluconazole PO
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity increased with cyclosporine
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Infusion-related adverse effects are common and may require pretreatment with acetaminophen, diphenhydramine, and hydrocortisone; dose-limiting renal toxicity limits use; monitor renal function, serum electrolyte levels (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients who are neutropenic and receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion)

Drug Name	Caspofungin (Cancidas)
Description	Used to treat refractory invasive aspergillosis. First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall.
Adult Dose	70 mg IV over 1 h on day 1; 50 mg IV qd thereafter
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Coadministration with cyclosporine may increase risk of hepatotoxicity; carbamazepine, nelfinavir, efavirenz, or dexamethasone may decrease levels; may decrease levels of tacrolimus; rifampin decreases levels by 30% (ie, adjust dose to 70 mg/d)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in moderate hepatic dysfunction (ie, decrease dose to 35 mg/d); may exacerbate preexisting renal dysfunction or myelosuppression

Drug Name	Anidulafungin (Eraxis)
Description	Antifungal agent of the echinocandin class. Inhibits synthesis of 1,3-beta-D-glucan, an essential component of fungal cell walls. Indicated to treat esophageal candidiasis, candidemia, and other forms of candidal infections (eg, intraabdominal abscesses, peritonitis).
Adult Dose	Candidemia or other candidal infections: 200 mg IV on day 1; decrease dose on day 2 and thereafter to 100 mg/d IV; do not exceed infusion rate of 1.1 mg/min
Pediatric Dose	Not established for <2 y For >2 y, similar drug levels as in adults can be achieved using the following: 0.75 mg/kg/d = 50 mg/d in adults for esophageal candidiasis 1.5 mg/kg/d = 100 mg/d in adults for invasive candidiasis or aspergillosis
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Common adverse effects include hypokalemia, diarrhea, elevated hepatic enzyme levels, and headache; rare reports of serious hepatotoxicity; infusion-related reactions (eg, rash, urticaria, flushing, pruritus, dyspnea, hypotension) may occur, particularly with rapid infusion; following reconstitution, dilute further with D5W or NS before administration

Drug Name	Micafungin (Mycamine)
Description	Member of new class of antifungal agents, echinocandins, that inhibit cell wall synthesis. Inhibits synthesis of 1,3-beta-D-glucan, an essential fungal cell wall component not present in mammalian cells. Indications include (1) prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation and (2) treatment of esophageal candidiasis.
Adult Dose	Candidiasis prophylaxis: 50 mg IV qd infused over 1 h Esophageal candidiasis: 150 mg IV qd infused over 1 h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Increases sirolimus and nifedipine AUC approximately 20%
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Common adverse effects may include headache, nausea, vomiting, and abdominal pain; other adverse effects include rash, delirium, phlebitis, shock, leukopenia, and hyperbilirubinemia; rare cases of elevated hepatic enzyme, BUN, and creatine levels have been reported; transient acute intravascular hemolysis and hemoglobinuria may occur; do not mix or infuse in same IV line with other medications because precipitate forms with other commonly used medications (flush existing IV line with 0.9% NaCl before and after infusion); protect from light following dilution

Drug Name	Posaconazole (Noxafil)
Description	Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus infections in patients at high risk because of severe immunosuppression.
Adult Dose	200 mg (5 mL) PO tid with food or liquid nutritional supplement to enhance absorption
Pediatric Dose	<13 years: Not established >13 years: Administer as in adults
Contraindications	Documented hypersensitivity; coadministration with ergot alkaloids; coadministration with CYP3A4 substrates likely to result in serious toxicities (eg, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine)
Interactions	Metabolized via UDP glucuronidation; P-gp efflux substrate; CYP3A4 inhibitor; UDP-G inducers (eg, rifabutin, phenytoin) and drugs that increase gastric pH (eg, cimetidine) decrease serum levels (avoid concomitant use unless benefit outweighs risk); inhibits CYP3A4 and may elevate serum levels of cyclosporine, tacrolimus, sirolimus, rifabutin, midazolam, phenytoin, calcium channel blockers (eg, nifedipine, bepridil), HMG-CoA reductase inhibitors (eg, lovastatin, pravastatin), ergot alkaloids, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, or vinca alkaloids (eg, vincristine, vinblastine)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Common adverse effects include nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and elevated liver enzyme levels; closely monitor patients with severe diarrhea or vomiting for breakthrough fungal infections; rare adverse events include arrhythmias caused by QTc prolongation, bilirubinemia, or liver function impairment; caution with preexisting cardiac risk factors (eg, history of arrhythmia, hypokalemia, hypomagnesemia); food improves absorption and provides optimal serum concentration; shake well before use; administer with measuring spoon provided in package; avoid if breastfeeding

Drug Name	Fluconazole (Diflucan)
Description	First of a new subclass of synthetic triazole antifungal agents is available as tab for oral administration, as a powder for oral susp, and as a sterile solution for IV use. Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha demethylation. In general, a loading dose of twice the daily dose is recommended on first day of therapy to result in plasma concentrations close to steady state by second day of therapy. Base daily dose for treatment of infections other than vaginal candidiasis on infecting organism and patient response to therapy. Continue treatment until clinical parameters or laboratory test results indicate active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse.
Adult Dose	Systemic candidiasis: 400 mg PO/IV qd; continue for a minimum of 4 wk and for at least 2 wk after symptoms resolve Cryptococcal meningitis: 400 mg PO/IV for 1 d; then 200-400 mg PO/IV qd; continue for 10-12 wk after cerebrospinal fluid becomes culture negative; 200 mg PO/IV qd for relapse in patients with AIDS Coccidioidomycosis: 400 mg PO/IV for 1 d; then 200-400 mg PO/IV mg qd; 400-800 mg PO/IV qd for patients infected with AIDS Blastomycosis/histoplasmosis: 400-800 mg PO/IV qd Prophylaxis against candidiasis in patients undergoing bone marrow transplantation: 400 mg PO/IV qd; if patient is anticipated to have severe granulocytopenia (<500 neutrophils/mL), start fluconazole prophylaxis several days before anticipated onset of neutropenia; continue for 7 d after neutrophil count is >1000 cells/mL
Pediatric Dose	Usual range: 3-12 mg/kg PO/IV qd; not to exceed 600 mg qd; dose of 3, 6, or 12 mg/kg qd in pediatric patients is equivalent to a dosage of 100, 200, or 400 mg qd, respectively, in adults; for neonates <2 wk, administer same daily dose as older children, but administer q72h Systemic candidiasis: 6-12 mg/kg/d PO/IV Cryptococcal meningitis: 12 mg/kg PO/IV for 1 d; then, 6-12 mg/kg PO/IV qd; for initial therapy, continue for 10-12 wk after cerebrospinal fluid becomes culture negative; give 6 mg/kg PO/IV qd for relapse in children with AIDS Long-term suppressive therapy: 3-6 mg/kg PO/IV qd for cryptococcosis/histoplasmosis in children with HIV Coccidioidomycosis: 6 mg/kg PO/IV qd Long-term suppressive therapy for cryptococcosis or histoplasmosis in children with HIV: 3-6 mg/kg/d PO/IV
Contraindications	Documented hypersensitivity
Interactions	Levels may increase with hydrochlorothiazides; fluconazole levels may decrease with long-term coadministration of rifampin; may increase concentrations of theophylline, phenytoin, tolbutamide, cyclosporine, glyburide, and glipizide; effects of anticoagulants may increase with fluconazole coadministration
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Monitor closely if rashes develop, and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) with underlying medical conditions (eg, AIDS, malignancy) and while taking multiple concomitant medications; not recommended during breastfeeding; weigh convenience and efficacy of single-dose regimen for treatment of vaginal yeast infections against difficulties resulting from a higher incidence of adverse reactions reported with oral fluconazole vs intravaginal agents

Drug Name	Itraconazole (Sporanox)
Description	Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes. Fungistatic activity demonstrated against disseminated fungal infections caused by B dermatitidis, H duboisii, A fumigatus, C immitis, C neoformans, P brasiliensis, Sporothrix schenckii, Trichophyton rubrum, and Trichophyton mentagrophytes. New IV formulation indicated for treatment of patients with pulmonary and extrapulmonary aspergillosis who are intolerant of or are refractory to amphotericin B therapy.
Adult Dose	Aspergillosis 200-400 mg PO qd for 1 y Blastomycosis 200-400 mg PO qd for 6 mo Coccidioidomycosis 200 mg PO bid for 12-18 mo Histoplasmosis Moderate: 200 mg PO qd for 9 mo Life-threatening: 200 mg PO tid for 3 d; then, 200 mg PO bid until response Patients with HIV: 400 mg PO qd for 12 wk (85-90% response); then, 200 mg PO qd Paracoccidioidomycosis 200 mg PO qd for 6 mo Recommended IV dose: 200 mg IV bid for 4 doses; then, 200 mg IV qd for maximum of 14 d; each dose infused over 1 h
Pediatric Dose	Not established; suggested dose of 100 mg/d for systemic fungal infections
Contraindications	Documented hypersensitivity; coadministration with cisapride may cause adverse cardiovascular effects (possibly death)
Interactions	Antacids may reduce absorption; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce levels (phenytoin metabolism may be altered)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in hepatic insufficiencies; do not use injection in patients with severe renal dysfunction (CrCl <30 mL/min)

Drug Name	Flucytosine (Ancobon)
Description	Although exact mode of action is unknown, it is proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against Candida and Cryptococcus species and generally used in combination with amphotericin B.
Adult Dose	50-150 mg/kg/d PO divided q6h Pulmonary candidiasis or cryptococcosis: May be added to amphotericin B; 37.5 mg/kg PO qid for 6 wk; measure levels to get peaks of 70-80 mg/L and troughs of 30-40 mg/L
Pediatric Dose	Not established; administration as in adults suggested
Contraindications	Documented hypersensitivity
Interactions	Amphotericin B may increase toxicity; cytosine may inactivate flucytosine
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in bone marrow suppression; adjust dose in renal impairment

Drug Name	Ketoconazole (Nizoral)
Description	Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death
Adult Dose	Histoplasmosis: 400 mg PO qd; less active and more poorly tolerated than itraconazole Coccidioidomycosis: 400 mg PO qd; response rate of 28-76%; more than 50% relapses Paracoccidioidomycosis: 400 mg PO qd for 6-18 mo Blastomycosis: 400-800 mg PO qd for 6-18 mo
Pediatric Dose	<2 years: Not established >2 years: 3.3-6.6 mg/kg/d PO qd
Contraindications	Documented hypersensitivity; immunosuppression; fungal meningitis; coadministration of cisapride and triazolam
Interactions	Isoniazid may decrease bioavailability; coadministration decreases effects of either rifampin or ketoconazole; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dosage can be adjusted); may decrease theophylline levels
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Hepatotoxicity may occur; may reversibly decrease corticosteroid serum levels (adverse effects avoided with dose of 200-400 mg/d); administer antacids, anticholinergics, or H2-blockers at least 2 h after taking ketoconazole

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Watch for rapidly progressive respiratory failure in patients who are neutropenic; patients may need ventilatory support.
• Consider rapidly reducing or withdrawing immunosuppressive therapy (eg, corticosteroids) if feasible.
• Correct hyperglycemia and acidosis.
• Consider correction of neutropenia by administration of growth factors (eg, filgrastim [Neupogen], pegfilgrastim [Neulasta], sargramostim [Leukine]) or leukocyte transfusions.

Further Outpatient Care

• Offer maintenance therapy to suppress reactivation or recurrent disease in patients infected with HIV or other individuals who are immunocompromised.
• Ensure appropriate follow-up care to monitor for possible recurrence.

Deterrence/Prevention

• Instruct patients to avoid travel to and exposure in endemic areas.
• For patients undergoing bone marrow transplantation, solid organ transplantation, or antileukemic chemotherapy, use air filtration systems in the treatment units to minimize patient risk of exposure to Aspergillus spores.
• Administer prophylactic antifungal (ie, intranasal or intravenous amphotericin B or its other formulations) therapy in patients at high risk for opportunistic fungal infection, including patients with a history of fungal infection.

Complications

• Disease dissemination to other sites (ie, brain, meninges, skin, liver, spleen, kidneys, adrenals, heart, eyes) and sepsis syndrome
• Blood vessel invasion: This can lead to pulmonary hemoptysis, infarction, myocardial infarction, cerebral emboli, cerebral infarction, or blindness.
• Other complications
• • Bronchopleural or tracheoesophageal fistulas
  • Chronic pulmonary symptoms
  • Mediastinal fibrosis (histoplasmosis)
  • Broncholithiasis (histoplasmosis)
  • Pericarditis and other rheumatologic symptoms

Prognosis

• The mortality rate for untreated disseminated histoplasmosis is 80%, and it is reduced to 25% with treatment.
• Coccidioidomycosis has a mortality rate of 70% in patients with AIDS.
• Aspergillosis and mucormycosis have mortality rates of 50-85% in transplant recipients, especially bone marrow transplants.
• The individual prognosis ultimately is linked to the severity and outcome of the underlying disease and to whether the reversal of factors affecting the patient's immune status is possible.

Patient Education

• Patients undergoing bone marrow transplantation or any period of prolonged neutropenia are advised to avoid activities (eg, gardening, cleaning, agitating debris) or objects (eg, potted plants, flowers, fresh fruits, vegetables) that may unduly cause exposure to spores of Aspergillus species or other ubiquitous fungi.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• In patients who are severely neutropenic, rapid progression of fungal pneumonia and dissemination of fungal infection (eg, aspergillosis) necessitate a high degree of suspicion, early empiric antifungal therapy, and corrective measures (if possible) to reverse neutropenia or other causes of immunosuppression.
• Patients with ongoing immune deficiencies may require prolonged or lifelong maintenance therapy with triazole agents to prevent recurrences.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Chest radiograph showing multiple pulmonary nodules. The patient was treated with corticosteroids for acute graft versus host disease following bone marrow transplantation for chronic myeloid leukemia. The patient smoked marijuana for 2 weeks prior to this chest radiograph being taken. Bronchoalveolar lavage revealed Aspergillus niger and other species on fungal cultures.
	View Full Size Image
Media type:  X-RAY

Media file 2:  CT scan of a patient with invasive aspergillosis showing multiple lung lesions, some with cavitation.
	View Full Size Image
Media type:  CT

Media file 3:  CT scan of aspergillosis of the lungs showing multiple pleural-based and lung parenchymal lesions. One of the parenchymal lesions on the right gives a suggestion of the halo sign.
	View Full Size Image
Media type:  CT

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Benjamin DK Jr, Driscoll T, Seibel NL, Gonzalez CE, Roden MM, Kilaru R, et al. Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infections. Antimicrob Agents Chemother. Feb 2006;50(2):632-8. [Medline].
• Buchheidt D, Hummel M, Schleiermacher D, Spiess B, Hehlmann R. Current molecular diagnostic approaches to systemic infections with aspergillus species in patients with hematological malignancies. Leuk Lymphoma. Mar 2004;45(3):463-8. [Medline].
• Catanzaro A. Fungal pneumonias. Curr Opin Pulm Med. Mar 1997;3(2):146-50. [Medline].
• Conces DJ Jr. Endemic fungal pneumonia in immunocompromised patients. J Thorac Imaging. Jan 1999;14(1):1-8. [Medline].
• Connolly JE Jr, McAdams HP, Erasmus JJ, Rosado-de-Christenson ML. Opportunistic fungal pneumonia. J Thorac Imaging. Jan 1999;14(1):51-62. [Medline].
• Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. Jan 25 2007;356(4):348-59. [Medline].
• Crawford SW. Respiratory Disease in Bone Marrow and Hematopoietic Stem Cell Transplantation. In: Fishman AP, ed. Fishman's Pulmonary Diseases and Disorders. Vol. 2. 3^rd ed. New York, NY: McGraw-Hill; 1998:2147-8.
• Denning DW, Ribaud P, Milpied N, Caillot D, Herbrecht R, Thiel E, et al. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis. Mar 1 2002;34(5):563-71. [Medline].
• Fishman JA. HIV Infection and Opportunistic Pulmonary Infections in AIDS. In: Fishman AP, ed. Fishman's Pulmonary Diseases and Disorders. Vol. 2. 3^rd ed. New York, NY: McGraw-Hill; 1998:2114-5.
• Fishman JA. Pulmonary infections in Neutropenia and Cancer. In: Fishman AP, ed. Fishman's Pulmonary Diseases and Disorders. Vol. 2. 3^rd ed. New York, NY: McGraw-Hill; 1998:2124-6.
• Goldman M, Wheat LJ. Cryptococcal Infections. In: Fishman AP, ed. Fishman's Pulmonary Diseases and Disorders. Vol 2. 3^rd ed. New York, NY: McGraw-Hill; 1998:2305-12.
• Hamza NS, Ghannoum MA, Lazarus HM. Choices aplenty: antifungal prophylaxis in hematopoietic stem cell transplant recipients. Bone Marrow Transplant. Sep 2004;34(5):377-89. [Medline].
• Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. Aug 8 2002;347(6):408-15. [Medline].
• Herbrecht R, Letscher-Bru V, Oprea C, Lioure B, Waller J, Campos F, et al. Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients. J Clin Oncol. Apr 1 2002;20(7):1898-906. [Medline].
• Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Dis. Mar 1 2003;36(5):630-7. [Medline].
• Larone DH, Mitchell TG, Walsh TJ. Histoplasma, Blastomyces, Coccidioided, and other Dimorphic Fungi causing systemic Mycoses. In: Murray PR, ed. Manual of Clinical Microbiology. 7^th ed. Washington DC: ASM Press; 1999:1259-74.
• Lass-Flörl C, Gunsilius E, Gastl G, Freund M, Dierich MP, Petzer A. Clinical evaluation of Aspergillus-PCR for detection of invasive aspergillosis in immunosuppressed patients. Mycoses. 2005;48 Suppl 1:12-7. [Medline].
• Maertens J, Raad I, Petrikkos G, Boogaerts M, Selleslag D, Petersen FB, et al. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis. Dec 1 2004;39(11):1563-71. [Medline].
• Mennink-Kersten MA, Donnelly JP, Verweij PE. Detection of circulating galactomannan for the diagnosis and management of invasive aspergillosis. Lancet Infect Dis. Jun 2004;4(6):349-57. [Medline].
• Musher B, Fredricks D, Leisenring W, Balajee SA, Smith C, Marr KA. Aspergillus galactomannan enzyme immunoassay and quantitative PCR for diagnosis of invasive aspergillosis with bronchoalveolar lavage fluid. J Clin Microbiol. Dec 2004;42(12):5517-22. [Medline].
• Pound MW, Drew RH, Perfect JR. Recent advances in the epidemiology, prevention, diagnosis, and treatment of fungal pneumonia. Curr Opin Infect Dis. Apr 2002;15(2):183-94. [Medline].
• Reboli AC, Rotstein C, Pappas PG, Chapman SW, Kett DH, Kumar D. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. Jun 14 2007;356(24):2472-82. [Medline].
• Rickerts V, Bialek R, Tintelnot K, Jacobi V, Just-Nübling G. Rapid PCR-based diagnosis of disseminated histoplasmosis in an AIDS patient. Eur J Clin Microbiol Infect Dis. Nov 2002;21(11):821-3. [Medline].
• Sarosi GA. Cryptococcal pneumonia. Semin Respir Infect. Mar 1997;12(1):50-3. [Medline].
• Segal BH, Walsh TJ. Current approaches to diagnosis and treatment of invasive aspergillosis. Am J Respir Crit Care Med. Apr 1 2006;173(7):707-17. [Medline].
• Sugar AM, Olek EA. Aspergillus syndromes, Mucormycosis, and Pulmonary Candidiasis. In: Fishman AP, ed. Fishman's Pulmonary Diseases and Disorders. Vol. 2. 3^rd ed. New York, NY: McGraw-Hill; 1998:2265-87.
• Turner MS, Drew RH, Perfect JR. Emerging echinocandins for treatment of invasive fungal infections. Expert Opin Emerg Drugs. May 2006;11(2):231-50. [Medline].
• Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. Jan 25 2007;356(4):335-47. [Medline].
• Viscoli C, Machetti M, Cappellano P, Bucci B, Bruzzi P, Van Lint MT, et al. False-positive galactomannan platelia Aspergillus test results for patients receiving piperacillin-tazobactam. Clin Infect Dis. Mar 15 2004;38(6):913-6. [Medline].
• Wheat LJ. Endemic Mycoses of North America: Histoplasmosis, Coccidioidomycosis, and Blastomycosis. In: Fishman AP, ed. Fishman's Pulmonary Diseases and Disorders. Vol. 2. 3^rd ed. New York, NY: McGraw-Hill; 1999:2289-2303.
• White PL, Archer AE, Barnes RA. Comparison of non-culture-based methods for detection of systemic fungal infections, with an emphasis on invasive Candida infections. J Clin Microbiol. May 2005;43(5):2181-7. [Medline].
• Won HJ, Lee KS, Cheon JE, Hwang JH, Kim TS, Lee HG, et al. Invasive pulmonary aspergillosis: prediction at thin-section CT in patients with neutropenia--a prospective study. Radiology. Sep 1998;208(3):777-82. [Medline].
• Worthy SA, Flint JD, Muller NL. Pulmonary complications after bone marrow transplantation: high-resolution CT and pathologic findings. Radiographics. Nov-Dec 1997;17(6):1359-71. [Medline].
• Yamada H, Kotaki H, Takahashi T. Recommendations for the treatment of fungal pneumonias. Expert Opin Pharmacother. Aug 2003;4(8):1241-58. [Medline].

Article Last Updated: Sep 24, 2007