eMedicine Specialties > Pulmonology > Infectious Lung Diseases
Aspergillosis: Treatment & Medication
Updated: Mar 7, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
The treatment of invasive aspergillosis and chronic necrotizing aspergillosis differs significantly from the treatment of ABPA and aspergilloma.
This is often rapidly progressive and has a high mortality rate; therefore, preventive therapy and rapid institution of therapy in patients in whom invasive aspergillosis is suggested may be lifesaving. Prophylactic antifungal therapy and the use of laminar airflow (LAF) or high-efficiency particulate air (HEPA) filtration of patient rooms in patients who receive bone marrow transplants and other high-risk patients may prevent invasive aspergillosis. In patients with solid organ transplants, especially lung, in whom Aspergillus is cultured from sputum without evidence of pneumonia (colonization), inhaled amphotericin B may be administered.
When high-risk patients develop a compatible clinical picture, empiric treatment for aspergillosis should be initiated as diagnostic testing is undertaken. Voriconazole is now considered the drug of choice for invasive aspergillosis because of better tolerance and improved survival with its use when compared with amphotericin.13 Posaconazole, amphotericin B, or amphotericin B lipid formulations may be considered as empiric therapy in critically ill patients if the clinical picture, particularly the presence of sinusitis, could be compatible with mucormycosis, because voriconazole is ineffective for Zygomycetes infection. Caspofungin has also been approved for treatment of invasive aspergillosis in patients who are unable to tolerate or are resistant to other therapies.14 Initial combination therapy is usually not indicated and should generally be reserved for treatment failures.15
If possible, the level of immunosuppression should be decreased. For example, patients who are neutropenic may receive growth factors (ie, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor), and patients with certain types of transplants, in which transplanted organ dysfunction will not be life threatening (eg, renal transplant), may have immunosuppressive medications, including corticosteroids, reduced or discontinued.
Combination antifungal therapy is sometimes used for patients whose disease progresses while on single-drug therapy. Concomitant therapy with azole antifungals and amphotericin is controversial because the azole antifungals decrease amphotericin-binding sites and may therefore diminish its effectiveness. Be alert to the possibility of diminished effectiveness of amphotericin in any patient who has received prior treatment with an azole antifungal, including voriconazole, itraconazole, fluconazole, or ketoconazole. Newer antifungal azoles are under study (eg, ravuconazole) and may be available for compassionate use in patients in whom other therapies have failed. Posaconazole, a new triazole, was recently approved by the US Food and Drug Administration.16
Aspergilloma
Treatment is considered when patients become symptomatic, usually with hemoptysis. Surgical resection is curative but may not be possible in patients with limited pulmonary function. Oral itraconazole may provide partial or complete resolution of aspergillomas in 60% of patients. Successful intracavitary treatment, using CT-guided, percutaneously placed catheters to instill amphotericin alone or in combination with other drugs, including acetylcysteine and aminocaproic acid, has been reported in small numbers of patients.17
Bronchial artery embolization may be used for life-threatening hemoptysis in patients thought to have insufficient pulmonary reserve to tolerate surgery or in patients with recurrent hemoptysis (eg, patients with CF in whom hemoptysis may be related to underlying bronchiectasis with or without aspergilloma).18 Bronchial artery embolization requires a skilled and experienced radiologist because localizing the abnormal vessel(s) may be challenging. Because the anterior spinal arteries may originate from the bronchial vessels, serious neurologic complications, although rare, may occur.
Allergic bronchopulmonary aspergillosis
This is a hypersensitivity reaction that requires treatment with oral corticosteroids. Inhaled steroids are not effective.
Adding oral itraconazole to steroids in patients with recurrent or chronic ABPA may be helpful.19,20,21,22 This may allow more rapid resolution of infiltrates and symptoms, facilitating steroid tapering or lowering the needed maintenance corticosteroid dosage. In CF patients with ABPA, the concomitant use of itraconazole and inhaled corticosteroids may increase the risk of adrenal insufficiency.
Patients who have associated allergic fungal sinusitis benefit from surgical resection of obstructing nasal polyps and inspissated mucus in addition to corticosteroid therapy. Nasal washes with amphotericin or itraconazole have also been used.
Case reports have described the beneficial use of the anti-IgE monoclonal antibody omalizumab (Xolair) in patients with ABPA.23
Chronic necrotizing pulmonary aspergillosis
Treatment consists of therapy with voriconazole, or, in some cases, itraconazole (if expense is an issue), caspofungin, or amphotericin B or amphotericin lipid formulation. A prolonged course of therapy with the goal of radiographic resolution is needed. In addition, reduction or elimination of immunosuppression should be attempted, if possible.
Surgical resection may be considered when localized disease fails to respond to antifungal therapy.
Surgical Care
Invasive aspergillosis and CNPA
Surgical resection is a consideration for localized disease that has failed to respond to prolonged antifungal therapy.24 Aspergillomas may occasionally form in areas of necrotizing pneumonia. These necrotic areas may bleed, sometimes massively, necessitating consideration of surgical resection. Patients may be high-risk surgical candidates because of underlying disease, coagulopathy, or thrombocytopenia and limited pulmonary reserve.
Aspergilloma
Surgical resection may be considered for massive hemoptysis if pulmonary function is sufficient enough for this sort of intervention. Assessment of operative risk necessitates obtaining pulmonary function studies, arterial blood gas determinations, and, possibly, split lung function studies (eg, quantitative perfusion lung scanning). Because aspergilloma occurs in cavitary areas, the affected lung may not be functional. Surgical resection may be difficult because of scarring, pleural adhesion, and the presence of abnormal vasculature.
Allergic bronchopulmonary aspergillosis
Areas of mucoid impaction may have a masslike appearance and are sometimes resected as an undiagnosed lung mass; however, steroid therapy and oral itraconazole therapy are preferred. Allergic fungal sinusitis usually requires endoscopic sinus surgery to improve drainage.
Consultations
Consultation with a pulmonologist may be helpful for patients suggested to have invasive aspergillosis or chronic necrotizing Aspergillus pneumonia in order to establish a definitive diagnosis. Once the diagnosis is established, consultation with an infectious diseases specialist is usually helpful in management, especially if patients do not respond to initial fungal therapy.
Patients with ABPA or allergic fungal sinusitis should be treated by a pulmonologist or allergist familiar with the management of these conditions. Consultation with a pulmonologist is also indicated in patients with aspergilloma. Input from a thoracic surgeon may also be needed if surgical resection is feasible. In selected patients, consultation with an invasive radiologist may be indicated for CT-directed catheter placement to allow intracavitary therapy or bronchial artery embolization.
Medication
The treatment of invasive aspergillosis and chronic necrotizing aspergillosis requires intravenous antifungal therapy. Voriconazole is usually first-line therapy, sometimes in combination with other agents such as caspofungin. Amphotericin may sometimes be used in treatment failures. ABPA is a hypersensitivity reaction treated with corticosteroids. The addition of oral antifungal therapy with itraconazole is beneficial in the management of ABPA. Aspergillomas may respond to prolonged oral itraconazole therapy. Intracavitary therapy with amphotericin has also been used in small numbers of patients.
Antifungal agents
Mechanism of action may involve increasing the permeability of the cell membrane, which, in turn, causes intracellular components to leak.
Amphotericin B (Abelcet, AmBisome, Amphotec)
Polyene antibiotic produced by a strain of Streptomyces nodosus. Can be fungistatic or fungicidal. Binds to sterols (eg, ergosterol) in the fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death. Newer lipid formulations are as effective as original formulation and have less nephrotoxicity. May be associated with fever, rigors, and nausea (premedication with hydrocortisone and meperidine may be beneficial). Adequate hydration may decrease nephrotoxicity, and patients who can tolerate fluid should be administered pre- and post-hydration.
Adult
Amphotericin: 0.5-1.5 mg/kg/d IV
Abelcet: 5 mg/kg/d IV
Amphotec: 3-4 mg/kg/d IV; as much as 7.5 mg/kg/d IV may be required in severe illness
AmBisome: 3-5 mg/kg/d IV
Inhaled amphotericin for Aspergillus prophylaxis or colonization: 50 mg/d preceded by albuterol
Pediatric
Administer as in adults
Antineoplastic agents may enhance potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine, aminoglycosides, cidofovir, cyclosporine, pentamidine, tacrolimus, and vancomycin; previous treatment with azole antifungals may diminish efficacy of amphotericin; may have added nephrotoxicity and myelotoxicity when coadministered with zidovudine; may increase toxicity of flucytosine and enhance activity of daunorubicin and doxorubicin
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Severe reactions during infusion not blocked by premedication may preclude use; potential adverse effects include electrolyte abnormalities and anemia; monitor renal function, serum electrolytes (eg, magnesium and potassium), liver function, CBC count, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when interrupted for >7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients who are neutropenic and are receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock
Itraconazole (Sporanox)
Synthetic triazole antifungal agent with greater activity against Aspergillus than fluconazole or ketoconazole. Fungistatic activity. Slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.
Available in PO formulations (eg, cap, susp) and is useful for prolonged antifungal therapy. IV formulation has recently become available. Because it is insoluble in water, the PO and IV susp are solubilized with hydroxypropyl-beta-cyclodextrin.
Adult
Cap: 200-400 mg/d PO with food or cola
Life-threatening infections: 200 mg PO tid for 3 d initially, followed by 200 mg PO bid
PO susp: 200-400 mg/d on empty stomach
IV: 200 mg bid for 2 d, followed by 200 mg/d
Pediatric
Not established
Suggested dose 3-16 years: 5-10 mg/kg/d PO for Aspergillus prophylaxis in children with chronic granulomatous disease (use PO susp)
Inhibits hepatic cytochrome P-450, increasing levels of many drugs; serious cardiac toxicity may occur when coadministered with cisapride, dofetilide, pimozide, or quinidine; may interfere with metabolism of some benzodiazepines, resulting in prolonged sedation; coadministration with lovastatin or simvastatin increases risk of rhabdomyolysis; monitor levels of cyclosporine, tacrolimus, and digoxin (itraconazole raises levels and dose adjustment needed); absorption of PO itraconazole requires acidic environment in stomach (H2 blockers and proton pump inhibitors should not be administered concurrently)
Documented hypersensitivity; breastfeeding; renal failure; left ventricular failure
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; caution in patients with cardiac risk factors (left ventricular dysfunction has been noted)
Caspofungin (Cancidas)
Antifungal with efficacy against A fumigatus, A flavus, and Aspergillus terreus. First of a new class of antifungals called echinocandins. Works on a component of fungal cell walls that is not present in mammalian cells. Indicated for Aspergillus infection in patients who are refractory to or cannot tolerate other therapies. Has not been studied for primary therapy.
Adult
70 mg IV loading dose on day 1, followed by 50 mg/d IV; duration depends on response to therapy (averages 1 mo)
Pediatric
Not established
Coadministration with cyclosporine may cause transient increases in liver enzyme levels
Documented hypersensitivity
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; adverse effects include fever, complications in infusion vein, headache, nausea, vomiting, rash, and skin flushing
Voriconazole (VFEND)
Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal cytochrome P-450–mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.
Adult
Loading dose: 6 mg/kg IV q12h infused over 2 h for 2 doses
Maintenance: 4 mg/kg IV q12h infused over 2 h; when able to tolerate PO, may switch to 200 mg PO q12h
Note: For inadequate response, may increase to 300 mg PO q12h; <40 kg, administer PO maintenance dose of 100 mg PO q12h (may increase to 150 mg PO q12h)
Pediatric
<12 years: Not established
>12 years: Data limited; administer as in adults
CYP-450 2C19 (highest affinity), 2C9, and 3A4 (minor) substrate and inhibitor; CYP-450 inducers (eg, rifampin) have been shown to decrease steady-state peak plasma levels by up to 93%; may increase serum levels of drugs metabolized by CYP-450 2C19 or 2C9, of which some are contraindicated (eg, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids); others may require more frequent monitoring (eg, cyclosporine, tacrolimus, warfarin, HMG CoA inhibitors, benzodiazepines, calcium channel blockers)
Documented hypersensitivity; do not administer IV form with CrCl <50 mL/min (decreased excretion of IV vehicle); coadministration with rifampin, rifabutin, carbamazepine, barbiturates, sirolimus, pimozide, quinidine, cisapride, or ergot alkaloids
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Decrease maintenance dose with hepatic dysfunction; common adverse effects include visual disturbances, fever, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, rash (including Stevens-Johnson syndrome and phototoxicity), and respiratory disorder; rare cases of severe hepatotoxicity have been reported; administer PO 1 h ac or pc
Posaconazole (Noxafil)
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 and Candida infections in patients at high risk because of severe immunosuppression.
Adult
200 mg (5 mL) PO tid with food or liquid nutritional supplement to enhance absorption
Pediatric
<13 years: Not established
>13 years: Administer as in adults
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)
Documented hypersensitivity; coadministration with ergot alkaloids; coadministration with CYP3A4 substrates likely to result in serious toxicities (eg, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine)
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
Corticosteroids
Useful in the management of allergic reactions. These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.
Prednisone (Deltasone, Meticorten, Orasone)
May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Adult
0.5-1 mg/kg/d PO for 2 wk; taper over 3-6 mo for management of ABPA or allergic fungal sinusitis
Pediatric
Administer as in adults
Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective-tissue infections; fungal or tubercular skin infections; GI bleeding or ulceration
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur
More on Aspergillosis |
| Overview: Aspergillosis |
| Differential Diagnoses & Workup: Aspergillosis |
 Treatment & Medication: Aspergillosis |
| Follow-up: Aspergillosis |
| References |
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Further Reading
Keywords
aspergillosis, fungus, fungal infection, inhalational fungal disease, mold infection, invasive pulmonary aspergillosis, allergic bronchopulmonary aspergillosis, ABPA, chronic necrotizing pulmonary aspergillosis, CNPA, chronic necrotizing Aspergillus pneumonia, aspergilloma, mycetoma, fungus ball, disseminated aspergillosis, fungal endocarditis, Aspergillus fumigatus, A fumigatus, Aspergillus niger, A niger, Aspergillus flavus, A flavus, Aspergillus clavatus, A clavatus, bronchocentric granulomatosis, malt worker's lung
