eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease
Aspergillosis: Treatment & Medication
Updated: Oct 17, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
Aspergillosis treatment is based on the disease manifestation, which includes invasive disease in an immunocompromised host or allergic disease that includes allergic bronchopulmonary aspergillosis (ABPA) and colonizing syndromes (eg, aspergilloma, otomycosis) in an immunocompetent host.
- When invasive aspergillosis (IA) is strongly suspected in an immunocompromised patient, empiric treatment with antifungal medications is the consensus therapy. Suspicion may be based on the clinical course of the illness, isolation of the fungus from the pulmonary and/or nasopharyngeal secretions, and failure to respond to initial antibacterial treatment. If a patient with profound neutropenia does not respond to broad spectrum antibiotics within 5-7 days, empiric treatment for invasive aspergillosis with antifungals is indicated.
- Voriconazole has now become the drug of choice for invasive aspergillosis. This is due to the increased efficacy and significantly less toxicity compared to amphotericin B.
- Caspofungin is a newer antifungal agent that is effective against invasive aspergillosis but more pediatric studies are needed prior to its widespread use. Currently caspofungin has been approved for use as salvage therapy for invasive aspergillosis that does not respond to existing antifungals.
- Treatment duration has not been well defined and is based on the clinical response and the tolerance to the drug. Continue therapy 4-12 weeks or longer.
- Itraconazole is used as prophylaxis in some cancer centers for immunocompromised patients.
- ABPA exacerbations are treated with corticosteroids.
- The desired goal is to reduce serum immunoglobulin E (IgE) levels to a range consistent with levels obtained from patients with asthma (without ABPA) living in the same geographic area. Reinstitution of corticosteroid therapy may be required if the serum IgE levels rise to twice this level or higher.
- Immediately obtain IgE levels after corticosteroid therapy.
- For asthma exacerbation, as indicated, administer other agents, such as beta-adrenergic agonists, high-dosage inhaled corticosteroids, and, possibly, nedocromil or theophylline.
- Administer prednisone as a single morning dose for 2 weeks and then convert to an alternate-day dosage for 3 months.
- Systemic antifungal therapy is not indicated for ABPA.
Surgical Care
- Invasive aspergillosis requires surgical care in the following situations:
- In invasive pulmonary aspergillosis, resection of the fungal lesion is indicated when the lesion in localized, and or if disease is likely to cause perforation of the pulmonary artery with consequent hemoptysis.
- In immunocompromised patients, resection and surgical reduction of the Aspergillus mass is indicated before myeloablative procedures.
- In patients with osteomyelitis, surgical intervention, including thorough debridement, may help chronic invasive sinusitis and cutaneous lesions.
- Surgical care is recommended in patients with aspergilloma only when severe hemoptysis occurs.
- Resection is the mainstay therapy for patients with adequately functioning lungs, although bronchial artery embolization may be considered for patients who are not candidates for resectional surgery.
- Systemic antifungal therapy is not indicated in patients with nonallergic colonization.
Medication
Voriconazole is now the drug of choice for the treatment of invasive aspergillosis (IA). Although disease outcomes substantially improve with antifungal treatment, patient survival and infection resolution depend on improved immunosuppression. Response rates are low if the patient remains neutropenic. Voriconazole has shown a good outcome in 34% of patients with cerebral aspergillosis, which was previously associated with a high mortality. Caspofungin is an echinocandin that is primarily used as a salvage drug either alone or in combination with amphotericin B lipid preparations.
Amphotericin B has a broad antifungal spectrum but has limited use in view of significant nephrotoxicity and dose-limiting side effects. Various amphotericin B lipid preparations are available to help reduce nephrotoxicity. Lipid preparations of amphotericin B (ABLC, Abelcet) are approved by the FDA to treat invasive fungal infections in patients who are intolerant or refractory to conventional amphotericin (ie, deoxycholate). Amphotericin B cholesteryl sulfate complex (Amphotec) and the liposomal formulation of amphotericin B (AmBisome) have received FDA approval for the treatment of invasive aspergillosis in patients who cannot tolerate or who fail to respond to conventional amphotericin B deoxycholate. These lipid formulations are picked up preferentially by the reticuloendothelial system and are broken down by lipases locally at the site of infection.
Caspofungin and voriconazole combinations have also shown to be successful as salvage drug therapy for invasive aspergillosis. Posaconazole is a new triazole that was recently approved by the FDA. Itraconazole has a status of a prophylaxis drug and is used in neutropenic patients in several centers. Steroid administration is the mainstay treatment for allergic bronchopulmonary aspergillosis (ABPA).
Antifungal agents
The mechanism of action in these agents may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.
The azole group of drugs, including voriconazole, inhibit the cytochrome P450 (CYP)-dependent enzyme, 14-a-demethylase, which leads to the accumulation of toxic sterol precursors. Echinocandins (eg, caspofungin) inhibit synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall.
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 CYP450-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 oral maintenance dose of 100 mg PO q12h (may increase to 150 mg PO q12h)
Administer PO dose on empty stomach (ie, 1 h ac or 1 h pc)
Pediatric
<12 years: Not established
>12 years: Administer as in adults
CYP450 2C19 (highest affinity), 2C9, and 3A4 (minor) substrate and inhibitor; CYP450 inducers (eg, rifampin) have shown to decrease steady state peak plasma levels by as much as 93%; may increase serum levels of drugs metabolized by CYP450 2C19 or 2C9, of which, some are contraindicated (eg, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids), others may need 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, ergot alkaloids
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Dilute parenteral solution before IV infusion; do not administer undiluted or by IV bolus; decrease maintenance dose with hepatic dysfunction; common adverse effects include visual disturbances, fever, rash, 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
Amphotericin B (Amphocin, Fungizone)
Polyene antibiotic produced by a strain of Streptomyces nodosus; can be fungistatic or fungicidal. Binds to sterols in the fungal cell membrane, such as ergosterol, causing intracellular components to leak and the subsequent death of fungal cell.
Adult
0.25-0.5 mg/kg IV initially; gradually increase as tolerated to 0.5-1.5 mg/kg; infuse as a single dose over 2-3 h
A test dose of 1 mg is often given before initiating the dosage regimen
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 increases with cyclosporine, aminoglycosides, tacrolimus, cisplatin, and acetazolamide; in vitro and animal studies suggest development of fungal resistance to amphotericin B when administered concurrently with imidazoles; concurrent administration of zidovudine leads to increased risk of nephrotoxicity and hematologic toxicity via an unknown mechanism
Documented hypersensitivity, unless physician believes patient's condition is life threatening and amenable only to this therapy
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Monitor closely; infusion-related reactions include fever, chills, and (sometimes) nausea, vomiting, headache, generalized malaise, hypotension, and arrhythmias
Premedication with acetaminophen alone or combined with diphenhydramine may alleviate febrile reactions; premedications may be repeated at appropriate dosing interval, if infusion is prolonged; pretreatment with hydrocortisone also has been used to reduce infusion-related symptoms; tolerance to febrile reactions develops with time, allowing tapering and eventual discontinuation of hydrocortisone and, often, antipyretics; meperidine and ibuprofen have been effective to prevent or treat fever and chills in patients refractory to conventional regimen
Monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; suspend infusion if serum potassium level is <3 mg/dL or serum creatinine level increases to >2-3 mg/dL
Administer 0.9% saline infusions before each dose to decrease dose-dependent renal
insufficiency; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for >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)
Amphotericin B lipid complex (Abelcet) - - Amphotericin B liposome (AmBisome)
FDA approved to treat invasive fungal infections in patients who are intolerant to or refractory to conventional amphotericin therapy.
Adult
5 mg/kg IV infused over 2 h at 2.5 mg/kg/h
Pediatric
Administer as in adults
Antineoplastic agents may enhance potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; renal toxicity risk is increased with cyclosporine, aminoglycosides, tacrolimus, cisplatin, and acetazolamide; in vitro and animal studies have suggested development of fungal resistance when administered concurrently with imidazoles; coadministration with zidovudine leads to increased risk of nephrotoxicity and hematologic toxicity via an unknown mechanism
Documented hypersensitivity, unless physician believes patient's condition is life threatening and amenable only to this therapy
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
Closely monitor initial dosing; frequently monitor serum creatinine levels during ABLC treatment (although ABLC causes less nephrotoxicity than amphotericin B); perform LFT and CBC count and monitor electrolyte, magnesium, and potassium levels
Itraconazole (Sporanox)
Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP450–dependent synthesis of ergosterol. Used alone as an alternative treatment for nonmeningeal cases and for patients who are intolerant of or whose infections are refractory to amphotericin B therapy.
Adult
200 mg PO qd; increase in 100-mg increments if no improvement; not to exceed 400 mg/d total dose; administer doses >200 mg/d in divided doses
Pediatric
5-10 mg/kg/d PO qd or divided bid
Antacids may reduce absorption of itraconazole; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; itraconazole inhibits CYP450 3A4; coadministration may increase tacrolimus and cyclosporine plasma concentrations; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (lovastatin or simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; CYP450 3A4 inducers (eg, phenytoin, rifampin) may reduce itraconazole levels; phenytoin metabolism may also be altered
Documented hypersensitivity; coadministration with cisapride may cause adverse cardiovascular effects and possibly death
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; may lead to GI symptoms, rash, edema, headache, hypokalemia, thrombocytopenia, and leukopenia
Caspofungin (Cancidas)
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
70 mg IV infused over 1 h on day 1; 50 mg IV qd thereafter
Pediatric
<3 months: Not established
3 months to 17 years: 70 mg/m2 IV infused over 1 h on day 1; 50 mg/m2/d IV thereafter; not to exceed 70 mg/d for either loading dose or maintenance dose
>18 years: Administer as in adults
Coadministration with cyclosporine may increase risk of hepatotoxicity; carbamazepine, nelfinavir, efavirenz, or dexamethasone may decrease levels of caspofungin; caspofungin may decrease levels of tacrolimus; rifampin decreases caspofungin levels by 30% (ie, adjust dose to 70 mg/d)
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 moderate hepatic dysfunction (ie, decrease dose to 35 mg/d); may exacerbate pre-existing renal dysfunction or myelosuppression
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 PO susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk due to 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
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. These agents also modify the body's immune response to diverse stimuli.
Prednisone (Deltasone, Orasone, Meticorten, Sterapred)
Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Adult
5-60 mg PO qd
Pediatric
0.5 mg/kg/d PO for 2 wk, followed by same dose qod for 3 mo
Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and 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 with use
More on Aspergillosis |
| Overview: Aspergillosis |
| Differential Diagnoses & Workup: Aspergillosis |
 Treatment & Medication: Aspergillosis |
| Follow-up: Aspergillosis |
| References |
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Further Reading
Keywords
aspergillosis, Aspergillus, Aspergillus fumigatus, Aspergillus flavus, allergic bronchopulmonary aspergillosis, ABPA, aspergilloma, invasive aspergillosis, IA, noninvasive aspergillosis, Aspergillus niger, Aspergillus terreus, Aspergillus amstelodami, Aspergillus avenaceus, Aspergillus caesiellus, Aspergillus carneus, Aspergillus clavatus, Aspergillus oryzae, Aspergillus versicolor, Aspergillus wentii, allergic sinusitis, asthma, alveolitis, cellulitis, pneumonia, esophagitis, cystic fibrosis, CF, tuberculosis, sarcoidosis, bone marrow transplantation, graft versus host disease, graft rejection, hematopoietic stem cell transplantation, HSCT, heart and lung transplantation, chronic granulomatous disease, leukemia, diabetes mellitus, respiratory failure
