Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

suspected invasive aspergillosis

1st line – empirical antifungal therapy

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INITIAL
|
suspected invasive aspergillosis
1st line – 

empirical antifungal therapy

In high-risk patients, empirical therapy may be used when the diagnosis of invasive aspergillosis is suspected: for example, neutropenic patients with fever unresponsive to broad-spectrum antibacterial agents without an obvious focus of infection. Fever may be due to non-fungal aetiology. However, since the diagnosis is difficult to confirm, antifungal drugs are frequently employed. Lipid formulations of amphotericin B or an echinocandin are used in these cases.[96]

The Infectious Diseases Society of America (IDSA) guidelines also recommend voriconazole.[2]

Primary options

amphotericin B liposomal: 3-5 mg/kg intravenously once daily

OR

amphotericin B lipid complex: 5 mg/kg intravenously once daily

OR

caspofungin: 70 mg intravenously on day 1, followed by 50 mg once daily

OR

voriconazole: 6 mg/kg intravenously every 12 hours on day 1, followed by 4 mg/kg intravenously every 12 hours

ACUTE

confirmed invasive aspergillosis

1st line – antifungal therapy

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ACUTE
|
confirmed invasive aspergillosis
1st line – 

antifungal therapy

Voriconazole or isavuconazole are the drugs of choice in the treatment of confirmed/probable invasive aspergillosis (IA). Although efficacies of isavuconazole and voriconazole are similar, the former appears to have a better safety profile.[16]

Isavuconazole, a broad-spectrum antifungal agent with activity against both Aspergillus and Mucor, is indicated for the treatment of adults with IA.[119]

High-risk patients with a suggestive computed tomography (CT) scan and/or positive biomarkers (e.g., serum galactomannan) are also candidates for pre-emptive therapy. Invasive procedures may not yield positive results or may be difficult to perform, so these treatments may be employed on the basis of a presumptive diagnosis.[113]

Within a few days, administration may be changed from the intravenous to the oral route.

Clinical improvement may be noted within 5 to 7 days of therapy; radiologically the condition may worsen before improvement.

The alternatives to these agents are posaconazole or a lipid formulation of amphotericin B, either amphotericin B lipid complex or liposomal amphotericin B.[104][105][106] Posaconazole demonstrated non-inferiority to voriconazole in the treatment of invasive aspergillosis in one randomised controlled trial; posaconazole was also associated with fewer treatment-related adverse events.[107] In areas of known and increasing azole-resistance, a lipid formulation of amphotericin B should be considered a first-line agent until the results of resistance testing are available.[16]

Treatment with echinocandins (e.g., caspofungin and micafungin) may be used as monotherapy or in combination with a lipid formulation of amphotericin B or voriconazole.[120] In critically ill patients, combination therapy may be attempted.

Duration of therapy is decided in the light of clinical/radiological improvement and restoration of immune status. Optimal duration is unclear; in general, therapy may be given for 6 to 12 weeks.[2]

Primary options

voriconazole: 6 mg/kg intravenously every 12 hours on day 1, followed by 4 mg/kg intravenously every 12 hours, can switch to oral therapy when clinical improvement; 200 mg orally twice daily

OR

isavuconazole: 200 mg intravenously/orally every 8 hours for 6 doses as a loading dose, followed by 200 mg intravenously/orally once daily (starting 12-24 hours after the last loading dose)

OR

posaconazole: 300 mg intravenously every 12 hours on day 1, followed by 300 mg every 24 hours, can switch to oral therapy when clinical improvement; 300 mg orally (delayed-release) twice daily on day 1, followed by 300 mg once daily

OR

amphotericin B liposomal: 3-5 mg/kg intravenously once daily

Secondary options

caspofungin: 70 mg intravenously on day 1, followed by 50 mg once daily

OR

micafungin: 100-150 mg intravenously once daily

Tertiary options

caspofungin: 70 mg intravenously on day 1, followed by 50 mg once daily

or

micafungin: 100-150 mg intravenously once daily

-- AND --

voriconazole: 6 mg/kg intravenously every 12 hours on day 1, followed by 4 mg/kg intravenously every 12 hours, can switch to oral therapy when clinical improvement; 200 mg orally twice daily

or

amphotericin B liposomal: 3-5 mg/kg intravenously once daily

or

amphotericin B lipid complex: 5 mg/kg intravenously once daily

Plus – reversal of the underlying immune deficiency

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ACUTE
|
confirmed invasive aspergillosis
Plus – 

reversal of the underlying immune deficiency

Treatment recommended for ALL patients in selected patient group

The use of colony-stimulating factors may reduce the duration of neutropenia. Discontinuing or reducing the dose of corticosteroids may help to restore immune function. However, in many situations the underlying immunological deficiency may not be correctable (e.g., in severe graft-versus-host disease). In such cases, the prognosis is generally poor. Early diagnosis followed by early initiation of therapy with antifungal agents improves outcome.[98]

Consider – surgical resection of the infected focus

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ACUTE
|
confirmed invasive aspergillosis
Consider – 

surgical resection of the infected focus

Additional treatment recommended for SOME patients in selected patient group

Surgical intervention may be indicated in cases of invasive aspergillosis lesions that are contiguous with the great vessels or the pericardium, severe haemoptysis from a single cavity, or invasion of the chest wall. A single pulmonary lesion prior to intensive chemotherapy or stem cell transplantation is another relative indication for surgical resection.[2][114]

aspergilloma with life-threatening haemoptysis

1st line – stabilisation with intravenous fluids and blood transfusion + surgical resection

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ACUTE
|
aspergilloma with life-threatening haemoptysis
1st line – 

stabilisation with intravenous fluids and blood transfusion + surgical resection

Patients with severe haemoptysis need to be stabilised with intravenous fluids and blood.

There is insufficient evidence that aspergilloma responds to antifungal agents.

In symptomatic patients with severe haemoptysis, bronchial artery embolisation may be helpful as a temporising measure. However, the presence of massive collateral blood vessels makes the procedure suboptimal.[116]

Surgical resection may be necessary in life-threatening haemoptysis, although the postoperative morbidity/mortality remains a major concern. Major complications include bleeding, bronchopulmonary fistula, empyema, and respiratory failure.[117][118]

Peri- and post-operative antifungal therapy is not routinely required, but guidelines suggest that if there is a moderate risk of surgical spillage of the aspergilloma, antifungal therapy with an azole or an echinocandin may be used to prevent Aspergillus empyema.[2]

ONGOING

chronic pulmonary aspergillosis

1st line – monitoring

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ONGOING
|
chronic pulmonary aspergillosis
|
aspergilloma without life-threatening haemoptysis
1st line – 

monitoring

Patients with stable, simple aspergilloma who have minimal or no symptoms require no treatment.[2][115] Periodic monitoring with chest x-ray is appropriate.

1st line – antifungal therapy and monitoring

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ONGOING
|
chronic pulmonary aspergillosis
|
chronic cavitary pulmonary aspergillosis or chronic fibrosing pulmonary aspergillosis
1st line – 

antifungal therapy and monitoring

Patients with chronic cavitary pulmonary aspergillosis (CCPA) are treated with antifungal therapy to halt progression, improve symptoms, and minimise haemoptysis.[115]

Oral itraconazole and oral voriconazole are the preferred options.[2][115] Oral posaconazole may also be considered as an alternative option if the preferred options cannot be used.

Treatment is for a minimum of 6 months and may be extended in some patients. Treatment requires therapeutic drug monitoring and monitoring for drug-related side effects or toxicity.[2][3] Patients should be managed by physicians with experience of antifungal therapy.

Intravenous antifungal therapy may be considered in patients with progressive disease, or who are intolerant to azoles or develop resistance. An initial course of intravenous antifungal therapy may also be considered for some acutely ill patients.[2][3] Options include amphotericin B deoxycholate, liposomal amphotericin B, or an echinocandin (e.g., micafungin, caspofungin).

Chronic fibrosing pulmonary aspergillosis (CFPA) generally results from untreated CCPA, though may represent treatment failure and disease progression. Antifungal treatment is the same as CCPA, and may be continued indefinitely.[3][4]

Primary options

voriconazole: 200-300 mg orally twice daily

OR

itraconazole: 200 mg orally twice daily

Secondary options

posaconazole: 300 mg orally (delayed-release) twice daily for 2 doses, followed by 300 mg once daily

Tertiary options

amphotericin B deoxycholate: 1 to 1.5 mg/kg intravenously once daily

OR

amphotericin B liposomal: 3-5 mg/kg intravenously once daily

OR

caspofungin: 70 mg intravenously on day 1, followed by 50 mg once daily

OR

micafungin: 100-150 mg intravenously once daily

1st line – antifungal therapy

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ONGOING
|
chronic pulmonary aspergillosis
|
subacute invasive aspergillosis
1st line – 

antifungal therapy

Subacute invasive aspergillosis should be treated in the same way as acute invasive aspergillosis (see confirmed invasive aspergillosis).[3]

1st line – monitoring and consider antifungal therapy

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ONGOING
|
chronic pulmonary aspergillosis
|
aspergillus nodule
1st line – 

monitoring and consider antifungal therapy

Aspergillus nodules are diagnosed after excision biopsy, usually following suspicion for malignancy. Single nodules that are completely excised may not need antifungal therapy, unless the patient is immunocompromised.[3][4] Single nodules that are not completely resected should be closely monitored. Antifungal therapy may be considered in patients with multiple nodules.[3] Consult an infectious disease specialist for guidance on the choice of an appropriate antifungal regimen for these patients.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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