Aspergillosis Treatment

• When invasive disease is suspected or confirmed, prompt, aggressive antifungal treatment is essential
  • Reversal of neutropenia, if possible, is necessary for recovery in almost all patients
  • Antifungal susceptibility testing should be considered when choosing the initial antifungal agent
• Reduction of immunosuppression as an adjunct to antifungal therapy may be considered to help improve treatment outcome
• Combination therapy may be considered in patients with invasive pulmonary disease, with suspected azole resistance or who are critically ill
  • Includes Voriconazole and an echinocandin, liposomal amphotericin B and an echinocandin, and Amphotericin B and triazoles
• Salvage therapy is given to patients with refractory or progressive aspergillosis
  • Involves switching to a different antifungal class, tapering or reversal of underlying immunosuppression if feasible and surgical resection of necrotic lesions when possible

Polyenes

• Prototype is deoxycholate Amphotericin B
  • Liposomal Amphotericin B and Amphotericin B lipid complex are other lipid-associated formulations that are less nephrotoxic than deoxycholate Amphotericin B
  • Lipid formulations of Amphotericin B are used as salvage therapy for invasive aspergillosis (IA)
  • Local instillation of deoxycholate Amphotericin B may be used for renal aspergillosis with ureteral obstruction
• Bind to ergosterol in the fungal cell membrane, form a transmembrane channel that precipitates cell leakage and death
  • Second mechanism of action is oxidative damage of the cell through a cascade of oxidative reactions linked to lipoperoxidation of the cell membrane
• Administered intravenously (IV) as these are not orally absorbed and are associated with a broad range of side effects
• Patients with renal insufficiency should be monitored closely
• Should not be administered simultaneously with leukocytes
• May cause acute infusion-related reactions and dose-limiting nephrotoxicity

Lipid Formulations of Amphotericin B

• Eg Amphotericin B colloidal dispersion (ABCD), Amphotericin B lipid complex (ABLC), small unilamellar vesicle liposomal Amphotericin B (L-AmB)
• Recommended treatment options for IA due to species with intrinsic high azole minimum inhibitory concentration (MIC)
  • L-AmB is a recommended option for treatment of IA with azole resistance >10%, breakthrough IA (IA infection occurring during antifungal prophylaxis) while receiving azole antifungals or Voriconazole intolerance
    • 2nd-line treatment option for proven, probable or possible azole-sensitive CAPA and 1st-line treatment for azole-resistant CAPA
• Alternative therapy to Voriconazole for the treatment of IA, central nervous system (CNS) aspergillosis, chronic pulmonary aspergillosis (CPA), aspergillosis of the paranasal sinuses, Aspergillus endocarditis/pericarditis/myocarditis, and hepatic aspergillosis 
• Causes reduced nephrotoxicity thus may be infused in higher doses

Triazoles

• Targets the 14-alpha-demethylase enzyme that mediates the conversion of lanosterol to ergosterol in the fungus
• Contraindicated during pregnancy
• Recommended for the prevention and treatment for most forms of aspergillosis
• Therapeutic drug monitoring should be conducted once steady state has been achieved

Fluconazole

• Has reduced lipophilicity that allows easier administration
• Not active against IA

Isavuconazole

• A triazole antifungal that is used for the treatment of IA
  • Recommended 1st-line treatment option for proven, probable or possible CAPA
  • Recommended treatment option for IA due to species with high Amphotericin B MIC or breakthrough IA during Amphotericin therapy
  • Recommended alternative for Voriconazole in the setting of severe and prolonged immunosuppression where coinfection by >1 fungus may be of concern, and patients with a prolonged QTc or those requiring IV therapy
• Active against most strains of A flavus, A fumigatus, A niger, Rhizopus oryzae, and Mucormycetes sp
• Exerts its antifungal activity by inhibiting the synthesis of ergosterol, an essential component of fungal cell membrane
• Found to be non-inferior to Voriconazole as primary treatment for the suspected invasive disease

Itraconazole

• Contains a 4-ring lipophilic tail that enhances its interactions with the CYP51 cytochrome rendering it active against molds
• Recommended after disease progression has been arrested with either Voriconazole or Amphotericin B
• For treatment of IA in patients who are refractory to or intolerant of standard antifungal therapy
• Recommended in the treatment of CCPA
  • Oral therapy is preferred used due to required long-term treatment
• Used as a corticosteroid-sparing agent in allergic bronchopulmonary aspergillosis (ABPA)
  • Diminishes the antigenic stimulus for bronchial inflammation
• Recommended for consideration in allergic Aspergillus sinusitis (AAS) treatment for refractory disease and to prevent relapse in patients with frequent recurrences

Posaconazole

• Salvage therapy for invasive aspergillosis and chronic pulmonary aspergillosis
  • Can be used in IA if Voriconazole is not possible
• Prophylaxis of IA in neutropenic patients with leukemia and myelodysplasia and in allogeneic hematopoietic stem cell transplantation (HSCT) recipients with graft-versus-host disease (GVHD)
• Alternative 2nd-line treatment for proven, probable or possible CAPA

Voriconazole

• Primary treatment option for invasive aspergillosis, chronic pulmonary aspergillosis, central nervous system aspergillosis, Aspergillus endocarditis, Aspergillus endophthalmitis, cutaneous aspergillosis, Aspergillus peritonitis, hepatic and renal aspergillosis
  • Recommended treatment option for IA due to species with high Amphotericin B MIC or breakthrough IA during Amphotericin therapy
  • Recommended 1st-line therapy for IA with azole resistance >10%, in combination with an echinocandin
  • Recommended for Aspergillus osteomyelitis in combination with surgery
  • Recommended 1st-line treatment option for proven, probable or possible CAPA
• Alternative treatment option for ABPA 
• Showed favorable improvement in symptoms and stabilization or improvement in Aspergillus antibody titers and radiologic findings in chronic cavitary pulmonary aspergillosis (CCPA)

Echinocandins

• Disrupt fungal cell walls through inhibition of the 1,3-β-glucan synthase complex
• Alternative treatment for patients with contraindications to azole and polyene antifungal therapy 
• May be used for salvage therapy of IA and CAPA in combination with other antifungal agents
• Only for intravenous administration
• May be used in combination with antifungal agents

Caspofungin

• Exhibits fungistatic activity against Aspergillus sp
• Only administered via intravenous infusion with dosage adjustment being required in the case of hepatic impairment
• Salvage therapy for invasive aspergillosis and chronic pulmonary aspergillosis
• Indicated in patients with probable or proven IA that is refractory to or intolerant of other approved therapies

Micafungin

• Salvage therapy for invasive aspergillosis and chronic pulmonary aspergillosis
• Also used as a prophylactic agent against invasive aspergillosis

Anidulafungin

• Not Food and Drug Administration (FDA) approved for IA however may be considered as a treatment option for salvage therapy in combination with another antifungal agent due to its activity against Aspergillus sp
• Well tolerated but should be infused slowly

Corticosteroids

• Mainstay therapy of ABPA
• Current findings showed improved pulmonary function and fewer episodes of recurrent consolidation in ABPA
• Short-term treatment is recommended as long-term treatment may result in immunosuppression
  • May only be considered in chronic pulmonary aspergillosis in patients who have been adequately treated with antifungals
• May be useful treatment for AAS

Other Treatments

• Hemoptysis in CPA may be controlled by oral Tranexamic acid therapy
• Anti-IgE therapy (eg Omalizumab) may be considered in patients with allergic bronchopulmonary aspergillosis
• Colony-stimulating factors may be considered in neutropenic patients with IA

• Topical therapy with irrigating solutions of Boric acid, Acetic acid or azole cream
• Treatment with systemic Voriconazole, combined with surgical debridement is recommended
• For refractory cases and in patients with perforated tympanic membranes, use of Voriconazole PO or Itraconazole PO may be appropriate

Duration of Therapy
Invasive Aspergillosis (IA)

• Treatment should be continued for a minimum of 6-12 weeks
  • Suggested optimal duration of treatment for CAPA is 6-12 weeks which may be prolonged in immunocompromised patients
    • Weekly therapeutic drug monitoring is recommended in patients treated with triazoles and echinocandins
• In immunosuppressed patients, therapy should be continued throughout the period of immunosuppression and until lesions have resolved
• Prerequisites for discontinuing treatment include clinical and radiographic resolution, microbiologic clearance, and reversal of immunosuppression

Chronic Pulmonary Aspergillosis

• Treatment should be continued for a minimum of 6 months
• Long-term antifungal therapy may be needed in patients with progressive disease

• Susceptibility testing remains the gold standard to detect and diagnose antifungal resistance
• The 2016 Infectious Diseases Society of America (IDSA) and the 2021 Royal Australasian College of Physicians (RACP) guidelines recommend antifungal susceptibility testing to be routinely performed in patients who are previously exposed to azole antifungals, who do not respond to therapy, or for epidemiological purposes
  • The 2017 European Society of Clinical Microbiology and Infectious Diseases (ESCMID)-European Confederation of Medical Mycology (EMM)-European Respiratory Society (ERS) joint guideline recommends routine susceptibility testing except for azole-naive patients in regions with no resistance found in contemporary surveillance programs

Bronchial Artery Embolization

• Treatment option for patients with life-threatening hemoptysis who are poor candidates for surgery or those with extensive disease
• Recurrence of hemoptysis may occur

Suction Evacuation

• Preferred 1st step in cleaning the external auditory canal; application of topical antifungal drops should follow
  • Syringing with normal saline and antifungal powder may be considered in facilities without suction evacuation; thorough drying of the ear canal should be done afterwards