aspergillosis
ASPERGILLOSIS
Treatment Guideline Chart
Aspergillosis encompasses a variety of clinical syndromes depending on host immunity factors.
It is caused by Aspergillus, an ubiquitous, soil-dwelling, filamentous fungus that grows on soil, food, dead leaves, household dust, etc. It grows best at 37ºC and the small spores are easily inhaled and deposited deep in the lungs.
The most common pathogens are Aspergillus fumigatus, A. flavus, A. niger and A. terreus.
Aspergilloma is a conglomeration of intertwined Aspergillus hyphae, fibrin, mucus and cellular debris within a pulmonary cavity or an ectatic bronchus.

Aspergillosis Treatment

Principles of Therapy

  • 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 aspergillosis who are critically ill, suspected azole resistance or refractory disease 
    • 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

Pharmacotherapy

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 an alternative to azoles for invasive aspergillosis (IA)
    • Local instillation of deoxycholate Amphotericin B may be used for patients with renal aspergillosis with ureteral obstruction together with decompression
  • 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
  • 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
      • Second-line treatment option for proven, probable or possible azole-sensitive CAPA and first-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 
  • Less toxic compared to other forms of Amphotericin 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
  • When azole resistance is >10%, other class of antifungal should be used


Fluconazole

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

Isavuconazole

  • A triazole antifungal that is used for the treatment of IA
    • Non-inferior to Voriconazole for the treatment of IA
      • Recommended alternative for Voriconazole in the setting of severe and prolonged immunosuppression where coinfection by >1 fungus may be of concern
    • Better tolerated compared to Voriconazole, with significantly fewer adverse events
    • Recommended first-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
  • Active against most strains of A flavus, A fumigatus, and A niger
  • 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 IA

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, Isavuconazole 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, with oral form used for long-term treatment if required
  • Used as a replacement treatment to steroids in patients with ABPA with frequent exacerbations and/or falling FEV1 who cannot taper off steroid therapy
    • 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 and Isavuconazole are unavailable or contraindicated
  • 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 salvage therapy 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, and 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 for Aspergillus osteomyelitis in combination with surgery
  • 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 required in moderate to severe hepatic impairment
  • Salvage therapy for IA and CPA
  • Indicated in patients with probable or proven IA that is refractory to or intolerant of other approved therapies

Micafungin

  • Salvage therapy for IA and CPA
  • Also used as a prophylactic agent against IA

Anidulafungin

  • Used off-label as salvage therapy for IA in combination with another antifungal agent

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

  • Agents currently being studied for the treatment against Aspergillus sp include Olorofim, Fosmanogepix, Ibrexafungerp, Opelconazole and Rezafungin
  • Immunomodulation as add-on therapy in IA is also being investigated
Otic Aspergillosis/Otomycosis
  • Topical therapy with irrigating solutions of Boric acid, Acetic acid or azole cream
  • For refractory cases and in patients with perforated tympanic membranes, use of Voriconazole PO or Itraconazole PO may be appropriate
    • Treatment with systemic Voriconazole, combined with surgical debridement is recommended

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 specifically with Voriconazole and Posaconazole, and may be considered in patients on renal replacement therapy or other extracorporeal treatments and with obesity on Isavuconazole therapy
      • Therapeutic drug monitoring for echinocandins may be considered in patients with obesity taking Dexamethasone to ensure doses remain above the minimal effective concentration of the fungus
  • 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

Non-Pharmacological Therapy

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 first step in cleaning the external auditory canal; application of topical antifungal drops should follow     
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