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aspergillosis
ASPERGILLOSIS
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

Pharmacotherapy

  • 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
  • Combination therapy may be considered in patients with invasive pulmonary disease
  • 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 intravenous (IV) as it is not orally absorbed with a broad range of side effects
  • Patients with renal insufficiency should be closely monitored
  • 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)
    • Liposomal Amphotericin B is a recommended option for treatment of IA with azole resistance >10
  • Alternative therapy to Voriconazole for the treatment of IA, central nervous system 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 treatment option for IA due to species with high Amphotericin B MIC
  • Active against most strains of Aspergillus flavus, A. fumigatus, A. niger, Rhizopus oryzae, and Mucormycetes species
  • Exerts its antifungal activity by inhibiting the synthesis of ergosterol, an essential component of fungal cell membrane
  • Isavuconazole was 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 is 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 preferably 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
  • Recommend 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
  • Prophylaxis of IA in neutropenic patients with leukemia and myelodysplasia and in allogenic hematopoietic stem cell transplantation (HSCT) recipients with graft-versus-host disease (GVHD)

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
    • Recommended 1st-line therapy for IA with azole resistance >10%, in combination with an echinocandin
    • Recommended for Aspergillus osteomyelitis in combination with surgery
  • 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 in combination with other antifungal agents
  • Only for intravenous administration
  • May be used in combination with antifungal agents

Caspofungin

  • Exhibits fungistatic activity against Aspergillus species
  • 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

  • Most recently approved echinocandin
  • 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

Duration of Therapy for Invasive Aspergillosis (IA)

  • Treatment should be continued for a minimum of 6-12 weeks
  • 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
Otic Aspergillosis
  • 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
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