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
- 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