Drug | Recommendation |
(Vfend) Preferred drug for Aspergillus infections based on improved mortality compared to AmB in the treatment of invasive aspergillosis. Advantages are PO and IV formulations, good tolerance, Good CNS penetration and good in vitro and in vivo activity. Drug interactions may be troublesome especially in transplant populations. The parenteral form might be problematic in renal failure, but recent data more reassuring regarding safety. Therapeutic drug monitoring (serum trough levels) seems to be important for improving efficacy and reducing toxicity. | |
Well tolerated parenteral drugs; however, the exact role of monotherapy in the treatment of serious Aspergillus infection is unclear. Use in combination therapy with voriconazole and may result in improved outcomes. | |
Well tolerated parenteral drugs; however, the exact role of monotherapy in the treatment of serious Aspergillus infection is unclear. Use in combination therapy with voriconazole and may result in improved outcomes. | |
Well tolerated parenteral drugs; however, the exact role of monotherapy in the treatment of serious Aspergillus infection is unclear. Use in combination therapy with voriconazole and may result in improved outcomes. | |
Isavuconazonium (prodrug of isavuconazole) | (Cresemba) Azole antifungal agent FDA approved for invasive aspergillosis and invasive mucormycosis. Available as IV and oral formulations. Drug interactions with immunosuppressants (e.g., cyclosporine, tacrolimus, sirolimus) and digoxin. Isavuconazole levels impacted by CYP3A4 inhibitors and inducers. |
(Ambisome) The lipid formulations of amphotericin B were initially compared w/ conventional AmB in pts with aspergillosis. The results of these studies show an advantage for the lipid amphotericin formulations, but only for a reduction in adverse reactions. The clinical outcome compared to conventional has generally been the same, but the side effects are substantially reduced with the lipid preparations. The cost differential is large. | |
The lipid formulations of amphotericin B were initially compared w/ conventional AmB in pts with aspergillosis. The results of these studies show an advantage for the lipid amphotericin formulations, but only for a reduction in adverse reactions. The clinical outcome compared to conventional has generally been the same, but the side effects are substantially reduced with the lipid preparations. The cost differential is large. | |
Amphotericin B deoxycholate | Used for severe disease (invasive aspergillosis). In one of the most common forms, invasive pulmonary in compromised hosts especially with neutropenia +/- reduced cell-mediated immunity, initial reports showed almost 100% mortality. Now there is substantial survival due to rapid dx and if very high doses of amphotericin are used, though voriconazole has now supplanted as first-line therapy. |
(Noxafil) Alternative azole is available in oral solution, delayed-release tablet and IV formulation that is FDA approved for the prevention of Aspergillus and Candida as invasive fungal infections in patients at risk. An alternative to voriconazole for patients with aspergillosis. Time to steady-state levels can be nearly a week for the tablet and even longer for the solution formulations. | |
The clinical experience is extensive and reasonably good, but serious invasive disease requires voriconazole, isavuconazole, posaconazole or amphotericin B. | |
It cannot be used as a single agent for Aspergillus infections. It is sometimes combined with amphotericin B as a desperation maneuver, especially with CNS infections due to the more favorable penetration of 5FC across the blood-brain barrier. |
Prevention:
Comment: Clinical guidelines for management and prevention of aspergillosis in solid organ transplant recipients. Source of recommendations for such patients in this module
Comment: Updated and revised formal definitions for invasive fungal infections. Useful as a guide, but patients with conditions not fulfilling the requirements of these definitions may still have an invasive fungal infection.
Comment: Multinational guidelines for diagnosis and management of aspergilliosis.
Comment: Practice guidelines published by IDSA for aspergillosis. Source for recommendations in this module
Comment: Randomized study of voriconazole +/-anidulafungin in patients with hematological malignancy or hematopoietic stem cell transplant and invasive aspergillosis. Key findings: a. Overall mortality was the same in monotherapy and combination group, b. Survival was better in combination therapy than monotherapy for those whose aspergillosis diagnosis was established by radiographic findings and galactomannan positivity.
Comment: This study is based on 181 measurements of voriconazole levels and showed, despite standard dosing, 31% showed levels considered potentially toxic and 25% showed levels considered subtherapeutic.
Comment: Large multicenter study of 144 patients with invasive aspergillosis randomized to receive voriconazole or amphotericin B. Voriconazole was superior in rates of success (53% vs 32%), survival (71% vs 58%) and reduced adverse effects. Few infectious diseases studies have ever shown the superiority of a particular drug.
Comment: Comprehensive review of newly recognized microbiology of Aspergillus species. Multiple newly discovered species are detailed
Comment: Review highlighting clinical and microbiological features of newly discovered species within the Aspergillus fumigatus species complex.
Rating: Important
Comment: Comprehensive review of diagnosis and management of filamentous fungal infections of the CNS
Rating: Important
Comment: Voriconazole penetrates well into tissue based on autopsies from patients: lung (median level 6.3 ug/gm), brain (3.4 ug/gm), liver (6.9 ug/gm), kidneys (6.2 ug/gm), spleen (11.5 ug/gm) and myocardium (16.6 ug/gm).
Comment: A meta-analysis of 15 studies to evaluate the use of (1-3)-B-D-Glucan (BG). Sensitivity and specificity were 0.76 and 0.85, respectively. Subset analysis showed better specificity with positive results with two positive tests in patients with hematologic malignancies and when combined with galactomannan.
Rating: Important
Comment: The author is a major authority on aspergillus. For galactomannan, the sensitivity for detecting invasive aspergillosis is best in a high-risk patient. It is reported as high as 92%, but more recent studies show 40-50% sensitivity. Specificity in high risk patients is >90%. The 1, 3 beta-D-glucan test is somewhat early in development and nonspecific since other fungi including Candida have this cell wall constituent.
Rating: Important
Comment: Review of PCR to detect aspergillus in blood samples to facilitate the diagnosis of invasive aspergillus. Summary of 17 studies with 1,191 at-risk patients showed a sensitivity of 0.91 and specificity of 0.92. However, the authors concluded that the technique still needs to be standardized.
Rating: Important
Comment: Comparison of serum PCR and galactomannan in patients with hematological malignancies and chemotherapy. Results: sensitivity GM 88%, PCR 75%; specificity GM 93%, PCR 92%. BAL was sometimes positive by either method when serum was negative. Two or more positive tests improved the specificity of both.
Rating: Important
Comment: Treatment results of 79 patients with chronic pulmonary aspergillosis treated with posaconazole (400 mg bid). The response rate was 61% at 6 months and 46% at 12 months.
Comment: Randomized blinded trial of prophylactic fluconazole vs. voriconazole to prevent invasive aspergillosis in patients undergoing myeloablative allogeneic hematopoietic cell transplant. With intensive monitoring (serum galactomannan twice weekly x 60 days, then once weekly x 40 days). Aspergillosis occurred in 7.3% recipients of voriconazole vs. 11% for fluconazole (p=0.09).
Rating: Important
Comment: Transplant Surveillance Network with 23 US centers reviewed invasive fungal infections in hematopoietic stem cell transplant recipients -- 983 cases: aspergillus -- 43%, candidiasis -- 28%, zygomycetes (8%). The cumulative incidence in 16,200 HSCT was 7.7-8.1 invasive fungal infections/100 cases for matched and mismatched-related, respectively.
Rating: Important
Comment: A randomized study showed that the use of masks for preventing aspergillosis in high-risk patients did not work.
Comment: The authors show clinical response with voriconazole treatment of Aspergillus causing invasive otitis externa.
Rating: Important
Comment: In vitro studies of 49 strains of Aspergillus fumigatus showed all were sensitive to caspofungin, itraconazole, posaconazole and voriconazole.
Rating: Important
Comment: Review of non-invasive pulmonary aspergillosis that includes: 1) bronchoallergic form; 2) fungus ball and 3) "chronic pulmonary aspergillosis". The latter has also been called "semi-invasive aspergillosis.
Rating: Important
Comment: Allergic fungal sinusitis is a non-invasive form of sinusitis that accounts for 6-9% of surgeries for rhinosinusitis. Major pathogens: aspergillus, Bipolaris and Curvularia species.
Rating: Important
Comment: Serum galactomannan is a non-invasive, widely available, reproducible test that is FDA cleared for use as a surrogate marker of invasive aspergillosis. This paper is a correlation between serum aspergillus galactomannan levels and outcome.
Rating: Important
Comment: Retrospective analysis with 47 patients with AmB failure failures showed voriconazole and caspofungin was a good salvage regimen and were superior to voriconazole alone.
Rating: Important
Comment: A review of 83 cases showed mortality in 19/34 (56%) given voriconazole compared to 36/49 (73%) given other antifungals.
Comment: The allergic form is associated with Type I, II and IV allergic responses to Aspergillus antigens. Clinical presentation is bronchiectasis, and airway destruction. Maybe asymptomatic. Treatment is corticosteroids; surgery may be definitive in some cases but many have inadequate lung reserve.
Comment: A double-blind, placebo-controlled trial for allergic bronchopulmonary aspergillosis using itraconazole 200mg PO twice daily x 16wks. Benefits included a reduction in steroid dose, improved exercise tolerance, improved pulmonary function and decreased IgE.
Rating: Important
Comment: The authors show the value of CT scans to indicate probable aspergillosis in neutropenic patients and then employ surgical resection as a method of management
Comment: The initial trials for drug registration for the 3 commercially available lipid formulations of amphotericin B were done with aspergillosis. The initial FDA approval was consequently for aspergillosis. These trials showed the lipid formulations were not clinically superior to conventional amphotericin B, but they were less toxic.
Comment: The authors present a case and a graphic picture of aspergillosis at a Hickman catheter insertion site. The lesion showed concentric plaque lesions of diverse colors. Therapy required removal of the catheter and antifungals.
Comment: This is the original description of the "halo sign" (nodular lung lesion with surrounding area of low attenuation) as an early sign, and the later "crescent sign" (air crescent at periphery of lung nodule).
Comment: The operative mortality for surgical resection of aspergillus fungus balls was 7%, and post-op complications included B-P fistulae and hemorrhage. The recommendation is to reserve surgery for cases that show severe hemoptysis and show adequate pulmonary reserve.
Comment: Criteria are: 1) episodic asthma; 2) eosinophilia, 3) immediate scratch test reaction to Aspergillus antigen, 4) precipitating antibodies + aspergillus antigen, 5) elevated serum IgE, 6) hx of pulmonary infiltrates, and 7) central bronchiectasis
Aspergillus hyphae and conidia
Source: CDC