Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside

Abstract

Echinocandins (caspofungin, micafungin, anidulafungin), targeting ␤-1,3glucan synthesis of the cell wall, represent one of the three currently available antifungal drug classes for the treatment of invasive fungal infections. Despite their limited antifungal activity against Aspergillus spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA). This drug class exhibits several advantages, such as excellent tolerability and its potential for synergistic interactions with some other antifungals. The objective of this review is to discuss the in vitro and clinical efficacy of echinocandins against Aspergillus spp., considering the complex interactions between the drug, the mold, and the host. The antifungal effect of echinocandins is not limited to direct inhibition of hyphal growth but also induces an immunomodulatory effect on the host's response. Moreover, Aspergillus spp. have developed important adaptive mechanisms of tolerance to survive and overcome the action of echinocandins, such as paradoxical growth at increased concentrations. This stress response can be abolished by several compounds that potentiate the activity of echinocandins, such as drugs targeting the heat shock protein 90 (Hsp90)-calcineurin axis, opening perspectives for adjuvant therapies. Finally, the present and future places of echinocandins as prophylaxis, monotherapy, or combination therapy of IA are discussed in view of the emergence of pan-azole resistance among Aspergillus fumigatus isolates, the occurrence of breakthrough IA, and the advent of new long-lasting echinocandins (rezafungin) or other ␤-1,3-glucan synthase inhibitors (ibrexafungerp). KEYWORDS Aspergillus, anidulafungin, calcineurin, caspofungin, heat shock protein 90, ibrexafungerp, micafungin, paradoxical effect, rezafungin M olds of the genus Aspergillus (particularly, Aspergillus fumigatus) are the causal agents of invasive aspergillosis (IA), a life-threatening infection affecting immunocompromised hosts, such as hematological cancer or transplant patients. The current antifungal armamentarium for the treatment of IA is limited to three antifungal drug classes. Fungicidal drugs, such as the triazoles (e.g., voriconazole, posaconazole, or isavuconazole) and the polyenes (amphotericin B formulations) represent the firstchoice treatments, whereas the fungistatic echinocandins (caspofungin, anidulafungin, and micafungin) represent an alternative and are only marginally used as monotherapy (1, 2). However, use of echinocandins is gaining interest because of the emergence of acquired azole resistance in A. fumigatus isolates and the limitations related to drug interactions and/or toxicity with azoles and amphotericin B. The aim of this review is to discuss the role of the echinocandins in the treatment of IA, from the mechanistic point of view of drug-pathogen-host interactions to clinical application and perspectives. ECHINOCANDINS AGAINST ASPERGILLUSMechanisms of action. The echinocandin drugs are lipopeptides derived from fu...

Functional Characterization of Clinical Isolates of the Opportunistic Fungal Pathogen Aspergillus nidulans

“…The A. nidulans clinical isolates do not display increased resistance to azoles and amphotericin B. Since both CIs showed increased susceptibility to caspofungin, an echinocandin that is being used as a second-line treatment for fungal infections (33), and to other cell wall-perturbing agents, we expanded our analyses to include two additional antifungal drugs classes. Specifically, we followed guidelines for the diagnosis and management of aspergillosis, which, in most cases, recommends treating aspergillosis with azoles and polyene drugs (11), both of which are known to interfere with the biosynthesis or physicochemical properties of fungal membrane sterols (10).…”

Functional characterization of clinical isolates of the opportunistic fungal pathogenAspergillus nidulans

“…In contrast, both A. nidulans clinical strains were significantly more sensitive to the cell wall perturbing agents calcofluor white, congo red and caspofungin (33–35) than the reference strain. These results suggest differences in cell wall composition and/or organization between the clinical isolates and the reference strain.…”

“…Lastly, growth of all strains was assessed in the presence of the cell wall perturbing agents caspofungin, congo red (CR) and calcofluor white (CFW). The echinocandin caspofungin is a competitive inhibitor of the cell wall enzyme β-1,3-glucan synthase (33) while CR and CFW bind to glucan or chitin chains respectively (34, 35). CR and CFW therefore interfere with the cross-linking of cell wall polysaccharides, resulting in a reduction of cell wall stability.…”

“…Since both CIs showed increased susceptibility to caspofungin, an echinocandin that is being used as a second line treatment for fungal infections (33), and to other cell wall-perturbing agents, we expanded our analyses to include two additional antifungal drugs classes. Specifically, we followed the “Guidelines for the Diagnosis and Management of Aspergillosis”, which, in most of the cases, recommend to treat aspergillosis with azoles and polyene drugs (11), both of which are known to interfere with the biosynthesis or physicochemical properties of fungal membrane sterols (10).…”

Aspiring Antifungals: Review of Current Antifungal Pipeline Developments

“…Like echinocandins, it inhibits 1,3-β-d-glucan synthesis to achieve antifungal effect ( Figure 1). However, as a triterpenoid enfumafungin derivative, ibrexafungerp is structurally unique from the echinocandin class [18,19].…”