Antifungal chemotherapies and immunotherapies for the future

Abstract

Human fungal pathogens cause a broad plethora of infections, spanning cutaneous dermatophytoses to invasive infections in immunocompromised hosts. As eukaryotic pathogens are capable of morphotype switching, they present unique challenges both for drug development and the immunological response. Whilst current antifungal therapies are limited to the orally available triazoles, intravenous echonocandins and polyenes, and flucytosine and terbinafine, there has been recent significant progress in the antifungal armamentorium with ibrexafungerp, a novel orally available terpanoid that inhibits 1,3‐beta‐D‐glucan‐approved by Food and Drug Administration in 2021, and fosmanogepix, an orally available pro‐drug of manogepix, which targets glycosylphosphatidylinositol‐anchored protein maturation entering Phase 3 studies for candidaemia. A number of further candidates are in development. There has been significant use of existing immunotherapies such as recombinant interferon‐γ and G‐CSF for fungal disease in immunocompromised patients, and there are emerging opportunities for monoclonal antibodies targeting TH2 inflammation. Omalizumab, an anti‐IgE monoclonal antibody in asthma, is now used routinely for the treatment of allergic bronchopulmonary aspergillosis, and further agents targeting IL‐4 and IL‐5 are being evaluated. In addition, T‐cell CAR therapy is showing early promise for fungal disease. Thus, we are likely to see rapid advances to our approach to the management of fungal disease in the near future.

Update on the treatment of chronic pulmonary aspergillosis

“…Furthermore, the triazoles remain the only oral class of antifungal available with echinocandins and L-amB dosed i.v. resulting in additional challenges for outpatient delivery [18].…”

“…This paucity of suitable antifungal agents, and a lack of focus on the emergence of resistance in clinical studies has resulted in combination therapy being under-explored in treatment of CPA; however, a number of novel agents are likely to enter clinical use for the treatment of invasive Aspergillosis within the next 12–24 months [18] paving the way for their use in treatment of chronic disease. Rezafugin is a second-generation echinocandin-type glucan synthase inhibitor, and like its analogues is only available as in i.v.…”