Abstract
Currently available and recommended options for the treatment of pulmonary aspergillosis
include the triazoles, echinocandins, and amphotericin B products. These therapies
have significant limitations. Only the azoles are available orally, but their use
is often limited by toxicities, drug–drug interactions, pharmacokinetic variability,
and emerging resistance. While the echinocandins are safe agents and may have a role
in combination therapy, they are unproven as monotherapy. Amphotericin B preparations
are toxic and require intensive monitoring. Finally, aspergillosis continues to be
a disease conferring substantial morbidity and mortality, and clinical trials have
not identified a therapeutic approach clearly associated with improved outcomes. As
a result, there is a great need for new options in the treatment of invasive aspergillosis.
Ideally, such options would be safe, have high oral bioavailability, have favorable
pharmacokinetics to sequestered sites and retain activity against azole-resistant
isolates. Reassuringly, there is a robust pipeline of novel therapies in development.
Rezafungin (a once-weekly dosed echinocandin) and ibrexafungerp (oral agent with same
mechanism of action as echinocandins) will likely be reserved for combination therapy
or refractory/intolerance scenarios with no other options. Inhaled opelconazole is
an attractive option for combination therapy and prophylaxis of pulmonary aspergillosis.
Development of an oral form of amphotericin B that avoids nephrotoxicity and electrolyte
disturbances is an exciting development. Finally, olorofim and fosmanogepix, two agents
with novel mechanisms of action and oral formulations, hold significant potential
to challenge the triazole antifungals place as preferred therapies. However, many
questions remain regarding these novel agents, and at the time of this writing, none
of these agents have been robustly studied in Phase III studies of aspergillosis,
and so their promise remains investigational.
Keywords
Aspergillus
- aspergillosis - azole - antifungal - investigational
