In the continued search for optimal antifungal therapy against invasive aspergillosis, there have been a myriad of experimental and clinical explorations into the use of combination therapy using two different agents concurrently to maximize efficacy. This concept is relatively new as even 10 years ago there were not such a choice of available antifungals. The long list of in vitro and in vivo experimental data is confusing and offers no consistent answer. Often clear results in vitro do not extrapolate to animal models, and there is always the concern that data yielded in animal studies will not translate to clinical care. While voriconazole therapy over conventional amphotericin B therapy has increased clinical response, the next therapeutic step forward will likely not lead to an approximately 20% improvement. It is clear that at present there is no simple panacea, and the gains made in the future will be hard-fought. Considering that the patients with invasive aspergillosis are sicker than ever before, perhaps minor gains from adjunctive agents is all that we can expect from newer combination therapy. While some have explored combining existing antifungal agents, largely focused on concurrent use of agents from different antifungal classes with different mechanisms of action, others have advocated the addition of immunomodulation therapy or other non-traditional agents to augment a current antifungal. We will explore a brief history of the use of combination therapy against invasive aspergillosis, and then highlight the latest experimental and clinical thoughts. We will cover the nuances of experiments in vitro and in animal systems, and the pitfalls of each methodology for depicting a successful combination. We will focus on newer pathways amenable for targeting (such as calcineurin, Hsp90, and others), and how using non-orthodox approaches might be our best hope. We will conclude with an update on the largest clinical trial investigation of combination antifungal therapy which is currently enrolling patients around the world.
Full conference title:
4th Advances Against Aspergillosis
- AAA 4th (2010)