Evolution of antifungals for invasive mold infections in immunocompromised hosts, then and now

ABSTRACT

Introduction

The current armamentarium of antifungal agents for invasive mold infections (IMI) has dramatically improved over the last 50 years. Existing therapies are, however, associated with toxicities, drug interactions, and, in some cases, therapeutic failures. Novel antifungals are needed to address the increasing prevalence of IMI and the growing threat of antifungal resistance.

Areas covered

We review the history and development of the most commonly used antifungals. We discuss the current consensus guidelines and supporting data for treatment of invasive mold infection (IMI), the role of susceptibility testing, and the niche that novel antifungals could fill. We review the current data for aspergillosis, mucormycosis, and hyalohyphomycosis.

Expert opinion

Robust clinical trial data demonstrating the relative effectiveness of our current antifungal agents for treating IMI outside of A. fumigatus remains limited. Clinical trials are urgently needed to delineate the relationship between MICs and clinical outcomes for existing agents and to better evaluate the in vitro and in vivo aspects of antifungal synergy. Continued international multicenter collaboration and standardized clinical endpoints for trials evaluating both existing and new agents are necessary to advance the field.

KEYWORDS:

• Antifungal therapy
• aspergillosis
• mucormycosis
• fusariosis
• triazoles
• echinocandins
• amphotericin

Article highlights

• The introduction of azole antifungals provided an amphotericin-alternative with fewer severe toxicities.

• Despite improvements, current antifungal agents active against invasive mold infections (IMI) are still associated with toxicities, drug interactions, and therapeutic failures.

• Tri-azole resistance in Aspergillus spp. is becoming an increasing problem, particularly in parts of Europe and is linked to azole-containing fungicide use.

• Little is known about the efficacy of combination therapy versus monotherapy for any invasive mold infection. Combinations may be indicated for salvage therapy. In vitro synergy testing is not recommended or routinely performed at this time.

• Species-level identification can help guide empiric therapy for hyaline molds due to well-characterized species-specific resistance patterns but is less useful for treatment of Mucorales infection.

• MICs may not be predictive of clinical outcomes in some mold species, in particular Fusarium and Mucorales.

• Clinical studies on the efficacy of antifungal therapies for IMI, particularly non-Aspergillus IMI, are limited due to disease rarity and the high baseline mortality in affected immunocompromised populations.

• Novel antifungals are emerging with new mechanisms of action, reduced drug toxicities, and expanded susceptibility profiles.

Acknowledgments

This article is dedicated to the memory of our colleague and mentor Dr Francisco M. Marty. We appreciate Jackie Kustan’s artistic contribution.

Declaration of interest

SP Hammond has research support from F2G, GSK and Scynexis and has been an advisor for F2G and Pfizer in the past. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper was not funded.