# Multisystem Lomentospora prolificans progression on fosmanogepix despite in vitro activity: a call for expanding clinical research on novel antifungals

## TL;DR

A rare fungal infection worsened in a patient despite treatment with a new antifungal drug, highlighting the need for better clinical research on novel antifungals.

## Contribution

Highlights the gap between in vitro drug activity and real-world clinical outcomes for novel antifungals.

## Key findings

- Fosmanogepix failed to halt progression of Lomentospora prolificans in a patient with disseminated infection.
- In vitro susceptibility does not reliably predict clinical response in deep-seated fungal infections.
- Publication bias may overrepresent positive outcomes with new antifungal agents.

## Abstract

Lomentospora prolificans is a rare and often fatal cause of invasive mold disease (IMD), particularly in immunocompromised individuals. Treatment remains difficult due to intrinsic resistance to most antifungals and the challenges of achieving therapeutic drug levels in the central nervous system. Fosmanogepix and olorofim are novel antifungal agents with promising activity against difficult-to-treat molds, including L. prolificans, and show potential for excellent central nervous system penetration.

We report a case of disseminated L. prolificans infection with pulmonary, ocular, and central nervous system involvement in a 73-year-old man following haploidentical hematopoietic cell transplantation for peripheral T-cell lymphoma. Despite early neutrophil engraftment, the absence of graft-versus-host disease, and treatment with fosmanogepix, his infection progressed to fatal fungal meningitis.

This case underscores the limitations of relying on in vitro susceptibility results to predict clinical response in the absence of clinical breakpoints, particularly in deep-seated infections where drug penetration may be limited. While prior case reports have described successful outcomes with novel agents, publication bias may overrepresent favorable results. This case supports the urgent need for rigorous evaluation of emerging antifungal therapies in real-world settings.