Refractory Microascus Bronchopulmonary Infection Treated with Olorofim, France.

We report 3 cases of successful treatment of Microascus spp. bronchopulmonary infection in a multiple-traumatized patient and 2 lung transplant recipients in France. We emphasize the promising use of olorofim antifungal therapy in a rising context of intrinsically less-susceptible respiratory infections caused by mold.

Dihydroorotate dehydrogenase inhibitor olorofim has potent in vitro activity against Microascus/Scopulariopsis, Rasamsonia, Penicillium and Talaromyces species.

BACKGROUND: Treatment options against infections caused by rare but emerging moulds may be limited by their reduced susceptibility or resistance to clinically available antifungals. The investigational antifungal olorofim, which targets the biosynthesis of pyrimidines within fungi, has activity against different species of filamentous fungi, including Aspergillus and Scedosporium/Lomentospora prolificans isolates that are resistant to available antifungals. OBJECTIVE: We evaluated the in vitro activity of olorofim against 160 isolates within the genera Microascus/Scopulariopsis, Penicillium, Talaromyces and the Rasamsonia argillacea species complex. METHODS: One hundred sixty clinical isolates that had previously been identified to the species level by DNA sequence analysis were included. Antifungal susceptibility testing was performed by CLSI M38 broth microdilution for olorofim, amphotericin B, caspofungin, posaconazole and voriconazole. RESULTS: Olorofim demonstrated in vitro activity against each of the genera tested. Overall, olorofim MICs ranged from ≤0.008 to 0.5 mg/L against all isolates tested, with MIC90 and modal MIC values ranging from ≤0.008 to 0.25 mg/L and ≤0.008 to 0.03 mg/L, respectively. This activity was also maintained against individual isolates that had reduced susceptibility to or in vitro resistance against amphotericin B, posaconazole and/or voriconazole. CONCLUSIONS: The investigational agent olorofim demonstrated good in vitro activity against clinical isolates of emerging mould pathogens, including those with reduced susceptibility or resistance to clinically available antifungals. Further studies are warranted to determine how well this in vitro activity translates into in vivo efficacy against infections caused by these fungi.

Dual use of antifungals in medicine and agriculture: How do we help prevent resistance developing in human pathogens?

Azole resistance in Aspergillus fumigatus is a One Health resistance threat, where azole fungicide exposure compromises the efficacy of medical azoles. The use of the recently authorized fungicide ipflufenoquin, which shares its mode-of-action with a new antifungal olorofim, underscores the need for risk assessment for dual use of antifungals.

Investigational Antifungal Agents for Invasive Mycoses: A Clinical Perspective.

Treatment of invasive fungal infections (IFIs) remains challenging, because of the limitations of the current antifungal agents (ie, mode of administration, toxicity, and drug-drug interactions) and the emergence of resistant fungal pathogens. Therefore, there is an urgent need to expand our antifungal armamentarium. Several compounds are reaching the stage of phase II or III clinical assessment. These include new drugs within the existing antifungal classes or displaying similar mechanism of activity with improved pharmacologic properties (rezafungin and ibrexafungerp) or first-in-class drugs with novel mechanisms of action (olorofim and fosmanogepix). Although critical information regarding the performance of these agents in heavily immunosuppressed patients is pending, they may provide useful additions to current therapies in some clinical scenarios, including IFIs caused by azole-resistant Aspergillus or multiresistant fungal pathogens (eg, Candida auris, Lomentospora prolificans). However, their limited activity against Mucorales and some other opportunistic molds (eg, some Fusarium spp.) persists as a major unmet need.

EUCAST-Obtained Olorofim MICs against Aspergillus and Scedosporium Species and Lomentospora prolificans Showed High Agreements between Visual Inspection and Spectrophotometric Readings.

Previous studies show high agreement between MIC spectrophotometric readings and visual inspection of azoles and amphotericin B against Aspergillus fumigatus isolates. Here, we tested and compared the in vitro activity of a novel antifungal, olorofim, against Aspergillus spp., Scedosporium spp., and Lomentospora prolificans by visual inspection and spectrophotometric readings. Clinical isolates of Aspergillus (n = 686) and Scedosporium (n = 36) spp. and L. prolificans (n = 13) were tested. Olorofim MICs were evaluated-following the EUCAST E.Def 9.4 procedure-by visual inspection or spectrophotometric readings (combinations of either ≥90% or ≥95% fungal growth inhibition endpoints compared to drug-free control endpoints and different wavelengths [405 nm, 450 nm, 492 nm, 540 nm, and 620 nm]). We observed high in vitro activity of olorofim against all tested Aspergillus spp. (MICs up to 0.06 mg/L), except for A. calidoustus, and against L. prolificans and Scedosporium spp. (MICs up to 0.125 mg/L). The combination of ≥90% fungal growth inhibition endpoints at wavelengths of ≥492 nm resulted in high essential agreements with A. fumigatus and lesser agreement with non-fumigatus Aspergillus, Scedosporium spp., and L. prolificans, although the number of isolates studied was low. This single-center study shows high agreement among olorofim MICs against A. fumigatus by visual inspection and spectrophotometric readings (≥90% fungal growth inhibition endpoints and wavelengths of ≥492 nm) and encouraging results against non-fumigatus Aspergillus spp., Scedosporium spp., and L. prolificans.

Antifungal Susceptibility Profiles of Olorofim (Formerly F901318) and Currently Available Systemic Antifungals against Mold and Yeast Phases of Talaromyces marneffei.

In vitro antifungal susceptibility profiling of 32 clinical and environmental Talaromyces marneffei isolates recovered from southern China was performed against olorofim and 7 other systemic antifungals, including amphotericin B, 5-flucytosine, posaconazole, voriconazole, caspofungin, and terbinafine, using CLSI methodology. In comparison, olorofim was the most active antifungal agent against both mold and yeast phases of all tested Talaromyces marneffei isolates, exhibiting an MIC range, MIC50, and MIC90 of 0.0005 to 0.002 µg/ml, 0.0005 µg/ml, and 0.0005 µg/ml, respectively.

Olorofim Effectively Eradicates Dermatophytes In Vitro and In Vivo.

Superficial fungal infections are prevalent worldwide, with dermatophytes as the most common cause. Various antifungal agents including azoles and allylamines are commonly used to treat dermatophytosis. However, their overuse has yielded drug-resistant strains, calling for the development of novel antimycotic compounds. Olorofim is a newly developed antifungal compound that targets pyrimidine biosynthesis in molds. The purpose of this study was to determine the in vitro and in vivo antifungal effects of olorofim against common dermatophytes. The in vitro activity of olorofim against dermatophytes was assessed by microtiter broth dilution method. Bioinformatic analysis of olorofim binding to dihydroorotate dehydrogenase (DHODH) of dermatophytes was also performed, using Aspergillus fumigatus DHODH as a template. The in vivo efficacy of the drug was investigated, using a guinea pig model, experimentally infected with Microsporum gypseum. Microtiter assays confirmed the high in vitro sensitivity of dermatophytes to olorofim (MIC = 0.015-0.06 mg/liter). Amino acid sequence analysis indicated that DHODH is highly conserved among dermatophytes. The critical residues, in dermatophytes, involved in olorofim binding were similar to their counterparts in A. fumigatus DHODH, which explains their susceptibility to olorofim. Typical skin lesions of dermatophyte infection were observed in the guinea pig model at 7 days postinoculation. Following 1 week of daily topical administration of olorofim, similar to the clotrimazole group, the skin lesions were resolved and normal hair growth patterns appeared. In light of the in vitro and in vivo activity of olorofim against dermatophytes, this novel agent may be considered as a treatment of choice against dermatophytosis.

In Vivo Efficacy of Olorofim against Systemic Scedosporiosis and Lomentosporiosis.

Clinically relevant members of the Scedosporium/Pseudallescheria species complex and Lomentospora prolificans are generally resistant against currently available systemic antifungal agents in vitro, and infection due to these species is difficult to treat. We studied the in vivo efficacy of a new fungicidal agent, olorofim (formerly F901318), against scedosporiosis and lomentosporiosis in neutropenic animals. Cyclophosphamide-immunosuppressed CD-1 mice infected by Scedosporium apiospermum, Pseudallescheria boydii (Scedosporium boydii), and Lomentospora prolificans were treated by intraperitoneal administration of olorofim (15 mg/kg of body weight every 8 h for 9 days). The efficacy of olorofim treatment was assessed by the survival rate at 10 days postinfection, levels of serum (1-3)-ß-d-glucan (BG), histopathology, and fungal burdens of kidneys 3 days postinfection. Olorofim therapy significantly improved survival compared to that of the untreated controls; 80%, 100%, and 100% of treated mice survived infection by Scedosporium apiospermum, Pseudallescheria boydii, and Lomentospora prolificans, respectively, while less than 20% of the control mice (phosphate-buffered saline [PBS] treated) survived at 10 days postinfection. In the olorofim-treated neutropenic CD-1 mice infected with any of the three species, serum BG levels were significantly suppressed and fungal DNA detected in the target organs was significantly lower than in controls. Furthermore, histopathology of kidneys revealed no or only a few lesions with hyphal elements in the olorofim-treated mice, while numerous fungal hyphae were present in control mice. These results indicate olorofim to be a promising therapeutic agent for systemic scedosporiosis/lomentosporiosis, devastating emerging fungal infections that are difficult to treat with currently available antifungals.

In vitro activity of olorofim against clinical isolates of the Fusarium oxysporum and Fusarium solani species complexes.

BACKGROUND: Invasive fusariosis is associated with marked morbidity and mortality in immunocompromised hosts, and clinical outcomes are poor with conventional therapy. Olorofim (F901318) is an investigational antifungal in the orotomide class that selectively targets fungal dihydroorotate dehydrogenase (DHODH) causing inhibition of pyrimidine biosynthesis. OBJECTIVE: We evaluated the in vitro activity of olorofim against 61 clinical isolates of the Fusarium oxysporum and F solani species complexes (FOSC and FSSC, respectively), the most prevalent causes of invasive fusariosis. METHODS: Clinical isolates of FOSC (n = 45) and FSSC (n = 16) were identified using DNA sequence analysis of the translation elongation factor 1-alpha (TEF1α) and RNA polymerase II second largest subunit (RPB2). Antifungal susceptibility testing was performed by CLSI M38 broth microdilution for olorofim, amphotericin B, isavuconazole, posaconazole, voriconazole and micafungin. RESULTS: Olorofim demonstrated good in vitro activity against both FOSC and FSSC. Against the 45 FOSC isolates, olorofim MICs ranged between 0.03-0.5 mg/L and 0.06->4 mg/L at the 50% and 100% inhibition endpoints, respectively. Against FSSC isolates, olorofim MIC ranged between 0.25-1 mg/L and 1->4 mg/L at 50% and 100% inhibition, respectively. While amphotericin B also demonstrated similar in vitro activity (MIC ranges 1-4 and 0.25-4 mg/L against FOSC and FSSC, respectively), neither the triazoles nor micafungin demonstrated consistent in vitro activity against Fusarium isolates at clinically relevant concentrations. CONCLUSIONS: The investigational agent olorofim demonstrated good in vitro activity against FOSC and FSSC clinical isolates. Further studies are warranted to determine how well this in vitro activity translates into in vivo efficacy.

Olorofim Susceptibility Testing of 1,423 Danish Mold Isolates Obtained in 2018-2019 Confirms Uniform and Broad-Spectrum Activity.

Olorofim is a novel antifungal drug in phase 2 trials. It has shown promising in vitro activity against various molds, except for Mucorales. Initially, we observed a broad range of EUCAST MICs for Aspergillus fumigatus Here, we explored the MIC variability in more detail and prospectively investigated the susceptibility of contemporary clinical mold isolates, as population data are needed for future epidemiological cutoff (ECOFF) settings. Fifteen A. fumigatus isolates previously found with low/medium/high MICs (≤0.002 to 0.25 mg/liter) were tested repeatedly and EUCAST MICs read in a blinded fashion by three observers. pyrE, encoding the olorofim target enzyme dihydroorotate dehydrogenase (DHODH), was sequenced. A total of 1,423 mold isolates (10 Aspergillus species complexes [including 1,032 A. fumigatus isolates] and 105 other mold/dermatophyte isolates) were examined. Olorofim susceptibility (modal MIC, MIC50, MIC90, and wild-type upper limits [WT-ULs] [species complexes with ≥15 isolates]) was determined and compared to that of four comparators. MICs (mg/liter) were within two 2-fold dilutions (0.016 to 0.03) for 473/476 determinations. The MIC range spanned four dilutions (0.008 to 0.06). No significant pyrE mutations were found. Modal MIC/WT-UL97.5 (mg/liter) values were 0.03/0.06 (A. terreus and A. flavus), 0.06/0.125 (A. fumigatus and Trichophyton rubrum), and 0.06/0.25 (A. niger and A. nidulans). The MIC range for Scedosporium spp. was 0.008 to 0.25. Olorofim susceptibility was similar for azole-resistant and -susceptible isolates of A. fumigatus but reduced for A. montevidensis and A. chevalieri (MICs of >1). With experience, olorofim susceptibility testing is robust. The testing of isolates from our center showed uniform and broad-spectrum activity. Single-center WT-ULs are suggested.

Efficacy of Olorofim (F901318) against Aspergillus fumigatus, A. nidulans, and A. tanneri in Murine Models of Profound Neutropenia and Chronic Granulomatous Disease.

The emergence of azole resistance in Aspergillus fumigatus as well as an increasing frequency of multiresistant cryptic Aspergillus spp. necessitates exploration of new classes of antifungals. Olorofim (formerly F901318) is a new fungicidal agent that prevents the growth of ascomycetous mold species via inhibition of de novo pyrimidine biosynthesis, a mechanism of action distinct from that of currently available antifungal drugs. We studied the in vivo efficacy of olorofim intraperitoneal therapy (15 mg/kg of body weight every 8 h for 9 days) against infection with A. fumigatus, A. nidulans, and A. tanneri in both neutropenic CD-1 mice and mice with chronic granulomatous disease (CGD) (gp91-/-phox mice). In the neutropenic mouse model, 80% to 88% of treated mice survived for 10 days, and in the CGD group, 63% to 88% of treated mice survived for 10 days, depending on the infecting species, while less than 10% of the mice in the control groups survived for 10 days. In the olorofim-treated groups, galactomannan levels were significantly suppressed, with lower organ fungal DNA burdens being seen for all three Aspergillus spp. Histopathological slides revealed a limited number of inflammatory foci with or without detectable fungal elements in the kidneys of neutropenic CD-1 mice and in the lungs of CGD mice. Furthermore, the efficacy of olorofim was unrelated to the triazole MICs of the infecting Aspergillus spp. These results show olorofim to be a promising therapeutic agent for invasive aspergillosis.

The Orotomide Olorofim Is Efficacious in an Experimental Model of Central Nervous System Coccidioidomycosis.

Olorofim (formerly F901318) is an advanced analog of the orotomide class that inhibits fungal pyrimidine biosynthesis. We evaluated the in vitro and in vivo activities of olorofim against Coccidioides species. In vitro activity was assessed against 59 clinical Coccidioides isolates. Central nervous system infections were established in mice via intracranial inoculation with Coccidioides immitis arthroconidia. Oral therapy began 48 h postinoculation and consisted of vehicle control, olorofim daily doses of 20 mg/kg (6.67 mg/kg three times daily or 10 mg/kg twice daily) or 40 mg/kg (13.3 mg/kg three times daily or 20 mg/kg twice daily), or fluconazole (25 mg/kg twice daily). Treatment continued for 7 and 14 days in the fungal burden and survival arms, respectively. Fungal burdens were assessed by CFU counts in brains. Olorofim demonstrated potent in vitro activity (MIC range, ≤0.008 to 0.06 µg/ml). Survival was significantly enhanced in mice treated with olorofim. Reductions in brain tissue fungal burdens were also observed on day 9 in the olorofim-treated groups. Improvements in survival and reductions in fungal burdens also occurred with fluconazole. More frequent dosing of olorofim was associated with enhanced survival and greater reductions in fungal burdens. In the group treated with 13.3 mg/kg olorofim three times daily, fungal burdens remained low on day 30 (15 days after treatment was stopped), with undetectable levels in 7 of 10 mice. In contrast, fungal burdens rebounded in all other groups after therapy stopped. Olorofim was highly active in vitro and in vivo against Coccidioides These results demonstrate that olorofim may have a role in the treatment of coccidioidomycosis.

Effect of the Novel Antifungal Drug F901318 (Olorofim) on Growth and Viability of Aspergillus fumigatus.

F901318 (olorofim) is a novel antifungal drug that is highly active against Aspergillus species. Belonging to a new class of antifungals called the orotomides, F901318 targets dihydroorotate dehydrogenase (DHODH) in the de novo pyrimidine biosynthesis pathway. In this study, the antifungal effects of F901318 against Aspergillus fumigatus were investigated. Live cell imaging revealed that, at a concentration of 0.1 µg/ml, F901318 completely inhibited germination, but conidia continued to expand by isotropic growth for >120 h. When this low F901318 concentration was applied to germlings or vegetative hyphae, their elongation was completely inhibited within 10 h. Staining with the fluorescent viability dye bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC) showed that prolonged exposure to F901318 (>24 h) led to vegetative hyphal swelling and a decrease in hyphal viability through cell lysis. The time-dependent killing of F901318 was further confirmed by measuring the fungal biomass and growth rate in liquid culture. The ability of hyphal growth to recover in drug-free medium after 24 h of exposure to F901318 was strongly impaired compared to that of the untreated control. A longer treatment of 48 h further improved the antifungal effect of F901318. Together, the results of this study indicate that F901318 initially has a fungistatic effect on Aspergillus isolates by inhibiting germination and growth, but prolonged exposure is fungicidal through hyphal swelling followed by cell lysis.

EUCAST Determination of Olorofim (F901318) Susceptibility of Mold Species, Method Validation, and MICs.

Olorofim is a novel antifungal agent with in vitro activity against Aspergillus and some other molds. Here, we addressed technical aspects for EUCAST olorofim testing and generated contemporary MIC data. EUCAST E.Def 9.3.1 testing was performed comparing two plate preparation methods (serial dilution in medium [serial plates] versus predilution in DMSO [ISO plates]), two lots of olorofim, visual (visual-MIC) versus spectrophotometer (spec-MIC) reading, and four polystyrene plates using 34 to 53 Aspergillus isolates from five genera. Subsequently, olorofim MICs were compared to itraconazole, voriconazole, posaconazole, and amphotericin B MICs for 298 clinical mold isolates (2016 to 2017). Wild-type upper limits (WT-UL) were determined following EUCAST principles for epidemiologic cutoff value (ECOFF) setting. Olorofim median MICs comparing serial plates and ISO plates were identical (25/36 [69%]) or one dilution apart (11/36 [31%]). Interperson agreement for visual-MICs was 92% to 94%/100% for ≤1/≤2 dilutions, respectively. The visual-MIC values across tested microtiter plates and olorofim lots revealed only discrete differences (≤1 dilution lower for treated plates). No single spec-MIC criterion was applicable to all species. Olorofim MICs were low against 275 Aspergillus species isolates (modal MIC, 0.06 mg/liter; MIC range, < 0.004 to 0.25 mg/liter) and three dermatophytes (MICs 0.03 to 0.06 mg/liter). MICs against Fusarium were diverse, with full inhibition of F. proliferatum (MIC, 0.016), 50% growth inhibition of Fusarium solani at 1 to 2 mg/liter, and no inhibition of F. dimerum Olorofim displayed potent in vitro activity against most mold isolates and was associated with limited variation in EUCAST susceptibility testing.

Antifungal pipeline: Is there light at the end of the tunnel?

The misuse and overuse of classic antifungals have accelerated the development of resistance mechanisms, diminishing the efficacy of established therapeutic pathways and necessitating a shift towards alternative targets. Despite this pressing need for new treatments, the antifungal drug pipeline has been largely stagnant for the past three decades, primarily due to the high risks and costs associated with antifungal drug development, compounded by uncertain market returns. Extensive research durations, special patient populations and rigorous regulatory demands pose significant barriers to bringing novel antifungal agents to market. In response, the "push-pull" incentive model has emerged as a vital strategy to invigorate the pipeline and encourage innovation. This editorial critically examines the current clinical landscape and spotlights emerging antifungal agents, such as Fosmanogepix, Ibrexafungerp, and Olorofim, while also unraveling the multifaceted challenges faced in new antifungal drug development. The generation of novel antifungals offers a beacon of hope in the battle against antimicrobial resistance, but it is premature to declare them as definitive solutions. Their future role hinges on thorough clinical validation, cost-effectiveness assessments, and continuous post-marketing surveillance. Only through strategic implementation and integration with market strategies we can transform the landscape of antifungal development, addressing both the resistance crisis and the treatment challenges.

A case of Lomentospora prolificans endophthalmitis treated with the novel antifungal agent Olorofim.

PURPOSE: To report a case of endogenous Lomentospora prolificans endophthalmitis treated with the novel antifungal agent Olorofim. CASE REPORT: A 57-year-old man developed disseminated Lomentospora prolificans with right endophthalmitis on the background of immunosuppression following lung transplantation for interstitial lung disease. He was treated with early vitrectomy, intravitreal voriconazole, and systemic Olorofim, voriconazole and terbinafine. His symptoms improved and remained stable in the right eye. Eight weeks later the patient represented with Lomentopora prolificans endophthalmitis in the left eye when systemic voriconazole and terbinafine treatment were withdrawn. Despite aggressive treatment he ultimately succumbed due to vascular complications of extensive disseminated disease. CONCLUSION: We report a rare case of disseminated Lomentosporosis with panophthalmitis in an immunocompromised host with prolonged survival on systemic Olorofim, voriconazole and terbinafine in conjunction with pars plana vitrectomy and intravitreal voriconazole. Early suspicion of an opportunistic fungal infection is critical, as managing disseminated disease is often unsuccessful. Despite presumed inherent resistance, intravitreal and systemic voriconazole appeared to limit disease progression in the right eye. The potential synergistic effects of combined antifungal therapy with orotomides warrant further investigation.

Anti-Aspergillus activities of olorofim at sub-MIC levels during early-stage growth.

Olorofim, the first member of the novel class of antifungal drugs, the orotomides, shows promising anti-Aspergillus activity and is currently in phase III clinical development. Using high-throughput microscopy, we monitored olorofim's antifungal potential at sub-minimum inhibitory concentration (MIC) levels with a focus on early-stage growth. Unlike voriconazole, olorofim showed significant growth inhibitory activities against three main pathogenic Aspergillus species, Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger, at concentrations >100,000-fold below its MIC. IMPORTANCE: Among antifungal compounds in clinical development for systemic disease, the orotomide olorofim is one of only two that target a completely new mechanism of action. Olorofim is highly potent against pathogenic Aspergillus species including cryptic species that frequently show increased resistance to current agents. In this study, our primary focus was on evaluating in detail the inhibitory activity of voriconazole and olorofim against different pathogenic Aspergillus species employing high-throughput microscopy. Compared to standardized, less-sensitive visual assessment-based methods, microscopy-assisted growth monitoring allowed us to detect sub-MIC drug concentration ranges with significant inhibitory activity at early-stage growth. This revealed that olorofim exerts growth inhibition at concentrations that are several magnitudes below those of voriconazole.

The Role of Olorofim in the Treatment of Filamentous Fungal Infections: A Review of In Vitro and In Vivo Studies.

Invasive fungal infections have recently been recognized by the WHO as a major health, epidemiological, and economic issue. Their high mortality rates and the emergence of drug resistance have driven the development of new molecules, including olorofim, an antifungal belonging to a new family of compounds, the orotomides. A review was conducted on the PubMed database and the ClinicalTrials.gov website to summarize the microbiological profile of olorofim and its role in the treatment of filamentous fungal infections. Twenty-four articles were included from the search and divided into two groups: an "in vitro" group focusing on minimum inhibitory concentration (MIC) results for various fungi and an "in vivo" group evaluating the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and tolerability of olorofim in animal models of fungal infection and in humans. Olorofim demonstrated in vitro and in vivo activity against numerous filamentous fungi, including azole-resistant Aspergillus fumigatus, various dermatophytes, and endemic and dimorphic fungi. in vitro results showed higher MICs for certain Fusarium species and dematiaceous fungi Alternaria alternata and Exophiala dermatitidis; further in vivo studies are needed. Published PK-PD data in humans are limited. The results of the ongoing phase III clinical trial are eagerly awaited to evaluate olorofim's clinical impact.

In Vitro Activity of the Novel Antifungal Olorofim against Scedosporium and Lomentospora prolificans.

Scedosporium spp. and Lomentospora prolificans are an emerging group of fungi refractory to current antifungal treatments. These species largely affect immunocompromised individuals but can also be lung colonizers in cystic fibrosis patients. Although Scedosporium apiospermum is thought to be the predominant species, the group has been expanded to a species complex. The distribution of species within the S. apiospermum species complex and other closely related species in the United States is largely unknown. Here, we used ß-tubulin and ITS sequences to identify 37 Scedosporium isolates to the species level. These Scedosporium isolates as well as 13 L. prolificans isolates were tested against a panel of nine antifungal drugs, including the first in novel class orotimide, olorofim. IMPORTANCE Scedosporium and Lomentospora infections are notoriously hard to treat as these organisms can be resistant to numerous antifungals. The manuscript contributes to our knowledge of the activity of the new antifungal agent olorofim and comparator agents against Lomentospora and against Scedosporium isolates that have been molecularly identified to the species level. The efficacy of olorofim against all species of Scedosporium and Lomentospora was confirmed.

Antifungal resistance, combinations and pipeline: oh my!

Invasive fungal infections are a strong contributor to healthcare costs, morbidity and mortality, especially amongst hospitalized patients. Historically, Candida was responsible for approximately 15% of all nosocomial bloodstream infections. In the past 10 years, the epidemiology of Candida species has altered, with increasing prevalence of resistant species. With rising fungal resistance, especially in Candida spp., the demand for novel antifungal therapies has exponentially increased over the last decade. Newer antifungal agents have become an attractive option for patients needing long-term therapy for infections or those requiring antifungal prophylaxis. Despite advances in coverage of non-Candida pathogens with newer agents, clinical scenarios involving multidrug-resistant fungal pathogens continue to arise in practice. Combination antifungal therapy can lead to a host of side-effects, some of which can be drug limiting. Additional antifungal therapies with enhanced fungal spectrum of activity and decreased rates of adverse effects are warranted. Fosmanogepix, ibrexafungerp, olorofim and rezafungin may help fill some of these gaps in the antifungal armamentarium. This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections.