Abstract
Objectives
Olorofim is a novel antifungal agent with in vitro activity against Aspergillus and other opportunistic moulds. We investigated the in vitro activity of olorofim against a range of filamentous fungi comprising isolates of Aspergillus species, Scedosporium species, Alternaria alternata, dermatophytes, including terbinafine- and multidrug-resistant Trichophyton species, and Penicillium/Talaromyces species originating from patients in North India.
Methods
Antifungal susceptibility of olorofim was tested against 241 mould isolates of Penicillium/Talaromyces species, Trichophyton species, A. fumigatus and cryptic Aspergillus species, Scedosporium species, and Alternaria alternata using CLSI broth microdilution. The comparators were five systemic azoles, amphotericin B, terbinafine, and luliconazole.
Results
Overall, olorofim showed highly potent in vitro activity against dermatophytes and opportunistic moulds (MIC range of 0.004–0.125 mg/L) except for Alternaria alternata. Penicillium, and Talaromyces species and Trichophyton species exhibited a low geometric mean (GM) MIC (GM 0.027 mg/L and 0.015 mg/L, respectively) of olorofim. Importantly, a 2–12 dilution step decrease in in vitro activity of olorofim as compared with azoles was observed against Penicillium and Talaromyces. Notably, olorofim displayed potent in vitro activity against Trichophyton isolates including terbinafine-resistant and azole-resistant Trichophyton mentagrophytes/interdigitale with a modal MIC value of 0.008 mg/L. Further, azole-resistant A. fumigatus isolates harbouring mutations in azole target Cyp51A genes and several cryptic aspergilli displayed low MICs (range 0.004–0.03 mg/L) of olorofim. However, no in vitro activity of olorofim against Alternaria alternata was observed.
Conclusions
The potent in vitro activity of olorofim against drug-resistant dermatophytes and opportunistic moulds is promising, warranting evaluation of the clinical utility of olorofim.
Introduction
Emerging opportunistic filamentous fungal pathogens, such as Fusarium species, Scedosporium species, Penicillium species, Talaromyces species, and Lomentospora prolificans, are becoming significantly more prevalent worldwide as agents of invasive fungal infections.1 Other fungal pathogens that have gained global attention in the last few years are dermatophytes, specifically Trichophyton species exhibiting resistance to terbinafine, the first-line antifungal drug used for the treatment of dermatophytosis.2,3 Superficial fungal infections caused by dermatophytes are the most common fungal diseases in humans, affecting one billion people with skin, hair, and nail infections.4 Resistance in fungal pathogens to the currently available antifungals is presenting a major clinical challenge in human health care. In the given scenario of antifungal resistance, new antifungal therapies that act through novel mechanisms are needed to circumvent the emergence of resistance to existing therapies. Orotomides are a new class of antifungal drugs which act via the inhibition of fungal dihydroorotate dehydrogenase (DHODH), an important enzyme in pyrimidine biosynthesis that is essential for deoxyribonucleic acid synthesis. Olorofim (formerly F901318; F2G, Manchester, UK) is the most advanced representative of this novel class of antifungal compounds, and shows no significant activity against human DHODH and therefore selectively inhibits fungal pyrimidine biosynthesis, with limited toxicity and a favourable safety profile.5
This new antifungal is highly effective against a broad spectrum of filamentous moulds including Aspergillus species, and other difficult-to-treat moulds such as Fusarium species, Madurella mycetomatis, Rasamsonia species, Scedosporium species and Lomentospora prolificans, dimorphic fungi and limited number of Trichophyton species.6–9 In the present study we investigated the in vitro activity of olorofim against dermatophytes with emphasis on terbinafine and multidrug-resistant Trichophyton mentagrophytes/interdigitale species complex isolates causing epidemics of difficult-to-treat dermatophytosis in India.2,3 Terbinafine-resistant Indian Trichophyton interdigitale/mentagrophytes species complex isolates have recently been proposed as a new species, T. indotineae based on multigene phylogeny.10
Further, we also investigated the in vitro activity of olorofim against clinically significant species of Penicillium and Talaromyces (other than marneffei) isolated from patients with allergic, chronic and invasive respiratory disorders in India. Additionally, we report in vitro activity of olorofim against Alternaria alternata, Scedosporium species, azole-resistant Aspergillus fumigatus, and cryptic Aspergillus species.
Materials and methods
Fungal isolates and identification
A total of 241 mould isolates identified by sequencing the internal transcribed spacer region of the ribosomal DNA, calmodulin and β-tubulin genes were analysed. The isolates included Penicillium species (n = 47), Talaromyces species (n = 10), Trichophyton species (n = 56), Aspergillus species (n = 80), A. alternata (n = 35) and Scedosporium species (n = 13). The specimen distribution of these 185 filamentous moulds were sputum plugs and sputum (n = 109), bronchoalveolar lavage/bronchial aspirates (n = 38), endotracheal aspirates (n = 9), skin biopsies (n = 9), corneal scrapings (n = 6), nasal aspirates/polyps (n = 11), lung biopsy (n = 2) and pleural fluid (n = 1). A total of 56 Trichophyton isolates obtained from skin/scalp scrapings of patients with tinea corporis/cruris and tinea capitis were included.9,10
Antifungal susceptibility testing (AFST)
AFST was performed for olorofim (F2G Limited, Manchester, UK) and eight other drugs (itraconazole, voriconazole, isavuconazole, posaconazole, fluconazole, amphotericin B, terbinafine, and luliconazole) using the broth microdilution method according to CLSI M38-Ed3.11 For non-dermatophyte moulds, MIC endpoints were defined as the lowest concentration that produced complete inhibition of growth by visual inspection at 48 h of incubation except for Scedosporium species, which were interpreted at 72 h of incubation. The epidemiological cut-off values (ECVs) of azoles (itraconazole, voriconazole and isavuconazole, 1 mg/L) for Aspergillus fumigatus were used for analysis of MICs of azoles against filamentous moulds.12 Dermatophyte susceptibility testing was performed as described previously.2,3 MIC endpoints for all the drugs were defined as the lowest concentration that inhibited ≥80% of the growth as read visually at 72 h incubation at 35°C for T. indotineae isolates as they grew luxuriantly in 3 days, whereas, for Trichophyton rubrum and Trichophyton tonsurans, MICs were interpreted after 5 days. Terbinafine MICs of >2 mg/L for T. indotineae isolates were considered high based on the previous correlation of in vitro terbinafine MIC data with treatment outcome of patients with dermatophytosis treated with terbinafine.13
Results
Antifungal susceptibility testing
The species distribution and antifungal susceptibility profiles of isolates are shown in Table 1. Overall, olorofim had potent in vitro activity (MIC range 0.004–0.125 mg/L) with a low median MIC value of 0.008 mg/L against all filamentous moulds and dermatophytes except for A. alternata (MIC 8 mg/L). A total of 12 species of Penicillium and Talaromyces including six each were identified including the most frequently isolated species, Penicillium oxalicum (37%; n = 21) and Penicillium citrinum (31.5%; n = 18). Notably, olorofim had potent in vitro activity (MIC range 0.004–0.03 mg/L) across all isolates of Penicillium and Talaromyces species, with modal MIC value of 0.016 mg/L. Interestingly, no species-specific MIC was noted among Penicillium and Talaromyces. Further, in vitro activity of olorofim against Penicillium species was unaffected by the concomitant high multi-azole MICs in 54% of Penicillium isolates including P. citrinum, P. oxalicum, and P. chermesinum. Interestingly, all species of Talaromyces except T. atroroseus had high MICs for voriconazole (range 2–16 mg/L) but highly potent in vitro activity of olorofim (range 0.004–0.03 mg/L). Olorofim demonstrated a 2–12 dilution step decrease in in vitro activity in comparison with azoles amongst all species of Penicillium and Talaromyces.
Table 1.
The MIC distribution of tested species against olorofim and comparator antifungals using CLSI-BMD method
| Genus/species (no. of isolates) | MIC (mg/L) |
||||||
|---|---|---|---|---|---|---|---|
| OLO | ITC | VRC | ISA | POS | AMB | ||
| Penicillium | |||||||
| P. oxalicum (21) | Range | 0.008–0.03 | 0.5–2 | 0.25–8 | 0.5–8 | 0.25–1 | 0.06–1 |
| GM MICa | 0.013 | 1.26 | 1.26 | 2.69 | 0.42 | 0.12 | |
| MIC50b | 0.016 | 1 | 1 | 2 | 0.5 | 0.125 | |
| MIC90c | 0.016 | 2 | 2 | 8 | 1 | 0.25 | |
| P. citrinum (18) | Range | 0.004–0.016 | 1–4 | 1–16 | 2 | 0.25–2 | 0.25–1 |
| GM MIC | 0.12 | 2.33 | 13.72 | 2 | 0.79 | 0.63 | |
| MIC50 | 0.25 | 2 | 16 | 2 | 1 | 0.5 | |
| MIC90 | 0.25 | 4 | 16 | 2 | 1.3 | 1 | |
| P. chrysogenum (4) | Range | 0.008–0.016 | 0.125–0.5 | 0.5–1 | 0.5–1 | 0.06–0.25 | 1–2 |
| P. lanosocoeruleum (2) | Range | 0.016 | 0.25- 0.5 | 0.25 | 0.5 | 0.25 | 1 |
| P. griseofulvum (1) | MIC | 0.008 | 2 | 1 | 1 | 0.5 | 2 |
| P. chermesinum (1) | MIC | 0.004 | 4 | 4 | 2 | 1 | 0.5 |
| Talaromyces | |||||||
| T. islandicus (3) | Range | 0.016 | 0.5–4 | 2–4 | 0.5–2 | 0.5–1 | 0.5–2 |
| T. beijingensis (2) | Range | 0.008–0.03 | 16 | 4–8 | 4–8 | 0.125–16 | 0.06–0.125 |
| T. atroroseus (2) | Range | 0.004–0.016 | 1 | 0.25 | 0.25 | 0.125 | 0.06 |
| T. stollii (1) | MIC | 0.008 | 2 | 2 | 2 | 1 | 1 |
| T. cnidii (1) | MIC | 0.008 | 16 | 16 | 16 | 16 | 0.125 |
| T. fusiformis (1) | MIC | 0.016 | 2 | 4 | 1 | 1 | 1 |
| Trichophyton | |||||||
| T. indotineae d (46) | Range | 0.004–0.06 | 0.03–8 | 0.03–16 | 0.25–8 | 0.03–8 | 0.125–0.5 |
| GM MIC | 0.01 | 1.82 | 0.51 | 1.50 | 0.36 | 0.32 | |
| MIC50 | 0.008 | 4 | 0.5 | 2 | 0.25 | 0.5 | |
| MIC90 | 0.03 | 8 | 2 | 8 | 1 | 0.5 | |
| T. tonsurans e (7) | Range | 0.03–0.125 | 0.25–1 | 0.06–1 | 0.5–4 | 0.25–1 | 0.25 |
| T. rubrum f (3) | Range | 0.06 | 1 | 0.06–1 | 0.125–0.5 | 1–2 | 0.5 |
| Aspergillus | |||||||
| A. fumigatus TR34/L98H (13) | Range | 0.004 | 4–16 | 2–4 | 2–4 | 1–2 | 0.03–1 |
| GM MIC | 0.004 | 4.95 | 1.45 | 1.70 | 0.47 | 8.44 | |
| MIC50 | 0.004 | 4 | 2 | 2 | 0.5 | 8 | |
| MIC90 | 0.004 | 16 | 2 | 4 | 0.9 | 8 | |
| A. fumigatus TR46/Y121F/T289A (10) | Range | 0.004 | 0.25–1 | 4–16 | 2–8 | 0.25–0.5 | 0.125–1 |
| GM MIC | 0.004 | 0.41 | 12.13 | 6.50 | 0.33 | 8 | |
| MIC50 | 0.004 | 0.5 | 16 | 8 | 0.25 | 8 | |
| MIC90 | 0.004 | 0.55 | 16 | 8 | 0.5 | 8 | |
| A. fumigatus_G54W (6) | Range | 0.004 | 2–16 | 2–4 | 0.016–0.125 | 0.5–2 | 0.03–0.5 |
| A. fumigatus_M220I (3) | Range | 0.004 | 2–4 | 4 | 1–4 | 0.25–2 | 0.03–1 |
| A. fumigatus_F46Y (1) | MIC | 0.004 | 1 | 4 | 2 | 0.125 | 0.5 |
| A. fumigatus_ TR92/Y121F/T289A (1) | MIC | 0.004 | 0.5 | 16 | 8 | 0.5 | 80.5 |
| A. flavus (8) | Range | 0.004 | 0.25–16 | 0.125–2 | 0.125–4 | 0.125–0.5 | 0.5–2 |
| A. terreus (7) | Range | 0.004–0.016 | 0.03–0.25 | 0.03–0.125 | 0.03–0.125 | 0.03–0.125 | 0.5–2 |
| A. clavatus (7) | Range | 0.004 | 2 | 0.25–0.5 | 0.125–0.25 | 1 | 0.125–0.5 |
| A. nidulans (7) | Range | 0.004–0.016 | 0.06–2 | 0.03–16 | 0.016–8 | 0.03–1 | 0.03–8 |
| A. niger (5) | Range | 0.008–0.03 | 0.125–0.25 | 0.03–0.125 | 0.06–0.125 | 0.03–0.06 | 0.06–0.25 |
| A. tamarii (3) | Range | 0.004 | 0.06–0.125 | 0.125 | 0.125 | 0.125–0.25 | 0.03–1 |
| A. hortai (2) | Range | 0.004 | 0.125 | 0.06–0.125 | 0.03–0.125 | 0.125 | 4–16 |
| A. sydowii (2) | Range | 0.004 | 0.5–2 | 0.125–4 | 0.125–2 | 0.125–1 | 1–2 |
| A. flavipes (1) | MIC | 0.004 | 0.125 | 0.06–0.125 | 0.03–0.125 | 0.125 | 0.125 |
| A. fijiensis (1) | MIC | 0.004 | 0.125 | 0.03 | 0.06 | 0.125 | 0.06 |
| A. tritici (1) | MIC | 0.004 | 0.03 | 0.03 | 0.016 | 0.06 | 0.125 |
| A. aculeatus (1) | MIC | 0.004 | 0.03 | 0.06 | 0.125 | 0.125 | 0.03 |
| A. oryzae (1) | MIC | 0.004 | 0.5 | 0.125 | 0.125 | 0.125 | 0.25 |
| Alternaria | |||||||
| A. alternata (32) | Range | 8 | 0.03–16 | 0.03–1 | 0.25–2 | 0.125–0.5 | 1–8 |
| GM MIC | 2 | 0.94 | 0.38 | 0.91 | 0.36 | 2.16 | |
| MIC50 | 2 | 0.5 | 0.5 | 1 | 0.5 | 2 | |
| MIC90 | 2 | 16 | 0.8 | 2 | 0.5 | 4 | |
| Scedosporium | |||||||
| S. apiospermum (11) | Range | 0.004–0.06 | 0.06–2 | 0.03–0.5 | 0.016–4 | 0.25–8 | 0.25–16 |
| GM MIC | 0.009 | 0.34 | 0.11 | 0.44 | 1.13 | 7.05 | |
| MIC50 | 0.004 | 0.25 | 0.125 | 0.5 | 1 | 16 | |
| MIC90 | 0.03 | 1 | 0.25 | 2 | 4 | 16 | |
| S. aurantiacum (1) | MIC | 0.03 | 0.5 | 0.06 | 1 | 0.5 | 16 |
| S. dehoogii (1) | MIC | 0.06 | 0.25 | 0.25 | 0.5 | 0.5 | 8 |
OLO, olorofim; ITC, itraconazole; VRC, voriconazole; ISA, isavuconazole; POS, posaconazole; AMB, amphotericin B; FLC, fluconazole; TRB, terbinafine; LUZ, luliconazole. Drug concentration (10 dilutions) ranges were: ITC and VRC, 0.03–16 mg/L; ISA, POS, AMB, 0.016–8 mg/L; TRB, 0.06–32 mg/L; FLC, 0.25–128 mg/L; OLO and LUZ, 0.004–2 mg/L. For A. alternata a range of 0.016–8 mg/L were tested for OLO.
Geometric mean MICs.
MIC50, MIC at which 50% of test isolates were inhibited.
MIC90, MIC at which 90% of test isolates were inhibited.
For T. indotineae (mg/L): FLC, range, 4–128; GM MIC, 39.52; MIC50, 32; MIC90, 128. TRB, range, 0.5–32; GM MIC, 4.79; MIC50, 2; MIC90, 32. LUZ, range, 0.004–0.25; GM MIC, 0.004; MIC50, 0.004; MIC90, 0.004.
For T. tonsurans (mg/L): range for FLC, TRB and LUZ were 4–128, 0.25–2, 0.004–0.03, respectively.
For T. rubrum (mg/L): range for FLC, TRB and LUZ were 4–8, 0.25–0.5, 0.004, respectively.
Olorofim also displayed potent in vitro activity (modal MIC of 0.008 mg/L) for all Trichophyton isolates including terbinafine-resistant isolates. Notably, a low MIC range (0.004–0.06 mg/L) of olorofim against T. indotineae was observed including 67% of isolates that harboured known SQLE mutations (F397L, n = 19; and L393L, n = 3) conferring high terbinafine MICs (4–32 mg/L). Also, concomitant azole-resistant isolates of T. indotineae had low olorofim MICs (range 0.004–0.06 mg/L). Furthermore, among T. tonsurans and T. rubrum isolates, a 6 dilution step (12-fold) and a 3 dilution step (6-fold) decrease, respectively in MIC value of olorofim as compared with terbinafine was observed.
Olorofim showed potent in vitro activity against all Aspergillus species with a modal and geometric mean (GM) MIC of 0.004 mg/L including azole-resistant A. fumigatus isolates harbouring Cyp51A mutations. Interestingly, 35% of cryptic Aspergillus species that had elevated MICs of azoles (A. clavatus, A. nidulans, and A. sydowii) and a single multi-azole resistant A. flavus (itraconazole MIC >16 mg/L; voriconazole MIC 2 mg/L; isavuconazole MIC 4 mg/L) also showed a low MIC (0.004 mg/L) of olorofim. In an overall comparison of all Aspergillus species, olorofim exhibited a 5 dilution step (10-fold) decrease in modal MIC compared with voriconazole, a widely used first-line treatment drug. Further, olorofim demonstrated a low MIC range (0.004–0.06 mg/L) for Scedosporium apiospermum, Scedosporium aurantiacum, and Scedosporium dehoogii whereas A. alternata isolates showed no in vitro activity.
Discussion
In this study, olorofim displayed potent in vitro activity against clinical isolates of Penicillium species, Talaromyces species, and Trichophyton species. Notably, the potent in vitro activity of olorofim against Trichophyton included isolates of T. indotineae that exhibited multidrug and or terbinafine resistance. Similarly, potent in vitro activity was observed for multi-azole-resistant Talaromyces and Penicillium species. Further, a three dilution step difference (6-fold) among the modal MICs of T. indotineae (modal MIC 0.008 mg/L) as compared with T. tonsurans and T. rubrum isolates was observed, suggesting species-specific MIC differences among Trichophyton species. Recently, potent olorofim in vitro activity (MIC range 0.008–0.25 mg/L) against 30 Danish dermatophyte isolates has been reported using the EUCAST method.9 In recent years, T. indotineae isolates, predominantly comprising highly terbinafine-resistant Indian strains, seem to be driving an ongoing outbreak of dermatophytosis in countries other than India.10 The emergence of terbinafine resistance in dermatophytes has been observed in Iran, Japan, and Europe which can lead to epidemics or extensive infections.10,14,15 The present study also focused on the susceptibility profile of olorofim on the varied spectrum of non-marneffei species of Penicillium and Talaromyces, causative agents of rare invasive fungal diseases. Notably, species of Penicillium and Talaromyces are known for their inherent resistance to azoles and amphotericin B. A multi-centre epidemiological study conducted in Spain, FILPOP 2 (2016–17), showed a high voriconazole modal MIC of 16 mg/L against P. citrinum, which is in concordance with this study.16 Both P. citrinum and P. oxalicum have been previously reported as agents of invasive mycoses causing breakthrough infections in patients on voriconazole therapy.17,18 In the present study, a 1–9 dilution step (2–18-fold) and a 2–12 dilution step (4–24-fold) decrease in in vitro activity of olorofim as compared with amphotericin B and systemic azoles, respectively, were observed, suggesting the novel antifungal to be a promising candidate in treatment of infections with Penicillium and Talaromyces species.
In concordance with previous reports the Indian azole-resistant A. fumigatus isolates harbouring TR34/L98H, TR46/Y121F/T289A, and TR92/Y121F/T289A, and Scedosporium species showed high susceptibility to olorofim.19,20 The favourable in vitro activity of olorofim against multidrug- and terbinafine-resistant dermatophytes could indicate the drug as a potential antifungal agent against dermatophyte infections. Further studies on in vitro susceptibility data of olorofim encompassing geographically distinct dermatophytes and its evaluation in patients with superficial dermatophyte infections are warranted. In conclusion, olorofim in vitro activity against pathogenic moulds such as Penicillium species, Talaromyces species, Trichophyton species, Aspergillus species, and Scedosporium species shows a promising aid in treatment, as these pathogens are gaining global recognition in healthcare settings due to increasing antifungal resistance.
Funding
This work was supported by a grant from F2G to J.F.M. and in part by a research grant from the Council of Scientific & Industrial Research, India [F. No. 09/174(0068)/2014-EMR-I] to A.S.
Transparency declarations
J.F.M. received grants from F2G and Pulmozyme. He has been a consultant to Scynexis and has received speaker’s fees from United Medical, TEVA and Gilead. All other authors have none to declare. The authors alone are responsible for the content and writing of the paper.
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