The Role of Olorofim in the Treatment of Filamentous Fungal Infections: A Review of In Vitro and In Vivo Studies
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. In Vitro Studies
Genus and Species | Reference | Method | Number of Strains | GM MIC (mg/L) | MIC50 (mg/L) | MIC90 (mg/L) |
---|---|---|---|---|---|---|
Aspergillus spp. | ||||||
Aspergillus alabamensis (Terrei complex) | [11] | CLSI | 8 | 0.016 | 0.03 | |
Aspergillus alliaceus (Flavi complex) | [12] | EUCAST | 20 | 0.024 | 0.03 | 0.03 |
Aspergillus aureoterreus (Terrei complex) | [12] | EUCAST | 3 | 0.015 | ND | ND |
Aspergillus calidoustus (Usti complex) | [6] | EUCAST | 25 | 0.25 | 0.5 | |
[12] | EUCAST | 20 | 0.098 | 0.125 | 0.25 | |
Aspergillus carneus (Terrei complex) | [12] | EUCAST | 3 | 0.019 | ND | ND |
Aspergillus citrinoterreus (Terrei complex) | [12] | EUCAST | 5 | 0.015 | ND | ND |
[11] | CLSI | 27 | 0.016 | 0.03 | ||
Aspergillus flavus SC | [6] | EUCAST | 10 | 0.03 | 0.06 | |
[7] | EUCAST | 12 | 0.050 | |||
[8] | EUCAST | 48 | 0.029 | 0.03 | 0.06 | |
Aspergillus fumigatiaffinis (Fumigati complex) | [12] | EUCAST | 10 | 0.016 | 0.016 | 0.016 |
Aspergillus fumigatus stricto sensu azole-resistant | [6] | EUCAST | 133 | |||
25 TR34/L98H | 0.125 | 0.125 | ||||
25 TR46/Y121F/T289A | 0.125 | 0.125 | ||||
33 point mutations | 0.03 | 0.06 | ||||
50 other mechanism | 0.06 | 0.125 | ||||
[7] | EUCAST | 22 | 0.042 | |||
[8] | EUCAST | 112 | 0.058 | 0.06 | 0.125 | |
[9] | CLSI | 5 TR34/L98H | 0.008 | |||
[10] | EUCAST | 4 | 0.031 | |||
Aspergillus fumigatus wild-type | [6] | EUCAST | 10 | 0.06 | 0.125 | |
[7] | EUCAST | 213 | 0.037 | |||
[8] | EUCAST | 920 | 0.053 | 0.06 | 0.06 | |
[9] | CLSI | 246 | 0.008 | |||
[10] | EUCAST | 107 | 0.025 | 0.03 | 0.03 | |
Aspergillus hiratsukae (Fumigati complex) | [12] | EUCAST | 7 | 0.016 | 0.016 | 0.016 |
Aspergillus hortai (Terrei complex) | [12] | EUCAST | 2 | 0.015 | ND | ND |
[11] | CLSI | 13 | 0.016 | 0.03 | ||
Aspergillus insuetus (Usti complex) | [12] | EUCAST | 3 | 0.196 | ND | ND |
Aspergillus keveii (Usti complex) | [12] | EUCAST | 2 | 0.085 | ND | ND |
Aspergillus lentulus (Fumigati complex) | [12] | EUCAST | 20 | 0.017 | 0.016 | 0.03 |
Aspergillus nidulans SC | [6] | EUCAST | 10 | 0.125 | 0.125 | |
[8] | EUCAST | 17 | 0.069 | 0.06 | 0.125 | |
Aspergillus niger SC | [7] | EUCAST | 17 | 0.052 | ||
[8] | EUCAST | 129 | 0.08 | 0.06 | 0.125 | |
Aspergillus ochraceus (Circumdati complex) | [12] | EUCAST | 10 | 0.02 | 0.016 | 0.03 |
Aspergillus sclerotiorum (Circumdati complex) | [12] | EUCAST | 5 | 0.017 | ND | ND |
Aspergillus terreus SC | [7] | EUCAST | 5 | 0.022 | ||
[8] | EUCAST | 64 | 0.023 | 0.03 | 0.06 | |
Aspergillus terreus stricto sensu | [11] | CLSI | 42 | 0.004 | 0.008 | |
Aspergillus thermomutatus (Fumigati complex) | [8] | EUCAST | 11 | 0.057 | 0.06 | 0.125 |
[12] | EUCAST | 10 | 0.016 | 0.016 | 0.016 | |
Aspergillus tubingensis (Nigri complex) | [6] | EUCAST | 25 | 0.03 | 0.06 | |
[8] | EUCAST | 18 | 0.087 | 0.06 | 0.125 | |
[12] | EUCAST | 20 | 0.051 | 0.06 | 0.06 | |
Aspergillus udagawae (Fumigati complex) | [12] | EUCAST | 10 | 0.016 | 0.016 | 0.016 |
Other fungi | ||||||
Alternaria alternata | [16] | CSLI | 32 | 2 | 2 | 2 |
Coccidioides immitis | [23] | CLSI | 21 | 0.009 | <0.008 | 0.016 |
Coccidioides posadasii | [23] | CLSI | 24 | 0.009 | <0.008 | 0.016 |
Exophiala dermatitidis | [18] | EUCAST | 10 | ND | >4 | |
Fusarium oxysporum SC | [17] | CLSI | 45 | 0.515 | 0.5 | 4 |
[9] | CLSI | 5 | 2 | |||
Fusarium solani SC | [17] | CLSI | 16 | ND | >4 | >4 |
[9] | CLSI | 11 | >2 | |||
Lomentospora prolificans | [13] | CLSI | 7 | 0.168 | 0.125 | 0.25 |
[14] | CLSI | 30 | 0.26 | 0.25 | 0.25 | |
[15] | EUCAST | 30 | 0.115 | 0.125 | 0.25 | |
[18] | EUCAST | 20 | 0.202 | |||
Madurella mycetomatis | [19] | Modified CLSI | 21 | 0.016 | 0.06 | |
Microascus/Scopulariopsis spp. | [20] | CLSI | 59 | 0.033 | 0.03 | 0.125 |
penicillium spp. | [20] | CLSI | 28 | 0.021 | 0.016 | 0.25 |
pseudallescheria ellipsoidea (S. apiospermum complex) | [15] | EUCAST | 10 | 0.052 | 0.06 | 0.125 |
Rasamsonia argillacea SC | [18] | EUCAST | 23 | ND | <0.008 | |
[20] | CLSI | 46 | ND | <0.008 | <0.008 | |
Scedosporium apiospermum stricto sensu | [13] | CLSI | 43 | 0.079 | 0.06 | 0.25 |
[14] | CLSI | 10 | 0.016 | 0.125 | 0.25 | |
[15] | EUCAST | 30 | 0.05 | 0.06 | 0.125 | |
[16] | CLSI | 11 | 0.009 | 0.004 | 0.03 | |
Scedosporium aurantiacum | [13] | CLSI | 6 | 0.193 | 0.125 | 0.5 |
[15] | EUCAST | 20 | 0.13 | 0.125 | 0.25 | |
Scedosporium boydii (S. apiospermum complex) | [13] | CLSI | 15 | 0.046 | 0.06 | 0.06 |
[15] | EUCAST | 30 | 0.04 | 0.03 | 0.125 | |
Scedosporium dehoogii | [13] | CLSI | 2 | ND | 0.125 | 0.5 |
[15] | EUCAST | 3 | 0.095 | ND | ND | |
Sporothrix brasiliensis | [22] | CLSI | 52 | 0.026 | 0.03 | 0.125 |
Talaromyces spp. | [20] | CLSI | 27 (of which 7 T. marneffei) | 0.008 | <0.008 | 0.016 |
Talaromyces marneffei | [21] | CLSI | 32 | 0.0005 | 0.0005 | 0.0005 |
Trichophyton indotineae | [16] | CLSI | 46 | 0.01 | 0.008 | 0.03 |
Trichophyton rubrum | [8] | EUCAST | 24 | 0.048 | 0.06 | 0.06 |
3.2. In Vivo Studies
Reference Study Type | Population | OLR Dose Route | PK/PD | Safety Tolerability |
---|---|---|---|---|
[11] Preclinical | neutropenic CD-1 male mice infected by an Aspergillus terreus strain (OLR MIC = 0.008 mg/L) | 10 mg/kg/q12h orally or IV | Cmin orally = 0.8 mg/L Cmin IV = 0.3 mg/L AUC0–24h ≈ 22.5 mg·h/L | No adverse events |
[24] Preclinical | neutropenic CD-1 male mice infected by wild-type and TR34/L98H Aspergillus fumigatus strains (OLR MIC = 0.03 mg/L) | 24 mg/kg/q24h or 8 mg/kg/q8h or 15 mg/kg/q8h IV | Linear PK between 4 and 15 mg/kg/q8h; Protein binding ≈ 99%; Time-dependent antifungal effect:
| No adverse events * |
[25] Preclinical | neutropenic CD-1 male mice infected by Aspergillus flavus strains (OLR MIC = 0.03 mg/L) | 24 mg/kg/q24h or 8 mg/kg/q8h or 15 mg/kg/q8h IV | Serum GM total suppression for Cmin = 0.3 mg/L and Cmin/MIC ≈ 10 in the invasive sinusitis cellular model and near-total suppression for 15 mg/kg/q8h in the sinopulmonary aspergillosis murine model; 27% reduction in serum GM comparable to that of a posaconazole AUC = 47 mg·h/L achieved for a mean Cmin/MIC = 13.38 [9,10,11,12,13,14,15,16,17,18,19] | NM |
[26] Preclinical | neutropenic CD-1 female mice infected by a wild-type A. fumigatus strain (OLR MIC = 0.008 mg/L) | 2.5–5–10–15–20 mg/kg single dose IP | Linear PK between 2.5 and 20 mg/kg; Area under the concentration–time curve linearly correlated to the dose (R = 0.96); Tmax reached within 0.5 h between 2.5 and 15 mg/kg; Cmin above the efficacy level required as seen on other murine models for doses 10, 15 and 20 mg/kg | No adverse events |
[29] Phase I double-blind, randomized, placebo-controlled clinical trial | 40 healthy male volunteers aged between 18 and 45 years divided into 5 cohorts of 8 | 0.25–0.75–1.5–3–4 mg/kg single dose IV | NM | Serious AE: 0% Minor AE: 16.67% (i.e., epistaxis, paresthesia, headache, eczema) |
Reference | Infection Model Fungus (OLR MIC) Population | Control | OLR Route OLR Dose TT Duration | Measurement (Method) | Efficacy |
---|---|---|---|---|---|
[11] | Invasive systemic infection through IV inoculation in a neutropenic murine model Aspergillus terreus (0.008 mg/L) 10 male neutropenic CD-1 mice per group | Placebo IV excipient 1 mg/kg/day IV Amphotericin B | Oral or IV 10 mg/kg/q12h 9 days | Survival on day 10 (log-rank test) Renal fungal burden on death or on day 10 (CFU) | Survival on day 10 vs. placebo Better survival rates in OLR-treated mice than in placebo-treated mice (p ≤ 0.0001). No significant difference in survival rates between the IV and oral route. |
Renal fungal burden on day 10 Reduction in fungal burden in OLR-treated mice as compared to placebo-treated mice (p ≤ 0.0001). | |||||
[23] | CNS infection in a murine model Coccidioides immitis (0.016 mg/L) 10 male ICR mice per group | Placebo oral excipient 25 mg/kg × 2/day oral fluconazole | Oral 20 mg/kg/day in 2 or 3 administrations 40 mg/kg/day in 2 or 3 administrations 14 days | Survival on day 30 (log-rank test) | Survival on day 30 vs. placebo Significantly higher median survival time in OLR- and FLC-treated mice than in placebo-treated mice (p ≤ 0.0001), with no significant difference in the total survival rate compared to placebo for mice treated with OLR 20 mg/kg in 2 or 3 administrations nor mice treated with OLR 40 mg/kg in 2 administrations. Mice treated with OLR 40 mg/kg in 3 administrations presented the highest total survival rate (p = 0.0007). |
[23] | CNS infection in a murine model Coccidioides immitis (0.016 mg/L) 10 male ICR mice per group | Placebo oral excipient 25 mg/kg × 2/day oral fluconazole | Oral 20 mg/kg/day in 2 or 3 administrations 40 mg/kg/day in 2 or 3 administrations 14 days | Brain fungal burden on day 9 (CFU) Brain fungal burden at death or on day 30 for survivors (CFU) | Brain fungal burden on day 9 vs. placebo Significant log10 reduction of median fungal burden in mice treated with FLC and OLR 40 mg/kg (p ≤ 0.0001) as compared to placebo-treated mice and other OLR regimens. |
Brain fungal burden on day 30 vs. placebo Only mice treated with OLR 40 mg/kg maintained a significant log10 reduction of the median fungal burden on day 30. Mice treated with FLC or other OLR regimens showed no significant differences with placebo-treated mice. | |||||
[25] | Invasive sinopulmonary infection through nasal inoculation in a neutropenic murine model Aspergillus flavus 4 strains (0.03 mg/L) 10 male neutropenic CD-1 mice per group, per strain | Placebo IV excipient 20 mg/kg/day oral posaconazole | IV 24 mg/kg/q24h or 8 mg/kg/q8h or 15 mg/kg/q8h 3 days | Survival on day 10 (log-rank test) Pulmonary histology on day 3 (GMS) | Survival on day 10 vs. placebo Better apparent median survival time and total survival rates than placebo for OLR doses of 8 mg/kg/q8h and 15 mg/kg/q8h (p not mentioned). |
Pulmonary histology on day 3 vs. placebo Few or no fungal elements in OLR-treated mice as compared to placebo-treated mice, where severe inflammation, necrosis, hemorrhage, edema, necrotizing vasculitis, vascular invasion, and thrombosis were observed. | |||||
[26] | Invasive systemic infection through IV inoculation in a neutropenic murine model Aspergillus fumigatus (0.008 mg/L) Aspergillus nidulans (0.008 mg/L) Aspergillus tanneri (0.06 mg/L) 17 female neutropenic CD-1 mice per group: 10 for survival study, 3 for GM measurement and histology, 4 for fungal burden measurement | Placebo IP PBS | IP 15 mg/kg/q8h 9 days | Survival on day 10 (log-rank test) Serum GM On day 3 and day 10 (EIA) Renal fungal burden on day 3 (qpCR) Renal histology on day 3 (GMS) | Survival on day 10 vs. placebo Better apparent survival rates independently of the strain in OLR-treated mice as compared to placebo-treated mice (p not mentioned). |
Serum GM on day 3 vs. placebo Lower serum GM levels in OLR-treated mice than in placebo-treated mice (p not mentioned). | |||||
Renal fungal burden on day 3 vs. placebo Three- to six-fold significant reduction of the mean fungal burden in OLR-treated mice as compared to placebo-treated mice (p ≤ 0.0001 in the A. fumigatus model, p ≤ 0.05 in the A. nidulans and A. tanneri models). | |||||
Renal histology on day 3 vs. placebo Few or no fungal elements in OLR-treated mice as compared to placebo-treated mice, where abundant hyphae, severe inflammatory infiltrations, and necrosis were observed. | |||||
[26] | Invasive systemic infection through inhalation in a CGD murine model Aspergillus fumigatus (0.008 mg/L) Aspergillus nidulans (0.008 mg/L) Aspergillus tanneri (0.06 mg/L) 17 male gp91-/- phox CD-1 mice per group: 10 for survival study, 3 for GM measurement and histology, 4 for fungal burden measurement | Placebo IP PBS | IP 15 mg/kg/q8h 9 days | Survival on day 10 (log-rank test) Serum GM On day 3 and day 10 (EIA) Pulmonary fungal burden on day 3 (qpCR) Pulmonary histology on day 3 (GMS) | Survival on day 10 vs. placebo Better apparent survival rates independently of the strain in OLR-treated mice as compared to placebo-treated mice (p not mentioned). |
Serum GM on day 3 vs. placebo Lower serum GM levels in OLR-treated mice than in placebo-treated mice (p not mentioned). | |||||
Pulmonary fungal burden on day 3 vs. placebo Eight- to twenty-two-fold significant reduction in the mean fungal burden in OLR-treated mice as compared to placebo-treated mice (p ≤ 0.01 in the A. fumigatus model, p ≤ 0.001 in the A. nidulans model, p ≤ 0.0001 in the A. tanneri model). | |||||
Pulmonary histology on day 3 vs. placebo Few or no fungal elements in OLR-treated mice as compared to placebo-treated mice, where abundant hyphae and extensive necrotic granulomas were observed. | |||||
[26] | Invasive systemic infection through inhalation in a CGD murine model Aspergillus fumigatus (0.008 mg/L) Aspergillus nidulans (0.008 mg/L) Aspergillus tanneri (0.06 mg/L) 14 male gp91-/- phox CD-1 mice per group | Placebo IP PBS 20 mg/kg/day IP voriconazole | IP 15 mg/kg/q8h 9 days | Survival on day 10 (log-rank test) Pulmonary histology on day 3 (HE) | Survival on day 10 vs. placebo Better apparent survival rates independently of the strain in OLR-treated mice and VOR-treated mice as compared to placebo-treated mice (p not mentioned). VOR-treated mice seemed to have a better survival rate than OLR-treated mice in the A. fumigatus model. In the A. nidulans and A. tanneri models, OLR-treated mice seemed to have a better survival rate than VOR-treated mice. |
Pulmonary histology on day 3 vs. placebo Few or no fungal elements in OLR-treated mice as compared to placebo-treated mice, where abundant hyphae and extensive necrotic granulomas were observed. Few or no fungal elements in VOR-treated mice, except in the A. tanneri model, where abundant hyphae and extensive necrotic granulomas were observed, as in the placebo-treated mice. | |||||
[27] | Invasive systemic infection through IV inoculation in a neutropenic murine model Scedosporium apiospermum (0.016 mg/L) Scedosporium boydii (0.016 mg/L) Lomentospora prolificans (0.03 mg/L) 17 female neutropenic CD-1 mice per group: 10 for survival study, 3 for BD measurement and histology, 4 for fungal burden measurement | Placebo IP PBS | IP 15 mg/kg/q8h 9 days | Survival on day 10 (log-rank test) Serum BD on day 3 (colorimetric assay) Renal fungal burden on day 3 (qpCR) Renal histology on day 3 (GMS) | Survival on day 10 vs. placebo Better apparent survival rates independently of the strain in OLR-treated mice as compared to placebo-treated mice (p not mentioned). |
Serum BD on day 3 vs. placebo Significantly lower serum BD levels in OLR-treated mice than in placebo-treated mice (p ≤ 0.001 in the S. apiospermum and S. boydii models, p ≤ 0.0001 in the L. prolificans model). | |||||
Renal fungal burden on day 3 vs. placebo Four- to six-fold significant reduction in the mean fungal burden in OLR-treated mice as compared to placebo-treated mice (p ≤ 0.0001 in the S. apiospermum and S. boydii models, p ≤ 0.01 in the L. prolificans model). | |||||
Renal histology on day 3 vs. placebo Few or no fungal elements in OLR-treated mice as compared to placebo-treated mice, where abundant hyphae and extensive necrotic granulomas were observed. | |||||
[28] | Dermatophytosis in an immunosuppressed guinea pig model Microsporum gypseum (0.03 mg/L) 9 albino female guinea pigs immunosuppressed by corticosteroids, divided into 3 groups | Placebo topical PEG300 1% topical clotrimazole | Topical 100 µL of 0.1 mg/mL of olorofim in PEG300 7 days | Surface scrapings from inoculation site (optical microscopy) | Scrapings on day 7 of TT vs. placebo No fungal elements in OLR-treated guinea pigs as compared to placebo-treated guinea pigs, which presented persistent alopecia and skin lesions. OLR-treated guinea pigs also presented an apparent reduction in skin lesions and faster capillary regrowth in comparison to CTZ-treated guinea pigs. |
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Feuss, A.; Bougnoux, M.-E.; Dannaoui, E. The Role of Olorofim in the Treatment of Filamentous Fungal Infections: A Review of In Vitro and In Vivo Studies. J. Fungi 2024, 10, 345. https://doi.org/10.3390/jof10050345
Feuss A, Bougnoux M-E, Dannaoui E. The Role of Olorofim in the Treatment of Filamentous Fungal Infections: A Review of In Vitro and In Vivo Studies. Journal of Fungi. 2024; 10(5):345. https://doi.org/10.3390/jof10050345
Chicago/Turabian StyleFeuss, Aliosha, Marie-Elisabeth Bougnoux, and Eric Dannaoui. 2024. "The Role of Olorofim in the Treatment of Filamentous Fungal Infections: A Review of In Vitro and In Vivo Studies" Journal of Fungi 10, no. 5: 345. https://doi.org/10.3390/jof10050345