RESUMEN
Fosmanogepix [FMGX; active form manogepix (MGX)], a novel antifungal, is currently being studied for the treatment of invasive fungal diseases caused by Candida spp., Aspergillus spp., and other rare molds. This Phase 1, single-dose study used 14C-radiolabeled FMGX to determine the disposition and metabolism of FMGX. Ten healthy male participants were enrolled equally into: oral cohort {FMGX 500 mg oral + 3.1 megabecquerel [MBq, 84.0 microcurie (µCi)] 14C} and intravenous (IV) cohort [FMGX 600 mg IV + 3.4 MBq (93.0 µCi) 14C]. At the end of the sampling period (456 h post-dose), 90.2% of radioactivity administered was recovered (46.4% from urine; 43.8% from feces) in oral cohort (82.3% within 240 h), and 82.4% was recovered (42.5% from urine; 39.9% from feces) in IV cohort (76.2% within 264 h), indicating that FMGX elimination occurs via renal and hepatic routes. Radioactivity transformation pathways (oral and IV) indicated multiple major routes of metabolism of FMGX, mainly via MGX, and included oxidation, oxidative deamination, and conjugation. All except one key human plasma metabolite was observed in toxicity species, but its proportion (<10%) in the human area under the curve plasma samples was not of toxicological concern. No deaths, serious, or severe adverse events (AE) were reported, and there were no AE-related withdrawals. The results of this study indicated extensive metabolism of FMGX, with similar key human plasma metabolites observed in the animal studies. The elimination of FMGX was equally through renal and hepatic routes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04804059.
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Antifúngicos , Radioisótopos de Carbono , Voluntarios Sanos , Humanos , Masculino , Adulto , Antifúngicos/farmacocinética , Adulto Joven , Persona de Mediana Edad , Heces/química , Administración OralRESUMEN
Immunocompromised patients are susceptible to fungal infections, and drug-drug interactions with antifungals may occur due to concomitant medications. Fosmanogepix [FMGX; active moiety manogepix (MGX)] targets glycosylphosphatidylinositol-anchored mannoprotein synthesis and maturation, essential for fungal virulence. This phase 1, fixed-sequence study in healthy participants evaluated the effect of strong CYP3A4 inhibitor itraconazole [Cohort 1 (n = 18); FMGX 500 mg intravenous (IV) twice a day (BID )+ itraconazole 200 mg oral once a day (QD)] and pan-CYP inducer rifampin [Cohort 2 (n = 18); FMGX 1,000 mg IV BID + rifampin 600 mg oral QD] on the pharmacokinetics of FMGX and MGX. In cohort 1, geometric mean (GM) MGX Cmax, AUC0-t, and AUCinf were almost similar with and without itraconazole administration. In Cohort 2, GM MGX Cmax was slightly lower and AUC0-t and AUCinf were significantly lower after rifampin administration, with the least squares GM ratio associated 90% confidence intervals (CIs) below 80 - 125% (no effect window). No deaths, serious adverse events (SAEs), or FMGX-related withdrawals were reported. In both cohorts, a total of 188 AEs (n = 30; 186 mild; two moderate) were reported. In all, 37 of 188 AEs (n = 12) were considered FMGX related (most frequent: headache, nausea, and hot flush). Administration of FMGX alone and with itraconazole or rifampin was safe and well tolerated. A strong CYP3A4 inhibitor had no effect on FMGX or MGX exposure. A strong pan-CYP inducer had no effect on FMGX exposure but demonstrated ~45% decrease in MGX exposure. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04166669 and with EudraCT as number 2019-003586-17.
RESUMEN
Fosmanogepix (FMGX), a novel antifungal available in intravenous (IV) and oral formulations, has broad-spectrum activity against pathogenic yeasts and molds, including fungi resistant to standard of care antifungals. This multicenter, open-label, single-arm study evaluated FMGX safety and efficacy for treatment of candidemia and/or invasive candidiasis caused by Candida auris. Eligible participants were ≥18 years, with established candidemia and/or invasive candidiasis caused by C. auris, (cultured within 120 h [for candidemia] or 168 h [for invasive candidiasis without candidemia] with accompanying clinical signs) and limited treatment options. Participants were treated with FMGX (≤42 days; loading dose: 1000 mg IV twice daily [Day 1], followed by 600 mg IV once daily [QD]). Switching to oral FMGX 800 mg QD was permitted from Day 4. Primary endpoint was treatment success (survival and clearance of C. auris from blood/tissue cultures without additional antifungals) at the end of the study treatment (EOST), assessed by an independent data review committee (DRC). Day 30 survival was a secondary endpoint. In vitro susceptibility of Candida isolates was assessed. Nine participants with candidemia (male:6, female:3; 21 to 76 years) in intensive care units in South Africa were enrolled; all received IV FMGX only. DRC-assessed treatment success at EOST and Day 30 survival were 89% (8/9). No treatment related adverse events or study drug discontinuations were reported. FMGX demonstrated potent in vitro activity against all C. auris isolates (MIC range: 0.008 to 0.015 µg/mL [CLSI]; 0.004-0.03 µg/mL [EUCAST]), with the lowest MICs compared to other antifungals tested. Thus, the results showed that FMGX was safe, well-tolerated, and efficacious in participants with candidemia caused by C. auris.
Asunto(s)
Candidemia , Candidiasis Invasiva , Humanos , Masculino , Femenino , Antifúngicos/efectos adversos , Candidemia/microbiología , Candida auris , Candidiasis Invasiva/tratamiento farmacológico , Resultado del Tratamiento , Pruebas de Sensibilidad MicrobianaRESUMEN
Fosmanogepix (FMGX, APX001), a first-in-class, intravenous (i.v.) and oral (p.o.) antifungal prodrug candidate is currently in clinical development for the treatment of invasive fungal infections. Manogepix (MGX, APX001A), the active moiety of FMGX, interferes with cell wall synthesis by targeting fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, thereby causing loss of cell viability. Data from two phase 1, placebo-controlled, single-ascending dose (SAD) and multiple-ascending dose (MAD) studies evaluating safety, tolerability, and pharmacokinetics of FMGX (doses up to 1,000 mg, i.v. and p.o.) are presented. Eligible participants were healthy adults (aged 18 to 55 years) randomized to receive either FMGX or placebo. Across both phase 1 studies, 151 of 154 participants (aged 23 to 35 years; FMGX: 116, placebo: 38) completed the study. Administration of FMGX i.v. demonstrated linear- and dose-proportional pharmacokinetics of MGX in terms of geometric mean maximum concentration of drug in serum (Cmax) (SAD: 0.16 to 12.0 µg/mL, dose: 10 to 1,000 mg; MAD: 0.67 to 15.4 µg/mL, dose: 50 to 600 mg) and area under the concentration-time curve (AUC) (SAD: 4.05 to 400, MAD: 6.39 to 245 µg · h/mL). With single and repeat p.o., dose-proportional increases in Cmax (SAD: 1.30 to 6.41 µg/mL, dose: 100 to 500 mg; MAD: 6.18 to 21.3 µg/mL, dose: 500 to 1,000 mg) and AUC (SAD: 87.5 to 205, MAD: 50.8 to 326 µg · h/mL) were also observed, with high oral bioavailability (90.6% to 101.2%). Administration of FMGX p.o. under post cibum conditions improved tolerability versus ante cibum conditions. No severe treatment-emergent adverse events (TEAEs), serious AEs, or withdrawals due to a drug-related TEAEs were reported with single or multiple i.v. and p.o. doses. Preclinical target exposures were achieved and were not accompanied by any serious/unexpected concerns with generally safe and well-tolerated dose regimens.
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Antifúngicos , Infecciones Fúngicas Invasoras , Adulto , Humanos , Antifúngicos/efectos adversos , Voluntarios Sanos , Disponibilidad Biológica , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Área Bajo la Curva , Método Doble Ciego , Relación Dosis-Respuesta a DrogaRESUMEN
We performed in vitro antifungal susceptibility testing of manogepix against the yeast phase of 78 Emergomyces africanus, 2 Emergomyces pasteurianus, and 5 Blastomyces emzantsi isolates using a reference broth microdilution method following Clinical and Laboratory Standards Institute recommendations. All three pathogens had low minimum inhibitory concentrations ranging from <0.0005 to 0.008 mg/L. Manogepix should be investigated in animal models and potentially in future human clinical trials for endemic mycoses.
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Blastomyces , Saccharomyces cerevisiae , Animales , Humanos , Sudáfrica , Pruebas de Sensibilidad Microbiana , Antifúngicos/farmacologíaRESUMEN
During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and rapidly progressing fungal infection associated with high mortality and morbidity in India as well as globally. The causative agents for this infection are collectively called mucoromycetes which are the members of the order Mucorales. The diagnosis of the infection needs to be performed as soon as the occurrence of clinical symptoms which differs with types of Mucorales infection. Imaging techniques magnetic resonance imaging or computed tomography scan, culture testing, and microscopy are the approaches for the diagnosis. After the diagnosis of the infection is confirmed, rapid action is needed for the treatment in the form of antifungal therapy or surgery depending upon the severity of the infection. Delaying in treatment declines the chances of survival. In antifungal therapy, there are two approaches first-line therapy (monotherapy) and combination therapy. Amphotericin B (1) and isavuconazole (2) are the drugs of choice for first-line therapy in the treatment of mucormycosis. Salvage therapy with posaconazole (3) and deferasirox (4) is another approach for patients who are not responsible for any other therapy. Adjunctive therapy is also used in the treatment of mucormycosis along with first-line therapy, which involves hyperbaric oxygen and cytokine therapy. There are some drugs like VT-1161 (5) and APX001A (6), Colistin, SCH 42427, and PC1244 that are under clinical trials. Despite all these approaches, none can be 100% successful in giving results. Therefore, new medications with favorable or little side effects are required for the treatment of mucormycosis.
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COVID-19 , Mucorales , Mucormicosis , Humanos , Antifúngicos/uso terapéutico , Antifúngicos/farmacología , Mucormicosis/tratamiento farmacológico , Mucormicosis/diagnóstico , Mucormicosis/microbiología , Anfotericina B/uso terapéutico , Anfotericina B/farmacologíaRESUMEN
Invasive aspergillosis is the most common invasive mold infection following a hematopoietic cell transplant. Widespread use of antifungal prophylaxis has led to the increasing incidence of cryptic Aspergillus species. Aspergillus calidoustus is one of those emerging species and is notorious for multidrug resistance to antifungals. Here, we report a case of disseminated A. calidoustus infection in a hematopoietic stem cell transplant recipient who was successfully treated with combination therapy that included a novel antifungal.
Asunto(s)
Aspergilosis , Trasplante de Células Madre Hematopoyéticas , Antifúngicos/uso terapéutico , Aspergilosis/microbiología , Aspergillus , Trasplante de Células Madre Hematopoyéticas/efectos adversos , HumanosRESUMEN
We evaluated the in vitro activity of manogepix and comparator agents against 1,435 contemporary fungal isolates collected worldwide from 73 medical centers in North America, Europe, the Asia-Pacific region, and Latin America during 2020. Of the isolates tested, 74.7% were Candida spp.; 3.7% were non-Candida yeasts, including 27 Cryptococcus neoformans var. grubii (1.9%); 17.1% were Aspergillus spp.; and 4.5% were other molds. All fungal isolates were tested by reference broth microdilution according to CLSI methods. Based on MIC90 values, manogepix (MIC50/MIC90, 0.008/0.06 mg/liter) was 16- to 64-fold more active than anidulafungin, micafungin, and fluconazole against Candida spp. isolates and the most active agent tested. Similarly, manogepix (MIC50/MIC90, 0.5/1 mg/liter) was ≥8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii. Based on minimum effective concentration for 90% of the isolates tested (MEC90) and MIC90 values, manogepix (MEC90, 0.03 mg/liter) was 16- to 64-fold more potent than itraconazole, posaconazole, and voriconazole (MIC90s, 0.5 to 2 mg/liter) against 246 Aspergillus spp. isolates. Aspergillus fumigatus isolates exhibited a wild-type (WT) phenotype for the mold-active triazoles, including itraconazole (87.0% WT) and voriconazole (96.4% WT). Manogepix was highly active against uncommon species of Candida, non-Candida yeasts, and rare molds, including 11 isolates of Candida auris (MIC50/MIC90, 0.004/0.015 mg/liter) and 12 isolates of Scedosporium spp. (MEC50/MEC90, 0.06/0.12 mg/liter). Additional studies are in progress to evaluate the clinical utility of the manogepix prodrug fosmanogepix in difficult-to-treat resistant fungal infections.
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Cryptococcus neoformans , Fluconazol , Anidulafungina/farmacología , Micafungina/farmacología , Fluconazol/farmacología , Voriconazol/farmacología , Itraconazol/farmacología , Pruebas de Sensibilidad Microbiana , Antifúngicos/farmacología , Candida , Aspergillus , Farmacorresistencia FúngicaRESUMEN
Invasive pulmonary aspergillosis (IPA), invasive mucormycosis (IM), and invasive fusariosis (IF) are associated with high mortality and morbidity. Fosmanogepix (FMGX) is a first-in-class antifungal in clinical development with demonstrated broad-spectrum activity in animal models of infections. We sought to evaluate the benefit of combination therapy of FMGX plus liposomal amphotericin B (L-AMB) in severe delayed-treatment models of murine IPA, IM, and IF. While FMGX was equally as effective as L-AMB in prolonging the survival of mice infected with IPA, IM, or IF, combination therapy was superior to monotherapy in all three models. These findings were validated by greater reductions in the tissue fungal burdens (determined by quantitative PCR) of target organs in all three models versus the burdens in infected vehicle-treated (placebo) or monotherapy-treated mice. In general, histopathological examination of target organs corroborated the findings for fungal tissue burdens among all treatment arms. Our results show that treatment with the combination of FMGX plus L-AMB demonstrated high survival rates and fungal burden reductions in severe animal models of invasive mold infections, at drug exposures in mice similar to those achieved clinically. These encouraging results warrant further investigation of the FMGX-plus-L-AMB combination treatment for severely ill patients with IPA, IM, and IF.
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Fusariosis , Aspergilosis Pulmonar Invasiva , Mucormicosis , Anfotericina B/uso terapéutico , Animales , Antifúngicos/uso terapéutico , Hongos , Fusariosis/tratamiento farmacológico , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Ratones , Mucormicosis/tratamiento farmacológicoRESUMEN
Candida endophthalmitis is a serious sight-threatening complication of candidemia that may occur before or during antifungal therapy. Hematogenous Candida meningoencephalitis (HCME) is also a serious manifestation of disseminated candidiasis in premature infants, immunosuppressed children, and immunocompromised adults. We evaluated the antifungal efficacy and pharmacokinetics of the prodrug fosmanogepix (APX001) in a rabbit model of endophthalmitis/HCME. Manogepix (APX001A), the active moiety of prodrug fosmanogepix, inhibits the fungal enzyme Gwt1 and is highly active in vitro and in vivo against Candida spp., Aspergillus spp., and other fungal pathogens. Plasma pharmacokinetics of manogepix after oral administration of fosmanogepix on day 6 at 25, 50, and 100 mg/kg resulted in maximum concentration of drug in plasma (Cmax) of 3.96 ± 0.41, 4.14 ± 1.1, and 11.5 ± 1.1 µg/ml, respectively, and area under the concentration-time curve from 0 to 12 h (AUC0-12) of 15.8 ± 3.1, 30.8 ± 5.0, 95.9 ± 14 µg·h/ml, respectively. Manogepix penetrated the aqueous humor, vitreous, and choroid with liquid-to-plasma ratios ranging from 0.19 to 0.52, 0.09 to 0.12, and 0.02 to 0.04, respectively. These concentrations correlated with a significant decrease in Candida albicans burden in vitreous (>101 to 103 log CFU/g) and choroid (>101 to 103 log CFU/g) (P ≤ 0.05 and P ≤ 0.001, respectively). The aqueous humor had no detectable C. albicans in treatment and control groups. The tissue/plasma concentration ratios of manogepix in meninges, cerebrum, cerebellum, and spinal cord were approximately 1:1, which correlated with a >102 to 104 decline of C. albicans in tissue versus control (P ≤ 0.05). Serum and cerebrospinal fluid (CSF) (1â3)-ß-d-glucan levels demonstrated significant declines in response to fosmanogepix treatment. These findings provide an experimental foundation for fosmanogepix in treatment of Candida endophthalmitis and HCME and derisk the clinical trials of candidemia and invasive candidiasis.
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Endoftalmitis , Meningoencefalitis , Animales , Antifúngicos/uso terapéutico , Candida , Candida albicans , Endoftalmitis/tratamiento farmacológico , Meningoencefalitis/tratamiento farmacológico , Pruebas de Sensibilidad Microbiana , ConejosRESUMEN
Invasive aspergillosis (IA) due to Aspergillus fumigatus is a deadly infection for which new antifungal therapies are needed. Here, we demonstrate the efficacy of a Gwt1 inhibitor, APX2041, and its prodrug, APX2104, against A. fumigatus. The wild-type, azole-resistant, and echinocandin-resistant A. fumigatus strains were equally susceptible to APX2041 in vitro. APX2104 treatment in vivo significantly prolonged survival of neutropenic mice challenged with the wild-type and azole-resistant strains, revealing APX2104 as a potentially promising therapeutic against IA.
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Aspergillus fumigatus , Profármacos , Animales , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Farmacorresistencia Fúngica/genética , Isoxazoles , Ratones , Pruebas de Sensibilidad Microbiana , Profármacos/farmacologíaRESUMEN
Intra-abdominal candidiasis (IAC) is one of the most common yet underappreciated forms of invasive candidiasis. IAC is difficult to treat, and therapeutic failure and drug-resistant breakthrough infections are common in some institutions despite the use of echinocandins as first-line agents. Fosmanogepix (FMGX, formerly APX001) is a first-in-class antifungal prodrug that can be administered both intravenously and orally. FMGX is currently in phase 2 clinical development for the treatment of life-threatening invasive fungal infections. To explore the pharmacological properties and therapeutic potential of FMGX for IAC, we evaluated both drug penetration and efficacy of the active moiety manogepix (MGX, formerly APX001A) in liver tissues in a clinically relevant IAC mouse model infected with Candida albicans Matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed absolute drug quantitation were employed to evaluate drug penetration into liver abscess lesions both spatially and quantitatively. The partitioning of MGX into lesions occurred slowly after a single dose; however, robust accumulation in the lesion was achieved after 3 days of repeated dosing. Associated with this drug penetration pattern, reduction in fungal burden and clearance in the liver were observed in mice receiving the multiday FMGX regimen. In comparison, administration of micafungin resulted in marginal reduction in fungal burden at the end of 4 days of treatment. These results suggest that FMGX is a promising candidate for the treatment of IAC.
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Antifúngicos , Candidiasis Invasiva , Animales , Antifúngicos/uso terapéutico , Candidiasis Invasiva/tratamiento farmacológico , Equinocandinas , Micafungina , Ratones , Pruebas de Sensibilidad MicrobianaRESUMEN
Fosmanogepix is a novel prodrug in a new class of antifungal agents. Manogepix is the active moiety. We evaluated the CLSI and EUCAST MICs of manogepix and eight comparators against Candida auris CLSI M27-A3 susceptibility testing of manogepix was performed for 122 C. auris isolates and compared to CLSI and EUCAST MICs for manogepix and eight comparators. Differences and agreement were calculated for each compound. Wild-type upper limits (WT-ULs; the upper MIC where the wild-type distribution ends) for manogepix and correlations with other drugs' MICs were determined. Manogepix MICs (CLSI/EUCAST [mg/liter]) and WT-ULs were as follows: MIC50s, 0.008/0.016; MIC90s, 0.03/0.03; ranges, 0.001 to 0.25/0.001 to 0.125; 97.5% and 99% WT-ULs, 0.03/0.125 and 0.06/0.125, respectively. The manogepix CLSI/EUCAST MIC distributions spanned 9/8 dilutions, respectively. Significant correlation was found for all azoles, particularly fluconazole (r = 0.22 to 0.74, P < 0.05). Isolates with EUCAST manogepix MICs of ≤0.004 had 7.6-/10.2-fold-lower fluconazole CLSI/EUCAST MICs than the remaining isolates that had higher manogepix MICs. The highest essential agreement between CLSI and EUCAST results was observed for manogepix and fluconazole, with a median difference of -1 to 0 2-fold dilutions, 90th percentile absolute difference of 1, and 90 to 92% and 98 to 100% agreement within ±1 and ±2 dilutions. The lowest agreements within ±1 and ±2 dilutions were found for isavuconazole and anidulafungin (44 to 50% and 69 to 76%). The correlation between CLSI and EUCAST manogepix MICs against C. auris was excellent. Differential MICs were found, and these correlated with fluconazole MICs, suggesting that the C. auris population is a mix of wild-type isolates and non-wild-type isolates with low-grade manogepix MIC elevation, probably involving efflux pump expression. However, manogepix was the most potent agent against C. auris in this in vitro study.
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Candida , Isoxazoles , Aminopiridinas , Antifúngicos/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
Manogepix is a broad-spectrum antifungal agent that inhibits glycosylphosphatidylinositol (GPI) anchor biosynthesis. Using whole-genome sequencing, we characterized two efflux-mediated mechanisms in the fungal pathogens Candida albicans and Candida parapsilosis that resulted in decreased manogepix susceptibility. In C. albicans, a gain-of-function mutation in the transcription factor gene ZCF29 activated expression of ATP-binding cassette transporter genes CDR11 and SNQ2 In C. parapsilosis, a mitochondrial deletion activated expression of the major facilitator superfamily transporter gene MDR1.
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Transportadoras de Casetes de Unión a ATP/genética , Aminopiridinas/farmacología , Antifúngicos/farmacología , Candida albicans/genética , Candida parapsilosis/genética , Isoxazoles/farmacología , Transporte Biológico/genética , Candida albicans/efectos de los fármacos , Candida albicans/metabolismo , Candida parapsilosis/efectos de los fármacos , Candida parapsilosis/metabolismo , Farmacorresistencia Fúngica/genética , Genoma Fúngico/genética , Pruebas de Sensibilidad Microbiana , Secuenciación Completa del GenomaRESUMEN
An ongoing Candida auris outbreak in the New York metropolitan area is the largest recorded to date in North America. Laboratory surveillance revealed NY C. auris isolates are resistant to fluconazole, with variable resistance to other currently used broad-spectrum antifungal drugs, and that several isolates are panresistant. Thus, there is an urgent need for new drugs with a novel mechanism of action to combat the resistance challenge. Manogepix (MGX) is a first-in-class agent that targets the fungal Gwt1 enzyme. The prodrug fosmanogepix is currently in phase 2 clinical development for the treatment of fungal infections. We evaluated the susceptibility of 200 New York C. auris isolates to MGX and 10 comparator drugs using CLSI methodology. MGX demonstrated lower MICs than comparators (MIC50 and MIC90, 0.03 mg/liter; range, 0.004 to 0.06 mg/liter). The local epidemiological cutoff value (ECV) for MGX indicated all C. auris isolates were within the population of wild-type (WT) strains; 0.06 mg/liter defines the upper limit of wild type (UL-WT). MGX was 8- to 32-fold more active than the echinocandins, 16- to 64-fold more active than the azoles, and 64-fold more active than amphotericin B. No differences were found in the MGX or comparators' MIC50, MIC90, or geometric mean (GM) values when subsets of clinical, surveillance, and environmental isolates were evaluated. The range of MGX MIC values for six C. auris panresistant isolates was 0.008 to 0.015 mg/liter, and the median and mode MIC values were 0.015 mg/liter, demonstrating that MGX retains activity against these isolates. These data support further clinical evaluation of fosmanogepix for the treatment of C. auris infections, including highly resistant isolates.
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Antifúngicos , Candida , Aminopiridinas , Antifúngicos/farmacología , Brotes de Enfermedades , Isoxazoles , Pruebas de Sensibilidad Microbiana , New York , América del NorteRESUMEN
Manogepix (APX001A) is the active moiety of the drug candidate fosmanogepix (APX001), currently in clinical development for the treatment of invasive fungal infections. We compared manogepix EUCAST minimum effective concentrations (MECs) to MICs of five comparators and CLSI MECs and MICs by a colorimetric method against contemporary molds. EUCAST susceptibility testing was performed for 161 isolates. Interlaboratory and intermethod reproducibility were determined by comparison with published manogepix MECs. Colorimetric MICs (measuring metabolic activity) were evaluated using three Aspergillus fumigatus isolates and one Aspergillus flavus isolate with four inocula at 24 to 48 h of incubation and 1 to 3 h 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide salt (XTT)/menadione (MEN) exposure. Manogepix modal MECs (range in mg/liter) against Aspergillus species were 0.03 to 0.06 (0.008 to 0.125) and unaffected by itraconazole resistance. Manogepix was as active against two Fusarium isolates but inactive against Trichophyton interdigitale, Lichtheimia ramosa, and Rhizomucor pusillus isolates (MECs >0.5). Modal MEC/MICs were ≥3 2-fold dilutions apart without overlapping ranges comparing manogepix with amphotericin B, isavuconazole, and voriconazole against Aspergillus isolates. Manogepix and posaconazole MECs/MICs correlated for Aspergillus niger (Pearson's r = 0.711; P = 0.0044). The MEC at which 50% of the isolates tested are inhibited (MEC50), mode, and MEC90 values were within ±1 dilution in all cases compared with published EUCAST and CLSI data. The colorimetric method showed excellent agreement with the MECs when plates were inoculated with the lowest inoculum (1 × 102 CFU/ml to 2.5 × 102 CFU/ml), incubated for 24 h, and exposed for 1 to 3 h to XTT/MEN. Broad-spectrum in vitro activity of manogepix against clinically relevant molds was confirmed with excellent agreement across EUCAST and CLSI methods reported from experienced mycology laboratories. Colorimetric MIC determination warrants further investigation as a potential alternative that is less dependent on mycology expertise.
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Antifúngicos , Colorimetría , Aminopiridinas , Antifúngicos/farmacología , Arthrodermataceae , Humanos , Isoxazoles , Pruebas de Sensibilidad Microbiana , Mucorales , Reproducibilidad de los Resultados , RhizomucorRESUMEN
Mucormycosis is a life-threatening infection with high mortality that occurs predominantly in immunocompromised patients. Manogepix (MGX) is a novel antifungal that targets Gwt1, a protein involved in an early step in the conserved glycosylphosphotidyl inositol (GPI) posttranslational modification pathway of surface proteins in eukaryotic cells. Inhibition of fungal inositol acylation by MGX results in pleiotropic effects, including inhibition of maturation of GPI-anchored proteins necessary for growth and virulence. MGX has been previously shown to have in vitro activity against some strains of Mucorales. Here, we assessed the in vivo activity of the prodrug fosmanogepix, currently in clinical development for the treatment of invasive fungal infections, against two Rhizopus arrhizus strains with high (4.0 µg/ml) and low (0.25 µg/ml) minimum effective concentration (MEC) values. In both invasive pulmonary infection models, treatment of mice with 78 mg/kg or 104 mg/kg fosmanogepix, along with 1-aminobenzotriazole to enhance the serum half-life of MGX in mice, significantly increased median survival time and prolonged overall survival by day 21 postinfection compared to placebo. In addition, administration of fosmanogepix resulted in a 1 to 2 log reduction in both lung and brain fungal burden. For the 104 mg/kg fosmanogepix dose, tissue clearance and survival were comparable to clinically relevant doses of isavuconazole (ISA), which is FDA approved for the treatment of mucormycosis. These results support continued development of fosmanogepix as a first-in-class treatment for invasive mucormycosis.
Asunto(s)
Antifúngicos , Mucormicosis , Animales , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Humanos , Isoxazoles , Ratones , Pruebas de Sensibilidad Microbiana , Mucormicosis/tratamiento farmacológico , Rhizopus , Rhizopus oryzaeRESUMEN
There are limited treatment options for immunosuppressed patients with lethal invasive fungal infections due to Fusarium and Scedosporium Manogepix (MGX; APX001A) is a novel antifungal that targets the conserved Gwt1 enzyme required for localization of glycosylphosphatidylinositol-anchored mannoproteins in fungi. We evaluated the in vitro activity of MGX and the efficacy of the prodrug fosmanogepix (APX001) in immunosuppressed murine models of hematogenously disseminated fusariosis and pulmonary scedosporiosis. The MGX minimum effective concentration (MEC) for Scedosporium isolates was 0.03 µg/ml and ranged from 0.015 to 0.03 µg/ml for Fusarium isolates. In the scedosporiosis model, treatment of mice with 78 mg/kg and 104 mg/kg of body weight fosmanogepix, along with 1-aminobenzotriazole (ABT) to enhance the serum half-life of MGX, significantly increased median survival time versus placebo from 7 days to 13 and 11 days, respectively. Furthermore, administration of 104 mg/kg fosmanogepix resulted in an â¼2-log10 reduction in lung, kidney, or brain conidial equivalents/gram tissue (CE). Similarly, in the fusariosis model, 78 mg/kg and 104 mg/kg fosmanogepix plus ABT enhanced median survival time from 7 days to 12 and 10 days, respectively. A 2- to 3-log10 reduction in kidney and brain CE was observed. In both models, reduction in tissue fungal burden was corroborated with histopathological data, with target organs showing reduced or no abscesses in fosmanogepix-treated mice. Survival and tissue clearance were comparable to a clinically relevant high dose of liposomal amphotericin B (10 to 15 mg/kg). Our data support the continued development of fosmanogepix as a first-in-class treatment for infections caused by these rare molds.
Asunto(s)
Aminopiridinas/farmacología , Antifúngicos/farmacología , Fusariosis/tratamiento farmacológico , Fusarium/efectos de los fármacos , Huésped Inmunocomprometido , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Isoxazoles/farmacología , Scedosporium/efectos de los fármacos , Aminopiridinas/sangre , Aminopiridinas/farmacocinética , Animales , Antifúngicos/sangre , Antifúngicos/farmacocinética , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/microbiología , Esquema de Medicación , Combinación de Medicamentos , Fusariosis/inmunología , Fusariosis/microbiología , Fusariosis/mortalidad , Fusarium/crecimiento & desarrollo , Fusarium/inmunología , Semivida , Humanos , Infecciones Fúngicas Invasoras/inmunología , Infecciones Fúngicas Invasoras/microbiología , Infecciones Fúngicas Invasoras/mortalidad , Isoxazoles/sangre , Isoxazoles/farmacocinética , Riñón/efectos de los fármacos , Riñón/inmunología , Riñón/microbiología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/microbiología , Masculino , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Profármacos , Scedosporium/crecimiento & desarrollo , Scedosporium/inmunología , Análisis de Supervivencia , Triazoles/farmacologíaRESUMEN
Manogepix (APX001A) is the active moiety of the novel drug candidate fosmanogepix (APX001). We previously reported the broad-spectrum activity of manogepix but also observed a correlation between increased manogepix and fluconazole MICs. Here, we extended this study and included isolates with acquired fluconazole resistance. Isolates (n = 835) were identified using CHROMagar, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), and, when needed, internal transcribed spacer (ITS) sequencing. EUCAST E.Def 7.3.1 susceptibility testing included manogepix, amphotericin B, anidulafungin, micafungin, fluconazole, and voriconazole. Manogepix wild-type-upper-limit (WT-UL) values were established following EUCAST principles for the epidemiological cutoff value (ECOFF) setting allowing wild-type/non-wild-type classification. Drug-specific MIC correlations were investigated using Pearson's correlation. Manogepix modal MICs were low (range, 0.004 to 0.06 mg/liter against 16/20 included species). Exceptions were Candida krusei and Candida inconspicua and, to a lesser extent, Candida kefyr and Pichia kluyveri The activity was independent of Fks echinocandin hot spot alterations (n = 17). Adopting the WT-UL established for Candida albicans, Candida dubliniensis, Candida glabrata, Candida parapsilosis, and Candida tropicalis, 14/724 (1.9%) isolates were non-wild type for manogepix. Twelve of these (85.7%) were also non-wild type for fluconazole. A statistically significant correlation was observed between manogepix and fluconazole MICs for C. albicans, C. dubliniensis, C. glabrata, C. parapsilosis, and C. tropicalis (Pearson's r = 0.401 to 0.575) but not between manogepix and micafungin or amphotericin B MICs for any species except C. tropicalis (r = 0.519 for manogepix versus micafungin). Broad-spectrum activity was confirmed for manogepix against contemporary yeast. However, a 1 to 4 2-fold dilutions increase in manogepix MICs is observed in a subset of isolates with acquired fluconazole resistance. Further studies on the potential underlying mechanism and implication for optimal dosing are warranted.
Asunto(s)
Antifúngicos , Fluconazol , Aminopiridinas , Antifúngicos/farmacología , Candida , Farmacorresistencia Fúngica/genética , Fluconazol/farmacología , Humanos , Isoxazoles , Kluyveromyces , Pruebas de Sensibilidad Microbiana , PichiaRESUMEN
APX001, the prodrug of APX001A, is a first-in-class antifungal agent that has a potent activity against Aspergillus fumigatus The goal of current study was to determine the pharmacodynamic (PD) index and target of APX001 in an immunocompromised murine model of invasive pulmonary aspergillosis against 6 A. fumigatus isolates. Minimum effective concentration (MEC) values ranged from 0.03 to 0.06 mg/liter. Dose fractionation was performed against isolate AF293 using total doses of APX001 ranging from 81 to 768 mg/kg of body weight/day fractionated into every 3-, 6-, and 8-h regimens over a 96-h treatment duration. Efficacy was assessed by A. fumigatus quantitative PCR (qPCR) of conidial equivalents from lung homogenates. Nonlinear regression analysis using the Hill equation demonstrated that the 24-h area under the concentration-time curve (AUC)/MEC ratio was the pharmacokinetic (PK)/PD index that best correlated with efficacy (coefficient of determination [R2] = 0.79). Treatment studies with the remaining strains utilized regimens of 40 to 1,536 mg/kg of APX001 administered every 3 h for a 96-h duration. Exposure-response relationships for all strains were similar, and the median free drug AUC/MEC PK/PD targets for stasis and 1-log-kill endpoints were 47.6 and 89.4, respectively. The present studies demonstrated in vitro and in vivo APX001A/APX001 potency against A. fumigatus These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints.