<i>In Vitro</i>
            Activity of Isavuconazole against Opportunistic Fungal Pathogens from Two Mycology Reference Laboratories

Pfaller, Michael A.; Rhomberg, Paul R.; Wiederhold, Nathan P.; Gibas, Connie Fe C.; Sanders, Carmita; Fan, Hongxin; Mele, James; Kovanda, Laura; Castanheira, Mariana

doi:10.1128/aac.01230-18

Cited by 46 publications

(60 citation statements)

References 74 publications

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“…The GIZs for ISA on C. parapsilosis were close to those previously described for voriconazole and POS [23]. Conversely, ISA appeared to be less potent than POS in inhibiting the fungal growth of A. fumigatus, as the K m of ISA was 7.07 mg/L versus 3.99 mg/L for POS, in accordance with a recent study on 1 189 A. fumigatus isolates, showing that ISA displayed higher MICs than those of POS [33]. The GIZs of ISA were wider for C. parapsilosis than A. fumigatus, although ISA is indicated for mold infections, confirming that ISA is highly active in vitro on C. parapsilosis [33,34].…”

Section: Discussionsupporting

confidence: 89%

“…Conversely, ISA appeared to be less potent than POS in inhibiting the fungal growth of A. fumigatus, as the K m of ISA was 7.07 mg/L versus 3.99 mg/L for POS, in accordance with a recent study on 1 189 A. fumigatus isolates, showing that ISA displayed higher MICs than those of POS [33]. The GIZs of ISA were wider for C. parapsilosis than A. fumigatus, although ISA is indicated for mold infections, confirming that ISA is highly active in vitro on C. parapsilosis [33,34]. Both strains had a similar P max by Michaelis-Menten modeling, but the K m was clearly higher for A. fumigatus, which means that a higher concentration of ISA is needed to observe the same effect on A. fumigatus as C. parapsilosis, consistent with the literature [33,35].…”

Section: Discussionsupporting

confidence: 88%

“…The GIZs of ISA were wider for C. parapsilosis than A. fumigatus , although ISA is indicated for mold infections, confirming that ISA is highly active in vitro on C. parapsilosis . Both strains had a similar P max by Michaelis–Menten modeling, but the K m was clearly higher for A. fumigatus , which means that a higher concentration of ISA is needed to observe the same effect on A. fumigatus as C. parapsilosis , consistent with the literature .…”

Section: Discussionsupporting

confidence: 87%

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Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach

Willeman¹,

Tonini²,

Garnaud

et al. 2019

Fundamemntal Clinical Pharma

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Therapeutic drug monitoring (TDM) of antifungal triazole was recommended, except for isavuconazole (ISA) whose target trough concentrations (Cmin) need to be specified. Concerning posaconazole (POS), tablet formulation results in higher exposure but no upper Cmin threshold has been yet proposed. We aimed to investigate the pharmacokinetic–pharmacodynamic relationship of POS and ISA, using a bioassay approach as surrogate marker of antifungal activity, in order to refine the therapeutic Cmin of both antifungals. A bioassay using a cellulose disk diffusion method was performed to determine the growth inhibition zone (GIZ) of POS and ISA on Aspergillus fumigatus and Candida parapsilosis (ISA only). GIZs of plasma from patients undergoing TDM for POS (n = 136) or ISA (n = 40) were determined. GIZs of plasma patients and antifungal Cmin were highly correlated for ISA (A. fumigatus: ρ = 0.942, P < 0.0001; C. parapsilosis: ρ = 0.949, P < 0.0001) and POS (ρ = 0.922, P < 0.0001), and these relationships were represented with a Michaelis–Menten model. Based on this modeling, the recommended thresholds of 0.7, 1, and 1.25 mg/L for the POS Cmin corresponded to 50.1, 55.2, and 59.1% of the maximal GIZ, respectively. We propose an upper threshold of 4.8 mg/L for the POS Cmin and a lower threshold of 2.0 mg/L for the Cmin of ISA, as they respectively corresponded to concentrations leading to 90% and 50% of the maximal GIZ on A. fumigatus. The determination of antifungal activity using this bioassay allowed refining target Cmin of POS and ISA, especially the upper threshold of POS (4.8 mg/L) and the lower threshold of ISA (2.0 mg/L).

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 87%

See 1 more Smart Citation

Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach

Willeman¹,

Tonini²,

Garnaud

et al. 2019

Fundamemntal Clinical Pharma

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“…invasive fungal infections continue to occur and increasingly involve yeast and mold isolates that are relatively uncommon and tend to exhibit decreased susceptibility to current antifungal agents (4)(5)(6). Data from multiple sources demonstrate that mortality rates and resource utilization increase significantly when therapy is delayed or inadequate (e.g., incorrect dose or resistant isolate), further highlighting the importance of detailed epidemiological data, including the evaluation of new classes of antifungal agents (1,(7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

“…Concurrent with the increasing number of invasive fungal infections, antifungal surveillance programs have become important in defining the species distribution and resistance patterns of the responsible pathogens, providing needed information for appropriate empirical antifungal treatment (23)(24)(25)(26)(27)(28). The SENTRY Antimicrobial Surveillance Program is a global program (https://www.jmilabs.com/sentry-surveillance -program) that has been ongoing for more than 20 years (from 1997 to 2019) and collects, in each calendar year, consecutive invasive isolates of Candida, Aspergillus, and other opportunistic fungi from medical centers located in North America, Europe, Latin America, and the Asia-Pacific region (1,(29)(30)(31). Applying modern methods for species identification (e.g., sequence-based identification and matrix-assisted laser desorption ionization-time of flight mass spectrometry [MALDI-TOF MS]), testing of antifungal susceptibility, and characterization of antifungal resistance mechanisms provides a level of standardization and clarity that makes these observations useful in the ongoing fight against resistance (1,4,9,25,29,(32)(33)(34).…”

mentioning

confidence: 99%

In Vitro Activity of APX001A (Manogepix) and Comparator Agents against 1,706 Fungal Isolates Collected during an International Surveillance Program in 2017

Pfaller

Huband

Flamm

et al. 2019

Antimicrob Agents Chemother

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Current antifungal agents cover a majority of opportunistic fungal pathogens; however, breakthrough invasive fungal infections continue to occur and increasingly involve relatively uncommon yeasts and molds, which often exhibit decreased susceptibility. APX001A (manogepix) is a first-in-class small-molecule inhibitor of the conserved fungal Gwt1 protein. This enzyme is required for acylation of inositol during glycosylphosphatidylinositol anchor biosynthesis. APX001A is active against the major fungal pathogens, i.e., Candida (except Candida krusei), Aspergillus, and hardto-treat molds, including Fusarium and Scedosporium. In this study, we tested APX001A and comparators against 1,706 contemporary clinical fungal isolates collected in 2017 from 68 medical centers in North America (37.3%), Europe (43.4%), the Asia-Pacific region (12.7%), or Latin America (6.6%). Among the isolates tested, 78.5% were Candida spp., 3.9% were non-Candida yeasts, including 30 (1.8%) Cryptococcus neoformans var. grubii isolates, 14.7% were Aspergillus spp., and 2.9% were other molds. All isolates were tested by CLSI reference broth microdilution. APX001A (MIC 50 , 0.008 g/ml; MIC 90 , 0.06 g/ml) was the most active agent tested against Candida sp. isolates; corresponding anidulafungin, micafungin, and fluconazole MIC 90 values were 16-to 64-fold higher. Similarly, APX001A (MIC 50 , 0.25 g/ml; MIC 90 , 0.5 g/ml) was Ն8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii. Against Aspergillus spp., AXP001A (50% minimal effective concentration [MEC 50 ], 0.015 g/ml; MEC 90 , 0.03 g/ml) was comparable in activity to anidulafungin and micafungin. Aspergillus isolates (Ͼ98%) exhibited a wild-type phenotype for the mold-active triazoles (itraconazole, posaconazole, and voriconazole). APX001A was highly active against uncommon species of Candida, non-Candida yeasts, and rare molds, including 11 isolates of Scedosporium spp. (MEC values, 0.015 to 0.06 g/ml). APX001A demonstrated potent in vitro activity against recent fungal isolates, including echinocandin-and fluconazole-resistant strains. The extended spectrum of APX001A was also notable for its potency against many less common but antifungal-resistant strains. Further studies are in progress to evaluate the clinical utility of the methyl phosphate prodrug, APX001, in difficult-to-treat resistant fungal infections.

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Successful isavuconazole salvage therapy for cerebral mucormycosis in a child with relapsed leukemia: A light in the dark tunnel

Alali

Balsara

Khaitan

et al. 2022

Pediatric Blood & Cancer

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Central nervous system mucormycosis (CNS-M) is a rare, 1 often deadly infection 2,3 with three forms: rhinocerebral mucormycosis, disseminated mucormycosis with CNS involvement, and isolated cerebral mucormycosis (ICM). 4 ICM is the rarest type 5,6 but can be rapidly progressive with high mortality (up to 65%) despite aggressive treatment. 5 We present a case of ICM in a child with relapsed leukemia where isavuconazole (ISAV) monotherapy was successfully used as salvage therapy and the patient was able to resume chemotherapy.A 10-year-old female was diagnosed with bone marrow and CNS relapse of B-cell acute lymphoblastic leukemia (B-ALL) > 3 years after completing chemotherapy for standard risk B-ALL. She was treated per the low-risk control arm of AALL1331. 7 She was in remission at the end of block 1 and continued protocol therapy. Two weeks into block 3, she was admitted with Enterobacter cloacae bacteremia and treated with cefepime. Fevers resolved but then recurred along with leftsided headache, photophobia, emotional lability, and a superficial scalp lesion. Brain magnetic resonance imaging (MRI) showed a 4.3 × 3.7 cm abnormality in the left parieto-occipital area (Figure 1A). Serum fungal biomarkers were negative. Liposomal amphotericin B and voriconazole were initiated. Biopsy of the enhancing scalp lesion was nonconclusive. Open brain biopsy showed no leukemic involvement, and initial fungal cultures were negative. polymerase chain reaction (PCR) testing returned positive for Rhizomucor pucillus, and immunostaining was consistent with mucormycosis (Supporting Information Figure S1).Based on otherwise negative imaging, she was diagnosed with ICM.Liposomal amphotericin B dose was increased. Although micafungin is not effective for Mucormycosis, but it was added for synergism, 2,8 and voriconazole was stopped.

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In Vitro Activity of Isavuconazole against Opportunistic Fungal Pathogens from Two Mycology Reference Laboratories

Cited by 46 publications

References 74 publications

Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach

Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach

In Vitro Activity of APX001A (Manogepix) and Comparator Agents against 1,706 Fungal Isolates Collected during an International Surveillance Program in 2017

Successful isavuconazole salvage therapy for cerebral mucormycosis in a child with relapsed leukemia: A light in the dark tunnel

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