Olorofim effectively eradicates dermatophytes in vitro and in vivo

2021 ◽  
Author(s):  
Esmat Mirbzadeh Ardakani ◽  
Atefeh Sharifirad ◽  
Nasrin Pashootan ◽  
Mahsa Nayebhashemi ◽  
Mozhgan Zahmatkesh ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Skin Lesions ◽  
Growth Patterns ◽  
Pig Model ◽  
Antifungal Compound ◽  
Post Inoculation ◽  
Microsporum Gypseum ◽  
Guinea Pig Model

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 anti-mycotic compounds. Olorofim, is a newly developed antifungal compound, which 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/L). 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 seven days post-inoculation. Following one 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.

scholarly journals 672. Activity of Ibrexafungerp (Formerly SCY-078) Against Candida auris: In vitro, In Vivo, and Clinical Case Studies of Candidemia

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S307-S307
Author(s):  
Stephen Barat ◽  
Katyna Borroto-Esoda ◽  
Mahmoud Ghannoum ◽  
Elizabeth Berkow ◽  
David A Angulo
Keyword(s):  
Guinea Pig ◽  
Murine Model ◽  
The United States ◽  
In Vitro Studies ◽  
Pig Model ◽  
Cutaneous Infection ◽  
Candida Auris ◽  
Guinea Pig Model

Abstract Background Candida auris is a growing global threat; a pathogen associated with high mortality (up to 60%), multidrug resistance, the ability to spread from person-to-person and surface-to-person, presenting high risk for outbreaks in healthcare facilities. Ibrexafungerp is a novel IV/oral glucan synthase inhibitor (triterpenoid) antifungal with activity against Candida, Aspergillus, and Pneumocystis spp., in Phase 3 development. Methods In vitro studies tested ibrexafungerp against >100 clinical isolates of C. auris. Other in vitro studies evaluated the effects of ibrexafungerp against C. auris biofilms. In vivo activity against C. auris was evaluated using a disseminated murine model and a cutaneous infection guinea pig model. In humans, an ongoing open-label trial of ibrexafungerp for treatment of patients with infections caused by C. auris (the CARES study) has been initiated in the United States and India. Results In vitro and in vivo studies demonstrated that ibrexafungerp is active against C. auris, including MDR strains. The MIC mode for ibrexafungerp was 1 μg/mL and the MIC50 and MIC90 were 0.5 and 1 μg/mL, respectively. Many echinocandin-resistant C. auris isolates have shown susceptibility to ibrexafungerp. Furthermore, ibrexafungerp has been shown to reduce biofilm thickness. In animal models of C. auris infection, treatment with ibrexafungerp resulted in improved survival and reduced fungal burden in both the murine model of disseminated infection and the guinea pig model of cutaneous infection as compared with untreated controls. In humans, two patients with difficult to treat C. auris candidemias were enrolled in the CARES study and responded positively to oral ibrexafungerp with eradication of the infection. Conclusion These data demonstrate that ibrexafungerp possess potent in vitro and in vivo activity as well as promising clinical activity. Therefore, continued clinical evaluation of ibrexafungerp as an option to treat C. auris infections is warranted. Disclosures All authors: No reported disclosures.

In vivo induction of neutrophil extracellular traps by Mycobacterium tuberculosis in a guinea pig model

2017 ◽  
Vol 23 (7) ◽  
pp. 625-637 ◽  
Author(s):  
Georgina Filio-Rodríguez ◽  
Iris Estrada-García ◽  
Patricia Arce-Paredes ◽  
María M Moreno-Altamirano ◽  
Sergio Islas-Trujillo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Guinea Pig ◽  
Neutrophil Extracellular Traps ◽  
Post Inoculation ◽  
Extracellular Traps ◽  
Guinea Pig Model ◽  
In Vivo Induction ◽  
Proteins And Peptides

In 2004, a novel mechanism of cellular death, called ‘NETosis’, was described in neutrophils. This mechanism, different from necrosis and apoptosis, is characterized by the release of chromatin webs admixed with microbicidal granular proteins and peptides (NETs). NETs trap and kill a variety of microorganisms. Diverse microorganisms, including Mycobacterium tuberculosis, are NET inducers in vitro. The aim of this study was to examine whether M. tuberculosis can also induce NETs in vivo and if the NETs are bactericidal to the microorganism. Guinea pigs were intradermally inoculated with M. tuberculosis H37Rv, and the production of NETs was investigated at several time points thereafter. NETs were detected as early as 30 min post-inoculation and were clearly evident by 4 h post-inoculation. NETs produced in vivo contained DNA, myeloperoxidase, elastase, histones, ROS and acid-fast bacilli. Viable and heat-killed M. tuberculosis, as well as Mycobacterium bovis BCG were efficient NET inducers, as were unilamellar liposomes prepared with lipids from M. tuberculosis. In vitro, guinea pig neutrophils also produced NETs in response to M. tuberculosis. However, neither the in vivo nor the in vitro-produced NETs were able to kill M. tuberculosis. Nevertheless, in vivo, neutrophils might propitiate recruitment and activation of more efficient microbicidal cells.

scholarly journals Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model

2015 ◽  
Vol 96 (12) ◽  
pp. 3484-3492 ◽  
Author(s):  
Stuart D. Dowall ◽  
Andrew Bosworth ◽  
Robert Watson ◽  
Kevin Bewley ◽  
Irene Taylor ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Ebola Virus ◽  
Pig Model ◽  
Human Populations ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Highly Pathogenic ◽  
Guinea Pig Model

Ebola virus (EBOV) is highly pathogenic, with a predisposition to cause outbreaks in human populations accompanied by significant mortality. Owing to the lack of approved therapies, screening programmes of potentially efficacious drugs have been undertaken. One of these studies has demonstrated the possible utility of chloroquine against EBOV using pseudotyped assays. In mouse models of EBOV disease there are conflicting reports of the therapeutic effects of chloroquine. There are currently no reports of its efficacy using the larger and more stringent guinea pig model of infection. In this study we have shown that replication of live EBOV is impaired by chloroquine in vitro. However, no protective effects were observed in vivo when EBOV-infected guinea pigs were treated with chloroquine. These results advocate that chloroquine should not be considered as a treatment strategy for EBOV.

scholarly journals VT-1161 Dosed Once Daily or Once Weekly Exhibits Potent Efficacy in Treatment of Dermatophytosis in a Guinea Pig Model

2015 ◽  
Vol 59 (4) ◽  
pp. 1992-1997 ◽  
Author(s):  
E. P. Garvey ◽  
W. J. Hoekstra ◽  
W. R. Moore ◽  
R. J. Schotzinger ◽  
L. Long ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Oral Treatment ◽  
Plasma Concentrations ◽  
Pig Model ◽  
Pharmacokinetic Studies ◽  
Once Daily ◽  
Guinea Pig Model ◽  
Oral Doses

ABSTRACTCurrent therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potentin vitroantifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 μg/ml. In pharmacokinetic studies supporting testing in a guinea pig model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potentialin vivoefficacy with once-daily and possibly once-weekly dosing. Subsequently, in a guinea pig dermatophytosis model utilizingTrichophyton mentagrophytesand at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction (P< 0.001) and improvement in clinical scores (P< 0.001). The efficacy profile of VT-1161 was equivalent to those for doses and regimens of itraconazole and terbinafine except that VT-1161 was superior to itraconazole when each drug was dosed once weekly (P< 0.05). VT-1161 was distributed into skin and hair, with plasma and tissue concentrations in all treatment and regimen groups ranging from 0.8 to 40 μg/ml (or μg/g), at or above the MIC against the isolate used in the model (0.5 μg/ml). These data strongly support the clinical development of VT-1161 for the oral treatment of onychomycosis using either once-daily or once-weekly dosing regimens.

Antifungal activities of Astragalus verus Olivier. against Trichophyton verrucosum on in vitro and in vivo guinea pig model of dermatophytosis

Mycoses ◽  
2011 ◽  
Vol 55 (4) ◽  
pp. 318-325 ◽  
Author(s):  
Ali Mikaeili ◽  
Masoud Modaresi ◽  
Isaac Karimi ◽  
Hamed Ghavimi ◽  
Mazyar Fathi ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Pig Model ◽  
Trichophyton Verrucosum ◽  
Antifungal Activities ◽  
Guinea Pig Model

Anti-dermatophytic activity of bakuchiol: In vitro mechanistic studies and in vivo tinea pedis-inhibiting activity in a guinea pig model

Phytomedicine ◽  
2014 ◽  
Vol 21 (7) ◽  
pp. 942-945 ◽  
Author(s):  
Kit-Man Lau ◽  
Jack Ho Wong ◽  
Yu-On Wu ◽  
Ling Cheng ◽  
Chun-Wai Wong ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Tinea Pedis ◽  
Pig Model ◽  
Inhibiting Activity ◽  
Mechanistic Studies ◽  
Guinea Pig Model

scholarly journals Delamanid Kills Dormant Mycobacteria In Vitro and in a Guinea Pig Model of Tuberculosis

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Xiuhao Chen ◽  
Hiroyuki Hashizume ◽  
Tatsuo Tomishige ◽  
Izuru Nakamura ◽  
Miki Matsuba ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Bactericidal Activity ◽  
Pig Model ◽  
Standard Regimen ◽  
Content Type ◽  
Tb Treatment ◽  
Guinea Pig Model ◽  
Multiple Drugs

ABSTRACT Tuberculosis (TB) treatment is long and requires multiple drugs, likely due to various phenotypes of TB bacilli with variable drug susceptibilities. Drugs with broad activity are urgently needed. This study aimed to evaluate delamanid's activity against growing or dormant bacilli in vitro as well as in vivo. Cultures of Mycobacterium bovis BCG Tokyo under aerobic and anaerobic conditions were used to study the activity of delamanid against growing and dormant bacilli, respectively. Delamanid exhibited significant bactericidal activity against replicating and dormant bacilli at or above concentrations of 0.016 and 0.4 mg/liter, respectively. To evaluate delamanid's antituberculosis activity in vivo, we used a guinea pig model of chronic TB infection in which the lung lesions were similar to those in human TB disease. In the guinea pig TB model, a daily dose of 100 mg delamanid/kg of body weight for 4 or 8 weeks demonstrated strong bactericidal activity against Mycobacterium tuberculosis. Importantly, histological examination revealed that delamanid killed TB bacilli within hypoxic lesions of the lung. The combination regimens containing delamanid with rifampin and pyrazinamide or delamanid with levofloxacin, ethionamide, pyrazinamide, and amikacin were more effective than the standard regimen (rifampin, isoniazid, and pyrazinamide). Our data show that delamanid is effective in killing both growing and dormant bacilli in vitro and in the guinea pig TB model. Adding delamanid to current TB regimens may improve treatment outcomes, as demonstrated in recent clinical trials with pulmonary multidrug-resistant (MDR) TB patients. Delamanid may be an important drug for consideration in the construction of new regimens to shorten TB treatment duration.

In vivo activity of pyrimidine-dispirotripiperaziniumin in the male guinea pig model of genital herpes

2020 ◽  
Vol 09 (01) ◽  
Author(s):  
Novoselova EA ◽  
Alimbarova LM ◽  
Monakhova NS ◽  
Lepioshkin AY ◽  
Ekins S ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Genital Herpes ◽  
Pig Model ◽  
Guinea Pig Model
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