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.

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.

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 Evaluation of the Efficacy of ME1111 in the Topical Treatment of Dermatophytosis in a Guinea Pig Model

2016 ◽  
Vol 60 (4) ◽  
pp. 2343-2345 ◽  
Author(s):  
L. Long ◽  
C. Hager ◽  
M. Ghannoum
Keyword(s):  
Guinea Pig ◽  
Topical Treatment ◽  
Liver Toxicity ◽  
Trichophyton Mentagrophytes ◽  
Pig Model ◽  
Once Daily ◽  
Content Type ◽  
The Past ◽  
Guinea Pig Model

ABSTRACTThe treatment of dermatophytoses, including onychomycosis, has come a long way over the past few decades with the introduction of oral antifungals (e.g., terbinafine and itraconazole). However, with these advancements in oral therapies come several undesirable effects, such as kidney and liver toxicity, along with drug-drug interactions. Consequently, there is a need for new topical agents that are effective against dermatophytosis. ME1111 is a topical antifungal under development. In this study, thein vivoefficacy of ME1111 was compared to that of ciclopirox in the topical treatment of dermatophytosis caused byTrichophyton mentagrophytesusing a guinea pig model. Animals were treated with the topical antifungals starting at 3 days postinfection, with each agent being applied once daily for seven consecutive days. After the treatment period, the clinical and mycological efficacies were evaluated. The data showed that both antifungals demonstrated significant clinical and mycological efficacies; however, ME1111 showed clinical efficacy superior to that of ciclopirox (46.9% and 25.0%, respectively, with aPvalue of <0.001). The potent efficacy of ME1111 could be attributed to its properties, such as low keratin binding.

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

scholarly journals Effect of Inflammatory Response onIn VivoCompetition between Two Chlamydial Variants in the Guinea Pig Model of Inclusion Conjunctivitis

2011 ◽  
Vol 80 (2) ◽  
pp. 612-619 ◽  
Author(s):  
Roger G. Rank ◽  
Anne K. Bowlin ◽  
Kati I. Tormanen ◽  
Yin Wang ◽  
Anthony T. Maurelli
Keyword(s):  
Inflammatory Response ◽  
Guinea Pig ◽  
Mixed Infection ◽  
Resistant Mutant ◽  
Pig Model ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Guinea Pig Model ◽  
The Impact

ABSTRACTIn order to study the interaction of variants inin vivoinfection, we employed an azithromycin-resistant mutant (AZ2) and its wild-type parent (SP6) in the guinea pig model ofChlamydia caviaeconjunctival infection. When each strain was inoculated individually into conjunctiva, both attained the same level of growth, but AZ2elicited less pathology. However, when equal numbers of the two strains were inoculated together into the guinea pig conjunctiva, SP6produced a significantly greater number of inclusion-forming units than AZ2, and the pathology reflected that of a SP6monoinfection. The goal of this study was to further characterize the dynamics of concomitant infection of these two distinct variants, with particular emphasis on the impact of the host response on thein vivogrowth of each organism and the development of pathology. Animals infected with AZ2had reduced conjunctival infiltration with CD45+cells and neutrophils as well as a reduced interleukin-8 (IL-8) response. Gene expression of gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), CCL2, and CCL5 was also significantly lower in AZ2-infected animals. The lower inflammatory response induced by AZ2was associated with its decreased ability to activate NF-κB via Toll-like receptor 2 (TLR2). In general, the inflammatory response in animals infected with both variants was greater than in infection with AZ2alone, resulting in lower numbers of AZ2than those of SP6in the mixed infection. Our results suggest that the ability to elicit an inflammatory response is an important factor in the dynamics of mixed infection with strains that display different pathological phenotypes.

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
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