The Long-Acting Echinocandin, Rezafungin, Prevents Pneumocystis Pneumonia and Eliminates Pneumocystis from the Lungs in Prophylaxis and Murine Treatment Models

Rezafungin is a novel echinocandin in Phase 3 development for prevention of invasive fungal disease caused by Candida spp., Aspergillus spp. and Pneumocystis jirovecii in blood and marrow transplantation patients. For such patients, standard antifungal prophylaxis currently comprises an azole for Candida and Aspergillus plus trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis pneumonia (PCP) despite drug-drug-interactions and intolerability that may limit their use, thus, alternatives are desirable. Rezafungin demonstrates a favorable safety profile and pharmacokinetic properties that allow for once-weekly dosing in addition, to antifungal activity against these predominant pathogens. Herein, the in vivo effects of rezafungin against Pneumocystis murina pneumonia were evaluated in immunosuppressed mouse models of prophylaxis and treatment using microscopy and qPCR assessments. In the prophylaxis model, immunosuppressed mice inoculated with P. murina were administered TMP-SMX (50/250 mg/kg 1×/week or 3×/week), caspofungin (5 mg/kg 3×/week), rezafungin (20 mg/kg, 1×/week or 3×/week; 5 mg/kg, 3×/week) intraperitoneally for 2, 4, 6 and 8 weeks, then immunosuppressed for an additional 6 weeks. Rezafungin administered for 4 weeks prevented P. murina from developing infection after rezafungin was discontinued. In the treatment model, immunosuppressed mice with P. murina pneumonia were treated with rezafungin 20 mg/kg 3×/week intraperitoneally for 2, 4, 6 and 8 weeks. Treatment with rezafungin for 8 weeks resulted in elimination of P. murina. Collectively, these studies showed that rezafungin could both prevent infection and eliminate P. murina from the lungs of mice. These findings support the obligate role of sexual reproduction for survival and growth of Pneumocystis spp. and warrant further investigation for treatment of P. jirovecii pneumonia in humans.

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Emerging Fungal Infections: New Patients, New Patterns, and New Pathogens

Journal of Fungi ◽

10.3390/jof5030067 ◽

2019 ◽

Vol 5 (3) ◽

pp. 67 ◽

Cited By ~ 36

Author(s):

Friedman ◽

Schwartz

Keyword(s):

North America ◽

Fungal Pathogens ◽

Fungal Infections ◽

Trichophyton Mentagrophytes ◽

Invasive Fungal Disease ◽

Multidrug Resistant ◽

Antifungal Prophylaxis ◽

Candida Spp ◽

Sporothrix Brasiliensis ◽

Emerging Fungal Infections

: The landscape of clinical mycology is constantly changing. New therapies for malignant and autoimmune diseases have led to new risk factors for unusual mycoses. Invasive candidiasis is increasingly caused by non-albicans Candida spp., including C. auris, a multidrug-resistant yeast with the potential for nosocomial transmission that has rapidly spread globally. The use of mould-active antifungal prophylaxis in patients with cancer or transplantation has decreased the incidence of invasive fungal disease, but shifted the balance of mould disease in these patients to those from non-fumigatus Aspergillus species, Mucorales, and Scedosporium/Lomentospora spp. The agricultural application of triazole pesticides has driven an emergence of azole-resistant A. fumigatus in environmental and clinical isolates. The widespread use of topical antifungals with corticosteroids in India has resulted in Trichophyton mentagrophytes causing recalcitrant dermatophytosis. New dimorphic fungal pathogens have emerged, including Emergomyces, which cause disseminated mycoses globally, primarily in HIV infected patients, and Blastomyces helicus and B. percursus, causes of atypical blastomycosis in western parts of North America and in Africa, respectively. In North America, regions of geographic risk for coccidioidomycosis, histoplasmosis, and blastomycosis have expanded, possibly related to climate change. In Brazil, zoonotic sporotrichosis caused by Sporothrix brasiliensis has emerged as an important disease of felines and people.

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In Vitro and In Vivo Effects of Quinupristin-Dalfopristin against Pneumocystis carinii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.11.3234-3237.2001 ◽

2001 ◽

Vol 45 (11) ◽

pp. 3234-3237 ◽

Cited By ~ 5

Author(s):

Peter D. Walzer ◽

Alan Ashbaugh ◽

Margaret Collins ◽

Melanie T. Cushion

Keyword(s):

Body Weight ◽

Toxoplasma Gondii ◽

Inhibitory Concentration ◽

Pneumocystis Carinii ◽

High Dose ◽

Dose Administration ◽

In Vivo Effects ◽

Immunosuppressed Mice

ABSTRACT Quinupristin-dalfopristin (Q-D), which is active against bacteria and Toxoplasma gondii, was examined for its activity against Pneumocystis carinii. After 72 h of incubation with rat P. carinii in an ATP cytotoxicity assay, the 50% inhibitory concentration of Q-D was 10.6 μg/ml, a level that can be achieved in serum with high-dose administration. Q-D administered intraperitoneally at doses of 50 to 200 mg per kg of body weight per day in the treatment and 100 mg/kg/day three times per week in the prophylaxis of pneumocystosis in immunosuppressed mice reduced the organism burden up to 15- and 302-fold, respectively. We conclude that Q-D has activity against P. carinii in vitro and in vivo.

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837 Absence of in-vivo effects of dental instruments on pacemaker function

EP Europace ◽

10.1016/s1099-5129(05)80575-6 ◽

2005 ◽

Vol 7 ◽

pp. 195-195

Keyword(s):

Dental Instruments ◽

Pacemaker Function ◽

In Vivo Effects

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In vivo effects of TGF-β1 in lung surfactant regulation, lung meachanics amd structure

Pneumologie ◽

10.1055/s-0034-1376812 ◽

2014 ◽

Vol 68 (06) ◽

Author(s):

E Lopez-Rodriguez ◽

C Boden ◽

S Knippenberg ◽

A Pascual ◽

J Perez-Gil ◽

...

Keyword(s):

Lung Surfactant ◽

In Vivo Effects ◽

Tgf Β1

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Evaluation of Sacroiliac Wedge Rotation to Increase Acetabular Ventroversion

Veterinary and Comparative Orthopaedics and Traumatology ◽

10.1055/s-0038-1632486 ◽

1999 ◽

Vol 12 (04) ◽

pp. 173-177 ◽

Cited By ~ 2

Author(s):

R. L. Aper ◽

M. D. Brown ◽

M. G. Conzemius

Keyword(s):

Hip Joint ◽

Hip Dysplasia ◽

Clinical Effect ◽

Pelvic Osteotomy ◽

Alternative Method ◽

Angular Measurements ◽

Si Joint ◽

In Vivo Effects ◽

Canine Hip Dysplasia

SummaryTreatment of canine hip dysplasia (CHD) via triple pelvic osteotomy (TPO) is widely accepted as the treatment that best preserves the existing hip joint. TPO, however, has several important disadvantages. In an effort to avoid some of the difficulties associated with TPO an alternative method of creating acetabular ventroversion (AW) was sought. The purpose of this study was to explore the effects of placement of a wedge in the sacroiliac (SI) joint on A W and to compare this to the effect of TPO on A W . On one hemipelvis a 30° pelvic osteotomy plate was used for TPO. The contralateral hemipelvis had a 28° SI wedge inserted into the SI joint. Pre- and postsurgical radiographs of each pelvis were taken and the angular measurements were recorded. On average, the 28° SI wedge resulted in 20.9° of A W, the 30° canine pelvic osteotomy plate resulted in 24.9° A W . Significant differences were not found (p >0.05) between the two techniques. Sacroiliac wedge rotation effectively creates A W and has several theoretical advantages when compared to TPO. The in vivo effects of sacroiliac wedge rotation should be studied in order to evaluate the clinical effect of the technique.Sacroiliac wedge rotation was tested as an alternative method to increase the angle of acetabular ventroversion. This technique effectively rotated the acetabulum and has several theoretical advantages when compared to triple pelvic osteotomy.

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THYROID STIMULATORS AND THYROID STIMULATION

Acta Endocrinologica ◽

10.1530/acta.0.0660558 ◽

1971 ◽

Vol 66 (3) ◽

pp. 558-576 ◽

Cited By ~ 15

Author(s):

Gerald Burke

Keyword(s):

Regulatory System ◽

Control Site ◽

Thyroid Cell ◽

Primary Control ◽

Physico Chemical ◽

Site Of Action ◽

Long Acting

ABSTRACT A long-acting thyroid stimulator (LATS), distinct from pituitary thyrotrophin (TSH), is found in the serum of some patients with Graves' disease. Despite the marked physico-chemical and immunologic differences between the two stimulators, both in vivo and in vitro studies indicate that LATS and TSH act on the same thyroidal site(s) and that such stimulation does not require penetration of the thyroid cell. Although resorption of colloid and secretion of thyroid hormone are early responses to both TSH and LATS, available evidence reveals no basic metabolic pathway which must be activated by these hormones in order for iodination reactions to occur. Cyclic 3′, 5′-AMP appears to mediate TSH and LATS effects on iodination reactions but the role of this compound in activating thyroidal intermediary metabolism is less clear. Based on the evidence reviewed herein, it is suggested that the primary site of action of thyroid stimulators is at the cell membrane and that beyond the(se) primary control site(s), there exists a multifaceted regulatory system for thyroid hormonogenesis and cell growth.

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