Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis
ABSTRACT Cryptococcus neoformans is an encapsulated yeast responsible for approximately a quarter of a million deaths worldwide annually despite therapy, and upwards of 11% of HIV/AIDS-related deaths, rivaling the impact of tuberculosis and malaria. However, the most effective antifungal agent, amph...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2019-06-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00724-19 |
| _version_ | 1819001859850895360 |
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| author | R. Lu C. Hollingsworth J. Qiu A. Wang E. Hughes X. Xin K. M. Konrath W. Elsegeiny Yoon-Dong Park L. Atakulu J. C. Craft E. C. Tramont R. Mannino P. R. Williamson |
| author_facet | R. Lu C. Hollingsworth J. Qiu A. Wang E. Hughes X. Xin K. M. Konrath W. Elsegeiny Yoon-Dong Park L. Atakulu J. C. Craft E. C. Tramont R. Mannino P. R. Williamson |
| author_sort | R. Lu |
| collection | DOAJ |
| description | ABSTRACT Cryptococcus neoformans is an encapsulated yeast responsible for approximately a quarter of a million deaths worldwide annually despite therapy, and upwards of 11% of HIV/AIDS-related deaths, rivaling the impact of tuberculosis and malaria. However, the most effective antifungal agent, amphotericin B, requires intravenous delivery and has significant renal and hematopoietic toxicity, making it difficult to utilize, especially in resource-limited settings. The present studies describe a new nanoparticle crystal encapsulated formulation of amphotericin B known as encochleated amphotericin B (CAmB) that seeks to provide an oral formulation that is low in toxicity and cost. Using a 3-day delayed model of murine cryptococcal meningoencephalitis and a large inoculum of a highly virulent strain of serotype A C. neoformans, CAmB, in combination with flucytosine, was found to have efficacy equivalent to parental amphotericin B deoxycholate with flucytosine and superior to oral fluconazole without untoward toxicity. Transport of fluorescent CAmB particles to brain as well as significant brain levels of amphotericin drug was demonstrated in treated mice, and immunological profiles were similar to those of mice treated with conventional amphotericin B. Additional toxicity studies using a standardized rat model showed negligible toxicity after a 28-day treatment schedule. These studies thus offer the potential for an efficacious oral formulation of a known fungicidal drug against intrathecal cryptococcal disease. IMPORTANCE Cryptococcus neoformans is a significant global fungal pathogen that kills an estimated quarter of a million HIV-infected individuals yearly and has poor outcomes despite therapy. The most effective therapy, amphotericin B, is highly effective in killing the fungus but is available only in highly toxic, intravenous formulations that are unavailable in most of the developing world, where cryptococcal disease in most prevalent. For example, in Ethiopia, reliance on the orally available antifungal fluconazole results in high mortality, even when initiated as preemptive therapy at the time of HIV diagnosis. Thus, alternative agents could result in significant saving of lives. Toward this end, the present work describes the development of a new formulation of amphotericin B (CAmB) that encapsulates the drug as a crystal lipid nanoparticle that facilitates oral absorption and prevents toxicity. Successful oral absorption of the drug was demonstrated in a mouse model that, in combination with the antifungal flucytosine, provided efficacy equal to a parental preparation of amphotericin B plus flucytosine. These studies demonstrate the potential for CAmB in combination with flucytosine to provide an effective oral formulation of a well-known, potent fungicidal drug combination. |
| first_indexed | 2024-12-20T22:55:55Z |
| format | Article |
| id | doaj.art-b61fbfbc462a4753904281af8020cf8f |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-20T22:55:55Z |
| publishDate | 2019-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-b61fbfbc462a4753904281af8020cf8f2022-12-21T19:24:08ZengAmerican Society for MicrobiologymBio2150-75112019-06-0110310.1128/mBio.00724-19Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal MeningoencephalitisR. Lu0C. Hollingsworth1J. Qiu2A. Wang3E. Hughes4X. Xin5K. M. Konrath6W. Elsegeiny7Yoon-Dong Park8L. Atakulu9J. C. Craft10E. C. Tramont11R. Mannino12P. R. Williamson13Matinas BioPharma, Bedminster, New Jersey, USALaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USALaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USANational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USANational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USANational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USANational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USALaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USALaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USALaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USAMatinas BioPharma, Bedminster, New Jersey, USADivision of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USAMatinas BioPharma, Bedminster, New Jersey, USALaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USAABSTRACT Cryptococcus neoformans is an encapsulated yeast responsible for approximately a quarter of a million deaths worldwide annually despite therapy, and upwards of 11% of HIV/AIDS-related deaths, rivaling the impact of tuberculosis and malaria. However, the most effective antifungal agent, amphotericin B, requires intravenous delivery and has significant renal and hematopoietic toxicity, making it difficult to utilize, especially in resource-limited settings. The present studies describe a new nanoparticle crystal encapsulated formulation of amphotericin B known as encochleated amphotericin B (CAmB) that seeks to provide an oral formulation that is low in toxicity and cost. Using a 3-day delayed model of murine cryptococcal meningoencephalitis and a large inoculum of a highly virulent strain of serotype A C. neoformans, CAmB, in combination with flucytosine, was found to have efficacy equivalent to parental amphotericin B deoxycholate with flucytosine and superior to oral fluconazole without untoward toxicity. Transport of fluorescent CAmB particles to brain as well as significant brain levels of amphotericin drug was demonstrated in treated mice, and immunological profiles were similar to those of mice treated with conventional amphotericin B. Additional toxicity studies using a standardized rat model showed negligible toxicity after a 28-day treatment schedule. These studies thus offer the potential for an efficacious oral formulation of a known fungicidal drug against intrathecal cryptococcal disease. IMPORTANCE Cryptococcus neoformans is a significant global fungal pathogen that kills an estimated quarter of a million HIV-infected individuals yearly and has poor outcomes despite therapy. The most effective therapy, amphotericin B, is highly effective in killing the fungus but is available only in highly toxic, intravenous formulations that are unavailable in most of the developing world, where cryptococcal disease in most prevalent. For example, in Ethiopia, reliance on the orally available antifungal fluconazole results in high mortality, even when initiated as preemptive therapy at the time of HIV diagnosis. Thus, alternative agents could result in significant saving of lives. Toward this end, the present work describes the development of a new formulation of amphotericin B (CAmB) that encapsulates the drug as a crystal lipid nanoparticle that facilitates oral absorption and prevents toxicity. Successful oral absorption of the drug was demonstrated in a mouse model that, in combination with the antifungal flucytosine, provided efficacy equal to a parental preparation of amphotericin B plus flucytosine. These studies demonstrate the potential for CAmB in combination with flucytosine to provide an effective oral formulation of a well-known, potent fungicidal drug combination.https://journals.asm.org/doi/10.1128/mBio.00724-19Cryptococcusamphotericinclinical therapeuticsfungus |
| spellingShingle | R. Lu C. Hollingsworth J. Qiu A. Wang E. Hughes X. Xin K. M. Konrath W. Elsegeiny Yoon-Dong Park L. Atakulu J. C. Craft E. C. Tramont R. Mannino P. R. Williamson Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis mBio Cryptococcus amphotericin clinical therapeutics fungus |
| title | Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis |
| title_full | Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis |
| title_fullStr | Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis |
| title_full_unstemmed | Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis |
| title_short | Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis |
| title_sort | efficacy of oral encochleated amphotericin b in a mouse model of cryptococcal meningoencephalitis |
| topic | Cryptococcus amphotericin clinical therapeutics fungus |
| url | https://journals.asm.org/doi/10.1128/mBio.00724-19 |
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