Oral Lipid Nanocrystal Amphotericin B for Cryptococcal Meningitis: A Randomized Clinical Trial.

Autor:	Boulware DR; Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Atukunda M; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Kagimu E; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Musubire AK; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Akampurira A; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Tugume L; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Ssebambulidde K; Infectious Diseases Institute, Makerere University, Kampala, Uganda.; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Kasibante J; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Nsangi L; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Mugabi T; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Gakuru J; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Kimuda S; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Kasozi D; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Namombwe S; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Turyasingura I; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Rutakingirwa MK; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Mpoza E; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Kigozi E; Department of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda., Muzoora C; Department of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda., Ellis J; Infectious Diseases Institute, Makerere University, Kampala, Uganda., Skipper CP; Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Matkovits T; Matinas Biopharma Nanotechnologies, Bedminster, New Jersey, USA., Williamson PR; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Williams DA; Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Fieberg A; Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA., Hullsiek KH; Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA., Abassi M; Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Dai B; Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA., Meya DB; Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.; Infectious Diseases Institute, Makerere University, Kampala, Uganda.
Jazyk:	angličtina
Zdroj:	Clinical infectious diseases : an official publication of the Infectious Diseases Society of America [Clin Infect Dis] 2023 Dec 15; Vol. 77 (12), pp. 1659-1667.
DOI:	10.1093/cid/ciad440
Abstrakt:	Background: Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed. Methods: In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus-associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA). Results: We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log10 colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log10  Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log10 CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin.Grade 3-4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P = .05), particularly for anemia (21% vs 44%; P = .01) and potassium (5% vs 17%; P = .04). Conclusions: This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin. Clinical Trials Registration: NCT04031833. Competing Interests: Potential conflicts of interest. T. M. is an employee of Matinas Biopharma and has an equity interest and receives support for attending meetings and/or travel and reports a role as board director for Apilli Therapeutics and GoodCap Pharmaceuticals. P. R. W. reports grants or contracts from Matinas BioPharma. D. R. B. serves on the scientific advisory board for Sfunga Therapeutics, who is developing a different antifungal therapeutic. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)
Databáze:	MEDLINE
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