AUTHOR=Li Yali , Li Sheng , Chen Min , Xiao Jialing , Fang Hong 

TITLE=Synergistic effect of pyrvinium pamoate and posaconazole against Cryptococcus neoformans in vitro and in vivo

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2022.1074903

DOI=10.3389/fcimb.2022.1074903

ISSN=2235-2988

ABSTRACT=<sec><title>Background</title><p>Cryptococcosis is a global invasive mycosis with high rates of morbidity and mortality, especially in AIDS patients. Its treatment remains challenging because of the limited antifungals and their unavoidable toxicity, and as such more efforts need to focus on the development of novel effective drugs. Previous studies have indicated that pyrvinium pamoate (PP) has individual and synergistic fungistatic effect. In this study, the effects of PP alone and in combination with azoles [fluconazole (FLU), itraconazole (ITR), voriconazole (VOR), posaconazole (POS)] or amphotericin B (AmB) were evaluated against <italic>Cryptococcus neoformans</italic> both <italic>in vitro</italic> and <italic>in vivo</italic>.</p></sec><sec><title>Methods</title><p>A total of 20 <italic>C. neoformans</italic> strains collected from cryptococcal pneumonia and cryptococcal meningitis were studied. The effects of PP alone, PP-azoles and PP-AmB interactions against <italic>C. neoformans</italic> were evaluated <italic>via</italic> the microdilution chequerboard technique, adapted from broth microdilution method according to the CLSI M27-A4. The <italic>in vivo</italic> antifungal activity of PP alone and in combination with azoles and AmB against <italic>C. neoformans</italic> infections was evaluated by <italic>Galleria mellonella</italic> survival assay.</p></sec><sec><title>Results</title><p>The <italic>in vitro</italic> results revealed that PP individually was ineffective against <italic>C. neoformans</italic> (MIC&gt;16 μg/ml). Nevertheless, the synergistic effects of PP with ITR, VOR, POS, FLU or AmB was observed in 13 (65.0%, FICI 0.188–0.365), 3 (15.0%, FICI 0.245-0.301), 19 (95.0%, FICI 0.188-0.375), 7 (35.0%, FICI 0.188-0.375), and 12(60.0%, FICI 0.281-0.375) strains of <italic>C. neoformans</italic>, respectively. There was no antagonism. The survival rates of larvae treated with PP (3.33%) showed almost no antifungal effective, but the larvae survival rates improved when PP combined with AmB (35% vs. 23.33%), FLU (40% vs. 25%), ITR (48.33% vs. 33.33%), VOR (48.33% vs. 53.33%) and POS (56.67% vs. 36.67%) comparison with AmB or azoles alone, and statistical significance was observed when PP combined with POS versus POS alone (<italic>P</italic> = 0.04). </p></sec><sec><title>Conclusions</title><p>In summary, the preliminary results indicated the potential of PP in reduction the MICs of azoles and AmB, also itself against <italic>C. neoformans</italic>; the combination of PP with AMB, FLU, ITR, VOR and POS improve the survival rates of <italic>C. neoformans</italic> infection larvae, compared with they are alone. The <italic>in vitro</italic> and <italic>in vivo</italic> data show that PP could enhance the activity of POS against <italic>C. neoformans.</italic> This study contributes with data of PP in combination with classical drugs of choice for cryptococcosis treatment.</p></sec>