<i>In Vitro</i> and <i>In Vivo</i> Study on the Synergistic Effect of Minocycline and Azoles against Pathogenic Fungi

Abstract

<i>In vitro</i> and <i>in vivo</i> interactions of minocycline and azoles, including itraconazole, voriconazole, and posaconazole, against filamentous pathogenic fungi were investigated. A total of 56 clinical isolates were studied <i>in vitro</i> via broth microdilution checkerboard technique, including 20 strains of <i>Aspergillus fumigatus</i>, 7 strains of <i>Aspergillus flavus</i>, 16 strains of <i>Exophiala dermatitidis</i>, 10 strains of <i>Fusarium solani</i>, and 3 strain s of <i>Fusarium oxysporum</i> The results revealed that minocycline did not exhibit any significant antifungal activity against any of the tested strains. However, favorable synergy of minocycline with itraconazole, voriconazole, or posaconazole was observed against 34 (61%), 28 (50%), and 38 (68%) isolates, respectively, including azole-resistant <i>A. fumigatus</i> and <i>Fusarium</i> spp. with inherently high MICs of azoles. Synergistic combinations resulted in 4-fold to 16-fold reduction of effective MICs of minocycline and azoles. No antagonism was observed. <i>In vivo</i> effects of minocycline-azole combinations were evaluated by survival assay in a <i>Galleria mellonella</i> model infected with <i>E. dermatitidis</i> strain BMU00034; <i>F. solani</i> strain FS9; and <i>A. fumigatus</i> strains AF293, AFR1, and AFR2. Minocycline acted synergistically with azoles and significantly increased larvae survival in all isolates (<i>P</i> < 0.001), including azole-resistant <i>A. fumigatus</i> and azole-inactive <i>Fusarium</i> spp. In conclusion, the results suggested that minocycline combined with azoles may help to enhance the antifungal susceptibilities of azoles against pathogenic fungi and had the potential to overcome azole resistance issues.