We investigated the potential synergy between two cell wall-active agents, the echinocandin FK463 (FK) and the chitin synthase inhibitor nikkomycin Z (NZ), against 16 isolates of filamentous fungi. Susceptibility testing was performed with a broth macrodilution procedure by NCCLS methods. The median minimal effective concentration (MEC) of FK against all Aspergillus species was 0.25 g/ml (range, 0.05 to 0.5 g/ml). For Fusarium solani and Rhizopus oryzae, MECs of FK were >512 g/ml. The median MEC of NZ against Aspergillus fumigatus was 32 g/ml (range, 8 to 64 g/ml), and that against R. oryzae was 0.5 g/ml (range, 0.06 to 2 g/ml); however, for the other Aspergillus species, as well as F. solani, MECs were >512 g/ml. A checkerboard inhibitory assay demonstrated synergy against A. fumigatus (median fractional inhibitory concentration index ‫؍‬ 0.312 [range, 0.15 to 0.475]). The effect was additive to indifferent against R. oryzae and indifferent against other Aspergillus spp. and F. solani. We further investigated the pharmacodynamics of hyphal damage by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and examined the time-sequenced changes in hyphal ultrastructure. Significant synergistic hyphal damage was demonstrated with the combination of NZ (2 to 32 g/ml) and FK (0.03 to 0.5 g/ml) over a wide range of concentrations (P < 0.001). The synergistic effect was most pronounced after 12 h of incubation and was sustained through 24 h. Time-sequenced light and electron microscopic studies demonstrated that structural alterations of hyphae were profound, with marked transformation of hyphae to blastospore-like structures, in the presence of FK plus NZ, while fungi treated with a single drug showed partial recovery at 24 h. The methods used in this study may be applicable to elucidating the activity and interaction of other cell wall-active agents. In summary, these two cell wall-targeted antifungal agents, FK and NZ, showed marked time-dependent in vitro synergistic activity against A. fumigatus.The frequency of life-threatening fungal infections caused by Aspergillus species and other filamentous fungi has increased dramatically in the past several years. The antifungal agents approved for treatment of invasive filamentous fungal infections are limited. The two currently used antifungal drugs have a variety of associated problems. Amphotericin B can cause serious side effects due to its nephrotoxicity (6). While lipid formulations of amphotericin B have reduced nephrotoxicity, renal impairment is still observed and infusion-related toxicity may be debilitating. Itraconazole may not be reliably absorbed in sufficiently high quantities to be therapeutic and may interact adversely with a wide spectrum of drugs (8). Furthermore, the overall efficacy of either drug is limited, as evidenced by the high mortality associated with aspergillosis and other filamentous fungal infections (2).The rise in serious fungal infections over the past decade has prompted the development of new antifungal agents with...

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