Ability of teicoplanin and vancomycin to induce contraction of, and histamine release from, pulmonary tissue of humans, monkeys and guinea pigs

Abstract

Amphotericin B (AmB) and fluconazole (FLU) are the major antifungal drugs used in the treatment of cryptococcosis. Both drugs are believed to exert their antifungal effects through actions on cell membrane sterols. In this study we investigated whether AmB and FLU had other, more subtle effects on C. neoformans that could contribute to their therapeutic efficacy. C. neoformans cells were grown in media with subinhibitory concentrations of either AmB or FLU and analyzed for cellular charge, phagocytosis by macrophages with antibody and complement opsonins, appearance by scanning electron and light microscopies, and release of the capsular polysaccharide glucuronoxylomannan into the culture medium. Growth in the presence of either AmB or FLU resulted in major reductions in cellular charge, as measured by determination of the zeta potential. Phagocytosis studies demonstrated that exposure of C. neoformans to subinhibitory concentrations of AmB or FLU enhanced phagocytosis by macrophages. Scanning electron microscopy revealed that a large proportion of cells had an altered capsular appearance. Cells grown in medium with either AmB or FLU were smaller and released more glucuronoxylomannan into the culture medium than cells grown without antibiotics. The results suggest additional mechanisms of action for AmB and FLU that may be operative in body compartments where drug levels do not achieve the MICs. Furthermore, the results suggest mechanisms by which AmB and FLU can cooperate with humoral and cellular immune defense systems in controlling C. neoformans infections.

Heteroresistance to Itraconazole Alters the Morphology and Increases the Virulence of Cryptococcus gattii

“…In this way, a positive correlation between the S/V ratio of the original cells and the LHI was observed, while a negative correlation between the capsule size of heteroresistant clones and the LHI also was seen. Similar effects have been reported following the exposure of Cryptococcus neoformans to subinhibitory concentrations of fluconazole, voriconazole, amphotericin B, and terbinafine (16,21). Indeed, the S/V ratio of a cell affects several aspects of its biology, since the rate of the cell's growth depends on, among other things, the rate of nutrient exchange.…”

“…These observations could be explained by the alterations in capsule (size and charge) observed in heteroresistant cells. Since cryptococcal cells are negatively charged, we hypothesized that the heteroresistance to itraconazole decreased the magnitude of the negative charge and reduced the electrostatic repulsion between the yeast cells and macrophages (16,17).…”

“…In addition, the surface-to-volume ratio (S/V) was calculated using the formula 3/r, where r is radius (15). The zeta potentials of the original and heteroresistant yeast cells were calculated using a zeta potential analyzer (Zetasizer NanoZS90; Malvern, United Kingdom) as described previously (16).…”

Cryptococcus gattii Virulence Composite: Candidate Genes Revealed by Microarray Analysis of High and Less Virulent Vancouver Island Outbreak Strains

“…However, a correlation between virulence and the ergosterol synthesis pathway has been suggested previously [60]. It was reported that a pre-treatment with subinhibitory concentrations of azoles in vitro reduced cryptococcal virulence in vivo [61]. However, no difference in the susceptibility to the azole, fluconazole, which targets ERG11 in the fungal cell, was found.…”

Environmental Triazole Induces Cross-Resistance to Clinical Drugs and Affects Morphophysiology and Virulence of Cryptococcus gattii and C. neoformans

“…For cells with irregular form, qualitative analyses were performed. The zeta potentials of the NA and A yeast cells were calculated using a zeta potential analyzer (Zetasizer NanoZS90; Malvern, United Kingdom) as described previously (39).…”