The role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice.

The main conclusions of this study are that BCG/PPD-activated macrophages, in contrast to macrophages from control mice, exhibit an increased PMA-induced production of H2O2, kill about one-third of the phagocytosed Candida albicans, and cause more than 50% inhibition of the intracellular formation of germ tubes by C. albicans. Peritoneal macrophages from mice that were colonized post-natally with C. albicans do not show increased production of H2O2 upon stimulation with PMA and the intracellular outgrowth of germ tubes is inhibited to only a limited degree. These macrophages are capable of killing about 20% of the ingested C. albicans. In vivo, the number of Candida in the kidney, spleen and liver after intravenous injection of Candida albicans is significantly lower in BCG-treated mice than in control mice. Post-natal colonization with C. albicans has only a limited effect on the outgrowth of intravenously injected C. albicans in the spleen and liver but does not influence growth in the kidney. These results indicate that acquired immunity against a systemic Candida infection involves both oxidative and non-oxidative mechanisms of intracellular killing and that these mechanisms may have different effects on the yeast and hyphal forms of C. albicans.

Combined effect of fluconazole and recombinant human interleukin-1 on systemic candidiasis in neutropenic mice.

The aim of the present study was to investigate the efficacy of treatment with a combination of fluconazole and human recombinant interleukin-1 alpha (IL-1 alpha) in normal or neutropenic mice with systemic Candida albicans infection. Six hours after intravenous injection of 5 x 10(4) CFU of C. albicans organisms, oral treatment twice daily with 2.5 or 10 mg of fluconazole per kg of body weight, a single intraperitoneal injection of 80 ng of IL-1, or a combination of the two was started. IL-1 had no influence on the antifungal activity of fluconazole in vitro or on the pharmacokinetics of fluconazole. For both normal and neutropenic mice, the number of C. albicans organisms cultured from the kidneys after 36 h of treatment was significantly lower in mice treated with IL-1 alone than in untreated animals. Treatment with fluconazole alone also significantly lowered the number of C. albicans organisms in the kidneys compared with that in untreated controls. In normal mice, the combination of fluconazole and IL-1 was not better than fluconazole alone. In neutropenic mice, combined treatment with IL-1 and 10 mg of fluconazole per kg led to significantly lower numbers of C. albicans organisms in the kidneys and the spleen than treatment with either agent alone. Although the precise mechanism by which IL-1 enhances resistance to infection is not clear, the additive effect of IL-1 and fluconazole in vivo indicates that combined therapy with immunomodulators and antifungal drugs is beneficial in immunocompromised mice with systemic fungal infections.

Effect of amphotericin B, fluconazole and itraconazole on intracellular Candida albicans and germ tube development in macrophages.

Candida albicans may resist intracellular killing by macrophages through the formation of germ tubes. Antifungal drugs that inhibit intracellular germ tube formation could therefore facilitate host defence against C. albicans. We assessed the effects of amphotericin B and the new triazole drugs fluconazole and itraconazole on the multiplication and intracellular germ tube formation of C. albicans phagocytosed by murine peritoneal macrophages, and compared the findings with the effects of these drugs on C. albicans in the absence of macrophages. The fungicidal effect of amphotericin B against C. albicans in macrophages was less prominent than that found for extracellular candida. However, amphotericin B completely blocked germ tube formation of C. albicans both in macrophages and extracellularly. Fluconazole and itraconazole had little effect on the number of candida but significantly, although incompletely, inhibited germ tube formation both inside macrophages and extracellularly. The inhibition of intracellular germ tube formation by the triazoles may facilitate host defences against C. albicans and contribute to the efficacies of these drugs in vivo.