Immunoadjuvant activity of amphotericin B as displayed in mice infected with Candida albicans

Bistoni, Francesco; Vecchiarelli, Anna; Mazzolla, Rosanna; Puccetti, Paolo; Marconi, Pierfrancesco; Garaci, Enrico

doi:10.1128/aac.27.4.625

Cited by 41 publications

(21 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AmB administered as a single 10-mg/kg dose to mice was protective against subsequent challenge with either C. albicans or Staphylococcus aureus. Effector cells from treated mice showed enhanced in vitro fungicidal activity in a 51Cr-release assay (4). Macrophages from intact mice 02- Chemilumines-~~Fungicidal treated with AmB in vitro also showed enhanced fungicidal activity (4).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of antifungal agents on the function of human neutrophils in vitro

Roilides

Walsh

Rubin

et al. 1990

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Polymorphonuclear leukocytes (PMNs) are an important component of the host defense against fungi. We investigated the influence of five antifungal agents on PMN function and compared them with amphotericin B (AmB). The in vitro effects of AmB, flucytosine, ketoconazole, fluconazole, Sch-39304, and cilofungin (LY121019) on chemotaxis, phagocytosis, oxidative metabolism of PMN as reflected by superoxide anion (02) generation, and intracellular killing of Candida albicans blastoconidia were examined. With regard to chemotaxis in response to N-formylmethionyl-leucyl-phenylalanine, as measured by the multiwell chamber method, AmB induced a marked decrease (.5 ,ug/ml), whereas ketoconazole at 5 ,ug/ml enhanced it. Phagocytosis was significantly decreased after pretreatment of PMNs with AmB and Sch-39304 (>5 and 1 to 10 ,ug/ml, respectively). 02 production after stimulation of PMNs with N-formylmethionyl-leucyl-phenylalanine was significantly decreased by AmB (>5 ,ug/ml) and enhanced by Sch-39304 (1 to 5 ,ug/ml). In contrast, intracellular killing, as tested by methylene blue staining, was enhanced by ketoconazole (5 ,ug/ml) and Sch-39304 (1 to 5 ,Ig/ml). Flucytosine, fluconazole, and cilofungin did not affect PMN function at therapeutic concentrations. The results of this comprehensive study indicate that AmB, flucytosine, cilofungin, and the newer azoles, at safely achievable concentrations, generally do not suppress PMN function in vitro and may enhance selective functions.Candida and Aspergillus species are the predominant fungal pathogens that cause life-threatening infections in neutropenic cancer patients. Since polymorphonuclear leukocytes (PMNs) are an important component of the host defense against opportunistic fungi, any suppression of their function could exacerbate further the ability of the host to control these infections.

show abstract

Section: Discussionmentioning

confidence: 99%

“…For all the drugs, the range of concentrations studied included and exceeded the achievable concentrations in plasma. The known upper limits of safely achievable concentrations in plasma are as follows: AmB, 4 ,ug/ml; 5-FC, 100 ,ug/ml; ketoconazole, 5 jig/ml; fluconazole, 25 p.g/ml; Sch-39304, 2 jig/ml; and cilofungin, 40 ,ug/ml. Viability of cells.…”

mentioning

confidence: 99%

Effects of antifungal agents on the function of human neutrophils in vitro

Roilides

Walsh

Rubin

et al. 1990

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…In addition, the drug reportedly can act on macrophages to stimulate [3H]thymidine uptake (5) and the respiratory burst (34, 35), promote tumor necrosis factor secretion (9), and enhance the tumoricidal (8, 26) and microbicidal (3,24,26,32) actions of these cells. The mechanisms underlying these processes and the relevance thereof remain unclear.…”

mentioning

confidence: 99%

Novel aspect of amphotericin B action: accumulation in human monocytes potentiates killing of phagocytosed Candida albicans

Martin¹,

Stüben²,

Görz³

et al. 1994

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The influence of low doses of amphotericin B on the capacity of human monocytes to kill Candida albicans was investigated. Killing rates were quantified by a novel flow cytometric assay and were found to be 37% 3% (standard error of the mean) after 3 h. Preincubation of monocytes for 6 to 20 h with low concentrations of amphotericin B (0.2 ,ug/ml) Despite its toxicity, amphotericin B has remained the prime drug for treating life-threatening fungal infections. This agent binds with high affinity to ergosterol. Its fungicidal action is generally ascribed to an enhancement of membrane permeability as a result of the formation of ion channels (5, 16) and perhaps also because of oxidative damage of membrane constituents (4, 6). Unfortunately, amphotericin B also binds to cholesterol in mammalian cell membranes and elicits severe toxic effects. Many efforts have therefore been devoted to establishing treatment regimens that combine the merits of antifungal activity with a minimum of untoward side effects. The possibilities of local amphotericin B application are also receiving increased attention. Aerosol application, first described nearly 20 years ago (23), and low-dose intravenous application are emerging as prophylactic measures against pulmonary fungal infections in neutropenic patients (13,20,29).General belief holds that the beneficial effect of amphotericin B derives mainly from its direct fungicidal action. In addition, the drug reportedly can act on macrophages to stimulate [3H]thymidine uptake (5) and the respiratory burst (34, 35), promote tumor necrosis factor secretion (9), and enhance the tumoricidal (8, 26) and microbicidal (3,24,26,32) actions of these cells. The mechanisms underlying these processes and the relevance thereof remain unclear.We performed with a high degree of accuracy (18,19). The assays were first introduced for quantifying granulocyte phagocytic function and have now been adapted to the analysis of monocytes. In the studies described here, we showed that monocytes preincubated for hours with low doses of amphotericin B acquire a remarkably augmented capacity to kill ingested Candida albicans. This effect appears to be due to the intracellular accumulation of the drug rather than to a nonspecific stimulation of the cells. Potentiation of the fungicidal capacity of monocytes is likely to be an important novel determinant underlying the therapeutic efficacy of amphotericin B. MATERIALS AND METHODSMicroorganisms. An isolate of C. albicans from our diagnostic laboratory or an amphotericin B-resistant mutant, kindly provided by H. Dermoumi, Essen, Germany, was cultured at 37°C in tryptic soy broth for 16 to 20 h. A total of 1.5 ml of yeast cell cultures was centrifuged and the pelleted cells were resuspended in 1 ml of saline and incubated with 2 ,uM bis-carboxyethyl-carboxyfluorescein pentaacetoxymethylester (BCECF-AM; Becton Dickinson, Heidelberg, Germany) for 30 min in an Eppendorf Thermomixer 5436

show abstract

“…Fluconazole, too, is of assistance in this regard. Other antifungal agents, such as amphotericin B and cylofungin, interact with various cell mechanisms and promote an immune response [28,29]. Fluconazole does not inhibit T cell proliferation, cytokine secretion (i.e.…”

Section: Discussionmentioning

confidence: 99%

Combined effect of fluconazole and thymosin α1 on systemic candidiasis in mice immunosuppressed by morphine treatments

Francesco

Gaziano

Casalinuovo

et al. 1994

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SUMMARY Treatment of systemic infection with Candida albicans with a combination of an antifungal agent (i.e. fluconazole) and a thymus‐derived immunostimulant (i.e. thymosin α1 (Tal)) in mice immunosuppressed by morphine treatments was investigated. In normal mice, fluconazole given after infection with 106 C. albicans cells was more effective than in mice treated with morphine. Combination treatment with fluconazole and Tal prolonged survival and reduced the fungal burden in the kidneys of immunosuppressed mice. We also investigated the influence of this combined treatment on killing properties of polymorphonuclear leucocytes (PMN) and natural killer (NK) cell activity, inhibited by morphine administrations. Treatment with TQI or fluconazole as single agents promoted a recovery of normal NK cell activity and intracellular killing of C. albicans by PMN, while the combination significantly increased both of these responses, probably through the modulation of lymphokine production. Our data suggest that the additive effect of T α 1 and fluconazole is due lo a direct antifungal action and activation of the immunocompetence.

show abstract

Immunoadjuvant activity of amphotericin B as displayed in mice infected with Candida albicans

Cited by 41 publications

References 13 publications

Effects of antifungal agents on the function of human neutrophils in vitro

Effects of antifungal agents on the function of human neutrophils in vitro

Novel aspect of amphotericin B action: accumulation in human monocytes potentiates killing of phagocytosed Candida albicans

Combined effect of fluconazole and thymosin α1 on systemic candidiasis in mice immunosuppressed by morphine treatments

Contact Info

Product

Resources

About