In-vivo therapeutic efficacy in experimental murine mycoses of a new formulation of deoxycholate-amphotericin B obtained by mild heating.
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Heat-induced 'superaggregation' of deoxycholate-amphotericin B (AmB-DOC, Fungizone) was shown previously to reduce the in-vitro toxicity of this antifungal agent. We compared AmB-DOC with the formulation obtained by heating the commercial form (Fungizone, Bristol Myers Squibb, Paris, France) for 20 min at 70 degrees C, in the treatment of murine infections. An improvement of antifungal activity was obtained with heated AmB-DOC formulations due to a lower toxicity which allowed the administration of higher drug doses than those achievable with the commercial preparation. Single intravenous injections of heated AmB-DOC solutions were demonstrated to be two-fold less toxic than unheated ones to healthy mice. For mice infected with Candida albicans, the maximum tolerated dose was higher with heated than with unheated AmB-DOC solutions. In the model of murine candidiasis, following a single dose of heated AmB-DOC 0.5 mg/kg, 85% of mice survived for 3 weeks, whereas at this dose the immediate toxicity of the standard formulation in infected mice restricted the therapeutic efficacy to 25% survival. Both formulations were equally effective in increasing the survival time for murine cryptococcal pneumonia and meningoencephalitis. Injection of heated AmB-DOC solutions at a dose two-fold higher than the maximal tolerated dose observed with the unheated preparation (1.2 mg/kg) increased the survival time by a factor of 1.4 in cryptococcal meningoencephalitis. These results indicate that mild heat treatment of AmB-DOC solutions could provide a simple and economical method to improve the therapeutic index of this antifungal agent by reducing its toxicity on mammalian cells. (+info)
A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergy and Infectious Diseases Mycoses Study Group.
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This study was designed to compare the effectiveness of fluconazole vs. itraconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. HIV-infected patients who had been successfully treated (achieved negative culture of CSF) for a first episode of cryptococcal meningitis were randomized to receive fluconazole or itraconazole, both at 200 mg/d, for 12 months. The study was stopped prematurely on the recommendation of an independent Data Safety and Monitoring Board. At the time, 13 (23%) of 57 itraconazole recipients had experienced culture-positive relapse, compared with 2 relapses (4%) noted among 51 fluconazole recipients (P = .006). The factor best associated with relapse was the patient having not received flucytosine during the initial 2 weeks of primary treatment for cryptococcal disease (relative risk = 5.88; 95% confidence interval, 1.27-27.14; P = .04). Fluconazole remains the treatment of choice for maintenance therapy for AIDS-associated cryptococcal disease. Flucytosine may contribute to the prevention of relapse if used during the first 2 weeks of primary therapy. (+info)
Cryptococcosis in children with AIDS.
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We compiled the clinical and immunologic features of Cryptococcus neoformans infections in human immunodeficiency virus (HIV)-infected children from 1985 to 1996 in a retrospective case series. Thirty cases of cryptococcosis were identified. These children had a median age of 9.8 years, a median CD4+ cell count of 54/microL at the time of diagnosis, and either a culture positive for C. neoformans or cryptococcal antigen in serum or cerebrospinal fluid. Sixty-three percent of the cases occurred in children vertically infected with HIV and in children between 6 and 12 years of age. The clinical and laboratory characteristics of this pediatric cohort were similar to those of adults with AIDS and cryptococcosis. On the basis of a subset of the cases, a 10-year point prevalence of cryptococcosis among children with AIDS of approximately 1% was estimated. (+info)
Variants of a Cryptococcus neoformans strain elicit different inflammatory responses in mice.
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The virulence of Cryptococcus neoformans isolates with high and low extracellular proteolytic activity was investigated in mice. No consistent relationship between proteolytic activity and virulence was observed, but isolates derived from one strain were shown to elicit different inflammatory responses. (+info)
Serotyping of Cryptococcus neoformans isolates from clinical and environmental sources in Spain.
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We determined biovars and serotypes of 154 isolates of Cryptococcus neoformans from clinical and environmental sources from different areas of Spain. All clinical isolates belonged to C. neoformans var. neoformans. Serotypes showed an irregular distribution. C. neoformans var. gattii serotype B was isolated from necropsy specimens from goats with pulmonary disease. (+info)
Heat shock protein 70 (hsp70) as a major target of the antibody response in patients with pulmonary cryptococcosis.
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Cryptococcus neoformans causes infection in individuals with defective T cell function, such as AIDS, as well as without underlying disease. It has been suggested that humoral as well as cellular immunity might play an important role in the immune response to C. neoformans infection. We have recently shown, using immunoblotting, that the 70-kD hsp family of C. neoformans was the major target molecule of the humoral response in murine pulmonary cryptococcosis. In this study we also used immunoblotting to define the antibody responses in the sera of 24 patients with pulmonary cryptococcosis: 21 proven and three suspected diagnoses. Anti-C. neoformans hsp70 antibody was detected in 16 of 24 (66.7%) patients with pulmonary cryptococcosis. Fourteen of 17 (82.3%) patients with high antigen titres (> or = 1:8) and two of seven (28.6%) patients with low titres (< or = 1:4) had detectable levels of anti-hsp70 antibody. Sera from patients positive for anti-hsp70 antibody showed high titres in the Eiken latex agglutination test for the detection of serum cryptococcal antigen. Our results indicate that the 70-kD hsp family from C. neoformans appears to be a major target molecule of the humoral response, not only in murine pulmonary cryptococcosis, but also in human patients with pulmonary cryptococcosis. (+info)
Role of the C-C chemokine, TCA3, in the protective anticryptococcal cell-mediated immune response.
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Activated T lymphocytes play a crucial role in orchestrating cellular infiltration during a cell-mediated immune (CMI) reaction. TCA3, a C-C chemokine, is produced by Ag-activated T cells and is chemotactic for neutrophils and macrophages, two cell types in a murine CMI reaction. Using a gelatin sponge model for delayed-type hypersensitivity (DTH), we show that TCA3 is a component of the expression phase of an anticryptococcal CMI response in mice. TCA3 mRNA levels are augmented in anticryptococcal DTH reactions at the same time peak influxes of neutrophils and lymphocytes are observed. Neutralization of TCA3 in immunized mice results in reduced numbers of neutrophils and lymphocytes at DTH reaction sites. However, when rTCA3 is injected into sponges in naive mice, only neutrophils are attracted into the sponges, indicating TCA3 is chemotactic for neutrophils, but not lymphocytes. We show that TCA3 is indirectly attracting lymphocytes into DTH-reactive sponges by affecting at least one other chemokine that is chemotactic for lymphocytes. Of the two lymphocyte-attracting chemokines assessed, monocyte-chemotactic protein-1 and macrophage-inflammatory protein-1alpha (MIP-1alpha), only MIP-1alpha was reduced when TCA3 was neutralized, indicating that TCA3 affects the levels of MIP-1alpha, which attracts lymphocytes into the sponges. TCA3 also plays a role in protection against Cryptococcus neoformans in the lungs and brains of infected mice, as evidenced by the fact that neutralization of TCA3 results in increased C. neoformans CFU in those two organs. (+info)
Antibody response to Cryptococcus neoformans proteins in rodents and humans.
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The prevalence and specificity of serum antibodies to Cryptococcus neoformans proteins was studied in mice and rats with experimental infection, in individuals with or without a history of potential laboratory exposure to C. neoformans, human immunodeficiency virus (HIV)-positive individuals who developed cryptococcosis, in matched samples from HIV-positive individuals who did not develop cryptococcosis, and in HIV-negative individuals. Rodents had little or no serum antibody reactive with C. neoformans proteins prior to infection. The intensity and specificity of the rodent antibody response were dependent on the species, the mouse strain, and the viability of the inoculum. All humans had serum antibodies reactive with C. neoformans proteins regardless of the potential exposure, the HIV infection status, or the subsequent development of cryptococcosis. Our results indicate (i) a high prevalence of antibodies reactive with C. neoformans proteins in the sera of rodents after cryptococcal infection and in humans with or without HIV infection; (ii) qualitative and quantitative differences in the antibody profiles of HIV-positive individuals; and (iii) similarities and differences between humans, mice, and rats with respect to the specificity of the antibodies reactive with C. neoformans proteins. The results are consistent with the view that C. neoformans infections are common in human populations, and the results have implications for the development of vaccination strategies against cryptococcosis. (+info)