Comparison of Fungizone, Amphotec, AmBisome, and Abelcet for Treatment of Systemic Murine Cryptococcosis

1998 ◽  
Vol 42 (4) ◽  
pp. 899-902 ◽  
Author(s):  
Karl V. Clemons ◽  
David A. Stevens
Keyword(s):  
Body Weight ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Rank Order ◽  
Yeast Cells ◽  
Treatment Regimens ◽  
Equal Dose ◽  
The Brain ◽  
All Treatment ◽  
Better Than

ABSTRACT Three lipid-based formulations of amphotericin B have been approved for use in various countries. The aim of this study was to compare Amphotec (ABCD; Sequus), AmBisome (AmBi; Nexstar), Abelcet (ABLC; The Liposome Co.), and conventional deoxycholate amphotericin B (Fungizone; Bristol Meyers Squibb) for the treatment of experimental systemic cryptococcosis. A model was established in 10-week-old female CD-1 mice by intravenous (i.v.) injection of 6.25 × 105 viableCryptococcus neoformans yeast cells. Therapy began 4 days later, with i.v. administration three times per week for 2 weeks. Mice received either no treatment, 1 mg of Fungizone per kg of body weight, or 1, 5, or 10 mg of ABCD, AmBi, or ABLC per kg. Ninety percent of control mice died between days 15 and 34. All treatment regimens except ABLC at 1 mg/kg prolonged survival compared with no treatment (P < 0.01 to 0.001). All mice receiving 5 or 10 mg of ABCD or AmBi per kg and 90% of mice given 10 mg of ABLC per kg survived, whereas ≤50% of those given other treatment regimens survived. Fungizone was the least effective of the four formulations, with 5 or 10 mg of ABCD, AmBi, or ABLC per kg resulting in a significantly better outcome than Fungizone (P < 0.001). Among the three formulations, ABCD and AmBi were equally effective, both being better than ABLC at equal 5- or 10-mg/kg doses (P < 0.001). Comparison of residual infectious burdens in various organs showed that each drug had some dose-responsive efficacy in three or more organs at escalating doses. In the brain, ABCD or AmBi at 5 or 10 mg/kg or ABLC at 10 mg/kg was more effective than Fungizone at 1 mg/kg or no treatment, while ABCD or AmBi at 1 mg/kg was as effective as ABLC at 10 mg/kg. Similar results were obtained for the kidneys and lungs. In the spleen, ABCD at 10 mg/kg cured all mice of infection and was superior to all other regimens. In the liver, AmBi at 5 mg/kg was superior to an equal dose of ABCD or ABLC. Overall, the efficacies of ABCD and AmBi were equal to that of Fungizone at 1 mg/kg and were about 10-fold better than that of ABLC, particularly in the brain; a comparative rank order of efficacies was ABCD ≅ AmBi > ABLC ≫ Fungizone. This is the first study that compared all four amphotericin B formulations.

scholarly journals Efficacy of Amphotericin B in Combination with Flucytosine against Flucytosine-Susceptible or Flucytosine-Resistant Isolates of Cryptococcus neoformans during Disseminated Murine Cryptococcosis

2006 ◽  
Vol 50 (1) ◽  
pp. 113-120 ◽  
Author(s):  
Patrick Schwarz ◽  
Françoise Dromer ◽  
Olivier Lortholary ◽  
Eric Dannaoui
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Resistant Isolate ◽  
Fungal Burden ◽  
Cryptococcal Infection ◽  
Susceptible Isolate ◽  
The Difference ◽  
The Brain ◽  
Better Than

ABSTRACT Whether or not flucytosine should be administered to patients infected with Cryptococcus neoformans isolates found to be resistant to flucytosine in vitro remains a controversial issue. Thus, the efficacy of amphotericin B and flucytosine in combination was investigated by mortality and fungal burden studies in a murine model of disseminated cryptococcosis using two clinical isolates of Cryptococcus neoformans, one susceptible and one resistant (i.e., 64 μg/ml) to flucytosine. Amphotericin B was given intraperitoneally at 0.25 or 0.5 mg/kg/day, while flucytosine was given at 100 or 250 mg/kg/day orally. Treatment was started 24 h or day 6 after inoculation and continued for 5 days in fungal burden and mortality studies, respectively. The combination of amphotericin B at 0.5 mg/kg/day and flucytosine at 250 mg/kg/day was significantly more effective than monotherapies for reducing fungal burden in brain, spleen, and lungs after infection by the flucytosine-susceptible isolate and in brain and spleen for the flucytosine-resistant isolate. For the flucytosine-resistant isolate, the combination of amphotericin B at 0.5 mg/kg/day with flucytosine at 100 mg/kg/day was significantly better than monotherapies for reducing the fungal burden in the brain. Survival obtained after the combination of amphotericin B at 0.5 mg/kg/day and flucytosine at 250 mg/kg/day increased compared to that obtained with monotherapies for both isolates, but the difference was statistically significant only for the flucytosine-susceptible isolate. Antagonism was never observed. This study demonstrates the beneficial effect of the addition of flucytosine to amphotericin B against experimental disseminated cryptococcal infection even when the C. neoformans isolate is resistant to flucytosine.

scholarly journals Fatty Acid Synthesis Is Essential for Survival of Cryptococcus neoformans and a Potential Fungicidal Target

2007 ◽  
Vol 51 (10) ◽  
pp. 3537-3545 ◽  
Author(s):  
Methee Chayakulkeeree ◽  
Thomas H. Rude ◽  
Dena L. Toffaletti ◽  
John R. Perfect
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Cryptococcus Neoformans ◽  
Fatty Acid Synthase ◽  
Acid Synthesis ◽  
Yeast Cells ◽  
Synthase Inhibitor ◽  
The Brain

ABSTRACT Fatty acid synthase in the yeast Cryptococcus neoformans is composed of two subunits encoded by FAS1 and FAS2 genes. We inserted a copper-regulated promoter (P CTR4-2 ) to regulate FAS1 and FAS2 expression in Cryptococcus neoformans (strains P CTR4-2 /FAS1 and P CTR4-2 /FAS2, respectively). Both mutants showed growth rates similar to those of the wild type in a low-copper medium in which FAS1 and FAS2 were expressed, but even in the presence of exogenous fatty acids, strains were suppressed in growth under high-copper conditions. The treatment of C. neoformans with fluconazole was shown to have an increased inhibitory activity and even became fungicidal when either FAS1 or FAS2 expression was suppressed. Furthermore, a subinhibitory dose of fluconazole showed anticryptococcal activity in vitro in the presence of cerulenin, a fatty acid synthase inhibitor. In a murine model of pulmonary cryptococcosis, a tissue census of yeast cells in P CTR4-2 /FAS2 strain at day 7 of infection was significantly lower than that in mice treated with tetrathiomolybdate, a copper chelator (P < 0.05), and a yeast census of P CTR4-2 /FAS1 strain at day 14 of infection in the brain was lower in the presence of more copper. In fact, no positive cultures from the brain were detected in mice (with or without tetrathiomolybdate treatment) infected with the P CTR4-2 /FAS2 strain, which implies that this mutant did not reach the brain in mice. We conclude that both FAS1 and FAS2 in C. neoformans are essential for in vitro and in vivo growth in conditions with and without exogenous fatty acids and that FAS1 and FAS2 can potentially be fungicidal targets for C. neoformans with a potential for synergistic behavior with azoles.

scholarly journals Posaconazole and Amphotericin B Combination Therapy against Cryptococcus neoformans Infection

2004 ◽  
Vol 48 (9) ◽  
pp. 3312-3316 ◽  
Author(s):  
Francesco Barchiesi ◽  
Elisabetta Spreghini ◽  
Anna M. Schimizzi ◽  
Monia Maracci ◽  
Daniele Giannini ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Combination Regimen ◽  
Fungal Burden ◽  
Cryptococcal Infection ◽  
Single Drug ◽  
Cd1 Mice ◽  
Survival Studies ◽  
The Brain

ABSTRACT To investigate the effects of posaconazole (POS) and amphotericin B (AMB) combination therapy in cryptococcal infection, we established an experimental model of systemic cryptococcosis in CD1 mice by intravenous injection of three distinct clinical isolates of Cryptococcus neoformans. Therapy was started 24 h after the infection and continued for 10 consecutive days. POS was given at 3 and 10 mg/kg of body weight/day, while AMB was given at 0.3 mg/kg/day. Combination therapy consisted of POS given at a low (combo 3) or at a high (combo 10) dose plus AMB. Survival studies showed that combo 3 was significantly more effective than POS at 3 mg/kg for two isolates tested (P value, ≤0.001), while combo 10 was significantly more effective than POS at 10 mg/kg for all three isolates (P values ranging from <0.001 to 0.005). However, neither combination regimen was more effective than AMB alone. For two isolates, combination therapy was significantly more effective than each single drug at reducing the fungal burden in the brain (P values ranging from 0.001 to 0.015) but not in the lungs. This study demonstrates that the major impact of POS and AMB combination therapy is on brain fungal burden rather than on survival.

scholarly journals A Novel Injectable Water-Soluble Amphotericin B-Arabinogalactan Conjugate

1999 ◽  
Vol 43 (8) ◽  
pp. 1975-1981 ◽  
Author(s):  
Rama Falk ◽  
Abraham J. Domb ◽  
Itzhack Polacheck
Keyword(s):  
Body Weight ◽  
Amphotericin B ◽  
Water Solubility ◽  
Fungal Infections ◽  
Water Soluble ◽  
Yeast Cells ◽  
High Yield ◽  
Target Organs ◽  
Natural Polysaccharide ◽  
Further Development

ABSTRACT New, stable, highly water-soluble, nontoxic polysaccharide conjugates of amphotericin B (AmB) are described. AmB was conjugated by a Schiff-base reaction with oxidized arabinogalactan (AG). AG is a highly branched natural polysaccharide with unusual water solubility (70% in water). A high yield of active AmB was obtained with the conjugates which were similarly highly water soluble and which could be appropriately formulated for injection. They showed comparable MICs forCandida albicans and Cryptococcus neoformans(MICs, 0.1 to 0.2 μg/ml). The reduced AmB conjugate, which was synthesized at pH 11 for 48 h at 37°C, was nonhemolytic and was much safer than conventional micellar AmB-deoxycholate. It was the least toxic AmB-AG conjugate among those tested with mice (maximal tolerated dose, 50 mg/kg of body weight), and histopathology indicated no damage to the liver or kidneys. This conjugate, similarly to the liposomal formulation (AmBisome), was more effective than AmB-deoxycholate in prolonging survival. It was more effective than both the liposomal and the deoxycholate formulations in eradicating yeast cells from target organs. The overall results suggest that after further development of the AmB-AG conjugate, it may be a potent agent in the treatment of fungal infections.

scholarly journals Posaconazole Prophylaxis in Experimental Systemic Zygomycosis

2006 ◽  
Vol 51 (1) ◽  
pp. 73-77 ◽  
Author(s):  
Francesco Barchiesi ◽  
Elisabetta Spreghini ◽  
Alfredo Santinelli ◽  
Annette W. Fothergill ◽  
Eleonora Pisa ◽  
...  
Keyword(s):  
Body Weight ◽  
Amphotericin B ◽  
Rhizopus Oryzae ◽  
Systemic Infection ◽  
Drug Efficacy ◽  
Antifungal Drugs ◽  
Active Infection ◽  
Absidia Corymbifera ◽  
The Brain

ABSTRACT Three isolates of zygomycetes belonging to two different genera (Rhizopus oryzae and Absidia corymbifera) were used to produce a systemic infection in neutropenic mice. On days −2 and −1 and at 2 h prior to infection, the mice received either posaconazole (POS) at doses ranging from 20 to 80 mg/kg of body weight/day or amphotericin B (AMB) at 1 mg/kg/day. Antifungal drug efficacy was assessed by determination of the prolongation of survival, determination of the percentage of infected organs (brain, lung, spleen, and kidney), and histological examination for the number of infection foci and their sizes in brain and kidney tissues. AMB significantly prolonged the survival of mice infected with all isolates. POS significantly prolonged the survival of mice infected with zygomycetes. Cultured organs from mice infected with R. oryzae were all positive, while treated mice challenged with A. corymbifera generally showed lower percentages of infected organs compared with the percentages for the controls. Zygomycete isolates established an active infection (the presence of hyphae) in the brains and the kidneys of all controls. In mice challenged with R. oryzae, both antifungal drugs were effective at reducing the number and the size of infection foci in the kidneys. Only AMB reduced the numbers, but not the sizes, of infection foci in the brain. Finally, both drugs significantly reduced the numbers and the sizes of infection foci in both tissues of mice infected with A. corymbifera. Our data suggest that prophylaxis with POS has some potential to prevent zygomycosis.

scholarly journals Efficacy of Micafungin Alone or in Combination against Systemic Murine Aspergillosis

2003 ◽  
Vol 47 (4) ◽  
pp. 1452-1455 ◽  
Author(s):  
Javier Capilla Luque ◽  
Karl V. Clemons ◽  
David A. Stevens
Keyword(s):  
Body Weight ◽  
Combination Therapy ◽  
Amphotericin B ◽  
Prolonged Survival ◽  
Nikkomycin Z ◽  
The Brain ◽  
Body Weight Dose

ABSTRACT We tested the efficacy of micafungin (FK) alone or in combination with other antifungals against systemic murine aspergillosis. FK alone at 10 mg/kg of body weight/dose prolonged survival (P = 0.01) and reduced CFU in the brain and kidney. Combination therapy that used suboptimal FK with amphotericin B or itraconazole prolonged survival. Although no survivors were free of infection, no antagonism was seen. Nikkomycin Z with FK showed significantly greater potency (P < 0.01) than either alone.

scholarly journals Activities of Sordarins in Murine Histoplasmosis

1999 ◽  
Vol 43 (7) ◽  
pp. 1716-1718 ◽  
Author(s):  
John R. Graybill ◽  
Laura Najvar ◽  
Annette Fothergill ◽  
Rosie Bocanegra ◽  
Federico Gomez de las Heras
Keyword(s):  
Body Weight ◽  
Amphotericin B ◽  
Histoplasma Capsulatum ◽  
Kidney Tissue ◽  
Elongation Factor ◽  
Antifungal Drugs ◽  
Yeast Cells ◽  
Fungal Protein ◽  
Elongation Factor 2 ◽  
Fungal Protein Synthesis

ABSTRACT Sordarins are new antifungals which inhibit fungal protein synthesis by blocking elongation factor 2. Three compounds were evaluated in a murine model of histoplasmosis. Immune-competent mice were infected intravenously with 106 to 108 CFU of Histoplasma capsulatum yeast cells. Mice were treated either orally with sordarins or fluconazole from day 2 through 8 after infection or intraperitoneally with amphotericin B during the same period. Protection was measured by increased rates of survival for 30 days after infection or reduction of lung or kidney tissue counts 9 days after infection. All three of the antifungal drugs tested were protective compared with controls. Sordarins were effective at doses as low as 2 mg/kg of body weight/day. This novel class of drugs compared favorably with amphotericin B and fluconazole for the treatment of histoplasmosis.

scholarly journals X-Linked Immunodeficient Mice Exhibit Enhanced Susceptibility to Cryptococcus neoformans Infection

mBio ◽  
2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Wendy A. Szymczak ◽  
Michael J. Davis ◽  
Steven K. Lundy ◽  
Chad Dufaud ◽  
Michal Olszewski ◽  
...  
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Cryptococcus Neoformans ◽  
Yeast Cells ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Content Type ◽  
Cell Functions ◽  
The Brain

ABSTRACTBruton’s tyrosine kinase (Btk) is a signaling molecule that plays important roles in B-1 B cell development and innate myeloid cell functions and has recently been identified as a target for therapy of B cell lymphomas. We examined the contribution of B-1 B cells to resistance toCryptococcus neoformansinfection by utilizing X-linked immunodeficient (XID) mice (CBA-CaHN-XID), which possess a mutation in Btk. XID mice had significantly higher brain fungal burdens than the controls 6 weeks after infection withC. neoformansstrain 52D (CN52D); however, consistent with the propensity for greater virulence ofC. neoformansstrain H99 (CNH99), CNH99-infected XID mice had higher lung and brain fungal burdens than the controls 3 weeks after infection. Further studies in a chronic CN52D model revealed markedly lower levels of total andC. neoformans-specific serum IgM in XID mice than in the control mice 1 and 6 weeks after infection. Alveolar macrophage phagocytosis was markedly impaired in CN52D-infected XID mice compared to the controls, with XID mice exhibiting a disorganized lung inflammatory pattern in which Gomori silver staining revealed significantly more enlarged, extracellularC. neoformanscells than the controls. Adoptive transfer of B-1 B cells to XID mice restored peritoneal B-1 B cells but did not restore IgM levels to those of the controls and had no effect on the brain fungal burden at 6 weeks. Taken together, our data support the hypothesis that IgM promotes fungal containment in the lungs by enhancingC. neoformansphagocytosis and restrictingC. neoformansenlargement. However, peritoneal B-1 B cells are insufficient to reconstitute a protective effect in the lungs.IMPORTANCECryptococcus neoformansis a fungal pathogen that causes an estimated 600,000 deaths per year. Most infections occur in individuals who are immunocompromised, with the majority of cases occurring in those with HIV/AIDS, but healthy individuals also develop disease. Immunoglobulin M (IgM) has been linked to resistance to disease in humans and mice. In this article, we found that X-linked immunodeficient (XID) mice, which have markedly reduced levels of IgM, were unable to containCryptococcusin the lungs. This was associated with reduced yeast uptake by macrophages, an aberrant tissue inflammatory response, an enlargement of the yeast cells in the lungs, and fungal dissemination to the brain. Since XID mice have a mutation in the Bruton’s tyrosine kinase (Btk) gene, our data suggest that treatments aimed at blocking the function of Btk could pose a higher risk for cryptococcosis.

Sign in / Sign up

Export Citation Format

Share Document