KMP027 Combined effect of liposomal and conventional amphotericin B in a mouse model of systemic infection with Candida albicans

2003 ◽  
Vol 293 ◽  
pp. 380
Keyword(s):  
Candida Albicans ◽  
Mouse Model ◽  
Amphotericin B ◽  
Systemic Infection ◽  
Combined Effect

scholarly journals High-dose ascorbate with low-dose amphotericin B attenuates severity of disease in a model of the reappearance of candidemia during sepsis in the mouse

2015 ◽  
Vol 309 (3) ◽  
pp. R223-R234 ◽  
Author(s):  
Asada Leelahavanichkul ◽  
Poorichaya Somparn ◽  
Tanabodee Bootprapan ◽  
Hongbin Tu ◽  
Pattarin Tangtanatakul ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Mouse Model ◽  
Amphotericin B ◽  
Low Dose ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Sodium Deoxycholate ◽  
High Dose ◽  
Phagocytic Cells

Amphotericin B (Ampho B) is a fungicidal drug that causes cell wall injury. Pharmacological ascorbate induces the extracellular prooxidants, which might enter the Ampho B-induced cell wall porosity and act synergistically. We tested low-dose Ampho B with a short course of pharmacological ascorbate using a mouse model of sepsis preconditioned with an injection of Candida albicans 6 h prior to cecal ligation and puncture (CLP). In this model, candidemia reappeared as early as 6 h after CLP with a predictably high mortality rate. This characteristic mimics sepsis in the phase of immunosuppression in patients. Using the model, at 12- and 18-h post-CLP, we administered isotonic (pH neutralized) pharmacological ascorbate intravenously with low-dose Ampho B or sodium deoxycholate, vehicle-controlled, administered IP. The survival rate of low-dose Ampho B plus ascorbate was 53%, compared with <11% for low-dose Ampho B or high-dose Ampho B alone. In addition, a beneficial effect was demonstrated in terms of kidney damage, liver injury, spleen histopathology, and serum markers at 24 h after CLP. Kidney injury was less severe in low-dose Ampho B plus ascorbate combination therapy due to less severe sepsis. Moreover, ascorbate enhanced the effectiveness of phagocytosis against C. albicans in human phagocytic cells. Taken together, the data indicate that the new mouse model simulates sepsis-induced immunosuppression and that the combination of pharmacological ascorbate with an antifungal drug is a potentially effective treatment that may reduce nephrotoxicity, and perhaps also increase fungicidal activity in patients with systemic candidiasis caused by Candida albicans.

Efficient treatment of murine systemic infection with Candida albicans using amphotericin B incorporated in nanosize range particles (emulsomes)

Mycoses ◽  
2001 ◽  
Vol 44 (7-8) ◽  
pp. 281-286 ◽  
Author(s):  
M. Kretschmar ◽  
S. Amselem ◽  
E. Zawoznik ◽  
K. Mosbach ◽  
A. Dietz ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Systemic Infection ◽  
Efficient Treatment

scholarly journals Candida albicans Uses Multiple Mechanisms To Acquire the Essential Metabolite Inositol during Infection

2008 ◽  
Vol 76 (6) ◽  
pp. 2793-2801 ◽  
Author(s):  
Ying-Lien Chen ◽  
Sarah Kauffman ◽  
Todd B. Reynolds
Keyword(s):  
Candida Albicans ◽  
Mouse Model ◽  
Double Mutant ◽  
De Novo ◽  
Systemic Infection ◽  
Bloodstream Infections ◽  
Wild Type Allele ◽  
Transporter Gene ◽  
Wild Type ◽  
Life Threatening

ABSTRACT Candida albicans is an important cause of life-threatening systemic bloodstream infections in immunocompromised patients. In order to cause infections, C. albicans must be able to synthesize the essential metabolite inositol or acquire it from the host. Based on the similarity of C. albicans to Saccharomyces cerevisiae, it was predicted that C. albicans may generate inositol de novo, import it from the environment, or both. The C. albicans inositol synthesis gene INO1 (orf19.7585) and inositol transporter gene ITR1 (orf19.3526) were each disrupted. The ino1Δ/ino1Δ mutant was an inositol auxotroph, and the itr1Δ/itr1Δ mutant was unable to import inositol from the medium. Each of these mutants was fully virulent in a mouse model of systemic infection. It was not possible to generate an ino1Δ/ino1Δ itr1Δ/itr1Δ double mutant, suggesting that in the absence of these two genes, C. albicans could not acquire inositol and was nonviable. A conditional double mutant was created by replacing the remaining wild-type allele of ITR1 in an ino1Δ/ino1Δ itr1Δ/ITR1 strain with a conditionally expressed allele of ITR1 driven by the repressible MET3 promoter. The resulting ino1Δ/ino1Δ itr1Δ/PMET3 ::ITR1 strain was found to be nonviable in medium containing methionine and cysteine (which represses the PMET3 promoter), and it was avirulent in the mouse model of systemic candidiasis. These results suggest a model in which C. albicans has two equally effective mechanisms for obtaining inositol while in the host. It can either generate inositol de novo through Ino1p, or it can import it from the host through Itr1p.

scholarly journals Interaction between Posaconazole and Amphotericin B in Concomitant Treatment against Candida albicans In Vivo

2005 ◽  
Vol 49 (2) ◽  
pp. 638-642 ◽  
Author(s):  
Anthony Cacciapuoti ◽  
Maya Gurnani ◽  
Judith Halpern ◽  
Christine Norris ◽  
Reena Patel ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mouse Model ◽  
Amphotericin B ◽  
Concomitant Treatment ◽  
Survival Curves ◽  
Immunocompetent Mice ◽  
Systemic Infections ◽  
Dose Levels

ABSTRACT The interaction of posaconazole and amphotericin B was evaluated in concomitant treatment of Candida albicans systemic infections in immunocompetent mice by using four strains of C. albicans with different susceptibilities to fluconazole. Posaconazole and amphotericin B were each tested at four dose levels alone and in all possible combinations against each C. albicans strain. Survival curves of mice treated with combinations of posaconazole and amphotericin B were statistically compared with those of mice treated with the component monotherapies. Of the 64 total combinations evaluated against the C. albicans strains (16 combinations per strain), 20.3% were more effective in prolonging mouse survival than both of the monotherapies, 45.3% were more effective than one of the monotherapies, and 32.8% were similar to both monotherapies. No evidence of antagonism was observed between posaconazole and amphotericin B in this mouse model, consistent with in vitro results against the same strains.

scholarly journals Interaction between Fluconazole and Amphotericin B in Mice with Systemic Infection Due to Fluconazole-Susceptible or -Resistant Strains of Candida albicans

1999 ◽  
Vol 43 (12) ◽  
pp. 2841-2847 ◽  
Author(s):  
Arnold Louie ◽  
Partha Banerjee ◽  
George L. Drusano ◽  
Mehdi Shayegani ◽  
Michael H. Miller
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Resistant Strain ◽  
Antifungal Agents ◽  
Survival Rates ◽  
Systemic Infection ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Quantitative Culture ◽  
Resistant Strains

ABSTRACT The interaction between fluconazole (Flu) and amphotericin B (AmB) was evaluated in a murine model of systemic candidiasis for one Flu-susceptible strain (MIC, 0.5 μg/ml), two strains with intermediate Flu resistance (Flu mid-resistant strains) (MIC, 64 and 128 μg/ml), and one highly Flu-resistant strain (MIC, 512 μg/ml) ofCandida albicans. Differences in fungal densities in kidneys of infected mice after 24 h of therapy and in survival rates at 62 days of mice treated with an antifungal drug or a combination of antifungal drugs for 4 days were compared. For the Flu-susceptible and Flu mid-resistant strains, the combination of Flu and AmB was antagonistic, as shown by both quantitative culture results and survival. The interaction was additive for the highly Flu-resistant strain. These results suggest that the combination of Flu and AmB should be used with caution in infections due to fungi that are usually susceptible to both antifungal agents and as empirical antifungal drug therapy.

scholarly journals Combined Inactivation of the Candida albicans GPR1 and TPS2 Genes Results in Avirulence in a Mouse Model for Systemic Infection

2008 ◽  
Vol 76 (4) ◽  
pp. 1686-1694 ◽  
Author(s):  
Mykola M. Maidan ◽  
Larissa De Rop ◽  
Miguel Relloso ◽  
Rosalia Diez-Orejas ◽  
Johan M. Thevelein ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mouse Model ◽  
Double Mutant ◽  
Systemic Infection ◽  
Antifungal Drugs ◽  
The Other ◽  
Growth Defect ◽  
Other Hand ◽  
Solid Media

ABSTRACT Inhibition of the biosynthesis of trehalose, a well-known stress protectant in pathogens, is an interesting approach for antifungal or antibacterial therapy. Deletion of TPS2, encoding trehalose-6-phosphate (T6P) phosphatase, results in strongly reduced virulence of Candida albicans due to accumulation of T6P instead of trehalose in response to stress. To further aggravate the deregulation in the pathogen, we have additionally deleted the GPR1 gene, encoding the nutrient receptor that activates the cyclic AMP-protein kinase A signaling pathway, which negatively regulates trehalose accumulation in yeasts. A gpr1 mutant is strongly affected in morphogenesis on solid media as well as in vivo in a mouse model but has only a slightly decreased virulence. The gpr1 tps2 double mutant, on the other hand, is completely avirulent in a mouse model for systemic infection. This strain accumulates very high T6P levels under stress conditions and has a growth defect at higher temperatures. We also show that a tps2 mutant is more sensitive to being killed by macrophages than the wild type or the gpr1 mutant. A double mutant has susceptibility similar to that of the single tps2 mutant. For morphogenesis on solid media, on the other hand, the gpr1 tps2 mutant shows a phenotype similar to that of the single gpr1 mutant. Taken together these results show that there is synergism between Gpr1 and Tps2 and that their combined inactivation results in complete avirulence. Combination therapy targeting both proteins may prove highly effective against pathogenic fungi with increased resistance to the currently used antifungal drugs.

scholarly journals Rapid proliferation due to better metabolic adaptation results in full virulence of a filament-deficient Candida albicans strain

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Christine Dunker ◽  
Melanie Polke ◽  
Bianca Schulze-Richter ◽  
Katja Schubert ◽  
Sven Rudolphi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mouse Model ◽  
Systemic Infection ◽  
Hyphal Growth ◽  
Metabolic Adaptation ◽  
Infection Model ◽  
Intraperitoneal Infection ◽  
Systemic Infections

AbstractThe ability of the fungal pathogen Candida albicans to undergo a yeast-to-hypha transition is believed to be a key virulence factor, as filaments mediate tissue damage. Here, we show that virulence is not necessarily reduced in filament-deficient strains, and the results depend on the infection model used. We generate a filament-deficient strain by deletion or repression of EED1 (known to be required for maintenance of hyphal growth). Consistent with previous studies, the strain is attenuated in damaging epithelial cells and macrophages in vitro and in a mouse model of intraperitoneal infection. However, in a mouse model of systemic infection, the strain is as virulent as the wild type when mice are challenged with intermediate infectious doses, and even more virulent when using low infectious doses. Retained virulence is associated with rapid yeast proliferation, likely the result of metabolic adaptation and improved fitness, leading to high organ fungal loads. Analyses of cytokine responses in vitro and in vivo, as well as systemic infections in immunosuppressed mice, suggest that differences in immunopathology contribute to some extent to retained virulence of the filament-deficient mutant. Our findings challenge the long-standing hypothesis that hyphae are essential for pathogenesis of systemic candidiasis by C. albicans.

Sign in / Sign up

Export Citation Format

Share Document