Treatment of Candida infection: a view from the trenches!

Bustamante, Carlos I.

doi:10.1097/01.qco.0000191516.43792.61

Cited by 42 publications

(41 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Candida species have been identified as the fourth leading cause of fungal infections in immunocompromised patients, with a fatality rate of around 40%. Among patients undergoing bone marrow transplants and intensive chemotherapy, the rate of mortality of this disease is higher than 80% (6).…”

mentioning

confidence: 99%

Comparison of Fluconazole Renal Penetration Levels in Healthy and Candida albicans-Infected Wistar Rats

Azeredo

Araújo

Haas

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The aims of this study were to evaluate free levels of fluconazole (FCZ) in the kidneys of healthy and Candida albicansinfected Wistar rats using microdialysis and to establish the relationship between free renal and total plasma levels under both conditions. Microdialysis recovery rates were determined in vitro by dialysis, and retrodialysis recovery rates were determined in vivo by retrodialysis. The recovery rate was around 50%, independent of the method, drug concentration, or condition (in vitro or in vivo) used. FCZ kidney penetration in healthy and infected rats was investigated after the administration of 10 mg/kg of body weight intravenously (i.v.) or 50 mg/kg orally (n ‫؍‬ 6/group) and blood and microdialysate sample harvesting at predetermined time points up to 24 and 18 h, respectively. There were no statistical differences between the area under the free concentration-time curve (AUC 0 -ؕ ) values in plasma and in tissue for either healthy or infected groups for the same dose regimen investigated. The antifungal tissue penetrations were similar for both doses and under all conditions investigated (ranging from 0.77 to 0.84). The unbound fraction of FCZ was concentration independent (86.0% ؎ 2.0%), allowing the prediction of free renal levels using pharmacokinetic parameters obtained from total plasma fitting. The results showed that free renal and free plasma levels are similar in healthy and systemically C. albicansinfected rats. Therefore, free plasma levels are a good surrogate to estimate free FCZ renal concentrations in systemic candidiasis and can be used to optimize dosing regimens for this drug.

show abstract

mentioning

confidence: 99%

Comparison of Fluconazole Renal Penetration Levels in Healthy and Candida albicans-Infected Wistar Rats

Azeredo

Araújo

Haas

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…In patients that are neutropenic, Candida species are associated with severe and deadly systemic bloodstream infections with a high mortality rate (31.8%) (27). In fact, Candida species are the fourth most common cause of catheter-related bloodstream infections in hospitalized patients in intensive care units, and C. albicans is the species most commonly isolated from patients with these infections (4).…”

mentioning

confidence: 99%

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

2008

View full text Add to dashboard Cite

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 ino1⌬/ino1⌬ mutant was an inositol auxotroph, and the itr1⌬/itr1⌬ 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 ino1⌬/ino1⌬ itr1⌬/itr1⌬ 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 ino1⌬/ino1⌬ itr1⌬/ITR1 strain with a conditionally expressed allele of ITR1 driven by the repressible MET3 promoter. The resulting ino1⌬/ ino1⌬ itr1⌬/P MET3 ::ITR1 strain was found to be nonviable in medium containing methionine and cysteine (which represses the P MET3 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.

show abstract

“…In the United States, candidemia is the fourth most common type of nosocomial bloodstream infection (5). Once C. albicans reaches the bloodstream, the immune system plays an important role in limiting candidiasis (51).…”

mentioning

confidence: 99%

Farnesol Induces Hydrogen Peroxide Resistance in Candida albicans Yeast by Inhibiting the Ras-Cyclic AMP Signaling Pathway

et al. 2010

View full text Add to dashboard Cite

Farnesol, a Candida albicans cell-cell signaling molecule that participates in the control of morphology, has an additional role in protection of the fungus against oxidative stress. In this report, we show that although farnesol induces the accumulation of intracellular reactive oxygen species (ROS), ROS generation is not necessary for the induction of catalase (Cat1)-mediated oxidative-stress resistance. Two antioxidants, ␣-tocopherol and, to a lesser extent, ascorbic acid effectively reduced intracellular ROS generation by farnesol but did not alter farnesol-induced oxidative-stress resistance. Farnesol inhibits the Ras1-adenylate cyclase (Cyr1) signaling pathway to achieve its effects on morphology under hypha-inducing conditions, and we demonstrate that farnesol induces oxidative-stress resistance by a similar mechanism. Strains lacking either Ras1 or Cyr1 no longer exhibited increased protection against hydrogen peroxide upon preincubation with farnesol. While we also observed the previously reported increase in the phosphorylation level of Hog1, a known regulator of oxidative-stress resistance, in the presence of farnesol, the hog1/hog1 mutant did not differ from wild-type strains in terms of farnesol-induced oxidative-stress resistance. Analysis of Hog1 levels and its phosphorylation states in different mutant backgrounds indicated that mutation of the components of the Ras1-adenylate cyclase pathway was sufficient to cause an increase of Hog1 phosphorylation even in the absence of farnesol or other exogenous sources of oxidative stress. This finding indicates the presence of unknown links between these signaling pathways. Our results suggest that farnesol effects on the Ras-adenylate cyclase cascade are responsible for many of the observed activities of this fungal signaling molecule.

show abstract

Treatment of Candida infection: a view from the trenches!

Cited by 42 publications

References 18 publications

Comparison of Fluconazole Renal Penetration Levels in Healthy and Candida albicans-Infected Wistar Rats

Comparison of Fluconazole Renal Penetration Levels in Healthy and Candida albicans-Infected Wistar Rats

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

Farnesol Induces Hydrogen Peroxide Resistance in Candida albicans Yeast by Inhibiting the Ras-Cyclic AMP Signaling Pathway

Contact Info

Product

Resources

About