Preemptive antifungal therapy: Do diagnostics help?

2019 ◽  
pp. 97-114
Author(s):  
Vidya Jagadeesan ◽  
Margaret Powers-Fletcher ◽  
Kimberly E. Hanson
Keyword(s):  
2018 ◽  
Vol 16 (1) ◽  
pp. 44-53
Author(s):  
Marina Campos Rocha ◽  
Camilla Alves Santos ◽  
Iran Malavazi

Different signaling cascades including the Cell Wall Integrity (CWI), the High Osmolarity Glycerol (HOG) and the Ca2+/calcineurin pathways control the cell wall biosynthesis and remodeling in fungi. Pathogenic fungi, such as Aspergillus fumigatus and Candida albicans, greatly rely on these signaling circuits to cope with different sources of stress, including the cell wall stress evoked by antifungal drugs and the host’s response during infection. Hsp90 has been proposed as an important regulatory protein and an attractive target for antifungal therapy since it stabilizes major effector proteins that act in the CWI, HOG and Ca2+/calcineurin pathways. Data from the human pathogen C. albicans have provided solid evidence that loss-of-function of Hsp90 impairs the evolution of resistance to azoles and echinocandin drugs. In A. fumigatus, Hsp90 is also required for cell wall integrity maintenance, reinforcing a coordinated function of the CWI pathway and this essential molecular chaperone. In this review, we focus on the current information about how Hsp90 impacts the aforementioned signaling pathways and consequently the homeostasis and maintenance of the cell wall, highlighting this cellular event as a key mechanism underlying antifungal therapy based on Hsp90 inhibition.


2019 ◽  
Vol 9 (4) ◽  
pp. 330-340
Author(s):  
Mitradev Pattoo ◽  
Vuyokazi Belewa ◽  
Benesh Munilal Somai

Background:In both the developed and developing world, the mortality rates of people afflicted with cryptococcosis are unacceptably high despite the availability of antifungal therapy. The disease is caused by Cryptococcus neoformans (predominantly in immunocompromised individuals) and by Cryptococcus gattii. Globally the disease is estimated to cause around 600,000 deaths annually. Antifungal therapy is available, but in the developing world, may be unaffordable to many people, there is an increasing threat of resistance to the available drugs and our repertoire of antifungal drugs is very limited. Consequently, more research has been focusing on the use of medicinal plants as therapeutic agents. The originality of the current study is that although Tulbaghia violacea is a well-documented medicinal plant, the chemical composition of aqueous extracts and their antifungal potential against pathogenic yeasts are unknown. This is the first study that evaluates the chemical constituents of aqueous T. violacea root, leaf, rhizome and tuber extracts and their corresponding antifungal activities against C. neoformans and C. gattii.Objectives:The study aimed to investigate the phytochemical composition and antifungal potential of Tulbaghia violacea root, leaf, rhizome and tuber extracts against Cryptococcus neoformans and Cryptococcus gattii.Methods:Roots, leaves, rhizomes and tubers were extracted with water only for 48 h at room temperature with continuous shaking. Extracts were filter sterilized, freeze-dried and, chemically analyzed for saponin, flavonol, phenolic and tannin content. Chemical constituents of each extract were also identified by GC-MS analysis. The Minimum Inhibitory Concentration (MIC) of suitably diluted extracts of each plant part were also performed against C. neoformans and C. gattii, yeast pathogens commonly associated with HIV/AIDS sufferers.Results:Phytochemical analysis showed different concentrations of saponins (between 1023 and 2896.73 µg/ml), phenolics (between 16.48 and 51.58 µg/ml) and tannins (between 122.30 and 543.07 µg/ml) present in the different extracts. No flavonols were detected. GC-MS analysis identified a complex mixture of phytochemicals composed predominantly of sulphide, pyran, furan and ketone containing compounds to be present in the different plant parts. All extracts were dominated by the presence of 4 H-pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6-methyl, a pyran known to have antifungal properties. Although the root, leaf, rhizome and tuber extracts exhibited antifungal activities against both fungi, the rhizome and tuber extract were found to possess the lowest MIC’s of 1.25 mg/ml and 2.5 mg/ml against Cryptococcus neoformans and Cryptococcus gattii respectively.Conclusion:T. violacea extracts have a complex constituent of phytochemicals and each plant part exhibited a strong antifungal activity against C. neoformans and C. gattii. The rhizome and tuber extracts showed the highest antifungal activity against C. neoformans and C. gattii respectively. Thus, T. violacea aqueous extracts are strong candidates for further development into an antifungal chemotherapeutic agent.


2019 ◽  
Vol 19 (12) ◽  
pp. 1281
Author(s):  
Masaya Taniwaki ◽  
Masahiro Yamasaki ◽  
Nobuhisa Ishikawa ◽  
Kazuma Kawamoto ◽  
Noboru Hattori

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yu Gu ◽  
Xianping Ye ◽  
Yu Wang ◽  
Kunlu Shen ◽  
Jinjin Zhong ◽  
...  

Abstract Background Lower respiratory tract (LRT) specimen culture is widely performed for the identification of Aspergillus. We investigated the clinical features and prognosis of patients with Aspergillus isolation from LRT specimens during acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods This is a 6-year single-center, real-world study. 75 cases out of 1131 hospitalized AECOPD patients were positive for Aspergillus. These patients were carefully evaluated and finally diagnosed of pulmonary aspergillosis (PA, 60 cases, 80%) or colonization (15 cases, 20%). Comparisons of clinical data were performed between these two groups. A cox regression model was used to confirm prognostic factors of Aspergillus infection. Results The PA group had worse lung function and higher rates of systemic corticosteroid use and broad-spectrum antibiotic use before admission than the colonization group. The PA group had significantly higher in-hospital mortality and 180-day mortality than the colonization group (45% (27/60) vs. 0% (0/15), p = 0.001, and 52.5% (31/59) vs. 6.7% (1/15), p < 0.001, respectively). By multivariable analysis among Aspergillus infection patients, antifungal therapy (HR 0.383, 95% CI 0.163–0.899, p = 0.027) was associated with improved survival, whereas accumulated dose of systemic steroids > 700 mg (HR 2.452, 95% CI 1.134–5.300, p = 0.023) and respiratory failure at admission (HR 5.983, 95% CI 2.487–14.397, p < 0.001) were independently associated with increased mortality. Significant survival differential was observed among PA patients without antifungals and antifungals initiated before and after Aspergillus positive culture (p = 0.001). Conclusions Aspergillus isolation in hospitalized AECOPD patients largely indicated PA. AECOPD patients with PA had worse prognosis than those with Aspergillus colonization. Empirical antifungal therapy is warranted to improve the prognosis for Aspergillus infection.


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