Journal Home. Close Print this page. Content: Citation Only. Citation and Abstract. Article Metrics PDF: Helle and G. Related Journals. Liposomal amphotericin B AmBisome in Mediterranean visceral leishmaniasis: a multi-centre trial.
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Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Correspondence: A. A1, Room Oxford Academic. Bart J A Rijnders. Thomas J Walsh. Jill Adler-Moore. Russell E Lewis. Select Format Select format. Permissions Icon Permissions. Abstract Since its introduction in the s, liposomal amphotericin B LAmB continues to be an important agent for the treatment of invasive fungal diseases caused by a wide variety of yeasts and molds.
Table 1. Open in new tab. Open in new tab Download slide. Table 2. Endpoints of Efficacy. Main Results. Overall mortality at 12 weeks after start of therapy. The rates of nephrotoxicity and hypokalemia were significantly higher in the high-dose group. Clinical complete or partial resolution of symptoms and mycological eradication or presumed eradication response at the end of treatment in the per protocol analysis. Treatment success was observed for patients Fewer treatment-related AEs and discontinuations were observed with micafungin.
Efficacy was similar among all 3 treatment groups; overall mortality at 10 weeks was Clinical success, conversion of baseline blood cultures to negative, survival during induction therapy, and acute toxicities that necessitated discontinuation of treatment.
Culture conversion rates were similar. Addition of systemic antifungals, development of systemic fungal infection, and persistent fever to study end were considered treatment failures. Composite of 5 criteria: survival for 7 days after initiation of the study drug; resolution of fever during the period of neutropenia; successful treatment of any baseline fungal infection; the absence of breakthrough fungal infections during administration of the study drug or within 7 days after the end of treatment; and absence of premature discontinuation of the study drug because of toxicity or lack of efficacy.
Fewer proved breakthrough fungal infections were observed in the LAmB group 3. Primary antifungal prophylaxis Open-label, randomized, single-center trial of low-dose LAmB 50 mg every other day versus no systemic antifungal therapy as antifungal prophylaxis in neutropenic episodes in patients with hematological malignancies and expected neutropenia for 10 days [ 45 ]. Failure of antifungal prophylaxis, defined as occurrence of proven or probable invasive fungal diseases under prophylactic study treatment.
Pneumonia without identification of a causative organism, mortality from any cause, and mortality related to invasive fungal disease were secondary endpoints. In the first episode of each patient, the incidences of proven or probable invasive fungal diseases were 6. Double-blind, randomized, placebo-controlled trial of LAmB 2.
Other endpoints were overall mortality and fungal infection-related mortality. There was no difference in overall and infection-related mortality rates. Development of proven or probable invasive fungal diseases. Secondary endpoints included those focused on the safety and tolerability of prophylactic LAmB. Rates of proven and probable invasive fungal diseases were 7.
Overall mortality rates were similar between the groups: 7. There were no differences in premature, treatment-related discontinuations. In addition, TGs can regulate cell primary metabolism to secondary metabolism, thereby affecting the synthesis of secondary metabolite AmB. In the study of amino acid metabolism, GSH maintained a relative high level at the fermentation early stage in mutant strain, as GSH could keep the cell intracellular redox balance through enzymatic reactions which helped strain adapt to environmental changes.
As a methyl donor of the secondary metabolite, SAM was a key metabolite and was found to be lack at the fermentation early stage for AmB biosynthesis. In the one carbon pool by folate, the levels of tetrahydrofolic acid and methyl-THF were higher in mutant S.
All these results showed the advantages in mutant S. As most of nucleic acids, amino acids and pantothenic acids in bacteria required tetrahydrofolic acid as a carrier of carbon units, tetrahydrofolic acid was deemed as the key metabolite in the mutant S. Moreover, 26 key metabolites that contributed to AmB productivity were identified, most of which were related to carbon metabolism, fatty acid metabolism, amino acid metabolism, purine metabolism and folate biosynthesis.
The relationships between these metabolism and amphotericin biosynthesis are summarized in Fig. According to the analyses and results of comparative metabolomics, one carbon pool by folate metabolic pathway was identified as the key metabolic pathway. Based on this, further study of the effects of precursors and key metabolites including serine, glycine and SAM addition on AmB production were carried out in our previous studies [ 10 , 11 ] and the addition of methionine and THF showed improved AmB yield Additional file 1 : Figure S3.
Later, gene overexpression strategies were conducted in mutant S. We screened the genes that were involved in one carbon pool by folate metabolic pathway. Through overexpression of single gene purN , metH , glyA , metF , purH or fmt , a strain with gene metH overexpression was obtained with its optimal AmB yield at 5. However, the yield of by-product AmA in those recombinant bacteria was unstable, as AmA decreased in the strain with purN overexpressed and obviously increased in the strain with other genes overexpressed.
Recently, Huang et al. Overall, based on the comparative metabolome analysis between mutant and wild-type S. By choosing the genes related to the one carbon pool by folate metabolic pathway for overexpression, three recombinant strains with the overexpression of key metabolic genes purN , glyA and metH in S. The production of AmB in metH overexpression strain reached 5. Our results indicated the application of gene overexpression strategy based on the comparative metabolomics analysis would be very effective for the rational design of other antibiotics production improvement.
The detailed ultraviolet mutagenesis method was reported by Zhang and co-workers [ 23 ]. All strains and recombinant plasmids with characteristics and resources used in this article were listed in Additional file 1 : Table S1. Before autoclaving, the pH value of the fermentation, seed and LB medium was adjusted to 7. The agar medium was prepared by adding soybean meal into a certain volume of distilled water and boiling for 1 h, then the volume was filled up to 1 L by distilled water.
Finally, mannitol and agar were quantitatively added into the medium and autoclaved. All used primers are listed in Additional file 1 : Table S2. The isolated pure culture was then grown on the GYM medium for 7 days for the harvest of spores. Culture samples 0. After centrifugation at 12, g for 2 min, the supernatant filtered through a 0. The dry cell weight DCW of strains were measured as follows.
In detail, 1 mL of culture was sampled and centrifuged at 12, g for 10 min. To remove calcium carbonate, appropriate amount of acetic acid was added and reacted for 10 min. The residual sugar in the fermentation broth was quantified using a commercial glucose assay kit. The pH value was detected using a commercial pH meter.
According to the AmB production curve Fig. Samples were taken at 24, 72, and h, respectively. Another 0. Cell samples were placed in the TissueLyser at 35 Hz and grind for 4 min. The supernatant was then taken out for liquid chromatography-mass spectrometry LC—MS analysis. Small molecules washed from liquid chromatography columns were collected using the positive ion mode and negative ion mode modes.
The capillary voltage and conical hole voltage in two positive and negative ion modes are 3 kV, 40 V and 1 kV, 40 V. Then break all the parent ions with 20—40 eV set energy, and the LE signal correction is performed every 3 s for all the collected fragments scanning time 0. Normally, to assess the accuracy and stability of the equipment during detection and collection process, QC samples mixture of all samples were prepared in advance and tested every 10 samples. Perform data alignment and normalization for the complete data set, composed of multiple analytical blocks [ 25 ].
The parameters used were retention time range 0. Isotopic peaks were excluded for analysis, noise elimination level was set at The internal standard was used for data QC.
And then the data was processed by two different standardized methods such as centralization mean-centering and automatic specification unit variance scaling, UV. Use the p value obtained by univariate analysis and the VIP value obtained by multivariate analysis to screen for differential metabolites.
It is similar to the metabolic pathway analysis result figure Additional file 1 : Figure S1. We plotted the top 10 metabolic pathways with the lowest p value Additional file 1 : Figure S2. Unless otherwise noted, all the reagents and solvents used in this study were purchased from Sigma Chemical Company St.
The p value was performed with t tests and fold change analysis to analyze the data obtained from LC—MS. The levels of metabolites in mutant S. Principle component analysis and orthogonal partial least-squares-discriminant analysis were carried out to visualize the metabolic alterations among experimental groups, after mean centering and unit variance scaling. In this study, in order to guard against overfitting, the default 7-round cross-validation was applied with a seventh of the samples being excluded from the mathematical model in each round.
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Trends Microbiol. Development of dextrin-amphotericin B formulations for the treatment of Leishmaniasis. Int J Biol Macromol. Chitosan coated PluronicF micelles for effective delivery of Amphotericin B in experimental visceral leishmaniasis. Lochlainn LN, Caffrey P. Phosphomannose isomerase and phosphomannomutase gene disruptions in Streptomyces nodosus : Impact on amphotericin biosynthesis and implications for glycosylation engineering.
Metab Eng. Enhancement of FK production by engineering secondary pathways of Streptomyces tsukubaensis and exogenous feeding strategies. J Ind Microbiol Biotechnol. Microb Cell Fact. Murtagh Collection. About Search. Enable Autosuggest. You have successfully created a MyAccess Profile for alertsuccessName.
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