scholarly journals In VitroCombination of Isavuconazole with Micafungin or Amphotericin B Deoxycholate against Medically Important Molds

2014 ◽  
Vol 58 (11) ◽  
pp. 6934-6937 ◽  
Author(s):  
Aspasia Katragkou ◽  
Matthew McCarthy ◽  
Joseph Meletiadis ◽  
Vidmantas Petraitis ◽  
Patriss W. Moradi ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Invasive Aspergillosis ◽  
Amphotericin B ◽  
Aspergillus Flavus ◽  
Aspergillus Terreus ◽  
Synergistic Activity ◽  
Content Type ◽  
Amphotericin B Deoxycholate ◽  
Combination Studies

ABSTRACTWhether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or amphotericin B for the treatment of invasive molds infections has not been studied. Ourin vitrocombination studies showed that isavuconazole and micafungin are synergistically active againstAspergillus fumigatus,Aspergillus flavus,Aspergillus terreus, andCunninghamella bertholletiae. These results suggest that isavuconazole, in combination with micafungin, may have a role in the treatment of invasive aspergillosis and warrants further investigation.

scholarly journals Evaluation of the Antifungal Activity of the Novel Oral Glucan Synthase Inhibitor SCY-078, Singly and in Combination, for the Treatment of Invasive Aspergillosis

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
M. Ghannoum ◽  
L. Long ◽  
E. L. Larkin ◽  
N. Isham ◽  
R. Sherif ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Amphotericin B ◽  
Synergistic Activity ◽  
Minimum Effective Concentration ◽  
Glucan Synthase ◽  
Content Type ◽  
Fungistatic Activity ◽  
Synthase Inhibitor

ABSTRACT Invasive aspergillosis remains a major cause of death among the immunocompromised population and those receiving long-term immunosuppressive therapy. In light of increased azole resistance, variable outcomes with existing echinocandin monotherapy and combination therapy, and persistent high mortality rates, new antifungal agents for the treatment of invasive aspergillosis are clearly needed. SCY-078 is the first-in-class triterpenoid antifungal, a novel class of glucan synthase inhibitors with broad in vitro and in vivo activity against a broad spectrum of Candida and Aspergillus species. In vitro testing of clinical strains of Aspergillus fumigatus and non- fumigatus Aspergillus strains showed that SCY-078 had potent fungistatic activity (minimum effective concentration for 90% of strains tested = 0.125 μg/ml) compared with the activities of amphotericin B (MIC 90 = 8 μg/ml) and voriconazole (MIC 90 = 2 μg/ml). Testing of SCY-078 in combination with isavuconazole or voriconazole demonstrated synergistic activity against the majority of the azole-susceptible strains tested, and SCY-078 in combination with amphotericin B was synergistic against the azole-susceptible strains, as well as one known resistant cyp51A mutant. SCY-078 may be an important additional antifungal for first-line or salvage monotherapy or combination treatment of invasive aspergillosis.

scholarly journals In VitroInteractions of Antifungal Agents and Tacrolimus against Aspergillus Biofilms

2015 ◽  
Vol 59 (11) ◽  
pp. 7097-7099 ◽  
Author(s):  
Lujuan Gao ◽  
Yi Sun
Keyword(s):  
Antifungal Activity ◽  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Aspergillus Flavus ◽  
Inhibitory Activity ◽  
Aspergillus Terreus ◽  
Antifungal Agents ◽  
Broth Microdilution ◽  
Content Type ◽  
Antagonistic Effects

ABSTRACTAspergillusbiofilms were prepared fromAspergillus fumigatus,Aspergillus flavus, andAspergillus terreusvia a 96-well plate-based method, and the combined antifungal activity of tacrolimus with azoles or amphotericin B againstAspergillusbiofilms was investigated via a broth microdilution checkerboard technique system. Our results suggest that combinations of tacrolimus with voriconazole or amphotericin B have synergistic inhibitory activity againstAspergillusbiofilms. However, combinations of tacrolimus with itraconazole or posaconazole exhibit no synergistic or antagonistic effects.

scholarly journals In VitroInteraction between Alginate Lyase and Amphotericin B against Aspergillus fumigatus Biofilm Determined by Different Methods

2012 ◽  
Vol 57 (3) ◽  
pp. 1275-1282 ◽  
Author(s):  
Francesca Bugli ◽  
Brunella Posteraro ◽  
Massimiliano Papi ◽  
Riccardo Torelli ◽  
Alessandro Maiorana ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Extracellular Polymeric Substances ◽  
Alginate Lyase ◽  
Antifungal Drugs ◽  
Antibiofilm Activity ◽  
Content Type ◽  
Time Kill

ABSTRACTAspergillus fumigatusbiofilms represent a problematic clinical entity, especially because of their recalcitrance to antifungal drugs, which poses a number of therapeutic implications for invasive aspergillosis, the most difficult-to-treatAspergillus-related disease. While the antibiofilm activities of amphotericin B (AMB) deoxycholate and its lipid formulations (e.g., liposomal AMB [LAMB]) are well documented, the effectiveness of these drugs in combination with nonantifungal agents is poorly understood. In the present study,in vitrointeractions between polyene antifungals (AMB and LAMB) and alginate lyase (AlgL), an enzyme degrading the polysaccharides produced as extracellular polymeric substances (EPSs) within the biofilm matrix, againstA. fumigatusbiofilms were evaluated by using the checkerboard microdilution and the time-kill assays. Furthermore, atomic force microscopy (AFM) was used to image and quantify the effects of AlgL-antifungal combinations on biofilm-growing hyphal cells. On the basis of fractional inhibitory concentration index values, synergy was found between both AMB formulations and AlgL, and this finding was also confirmed by the time-kill test. Finally, AFM analysis showed that whenA. fumigatusbiofilms were treated with AlgL or polyene alone, as well as with their combination, both a reduction of hyphal thicknesses and an increase of adhesive forces were observed compared to the findings for untreated controls, probably owing to the different action by the enzyme or the antifungal compounds. Interestingly, marked physical changes were noticed inA. fumigatusbiofilms exposed to the AlgL-antifungal combinations compared with the physical characteristics detected after exposure to the antifungals alone, indicating that AlgL may enhance the antibiofilm activity of both AMB and LAMB, perhaps by disrupting the hypha-embedding EPSs and thus facilitating the drugs to reach biofilm cells. Taken together, our results suggest that a combination of AlgL and a polyene antifungal may prove to be a new therapeutic strategy for invasive aspergillosis, while reinforcing the EPS as a valuable antibiofilm drug target.

scholarly journals New Insight into Amphotericin B Resistance in Aspergillus terreus

2013 ◽  
Vol 57 (4) ◽  
pp. 1583-1588 ◽  
Author(s):  
Gerhard Blum ◽  
Caroline Hörtnagl ◽  
Emina Jukic ◽  
Thomas Erbeznik ◽  
Thomas Pümpel ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Molecular Basis ◽  
Aspergillus Terreus ◽  
Minor Role ◽  
Content Type ◽  
Ergosterol Content ◽  
Disseminated Aspergillosis ◽  
A Minor

ABSTRACTAmphotericin B (AMB) is the predominant antifungal drug, but the mechanism of resistance is not well understood. We compared thein vivovirulence of an AMB-resistantAspergillus terreus(ATR) isolate with that of an AMB-susceptibleA. terreusisolate (ATS) using a murine model for disseminated aspergillosis. Furthermore, we analyzed the molecular basis of intrinsic AMB resistancein vitroby comparing the ergosterol content, cell-associated AMB levels, AMB-induced intracellular efflux, and prooxidant effects between ATR and ATS. Infection of immunosuppressed mice with ATS or ATR showed that the ATS strain was more lethal than the ATR strain. However, AMB treatment improved the outcome in ATS-infected mice while having no positive effect on the animals infected with ATR. Thein vitrodata demonstrated that ergosterol content is not the molecular basis for AMB resistance. ATR absorbed less AMB, discharged more intracellular compounds, and had better protection against oxidative damage than the susceptible strain. Our experiments showed that ergosterol content plays a minor role in intrinsic AMB resistance and is not directly associated with intracellular cell-associated AMB content. AMB might exert its antifungal activity by oxidative injury rather than by an increase in membrane permeation.

scholarly journals Rifampin Enhances the Activity of Amphotericin B against Fusarium solani Species Complex and Aspergillus flavus Species Complex Isolates from Keratitis Patients

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Yi He ◽  
Lutan Zhou ◽  
Chuanwen Gao ◽  
Lei Han ◽  
Yan Xu
Keyword(s):  
Amphotericin B ◽  
Aspergillus Flavus ◽  
Fusarium Solani ◽  
Species Complex ◽  
Content Type ◽  
Fusarium Solani Species Complex ◽  
Fungal Isolates

ABSTRACT The in vitro activities of amphotericin B in combination with rifampin were assessed against 95 ocular fungal isolates. The interactions between amphotericin B and rifampin at 4, 8, 16, and 32 μg/ml were synergistic for 11.8%, 51.0%, 90.2%, and 94.1%, respectively, of Fusarium solani species complex isolates and for 13.6%, 45.5%, 93.2%, and 95.5%, respectively, of Aspergillus flavus species complex isolates. Antagonism was never observed for the amphotericin B-rifampin combinations.

scholarly journals Genetic Diversity and In Vitro Antifungal Susceptibility of 200 Clinical and Environmental Aspergillus flavus Isolates

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Mojtaba Taghizadeh-Armaki ◽  
Mohammad Taghi Hedayati ◽  
Saham Ansari ◽  
Saeed Mahdavi Omran ◽  
Sasan Saber ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Aspergillus Flavus ◽  
Susceptibility Testing ◽  
Antifungal Susceptibility ◽  
Content Type ◽  
Microdilution Method ◽  
Microsatellite Genotype ◽  
Broth Microdilution Method ◽  
In Vitro Antifungal Susceptibility

ABSTRACT Aspergillus flavus has been frequently reported as the leading cause of invasive aspergillosis in certain tropical and subtropical countries. Two hundred A. flavus strains originating from clinical and environmental sources and collected between 2008 and 2015 were phylogenetically identified at the species level by analyzing partial β-tubulin and calmodulin genes. In vitro antifungal susceptibility testing was performed against antifungals using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution method. In addition, genotyping was performed using a short-tandem-repeat (STR) assay of a panel of six microsatellite markers (A. flavus 2A, 2B, 2C, 3A, 3B, and 3C), in order to determine the genetic variation and the potential relationship between clinical and environmental isolates. The geometric means of the minimum inhibitory concentrations/minimum effective concentrations (MICs/MECs) of the antifungals across all isolates were (in increasing order): posaconazole, 0.13 mg/liter; anidulafungin, 0.16 mg/liter; itraconazole, 0.29 mg/liter; caspofungin, 0.42 mg/liter; voriconazole, 0.64 mg/liter; isavuconazole, 1.10 mg/liter; amphotericin B, 3.35 mg/liter; and flucytosine, 62.97 mg/liter. All of the clinical isolates were genetically different. However, an identical microsatellite genotype was found between a clinical isolate and two environmental strains. In conclusion, posaconazole and anidulafungin showed the greatest in vitro activity among systemic azoles and echinocandins, respectively. However, the majority of the A. flavus isolates showed reduced susceptibility to amphotericin B. Antifungal susceptibility of A. flavus was not linked with the clinical or environmental source of isolation. Microsatellite genotyping may suggest an association between clinical and environmental strains, although this requires further investigation.

scholarly journals The Elevated Endogenous Reactive Oxygen Species Contribute to the Sensitivity of the Amphotericin B-Resistant Isolate of Aspergillus flavus to Triazoles and Echinocandins

2021 ◽  
Vol 12 ◽  
Author(s):  
Tianyu Liang ◽  
Wei Chen ◽  
Xinyu Yang ◽  
Qiqi Wang ◽  
Zhe Wan ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Invasive Aspergillosis ◽  
Amphotericin B ◽  
Aspergillus Flavus ◽  
Fungal Infections ◽  
Reactive Oxygen ◽  
Resistant Isolate ◽  
Oxygen Species ◽  
Endogenous Reactive Oxygen Species

Aspergillus flavus has been frequently reported as the second cause of invasive aspergillosis (IA), as well as the leading cause in certain tropical countries. Amphotericin B (AMB) is a clinically important therapy option for a range of invasive fungal infections including invasive aspergillosis, and in vitro resistance to AMB was associated with poor outcomes in IA patients treated with AMB. Compared with the AMB-susceptible isolates of A. terreus, the AMB-resistant isolates of A. terreus showed a lower level of AMB-induced endogenous reactive oxygen species (ROS), which was an important cause of AMB resistance. In this study, we obtained one AMB-resistant isolate of A. flavus, with an AMB MIC of 32 μg/mL, which was sensitive to triazoles and echinocandins. This isolate presented elevated endogenous ROS levels, which strongly suggested that no contribution of decreased AMB-induced endogenous ROS for AMB-resistance, opposite to those observed in A. terreus. Further, we confirmed that the elevated endogenous ROS contributed to the sensitivity of the AMB-resistant A. flavus isolate to triazoles and echinocandins. Further investigation is needed to elucidate the causes of elevated endogenous ROS and the resistance mechanism to AMB in A. flavus.

scholarly journals In VitroInteractions between Target of Rapamycin Kinase Inhibitor and Antifungal Agents against Aspergillus Species

2016 ◽  
Vol 60 (6) ◽  
pp. 3813-3816 ◽  
Author(s):  
Lujuan Gao ◽  
Xiaozhen Ding ◽  
Zhun Liu ◽  
Qingzhi Wu ◽  
Tongxiang Zeng ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Aspergillus Flavus ◽  
Antifungal Agents ◽  
Kinase Inhibitor ◽  
Synergistic Effects ◽  
Target Of Rapamycin ◽  
Broth Microdilution ◽  
Content Type ◽  
Tor Kinase

In vitrointeractions of INK128, a target of rapamycin (TOR) kinase inhibitor, and antifungals, including itraconazole, voriconazole, posaconazole, amphotericin B, and caspofungin, againstAspergillusspp. were assessed with the broth microdilution checkerboard technique. Our results suggested synergistic effects between INK128 and all azoles tested, against multipleAspergillus fumigatusandAspergillus flavusisolates. However, no synergistic effects were observed when INK128 was combined with amphotericin B or caspofungin. No antagonism was observed for any combination.

scholarly journals Antifungal Therapy of Murine Aspergillus terreus Infection

2004 ◽  
Vol 48 (10) ◽  
pp. 3715-3719 ◽  
Author(s):  
John R. Graybill ◽  
Steve Hernandez ◽  
Rosie Bocanegra ◽  
Laura K. Najvar
Keyword(s):  
Invasive Aspergillosis ◽  
Amphotericin B ◽  
Antifungal Therapy ◽  
Murine Model ◽  
Aspergillus Terreus ◽  
Treatment Alternatives

ABSTRACT Aspergillus terreus is a species which is being seen increasingly frequently and which is highly resistant to amphotericin B in vitro and clinically. We evaluated amphotericin B, caspofungin, and posaconazole in a murine model of acute invasive aspergillosis. Caspofungin and posaconazole both appeared beneficial and may be reasonable treatment alternatives for infection with A. terreus.

scholarly journals Anidulafungin in Combination with Amphotericin B against Aspergillus fumigatus

2009 ◽  
Vol 53 (9) ◽  
pp. 4035-4039 ◽  
Author(s):  
Elisabetta Spreghini ◽  
Fiorenza Orlando ◽  
Alfredo Santinelli ◽  
Eleonora Pisa ◽  
Cristian Loretelli ◽  
...  
Keyword(s):  
Body Weight ◽  
Combination Therapy ◽  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Fungal Burden ◽  
Single Drug

ABSTRACT We investigated the effects of anidulafungin alone and in combination with amphotericin B against Aspergillus fumigatus. Indifference was the only type of interaction observed in vitro. Anidulafungin at 1 and 5 mg/kg of body weight/day, amphotericin B at 1 mg/kg/day, and combination therapy prolonged the survival of mice with invasive aspergillosis. Anidulafungin at 5 mg/kg/day, alone and in combination with amphotericin B, reduced the kidney fungal burden. Overall, the combination was not superior to the most active single drug.

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