Activity of micafungin (FK463) against an itraconazole-resistant strain of Aspergillus fumigatus and a strain of Aspergillus terreus demonstrating in vivo resistance to amphotericin B

Infections due to Aspergillus species are an acute threat to human health; members of the Aspergillus section Fumigati are the most frequently occurring agents, but depending on the local epidemiology, representatives of section Terrei or section Flavi are the second or third most important. Aspergillus terreus species complex is of great interest, as it is usually amphotericin B resistant and displays notable differences in immune interactions in comparison to Aspergillus fumigatus . The latest epidemiological surveys show an increased incidence of A. terreus as well as an expanding clinical spectrum (chronic infections) and new groups of at-risk patients being affected.

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Dose Range Evaluation of Liposomal Nystatin and Comparisons with Amphotericin B and Amphotericin B Lipid Complex in Temporarily Neutropenic Mice Infected with an Isolate of Aspergillus fumigatus with Reduced Susceptibility to Amphotericin B

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.11.2592 ◽

1999 ◽

Vol 43 (11) ◽

pp. 2592-2599 ◽

Cited By ~ 38

Author(s):

David W. Denning ◽

Peter Warn

Keyword(s):

Aspergillus Fumigatus ◽

Amphotericin B ◽

Dose Range ◽

Respiratory Arrest ◽

Optimal Dosage ◽

Lipid Complex ◽

Amphotericin B Deoxycholate ◽

Liver And Kidney ◽

Amphotericin B Lipid Complex

ABSTRACT Using an isolate of Aspergillus fumigatus that is less susceptible in vivo to amphotericin B than most other isolates, we compared different doses of liposomal nystatin (L-nystatin), liposomal amphotericin B (L-amphotericin), and amphotericin B lipid complex (ABLC) with amphotericin B deoxycholate. Four experiments with intravenously infected neutropenic mice were conducted. A dose of L-nystatin at 10 mg/kg of body weight was toxic (the mice had fits or respiratory arrest). The optimal dosage of L-nystatin was 5 mg/kg daily on days 1, 2, 4, and 7 (90% survival). This was superior to L-amphotericin (5 mg/kg [P = 0.24] and 1 mg/kg [P < 0.0001]), ABLC (5 mg/kg [P = 0.014] and 1 mg/kg [P < 0.0001]), and amphotericin B deoxycholate (5 mg/kg [P = 0.008]). In terms of liver and kidney cultures, L-nystatin (5 mg/kg) was superior to all other regimens (P = 0.0032 and <0.0001, respectively). Higher doses of L-amphotericin (25 and 50 mg/kg) in one earlier experiment were more effective (100% survival) than 1 mg of L-amphotericin per kg and amphotericin deoxycholate (5 mg/kg) in terms of mortality and both liver and kidney culture results and to L-amphotericin (5 mg/kg) in terms of liver and kidney culture results only. ABLC (25 mg/kg) given daily for 7 days was superior to ABLC (50 mg/kg [P = 0.03]) but not to ABLC at 5 mg/kg or amphotericin B deoxycholate in terms of mortality, although it was in terms of liver and kidney culture results. No dose-response for amphotericin B (5 and 1 mg/kg) was demonstrable. In conclusion, in this stringent model, high doses of L-amphotericin and ABLC could overcome reduced susceptibility to amphotericin B deoxycholate, but all were inferior to 5- to 10-fold lower doses of L-nystatin.

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In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02479-16 ◽

2017 ◽

Vol 61 (6) ◽

Cited By ~ 3

Author(s):

Seyedmojtaba Seyedmousavi ◽

Johan W. Mouton ◽

Willem J. G. Melchers ◽

Paul E. Verweij

Keyword(s):

Invasive Aspergillosis ◽

Aspergillus Fumigatus ◽

Amphotericin B ◽

Liposomal Amphotericin ◽

Treated Group ◽

Liposomal Amphotericin B ◽

Wild Type ◽

Resistance Mutations ◽

Content Type

ABSTRACT Using an immunocompetent murine model of invasive aspergillosis (IA), we previously reported that the efficacy of liposomal amphotericin B (L-AmB) (Ambisome) is not hampered by the presence of azole resistance mutations in Aspergillus fumigatus (S. Seyedmousavi, W. J. G. Melchers, J. W. Mouton, and P. E. Verweij, Antimicrob Agents Chemother 57:1866–1871, 2013, https://doi.org/10.1128/AAC.02226-12 ). We here investigated the role of immune suppression, i.e., neutropenia and steroid treatment, in L-AmB efficacy in mice infected with wild-type (WT) A. fumigatus and with azole-resistant A. fumigatus harboring a TR34/L98H mutation in the cyp-51A gene. Survival of treated animals at day 14 in both immunosuppressed models was significantly better than that of nontreated controls. A dose-response relationship was observed that was independent of the azole-resistant mechanism and the immunosuppression method used. In the neutropenic model, 100% survival was reached at an L-AmB dose of 16 mg/kg of body weight for the WT strain and the TR34/L98H isolate. In the steroid-treated group, 90.9% survival and 100% survival were achieved for the WT isolate and the TR34/L98H isolate with an L-AmB dose of 16 mg/kg, respectively. The 50% effective dose (ED50) was 1.40 mg/kg (95% confidence interval [CI], 0.66 to 3.00 mg/kg) for the WT isolate and 1.92 mg/kg (95% CI, 0.60 to 6.17 mg/kg) for the TR34/L98H isolate in the neutropenic model and was 2.40 mg/kg (95% CI, 1.93 to 2.97 mg/kg) for the WT isolate and 2.56 mg/kg (95% CI, 1.43 to 4.56 mg/kg) for the TR34/L98H isolate in the steroid-treated group. Overall, there were no significant differences between the two different immunosuppressed conditions in the efficacy of L-AmB against the wild-type and azole-resistant isolates (P > 0.9). However, the required L-AmB exposure was significantly higher than that seen in the immunocompetent model.

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Efficacy of Caspofungin against Aspergillus flavus, Aspergillus terreus, and Aspergillus nidulans

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00485-06 ◽

2006 ◽

Vol 50 (12) ◽

pp. 4202-4205 ◽

Cited By ~ 30

Author(s):

J. C. Bowman ◽

G. K. Abruzzo ◽

A. M. Flattery ◽

C. J. Gill ◽

E. J. Hickey ◽

...

Keyword(s):

Aspergillus Nidulans ◽

Amphotericin B ◽

Filamentous Fungi ◽

Aspergillus Flavus ◽

Aspergillus Terreus ◽

Potent Inhibitor ◽

Murine Models ◽

Glucan Synthase ◽

Fungal Burden

ABSTRACT The echinocandin caspofungin is a potent inhibitor of the activity of 1,3-β-d-glucan synthase from Aspergillus flavus, Aspergillus terreus, and Aspergillus nidulans. In murine models of disseminated infection, caspofungin prolonged survival and reduced the kidney fungal burden. Caspofungin was at least as effective as amphotericin B against these filamentous fungi in vivo.

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In VitroInteractions of Antifungal Agents and Tacrolimus against Aspergillus Biofilms

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01510-15 ◽

2015 ◽

Vol 59 (11) ◽

pp. 7097-7099 ◽

Cited By ~ 12

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.

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New Insight into Amphotericin B Resistance in Aspergillus terreus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01283-12 ◽

2013 ◽

Vol 57 (4) ◽

pp. 1583-1588 ◽

Cited By ~ 40

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.

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In Vitro and In Vivo Exposure-Effect Relationship of Liposomal Amphotericin B against Aspergillus fumigatus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02673-18 ◽

2019 ◽

Vol 63 (6) ◽

Cited By ~ 1

Author(s):

Maria Siopi ◽

Johan W. Mouton ◽

Spyros Pournaras ◽

Joseph Meletiadis

Keyword(s):

Aspergillus Fumigatus ◽

Amphotericin B ◽

Liposomal Amphotericin ◽

Simulation Analysis ◽

Maximal Activity ◽

Liposomal Amphotericin B ◽

Content Type ◽

Exposure Effect

ABSTRACT In vitro pharmacokinetic/pharmacodynamic data of liposomal amphotericin B (L-AMB) were compared with animal data from neutropenic and nonneutropenic models of azole-susceptible and azole-resistant invasive aspergillosis. L-AMB was equally effective. The in vitro fCmax (maximum concentration of free drug)/MIC ratio associated with 50% of maximal activity was 0.31 (0.29 to 0.33), similar to that in neutropenic but not nonneutropenic mice (0.11 [0.06 to 0.20]). Simulation analysis indicated that standard L-AMB doses (1 to 3 mg/kg) are adequate for nonneutropenic patients, but higher doses (7.5 to 10 mg/kg) may be required for neutropenic patients for Aspergillus fumigatus isolates with MICs of 0.5 to 1 mg/liter.

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Efficacy of Amphotericin B at Suboptimal Dose Combined with Voriconazole in a Murine Model of Aspergillus fumigatus Infection with PoorIn VivoResponse to the Azole

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00563-13 ◽

2013 ◽

Vol 57 (9) ◽

pp. 4540-4542 ◽

Cited By ~ 3

Author(s):

Marcelo Sandoval-Denis ◽

F. Javier Pastor ◽

Javier Capilla ◽

Josep Guarro

Keyword(s):

Aspergillus Fumigatus ◽

Amphotericin B ◽

Murine Model ◽

Combined Treatment ◽

Content Type ◽

Disseminated Infection ◽

Suboptimal Dose ◽

Tissue Burden

ABSTRACTThe combination of amphotericin B at a suboptimal dose (0.3 mg/kg) with voriconazole has shown efficacy in prolonging survival and reducing tissue burden in a murine model of disseminated infection by an isolate ofAspergillus fumigatusthat had showed a poorin vivoresponse to the azole. The efficacy of the combined treatment was higher than that obtained with amphotericin B at 0.8 mg/kg.

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