Anidulafungin in Combination with Amphotericin B against Aspergillus fumigatus

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03261-14 ◽

2014 ◽

Vol 58 (11) ◽

pp. 6934-6937 ◽

Cited By ~ 25

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01875-12 ◽

2012 ◽

Vol 57 (3) ◽

pp. 1275-1282 ◽

Cited By ~ 32

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.

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Posaconazole and Amphotericin B Combination Therapy against Cryptococcus neoformans Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.9.3312-3316.2004 ◽

2004 ◽

Vol 48 (9) ◽

pp. 3312-3316 ◽

Cited By ~ 21

Author(s):

Francesco Barchiesi ◽

Elisabetta Spreghini ◽

Anna M. Schimizzi ◽

Monia Maracci ◽

Daniele Giannini ◽

...

Keyword(s):

Combination Therapy ◽

Cryptococcus Neoformans ◽

Amphotericin B ◽

Combination Regimen ◽

Fungal Burden ◽

Cryptococcal Infection ◽

Single Drug ◽

Cd1 Mice ◽

Survival Studies ◽

The Brain

ABSTRACT To investigate the effects of posaconazole (POS) and amphotericin B (AMB) combination therapy in cryptococcal infection, we established an experimental model of systemic cryptococcosis in CD1 mice by intravenous injection of three distinct clinical isolates of Cryptococcus neoformans. Therapy was started 24 h after the infection and continued for 10 consecutive days. POS was given at 3 and 10 mg/kg of body weight/day, while AMB was given at 0.3 mg/kg/day. Combination therapy consisted of POS given at a low (combo 3) or at a high (combo 10) dose plus AMB. Survival studies showed that combo 3 was significantly more effective than POS at 3 mg/kg for two isolates tested (P value, ≤0.001), while combo 10 was significantly more effective than POS at 10 mg/kg for all three isolates (P values ranging from <0.001 to 0.005). However, neither combination regimen was more effective than AMB alone. For two isolates, combination therapy was significantly more effective than each single drug at reducing the fungal burden in the brain (P values ranging from 0.001 to 0.015) but not in the lungs. This study demonstrates that the major impact of POS and AMB combination therapy is on brain fungal burden rather than on survival.

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Efficacy of 2-(3,4-Dimethyl-2,5-Dihydro-1H-Pyrrole-2-yl)-1-Methylethyl Pentanoate in a Murine Model of Invasive Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.10.4365-4367.2005 ◽

2005 ◽

Vol 49 (10) ◽

pp. 4365-4367 ◽

Cited By ~ 4

Author(s):

Rajesh Dabur ◽

S. K. Diwedi ◽

V. Yadav ◽

V. Mishra ◽

Rambir Singh ◽

...

Keyword(s):

Body Weight ◽

Survival Rate ◽

Invasive Aspergillosis ◽

Aspergillus Fumigatus ◽

Amphotericin B ◽

Murine Model ◽

Antifungal Compound ◽

Dose Dependent

ABSTRACT 2-(3,4-Dimethyl-2,5-dihydro-1H-pyrrole-2-yl)-1-methylethyl pentanoate, an antifungal compound, was found to be nontoxic to RAW cells up to a concentration of 312.5 μg/ml, whereas amphotericin B was lethal to all cells at 37.5 μg/ml. The treatment of Aspergillus fumigatus-infected mice with a dose of 200.0 mg of compound/kg of body weight increased their survival rate by 60%, with a decrease in CFU in organ tissues. The protection afforded by the compound against experimental aspergillosis was found to be dose dependent.

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Efficacies of Two New Antifungal Agents, the Triazole Ravuconazole and the Echinocandin LY-303366, in an Experimental Model of Invasive Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.12.3381-3388.2000 ◽

2000 ◽

Vol 44 (12) ◽

pp. 3381-3388 ◽

Cited By ~ 64

Author(s):

Jenna Roberts ◽

Kathleen Schock ◽

Susan Marino ◽

Vincent T. Andriole

Keyword(s):

Body Weight ◽

Invasive Aspergillosis ◽

Aspergillus Fumigatus ◽

Amphotericin B ◽

Antifungal Agent ◽

Oral Therapy ◽

Antifungal Agents ◽

Rabbit Model ◽

Active Agent ◽

Aspergillus Antigen

ABSTRACT The efficacy of ravuconazole, a new triazole antifungal agent, and the echinocandin LY-303366 were evaluated in an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis. Oral therapy with ravuconazole at a dosage of 30 mg/kg of body weight per day or the echinocandin LY-303366, given intravenously in a dosage of 5 or 10 mg/kg, was begun 24 h after a lethal or sublethal challenge, and results were compared with those for amphotericin B therapy and untreated controls. Prophylaxis was also studied with LY-303366 given at a dosage of 5 or 10 mg/kg/day 48 h before lethal or sublethal challenge. Ravuconazole eliminated mortality, cleared aspergillus antigen from the serum, and eliminated Aspergillus fumigatus organisms from tissues of both lethally and sublethally challenged immunosuppressed animals with invasive aspergillosis. Although LY-303366, at both doses, prolonged survival and reduced aspergillus antigenemia, it did not eliminate aspergillus organisms from organ tissues. The half-lives of ravuconazole and LY-303366 in rabbits were 13 and 12.5 h, respectively, and no accumulation of either drug was seen after 6 days of treatment. Although LY-303366 showed activity in this rabbit model of invasive aspergillosis, ravuconazole was the more active agent, comparable to amphotericin B. Additional studies are needed to determine the potential of ravuconazole for use in the treatment of this infection.

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Efficacy of LY303366 against Amphotericin B-Susceptible and -Resistant Aspergillus fumigatus in a Murine Model of Invasive Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.4.873 ◽

1998 ◽

Vol 42 (4) ◽

pp. 873-878 ◽

Cited By ~ 77

Author(s):

Paul E. Verweij ◽

Karen L. Oakley ◽

Jacqui Morrissey ◽

Graham Morrissey ◽

David W. Denning

Keyword(s):

Survival Rate ◽

Invasive Aspergillosis ◽

Aspergillus Fumigatus ◽

Amphotericin B ◽

Murine Model ◽

Survival Rates ◽

In Vitro Susceptibility ◽

Once Daily

ABSTRACT LY303366 is a novel antifungal echinocandin with excellent in vitro activity against Aspergillus spp. We compared four doses (1, 2.5, 10, and 25 mg/kg of body weight) of LY303366 with amphotericin B (0.5 to 5 mg/kg) in a temporarily neutropenic murine model of invasive aspergillosis against an amphotericin B-susceptible (AF210) and an amphotericin B-resistant (AF65) Aspergillus fumigatus isolate based on in vivo response. Mice were immunosuppressed with cyclophosphamide (200 mg/kg) and infected 3 days later. Treatment started 18 h after infection and lasted for 10 days. LY303366 was given once daily intravenously for 10 days, and amphotericin B (at 0.5, 2, and 5 mg/kg) was given once daily intraperitoneally for 10 days, or only on days 1, 2, 4, and 7 (at 5 mg/kg). Kidneys and lungs from survivors were cultured on day 11. Control mice in both experiments had 90 to 100% mortality. Amphotericin B at 0.5 mg/kg and LY303366 at 1 mg/kg yielded 10 to 20% survival rates for mice infected with either AF210 or AF65. Amphotericin B at 2 and 5 (both regimens) mg/kg yielded a 70 to 100% survival rate for mice infected with AF210 but a 10 to 30% survival rate for mice infected with AF65 (P = 0.01 to 0.04 compared with AF210). Against AF210 and AF65, LY303366 at 2.5, 10, and 25 mg/kg produced a survival rate of 70 to 80%, which was as effective as amphotericin B for AF210, but superior to amphotericin B for AF65 (P < 0.03 to 0.0006). For AF65, LY303366 at 10 and 25 mg/kg/day was superior to amphotericin B at 2 and 5 mg/kg/day in reducing tissue colony counts (P = 0.01 to 0.003), and for AF210, amphotericin B at 5 mg/kg/day and at 5 mg/kg in four doses was more effective than all four regimens of LY303366 in reducing renal culture counts (P = 0.01 to 0.0001). The present study shows, for the first time, that in vivo resistance of A. fumigatus to amphotericin B exists, although this could not be detected by in vitro susceptibility assays. Furthermore, LY303366 appears to be effective against amphotericin B-susceptible and -resistant A. fumigatus infection in this model and should be further evaluated clinically.

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The Novel Arylamidine T-2307 MaintainsIn VitroandIn VivoActivity against Echinocandin-Resistant Candida albicans

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04228-14 ◽

2014 ◽

Vol 59 (2) ◽

pp. 1341-1343 ◽

Cited By ~ 14

Author(s):

Nathan P. Wiederhold ◽

Laura K. Najvar ◽

Annette W. Fothergill ◽

Rosie Bocanegra ◽

Marcos Olivo ◽

...

Keyword(s):

Body Weight ◽

Candida Albicans ◽

Invasive Candidiasis ◽

Placebo Control ◽

The Novel ◽

Content Type ◽

Fungal Burden ◽

Potential Use

ABSTRACTWe evaluated thein vitroandin vivoactivities of the investigational arylamidine T-2307 against echinocandin-resistantCandida albicans. T-2307 demonstrated potentin vitroactivity, and daily subcutaneous doses between 0.75 and 6 mg/kg of body weight significantly improved survival and reduced fungal burden compared to placebo control and caspofungin (10 mg/kg/day) in mice with invasive candidiasis caused by an echinocandin-resistant strain. Thus, T-2307 may have potential use in the treatment of echinocandin-resistantC. albicansinfections.

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The in vitro effects of interferon-gamma, alone or in combination with amphotericin B, tested against the pathogenic fungi Candida albicans and Aspergillus fumigatus

BMC Research Notes ◽

10.1186/s13104-017-2696-4 ◽

2017 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Moufid El-Khoury ◽

Rogine Ligot ◽

Simon Mahoney ◽

Colin M. Stack ◽

Gabriel G. Perrone ◽

...

Keyword(s):

Candida Albicans ◽

Aspergillus Fumigatus ◽

Amphotericin B ◽

Interferon Gamma ◽

Pathogenic Fungi ◽

In Vitro Effects

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Azole-resistant and -susceptible Aspergillus fumigatus isolates show comparable fitness and azole treatment outcome in immunocompetent mice

Medical Mycology ◽

10.1093/mmy/myx109 ◽

2017 ◽

Vol 56 (6) ◽

pp. 703-710

Author(s):

Michaela Lackner ◽

Günter Rambach ◽

Emina Jukic ◽

Bettina Sartori ◽

Josef Fritz ◽

...

Keyword(s):

Body Weight ◽

Aspergillus Fumigatus ◽

Severe Disease ◽

Weight Ratio ◽

Clinical Parameters ◽

Fitness Advantage ◽

Significant Difference ◽

Immunocompetent Mice

Abstract No data are available on the in vivo impact of infections with in vitro azole-resistant Aspergillus fumigatus in immunocompetent hosts. Here, the aim was to investigate fungal fitness and treatment response in immunocompetent mice infected with A. fumigatus (parental strain [ps]) and isogenic mutants carrying either the mutation M220K or G54W (cyp51A). The efficacy of itraconazole (ITC) and posaconazole (PSC) was investigated in mice, intravenously challenged either with a single or a combination of ps and mutants (6 × 105 conidia/mouse). Organ fungal burden and clinical parameters were measured. In coinfection models, no fitness advantage was observed for the ps strain when compared to the mutants (M220K and G54W) independent of the presence or absence of azole-treatment. For G54W, M220K, and the ps, no statistically significant difference in ITC and PSC treatment was observed in respect to fungal kidney burden. However, clinical parameters suggest that in particular the azole-resistant strain carrying the mutation G54W caused a more severe disease than the ps strain. Mice infected with G54W showed a significant decline in body weight and lymphocyte counts, while spleen/body weight ratio and granulocyte counts were increased. In immunocompetent mice, in vitro azole-resistance did not translate into therapeutic failure by either ITC or PSC; the immune system appears to play the key role in clearing the infection.

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