scholarly journals Assessment of Efficacy of Antifungals against Aspergillus fumigatus: Value of Real-Time Bioluminescence Imaging

2013 ◽  
Vol 57 (7) ◽  
pp. 3046-3059 ◽  
Author(s):  
Célimène Galiger ◽  
Matthias Brock ◽  
Grégory Jouvion ◽  
Amélie Savers ◽  
Marianna Parlato ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Real Time ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Bioluminescence Imaging ◽  
Treatment Success ◽  
Drug Efficacy ◽  
Liposomal Amphotericin B

ABSTRACTAspergillus fumigatuscauses life-threatening infections, especially in immunocompromised patients. Common drugs for therapy of aspergillosis are polyenes, azoles, and echinocandins. However, despitein vitroefficacy of these antifungals, treatment failure is frequently observed. In this study, we established bioluminescence imaging to monitor drug efficacy underin vitroandin vivoconditions.In vitroassays confirmed the effectiveness of liposomal amphotericin B, voriconazole, and anidulafungin. Liposomal amphotericin B and voriconazole were fungicidal, whereas anidulafungin allowed initial germination of conidia that stopped elongation but allowed the conidia to remain viable.In vivostudies were performed with a leukopenic murine model. Mice were challenged by intranasal instillation with a bioluminescent reporter strain (5 × 105and 2.5 × 105conidia), and therapy efficacies of liposomal amphotericin B, voriconazole, and anidulafungin were monitored. For monotherapy, the highest treatment efficacy was observed with liposomal amphotericin B, whereas the efficacies of voriconazole and anidulafungin were strongly dependent on the infectious dose. When therapy efficacy was studied with different drug combinations, all combinations improved the rate of treatment success compared to that with monotherapy. One hundred percent survival was obtained for treatment with a combination of liposomal amphotericin B and anidulafungin, which prevented not only pulmonary infections but also infections of the sinus. In conclusion, combination therapy increases treatment success, at least in the murine infection model. In addition, our novel approach based on real-time imaging enablesin vivomonitoring of drug efficacy in different organs during therapy of invasive aspergillosis.

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

2019 ◽  
Vol 63 (6) ◽  
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.

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

2017 ◽  
Vol 61 (6) ◽  
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.

scholarly journals Investigation of the Efficacy of Micafungin in the Treatment of Histoplasmosis Using Two North American Strains of Histoplasma capsulatum

2011 ◽  
Vol 55 (9) ◽  
pp. 4447-4450 ◽  
Author(s):  
Chadi A. Hage ◽  
Patricia Connolly ◽  
Daniel Horan ◽  
Michelle Durkin ◽  
Melinda Smedema ◽  
...  
Keyword(s):  
Amphotericin B ◽  
North American ◽  
Liposomal Amphotericin ◽  
Histoplasma Capsulatum ◽  
Liposomal Amphotericin B ◽  
Content Type ◽  
Yeast Form

ABSTRACTMicafungin alone and combined with liposomal amphotericin B was evaluated against two strains ofHistoplasma capsulatum. Micafungin was activein vitroagainst the mold but not the yeast form but was ineffectivein vivo. Micafungin appears to be ineffective in treatment of histoplasmosis.

Comparison of antifungal efficacies of moxifloxacin, liposomal amphotericin B, and combination treatment in experimental Candida albicans endophthalmitis in rabbits

2010 ◽  
Vol 56 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Yudum Tiftikcioğlu Deren ◽  
Şengül Özdek ◽  
Ayşe Kalkanci ◽  
Nalan Akyürek ◽  
Berati Hasanreisoğlu
Keyword(s):  
Candida Albicans ◽  
Minimum Inhibitory Concentration ◽  
Amphotericin B ◽  
Combination Treatment ◽  
Liposomal Amphotericin ◽  
Inhibitory Concentration ◽  
Liposomal Amphotericin B ◽  
Control Group

The goal of this study was to compare in vitro and in vivo efficacy of moxifloxacin and liposomal amphotericin B (Amp-B) monotherapies and combination treatment against Candida albicans in an exogenous endophthalmitis model in rabbit eyes. Microplate dilution tests and checkerboard analysis were performed to detect in vitro efficacies. Endophthalmitis was induced by intravitreal injection of C. albicans in 40 rabbit eyes with simultaneous intravitreal drug injection according to prophylactic treatment groups. Group 1 (control group) received 0.1 mL of balanced salt solution, group 2 (moxi group) 100 µg moxifloxacin/0.1 mL, group 3 (Amp-B group) 10 µg liposomal Amp-B/0.1 mL, and group 4 (combi group) both 100 µg moxifloxacin/0.05 mL and 10 µg liposomal Amp-B/0.05 mL intravitreally. Clinical examination, quantitative analysis of microorganisms, and histopathologic examination were performed as in vivo studies. The minimum inhibitory concentration of liposomal Amp-B against C. albicans was found to be 1 µg/mL. Moxifloxacin showed no inhibition of in vitro C. albicans growth. The minimum inhibitory concentration values of liposomal Amp-B for C. albicans were reduced two- to eightfold with increasing concentrations of moxifloxacin in vitro. In vivo, there was no C. albicans growth in the combi group (zero of eight eyes), whereas three eyes (37.5%) showed growth in the Amp-B group. Vitreous inflammation, retinal detachment, focal retinal necrosis, and outer nuclear layer loss were found to be lower in the moxi group compared with the control group. Ganglion cell and inner nuclear layer loss was observed in all eyes (100%) in both the moxi and combi groups, whereas only in 25% (two of eight eyes) in the Amp-B group. Moxifloxacin strongly augments the efficacy of liposomal Amp-B against C. albicans in vitro, although it has no in vitro antifungal activity when used alone. It is interesting that we found a synergistic effect for in vitro tests but failed to demonstrate it in vivo. When 100 µg moxifloxacin/0.1 mL is given intravitreally, it has some toxic effects that are limited to the inner retinal layers.

scholarly journals Comparison of the Physicochemical, Antifungal, and Toxic Properties of Two Liposomal Amphotericin B Products

2007 ◽  
Vol 52 (1) ◽  
pp. 259-268 ◽  
Author(s):  
Jon A. Olson ◽  
Jill P. Adler-Moore ◽  
Gerard M. Jensen ◽  
Julie Schwartz ◽  
M. Cecilia Dignani ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Lethal Dose ◽  
Drug Efficacy ◽  
Liposomal Amphotericin B ◽  
In Vitro Tests ◽  
Tubular Necrosis ◽  
Weight Loss Data ◽  
Renal Tubular

ABSTRACT Small unilamellar amphotericin B liposomes can reduce the toxicity of amphotericin B. In this study, we compared the physical, antifungal, pharmocokinetic, and toxic properties of two liposomal amphotericin B products, AmBisome and Anfogen, that have the same chemical composition but are manufactured differently. In vitro tests included determinations of the MICs and the concentrations causing the release of 50% of the intracellular potassium from red blood cells (K50 values) to assess toxicity. The 50% lethal dose (LD50) was evaluated by using uninfected C57BL/6 mice and single intravenous (i.v.) doses of 1 to 100 mg/kg of body weight. Multiple i.v. dosing over 18 days was performed with 0.5, 1.0, or 5.0 mg of Anfogen/kg or 1.0, 5.0, or 25 mg of AmBisome/kg to evaluate chronic toxicity. DBA/2 mice were infected intranasally with 2.5 × 106 Aspergillus fumigatus conidia, treated for 3 or 4 days with 3.0, 5.0, or 7.5 mg of Anfogen/kg or 3, 5, 7.5, or 15 mg of AmBisome/kg, and evaluated to assess the toxicity of the drugs to the kidneys (by measurement of blood urea nitrogen and creatinine levels and histopathology) and the drug efficacy. The median particle size was 77.8 nm for AmBisome and 111.5 nm for Anfogen. In vitro K50 values were significantly lower for Anfogen (0.9 μg/ml) than for AmBisome (20 μg/ml), and the LD50 of AmBisome was >100 mg/kg, versus 10 mg of Anfogen/kg. There was significant renal tubular necrosis in uninfected and infected mice given Anfogen but no tubular necrosis in AmBisome-treated mice. AmBisome at 7.5 or 15 mg/kg was also more efficacious than 7.5 mg of Anfogen/kg for the treatment of pulmonary aspergillosis, based on survival and weight loss data and numbers of CFU per gram of lung. In conclusion, the efficacy and toxicity of these two liposomal amphotericin B products were significantly different, and thus, the products were not comparable.

scholarly journals Influence of Liposomal Amphotericin B on CD8 T-Cell Function

2001 ◽  
Vol 45 (8) ◽  
pp. 2383-2385 ◽  
Author(s):  
Marianne Kretschmar ◽  
Gernot Geginat ◽  
Thomas Bertsch ◽  
Simon Walter ◽  
Herbert Hof ◽  
...  
Keyword(s):  
T Cells ◽  
Body Weight ◽  
Amphotericin B ◽  
Cd8 T Cells ◽  
Liposomal Amphotericin ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Liposomal Amphotericin B

ABSTRACT Liposomal amphotericin B was immunosuppressive on target cell lysis in vitro and on protection mediated by cytotoxic CD8 T cells in murine listeriosis. When dosages usually used for therapy in humans were compared, the immunosuppressive effect of 5 mg of liposomal amphotericin B/kg of body weight/day was similar to that of standard amphotericin B at 1 mg/kg/day, but a dosage of liposomal amphotericin B of 1 mg/kg/day was not suppressive in vivo.

In vitro and in vivo antifungal activities of liposomal amphotericin B, and amphotericin B lipid complex

1994 ◽  
Vol 128 (1) ◽  
pp. 13-17 ◽  
Author(s):  
Kotaro Mitsutake ◽  
Shigeru Kohno ◽  
Yoshitsugu Miyazaki ◽  
Tetsuhiro Noda ◽  
Haruko Miyazaki ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Liposomal Amphotericin B ◽  
Lipid Complex ◽  
Antifungal Activities ◽  
Amphotericin B Lipid Complex

scholarly journals Antifungal efficacy of isavuconazole and liposomal amphotericin B in a rabbit model of Exserohilum rostratum meningoencephalitis: A preclinical paradigm for management of CNS phaeohyphomycosis

2020 ◽  
Author(s):  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Aspasia Katragkou ◽  
Bo Bo Win Maung ◽  
Patriss W Moradi ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Rabbit Model ◽  
In Vivo Studies ◽  
Liposomal Amphotericin B ◽  
Mortality And Morbidity ◽  
Amphotericin B Deoxycholate ◽  
Exserohilum Rostratum

Abstract Treatment options for Exserohilum rostratum meningoencephalitis and other causes of phaeohyphomycosis of the central nervous system (CNS) are limited, while mortality and morbidity remain high. We therefore evaluated isavuconazole, a new antifungal triazole in comparison to liposomal amphotericin B (LAMB), in vitro and in the rabbit model of Exserohilum rostratum meningoencephalitis. We hypothesized that isavuconazole alone or in combination with LAMB or micafungin may be alternative options for treatment of CNS phaeohyphomycosis. We therefore investigated the in vitro antifungal activity of isavuconazole alone or in combination with amphotericin B deoxycholate (DAMB) or micafungin and efficacy of treatment with isavuconazole and LAMB in a rabbit model of experimental E. rostratum meningoencephalitis. Combination checkerboard plates were used to determine the minimum inhibitory concentrations, minimal lethal concentrations, fractional inhibitory concentration indices, and Bliss surface analysis of isavuconazole and amphotericin B deoxycholate (DAMB), either alone or in combination. As there were no in vitro synergistic or antagonistic interactions for either combination of antifungal agents against the E. rostratum isolates, in vivo studies were conducted with isavuconazole and LAMB as monotherapies. Rabbits were divided in following groups: treated with isavuconazole at 60 mg/kg/d (ISAV60), LAMB at 5.0 (LAMB5), 7.5 (LAMB7.5), and 10 mg/kg/d (LAMB10), and untreated controls (UC). In ISAV60-, LAMB5-, LAMB7.5-, and LAMB10-treated rabbits, significant reductions of fungal burden of E. rostratum in cerebral, cerebellar, and spinal cord tissues (P < 0.01) were demonstrated in comparison to those of UC. These antifungal effects correlated with significant reduction of CSF (1→3)-β-D-glucan levels vs UC (P < 0.05). These data establish new translational insights into treatment of CNS phaeohyphomycosis.

scholarly journals 1577. Particle Characterization of Nebulized Liposomal Amphotericin B and Its Use in the Treatment of Murine Pulmonary Aspergillosis

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S576-S576
Author(s):  
Janam J Dave ◽  
Adilene Sandoval ◽  
Jon Olson ◽  
Jill Adler-Moore
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
In Vivo Studies ◽  
Liposomal Amphotericin B ◽  
Drug Penetration ◽  
Particle Characterization ◽  
Pulmonary Aspergillosis ◽  
Fungal Burden

Abstract Background Immunocompromised patients are very susceptible to pulmonary aspergillosis causing 50% mortality with present treatments, indicating a need for improved therapy. To address this, we standardized a nebulization method for effectively delivering liposomal amphotericin B (AmBisome®, AmBi) into lungs of Aspergillus fumigatus-infected mice. Methods AmBi particle characterization was done with a Cascade particle impactor and a Schuco S5000 nebulizer containing 1.33 mg/mL AmBi. For in vivo studies, AmBi was nebulized (neb) into a 12 compartment chamber (one mouse/compartment), following immunosuppression with 28 mg/kg triamcinolone IP (d-3, -1, +1). Mice were challenged d0 with 9 x 106A. fumigatus (ATCC#13073) and 4 hours post-challenge, divided into 5 groups (n = 12/gp): 5 days of 20 min/day neb AmBi (Gp1), 5 days of 10 min/day neb AmBi (Gp2), 20 min/day neb AmBi days 0, 1, 3, 5, 7 (Gp 3), 5 days of intravenous(IV) AmBi 7.5 mg/kg/day (Gp4) and IV PBS (Gp5). Seven mice/gp were monitored for survival to d21 and lungs, livers, kidneys, spleens (5 mice/gp) analyzed for mean amphotericin B µg/g and CFU/g. Results 87% of neb AmBi particles were between 0.43 mm to 3.3 mm allowing for drug penetration into 1°, 2° and terminal bronchi, bronchioles, and alveoli. This resulted in very good protection, with 20 min daily neb treatments (Gp1) giving 100% survival and 10 min daily neb treatments producing 71% survival (Gp2). There were no survivors in the PBS gp (P < 0.02 vs. Gp1 and Gp2). Every other day neb AmBi or daily IV AmBi was less effective (43% survival). In addition, neb AmBi for 20 min (Gp1) yielded significantly lower fungal burden in lungs vs. all other AmBi treatments (P < 0.02). While drug was detected in lungs of mice given 20 min of neb AmBi (2.6 µg/g), there was no drug detected in livers, kidneys or spleens of any mice given neb AmBi. In comparison, with IV AmBi, drug was detected in the lungs (7 µg/g), livers (204 µg/g), kidneys (38 µg/g), and spleens (114 µg/g). Conclusion Daily AmBi nebulization was an effective and potentially less nephrotoxic treatment for murine pulmonary aspergillosis since it achieved significantly lower tissue fungal burden and much better survival vs. daily IV AmBi, without delivering drug to the kidneys. Disclosures All authors: No reported disclosures.

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