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 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 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.

scholarly journals Biofilm Production and Antibiofilm Activity of Echinocandins and Liposomal Amphotericin B in Echinocandin-Resistant Yeast Species

2016 ◽  
Vol 60 (6) ◽  
pp. 3579-3586 ◽  
Author(s):  
Laura Judith Marcos-Zambrano ◽  
Marta Gómez-Perosanz ◽  
Pilar Escribano ◽  
Oscar Zaragoza ◽  
Emilio Bouza ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Metabolic Activity ◽  
Liposomal Amphotericin ◽  
Antifungal Susceptibility ◽  
Growth Control ◽  
Liposomal Amphotericin B ◽  
Antibiofilm Activity ◽  
Wild Type ◽  
Content Type ◽  
Type Strains

The echinocandins and liposomal amphotericin B are active against biofilm produced by echinocandin-susceptibleCandidastrains. However, few data have been reported on the production of biofilm by echinocandin-resistant isolates and their antifungal susceptibility. We studied the production of biofilm byfksmutantCandidastrains and intrinsically echinocandin-resistant non-Candidaisolates and the susceptibility of both entities to liposomal amphotericin B and echinocandins. We analyzed the production of biofilm by isolates from patients with fungemia (fksmutantCandida,n= 5; intrinsically echinocandin-resistant non-Candida,n= 12; andCandidawild type,n= 10). Biofilm formation was measured to classify strains according to biomass (crystal violet assay) and metabolic activity (XTT reduction assay). Preformed biofilms were tested against liposomal amphotericin B, caspofungin, micafungin, and anidulafungin. The sessile MIC was defined as the antifungal concentration yielding a 50% or 80% reduction in the metabolic activity of the biofilm compared to that of the growth control (SMIC50and SMIC80, respectively).fksmutantCandidaisolates formed biofilms in a fashion similar to that ofCandidawild-type strains. The echinocandins had the highest activity against biofilms formed by wild-typeCandidaisolates, followed byfksmutantCandidaisolates and non-Candidaisolates. Liposomal amphotericin B had the highest activity againstfksmutantCandidabiofilms. The formation of biofilm by echinocandin-resistant strains was similar to that of wild-type strains, although resistance to echinocandins remained high.

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.

Combination therapy with caspofungin and liposomal amphotericin B for invasive aspergillosis

2003 ◽  
Vol 22 (7) ◽  
pp. 653-656 ◽  
Author(s):  
ZIJU ELANJIKAL ◽  
JAN SÖRENSEN ◽  
HELGA SCHMIDT ◽  
WOLFGANG DUPUIS ◽  
KATHRIN TINTELNOT ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Invasive Aspergillosis ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Liposomal Amphotericin B

scholarly journals Sequential or Combination Antifungal Therapy with Voriconazole and Liposomal Amphotericin B in a Guinea Pig Model of Invasive Aspergillosis

2006 ◽  
Vol 50 (4) ◽  
pp. 1567-1569 ◽  
Author(s):  
William R. Kirkpatrick ◽  
Brent J. Coco ◽  
Thomas F. Patterson
Keyword(s):  
Guinea Pig ◽  
Invasive Aspergillosis ◽  
Amphotericin B ◽  
Antifungal Therapy ◽  
Liposomal Amphotericin ◽  
Pig Model ◽  
Liposomal Amphotericin B ◽  
Guinea Pig Model

ABSTRACT We evaluated combinations of voriconazole (VRC) and liposomal amphotericin B (L-AMB) in a guinea pig invasive aspergillosis model. Simultaneous VRC and L-AMB was most effective, although VRC monotherapy was also effective. These regimens as well as sequential L-AMB followed by VRC were more effective than L-AMB alone or VRC followed by L-AMB.

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.

Sign in / Sign up

Export Citation Format

Share Document