scholarly journals Liposomal Amphotericin B and Echinocandins as Monotherapy or Sequential or Concomitant Therapy in Murine Disseminated and Pulmonary Aspergillus fumigatus Infections

2010 ◽  
Vol 54 (9) ◽  
pp. 3884-3894 ◽  
Author(s):  
Jon A. Olson ◽  
Ancy George ◽  
David Constable ◽  
Peter Smith ◽  
Richard T. Proffitt ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Sequential Therapy ◽  
Liposomal Amphotericin B ◽  
Concomitant Therapy ◽  
Fungal Burden ◽  
Drug Levels ◽  
Drug Concentrations ◽  
Disseminated Aspergillosis

ABSTRACT Monotherapy and combination therapy were compared using optimal doses of liposomal amphotericin B, micafungin, or caspofungin in Aspergillus fumigatus pulmonary and disseminated infections. Mice were challenged intravenously (2.8 × 104 to 5.7 × 104 conidia) or intranasally (5.8 × 107 conidia) with A. fumigatus. Drugs (5, 10, or 15 mg/kg of body weight) were given for 3 or 6 days as single, concomitant, or sequential therapy (i.e., days 1 to 3 and then days 4 to 6). Mice were monitored for survival, and tissues were assayed for fungal burden and drug concentrations. Treatments starting 24 h postchallenge significantly prolonged survival in disseminated aspergillosis (P < 0.002), but only liposomal amphotericin B treatments or treatments beginning with liposomal amphotericin B increased survival to 100% in the pulmonary aspergillosis model. Fungi in kidneys and spleens (disseminated) and lungs (pulmonary) were significantly decreased (P ≤ 0.04) by liposomal amphotericin B, liposomal amphotericin B plus echinocandin, or liposomal amphotericin B prior to echinocandin. In the disseminated infection, liposomal amphotericin B and micafungin (10 or 15 mg/kg) had similar kidney drug levels, while in the spleen, 5 and 15 mg/kg liposomal amphotericin B gave higher drug levels than micafungin (P < 0.02). In the pulmonary infection, drug levels in lungs and spleen with 5-mg/kg dosing were significantly higher with liposomal amphotericin B than with caspofungin (P ≤ 0.002). In summary, treatment of A. fumigatus infections with liposomal amphotericin B plus echinocandin or liposomal amphotericin B prior to echinocandin was as effective as liposomal amphotericin B alone, and a greater decrease in the fungal burden with liposomal amphotericin B supports using liposomal amphotericin B prior to echinocandin.

scholarly journals 1639. Efficacy of Voriconazole Prophylaxis Followed by Therapeutic Liposomal Amphotericin B for the Treatment of Murine Pulmonary Aspergillosis Caused by Azole-Resistant Aspergillus fumigatus Strains

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S45-S45
Author(s):  
Jon Olson ◽  
Matthew Slarve ◽  
Jill Adler-Moore
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Therapeutic Option ◽  
The Other ◽  
Liposomal Amphotericin B ◽  
Post Challenge ◽  
Pulmonary Aspergillosis ◽  
Fungal Burden ◽  
Buffer Control

Abstract Background Antifungal treatment for pulmonary aspergillosis is more difficult if the fungal strain causing the infection is azole resistant. To investigate this problem, we used a murine model of pulmonary aspergillosis caused by azole-resistant Aspergillus fumigatus strains V29 and V45, and compared treatment with voriconazole (Vr, oral 40 mg/kg, bid) or liposomal amphotericin B (L-AmB, 5 mg/kg, IV) used alone or in combination. Methods Mice (n = 14/gp) were immunosuppressed with 24 mg/kg triamcinolone acetonide, IP, d-3, d-1, and d+1 relative to fungal challenge (d0). For 2 groups, Vr was given prophylactically (proph) d-3, d-2, d-1 followed by L-AmB or buffer, d+1, d+2, and d+3. The other groups were given Vr, L-AmB, Vr+L-AmB, or buffer d+1, d+2, and d+3. On d0, mice were given 1.3 to 1.6 × 107A. fumigatus spores intranasally (Vr MIC = 64 μg/mL, V29; Vr MIC = 8 μg/mL, V45). On d+3, lungs were collected from 7 mice/gp and fungal burden determined by plating for colony forming units; 7 mice/gp were then monitored for morbidity to d+21. Results Optimum treatment was observed when Vr was given proph, followed by L-AmB post-challenge (Vr/L-AmB), with better survival (100%) for both fungal strains vs. buffer or Vr post-challenge (P ≤ 0.04); for V29, significantly better survival was also seen with Vr/L-AmB vs. L-AmB or Vr+L-AmB post-challenge (P ≤ 0.01). For strain V45, lung fungal burden was significantly lower for Vr/L-AmB versus all other treatments (P ≤ 0.04), while for strain V29, fungal burden was lower for the Vf/L-AmB and L-AmB post-challenge groups versus the other groups, but the differences were not significant. Notably, although the lung fungal burden with Vr proph and Vr postchallenge were both similar to the buffer control, Vr proph yielded significantly better survival than Vr post-challenge (P ≤ 0.001). Conclusion These preclinical observations demonstrate that combining L-AmB with Vr for the postchallenge treatment of pulmonary aspergillosis caused by azole-resistant strains is not an effective therapeutic option. However, the results do show that Vr proph, but not Vr postchallenge, can have some limited antifungal activity, and can significantly enhance the antifungal effects of post-challenge L-AmB. This regimen could be considered in areas where there is a high incidence of azole-resistant A. fumigatus. Disclosures All authors: No reported disclosures.

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.

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 Plasma Protein Binding of Amphotericin B and Pharmacokinetics of Bound versus Unbound Amphotericin B after Administration of Intravenous Liposomal Amphotericin B (AmBisome) and Amphotericin B Deoxycholate

2002 ◽  
Vol 46 (3) ◽  
pp. 834-840 ◽  
Author(s):  
Ihor Bekersky ◽  
Robert M. Fielding ◽  
Dawna E. Dressler ◽  
Jean W. Lee ◽  
Donald N. Buell ◽  
...  
Keyword(s):  
Human Plasma ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
The Body ◽  
Liposomal Amphotericin B ◽  
Time Curve ◽  
Liposomal Drug ◽  
Drug Concentrations ◽  
Unique Composition

ABSTRACT Unilamellar liposomal amphotericin B (AmBisome) (liposomal AMB) reduces the toxicity of this antifungal drug. The unique composition of liposomal AMB stabilizes the liposomes, producing higher sustained drug levels in plasma and reducing renal and hepatic excretion. When liposomes release their drug payload, unbound, protein-bound, and liposomal drug pools may exist simultaneously in the body. To determine the amounts of drug in these pools, we developed a procedure to measure unbound AMB in human plasma by ultrafiltration and then used it to characterize AMB binding in vitro and to assess the pharmacokinetics of nonliposomal pools of AMB in a phase IV study of liposomal AMB and AMB deoxycholate in healthy subjects. We confirmed that AMB is highly bound (>95%) in human plasma and showed that both human serum albumin and α1-acid glycoprotein contribute to this binding. AMB binding exhibited an unusual concentration dependence in plasma: the percentage of bound drug increased as the AMB concentration increased. This was attributed to the low solubility of AMB in plasma, which limits the unbound drug concentration to <1 μg/ml. Subjects given 2 mg of liposomal AMB/kg of body weight had lower exposures (as measured by the maximum concentration of drug in serum and the area under the concentration-time curve) to both unbound and nonliposomal drug than those receiving 0.6 mg of AMB deoxycholate/kg. Most of the AMB in plasma remained liposome associated (97% at 4 h, 55% at 168 h) after liposomal AMB administration, so that unbound drug concentrations remained at <25 ng/ml in all liposomal AMB-treated subjects. Although liposomal AMB markedly reduces the total urinary and fecal recoveries of AMB, urinary and fecal clearances based on unbound AMB were similar (94 to 121 ml h−1 kg−1) for both formulations. Unbound drug urinary clearances were equal to the glomerular filtration rate, and tubular transit rates were <16% of the urinary excretion rate, suggesting that net filtration of unbound drug, with little secretion or reabsorption, is the mechanism of renal clearance for both conventional and liposomal AMB in humans. Unbound drug fecal clearances were also similar for the two formulations. Thus, liposomal AMB increases total AMB concentrations while decreasing unbound AMB concentrations in plasma as a result of sequestration of the drug in long-circulating liposomes.

scholarly journals Posaconazole Mono- or Combination Therapy for Treatment of Murine Zygomycosis

2008 ◽  
Vol 53 (2) ◽  
pp. 772-775 ◽  
Author(s):  
Ashraf S. Ibrahim ◽  
Teclegiorgis Gebremariam ◽  
Julie A. Schwartz ◽  
John E. Edwards ◽  
Brad Spellberg
Keyword(s):  
Combination Therapy ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Rhizopus Oryzae ◽  
Liposomal Amphotericin B ◽  
Fungal Burden ◽  
Better Than

ABSTRACT We compared the efficacy of combination posaconazole-liposomal amphotericin B (LAmB) therapy to monotherapy with either drug in diabetic ketoacidotic or neutropenic mice with disseminated zygomycosis caused by Rhizopus oryzae. Combination therapy was no better than LAmB alone, and posaconazole monotherapy did not improve survival or reduce fungal burden versus placebo.

scholarly journals Efficacy of Single-Dose Liposomal Amphotericin B or Micafungin Prophylaxis in a Neutropenic Murine Model of Invasive Pulmonary Aspergillosis

2008 ◽  
Vol 52 (11) ◽  
pp. 4178-4180 ◽  
Author(s):  
Russell E. Lewis ◽  
Nathaniel D. Albert ◽  
Dimitrios P. Kontoyiannis
Keyword(s):  
Body Weight ◽  
Amphotericin B ◽  
Murine Model ◽  
Liposomal Amphotericin ◽  
Invasive Pulmonary Aspergillosis ◽  
Liposomal Amphotericin B ◽  
Potential Utility ◽  
Pulmonary Aspergillosis ◽  
Fungal Burden ◽  
Animal Survival

ABSTRACT In a neutropenic murine model of invasive pulmonary aspergillosis, prophylaxis with single doses of liposomal amphotericin B or micafungin at ≥5 mg/kg of body weight improved animal survival and suppressed the lung fungal burden for up to 7 days after infection, demonstrating the potential utility of infrequent dosing with these antifungals.

scholarly journals Management of cerebral azole-resistant Aspergillus fumigatus infection: A role for intraventricular liposomal-amphotericin B

2020 ◽  
Vol 22 ◽  
pp. 354-357 ◽  
Author(s):  
A.F.A.D. Schauwvlieghe ◽  
R.G.M. Bredius ◽  
R.M. Verdijk ◽  
F.J.W. Smiers ◽  
M.T. van der Beek ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Liposomal Amphotericin B

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.

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