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

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.

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1441 ◽

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00715-08 ◽

2008 ◽

Vol 52 (11) ◽

pp. 4178-4180 ◽

Cited By ~ 17

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01554-09 ◽

2010 ◽

Vol 54 (9) ◽

pp. 3884-3894 ◽

Cited By ~ 21

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.

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Impact of liposomal amphotericin B therapy on chronic pulmonary aspergillosis

Journal of Infection ◽

10.1016/j.jinf.2016.06.001 ◽

2016 ◽

Vol 73 (5) ◽

pp. 485-495 ◽

Cited By ~ 17

Author(s):

Pippa J. Newton ◽

Chris Harris ◽

Julie Morris ◽

David W. Denning

Keyword(s):

Amphotericin B ◽

Liposomal Amphotericin ◽

Liposomal Amphotericin B ◽

Pulmonary Aspergillosis ◽

Chronic Pulmonary Aspergillosis

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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 Nebulized Liposomal Amphotericin B in Treatment of Experimental Pulmonary Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.7.3028-3030.2005 ◽

2005 ◽

Vol 49 (7) ◽

pp. 3028-3030 ◽

Cited By ~ 37

Author(s):

Joan Gavaldà ◽

María-Teresa Martín ◽

Pedro López ◽

Xavier Gomis ◽

José-Luís Ramírez ◽

...

Keyword(s):

Amphotericin B ◽

Murine Model ◽

Liposomal Amphotericin ◽

Invasive Pulmonary Aspergillosis ◽

Liposomal Amphotericin B ◽

Pulmonary Aspergillosis ◽

Lower Lung

ABSTRACT The efficacy of therapeutic aerosolized amphotericin B (AMB) was studied in a steroid-immunosuppressed murine model of invasive pulmonary aspergillosis. Nebulized liposomal AMB can be a valid approach to the treatment of this infection, with subjects showing significantly improved survival relative to that of subjects given intravenous deoxycholate AMB, as well as lower lung weights and pulmonary glucosamine levels.

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Successfully treated invasive pulmonary aspergillosis in a patient with diabetic ketoacidosis

Open Medicine ◽

10.2478/s11536-013-0188-z ◽

2013 ◽

Vol 8 (5) ◽

pp. 685-688

Author(s):

Ryo Kumagai ◽

Gen Ohara ◽

Shinya Sato ◽

Kunihiko Miyazaki ◽

Katsunori Kagohashi ◽

...

Keyword(s):

Early Intervention ◽

Invasive Aspergillosis ◽

Diabetic Ketoacidosis ◽

Amphotericin B ◽

Early Treatment ◽

Liposomal Amphotericin ◽

Invasive Pulmonary Aspergillosis ◽

Full Recovery ◽

Liposomal Amphotericin B ◽

Pulmonary Aspergillosis

AbstractWe report herein a case of diabetic ketoacidosis associated with invasive aspergillosis that was successfully treated with liposomal amphotericin-B (L-AMB). Early intervention after confirming the diagnosis of invasive pulmonary aspergillosis is very important, and initiating early treatment with L-AMB can lead to a full recovery.

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Case Report. Chronic necrotizing pulmonary aspergillosis in a non-neutropenic patient treated with liposomal amphotericin B

Mycoses ◽

10.1046/j.1439-0507.2000.00579.x ◽

2000 ◽

Vol 43 (7-8) ◽

pp. 313-315 ◽

Cited By ~ 1

Author(s):

N. Filippou ◽

K. Papachristou ◽

I. Ilias ◽

A. Pefanis ◽

E. Papaleftheris ◽

...

Keyword(s):

Case Report ◽

Amphotericin B ◽

Liposomal Amphotericin ◽

Neutropenic Patient ◽

Liposomal Amphotericin B ◽

Pulmonary Aspergillosis ◽

Chronic Necrotizing Pulmonary Aspergillosis

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Pharmacodynamics of Amphotericin B Deoxycholate, Amphotericin B Lipid Complex, and Liposomal Amphotericin B against Aspergillus fumigatus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04723-14 ◽

2015 ◽

Vol 59 (5) ◽

pp. 2735-2745 ◽

Cited By ~ 14

Author(s):

Zaid Al-Nakeeb ◽

Vidmantas Petraitis ◽

Joanne Goodwin ◽

Ruta Petraitiene ◽

Thomas J. Walsh ◽

...

Keyword(s):

Amphotericin B ◽

Liposomal Amphotericin ◽

Invasive Pulmonary Aspergillosis ◽

Liposomal Amphotericin B ◽

Complete Suppression ◽

Pulmonary Aspergillosis ◽

Lipid Complex ◽

Amphotericin B Deoxycholate ◽

Amphotericin B Lipid Complex ◽

Dose Dependent

ABSTRACTAmphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1→3)-β-d-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the “average” patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and (1→3)-β-d-glucan levels, but 20 to 30% of the patients still had a galactomannan index of >1 and (1→3)-β-d-glucan levels of >60 pg/ml. All formulations of amphotericin B induce a dose-dependent reduction in markers of lung injury and circulating fungus-related biomarkers. A clinical dosage of liposomal amphotericin B of 3 mg/kg/day is predicted to cause complete suppression of galactomannan and (1→3)-β-d-glucan levels in the majority of patients.

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