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

ABSTRACT The pharmacodynamic and pharmacokinetic (PK-PD) properties of amphotericin B (AmB) formulations against invasive pulmonary aspergillosis (IPA) are not well understood. We used an in vitro model of IPA to further elucidate the PK-PD of amphotericin B deoxycholate (DAmB), liposomal amphotericin B (LAmB) and amphotericin B lipid complex (ABLC). The pharmacokinetics of these formulations for endovascular fluid, endothelial cells, and alveolar cells were estimated. Pharmacodynamic relationships were defined by measuring concentrations of galactomannan in endovascular and alveolar compartments. Confocal microscopy was used to visualize fungal biomass. A mathematical model was used to calculate the area under the concentration-time curve (AUC) in each compartment and estimate the extent of drug penetration. The interaction of LAmB with host cells and hyphae was visualized using sulforhodamine B-labeled liposomes. The MICs for the pure compound and the three formulations were comparable (0.125 to 0.25 mg/liter). For all formulations, concentrations of AmB progressively declined in the endovascular fluid as the drug distributed into the cellular bilayer. Depending on the formulation, the AUCs for AmB were 10 to 300 times higher within the cells than within endovascular fluid. The concentrations producing a 50% maximal effect (EC50) in the endovascular compartment were 0.12, 1.03, and 4.41 mg/liter for DAmB, LAmB, and ABLC, respectively, whereas, the EC50 in the alveolar compartment were 0.17, 7.76, and 39.34 mg/liter, respectively. Confocal microscopy suggested that liposomes interacted directly with hyphae and host cells. The PK-PD relationships of the three most widely used formulations of AmB differ markedly within an in vitro lung model of IPA.

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123 A prospective French National Survey to assess renal safety of amphotericin B lipid complex and liposomal amphotericin B

International Journal of Infectious Diseases ◽

10.1016/s1201-9712(06)80119-0 ◽

2006 ◽

Vol 10 ◽

pp. S68-S69 ◽

Cited By ~ 3

Author(s):

F. Saliba ◽

N. Cheron ◽

Ph. Ichai ◽

A. Renault ◽

A. Sirvent ◽

...

Keyword(s):

Amphotericin B ◽

National Survey ◽

Liposomal Amphotericin ◽

Liposomal Amphotericin B ◽

Lipid Complex ◽

Amphotericin B Lipid Complex ◽

Renal Safety

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Budget Impact Analysis Of Liposomal Amphotericin B And Amphotericin B Lipid Complex For Treating Invasive Fungal Infections In Hospitalized Patients

Value in Health ◽

10.1016/j.jval.2013.03.385 ◽

2013 ◽

Vol 16 (3) ◽

pp. A83-A84

Author(s):

P. Chaudhari ◽

H. Yang ◽

Z.Y. Zhou ◽

C. Patel ◽

E.Q. Wu

Keyword(s):

Amphotericin B ◽

Liposomal Amphotericin ◽

Impact Analysis ◽

Budget Impact ◽

Fungal Infections ◽

Invasive Fungal Infections ◽

Hospitalized Patients ◽

Liposomal Amphotericin B ◽

Lipid Complex ◽

Amphotericin B Lipid Complex

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01681-10 ◽

2011 ◽

Vol 55 (9) ◽

pp. 4447-4450 ◽

Cited By ~ 15

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.

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

Canadian Journal of Microbiology ◽

10.1139/w09-112 ◽

2010 ◽

Vol 56 (1) ◽

pp. 1-7 ◽

Cited By ~ 16

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02673-18 ◽

2019 ◽

Vol 63 (6) ◽

Cited By ~ 1

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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