scholarly journals EDTA as an Adjunct Antifungal Agent for Invasive Pulmonary Aspergillosis in a Rodent Model

2006 ◽  
Vol 50 (5) ◽  
pp. 1823-1827 ◽  
Author(s):  
Ray Hachem ◽  
Paul Bahna ◽  
Hend Hanna ◽  
L. Clifton Stephens ◽  
Issam Raad
Keyword(s):  
Body Weight ◽  
Antifungal Agent ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Invasive Pulmonary Aspergillosis ◽  
Pulmonary Aspergillosis ◽  
Lipid Complex ◽  
Optimal Dosing ◽  
Amphotericin B Lipid Complex ◽  
Severe Lung

ABSTRACT Rats immunosuppressed by the administration of cyclophosphamide and cortisone acetate and then infected with Aspergillus fumigatus were treated with an antifungal drug, EDTA, or a combination of one of the antifungal agents, amphotericin B lipid complex (ABLC; 5 mg/kg of body weight/day for 7 days), and EDTA (30 mg/kg/day for 7 days). The mortality rate was reduced, the duration of survival was increased, fewer A. fumigatus organisms were recovered from the lungs, and less-severe lung lesions were seen histopathologically in the rats receiving the combination treatment than in the rats receiving either an antifungal agent or EDTA alone. Further studies regarding the mechanisms of EDTA and its interactions with ABLC are warranted, and further studies are needed to more fully examine the safety, tolerance, and optimal dosing of EDTA in the treatment of this and other fungal infections.

scholarly journals Activity of voriconazole (UK-109,496) against clinical isolates of Aspergillus species and its effectiveness in an experimental model of invasive pulmonary aspergillosis.

1997 ◽  
Vol 41 (3) ◽  
pp. 696-698 ◽  
Author(s):  
M Murphy ◽  
E M Bernard ◽  
T Ishimaru ◽  
D Armstrong
Keyword(s):  
Body Weight ◽  
Experimental Model ◽  
Antifungal Agent ◽  
Invasive Pulmonary Aspergillosis ◽  
Clinical Isolates ◽  
Aspergillus Species ◽  
Pulmonary Aspergillosis

Voriconazole, a new azole antifungal agent, showed potent activity against clinical isolates of Aspergillus spp. in vitro. For A. fumigatus, the MIC range was < 0.03 to 0.5 microgram/ml and the MIC at which 90% of isolates are inhibited was 0.25 microgram/ml. In an experimental model of invasive pulmonary aspergillosis which mimics infection in humans, oral voriconazole at dosages of 30 mg/kg of body weight per day significantly delayed or prevented mortality.

scholarly journals Pharmacokinetics and Pharmacodynamics of Amphotericin B Deoxycholate, Liposomal Amphotericin B, and Amphotericin B Lipid Complex in an In Vitro Model of Invasive Pulmonary Aspergillosis

2010 ◽  
Vol 54 (8) ◽  
pp. 3432-3441 ◽  
Author(s):  
Jodi M. Lestner ◽  
Susan J. Howard ◽  
Joanne Goodwin ◽  
Lea Gregson ◽  
Jayesh Majithiya ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Invasive Pulmonary Aspergillosis ◽  
Host Cells ◽  
Pulmonary Aspergillosis ◽  
Lipid Complex ◽  
Amphotericin B Deoxycholate ◽  
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.

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

2015 ◽  
Vol 59 (5) ◽  
pp. 2735-2745 ◽  
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.

scholarly journals Efficacy of prophylactic aerosol amphotericin B lipid complex in a rat model of pulmonary aspergillosis.

1997 ◽  
Vol 41 (2) ◽  
pp. 259-261 ◽  
Author(s):  
C E Cicogna ◽  
M H White ◽  
E M Bernard ◽  
T Ishimura ◽  
M Sun ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Rat Model ◽  
Parent Compound ◽  
Invasive Pulmonary Aspergillosis ◽  
Transplant Recipients ◽  
Pulmonary Aspergillosis ◽  
Lipid Complex ◽  
Prophylactic Efficacy ◽  
Similar Dose ◽  
Amphotericin B Lipid Complex

Invasive pulmonary aspergillosis remains an important cause of morbidity and mortality among transplant recipients and patients receiving cancer chemotherapy. The lipid-associated formulation of amphotericin B (AmB), AmB lipid complex (ABLC), was evaluated for its prophylactic efficacy when it was administered as an aerosol in a rat model of pulmonary aspergillosis. Aerosol ABLC (aero-ABLC), in doses from 0.4 to 1.6 mg/kg of body weight given 2 days before infection, significantly delayed mortality compared to the mortality of rats given placebo (P < 0.001). At day 10 postinfection, 50% of rats in the 0.4-mg/kg group and 75% of rats in the 1.6-mg/kg group were alive, while all control animals had died. In a second trial aero-ABLC was more effective than an equivalent dose of aerosol AmB (aero-AmB) in prolonging survival, with 100% survival at day 14 postinfection in the ABLC group, compared to 62.5% survival in the AmB group. Mean concentrations of AmB in lungs were 3.7 times higher at day 1 (P < 0.002) and almost six times higher at day 7 (P < 0.001) after treatment with aero-ABLC than after treatment with a similar dose of aero-AmB. We conclude that aero-ABLC provided higher and more prolonged levels of the parent compound in the lungs than aero-AmB and was more effective in delaying mortality from aspergillosis in this model.

scholarly journals Comparative Analysis of Amphotericin B Lipid Complex and Liposomal Amphotericin B Kinetics of Lung Accumulation and Fungal Clearance in a Murine Model of Acute Invasive Pulmonary Aspergillosis

2007 ◽  
Vol 51 (4) ◽  
pp. 1253-1258 ◽  
Author(s):  
Russell E. Lewis ◽  
Guangling Liao ◽  
Jinggou Hou ◽  
Georgios Chamilos ◽  
Randall A. Prince ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Invasive Pulmonary Aspergillosis ◽  
Drug Distribution ◽  
Pulmonary Aspergillosis ◽  
Tissue Concentrations ◽  
Lipid Complex ◽  
Fungal Burden ◽  
Amphotericin B Lipid Complex ◽  
Kinetics Of

ABSTRACT The reformulation of amphotericin B (AMB) into a lipid complex (AMB lipid complex [ABLC]) or liposomal carrier (liposomal AMB [L-AMB]) changes the rate and extent of drug distribution to the lung. The importance of pharmacokinetic differences among the various lipid AMB formulations in the treatment of invasive pulmonary aspergillosis (IPA) remains unknown. We compared the kinetics of AMB lung accumulation and fungal clearance of ABLC- and L-AMB-treated mice with acute IPA. BALB/c mice were immunosuppressed with cyclophosphamide and cortisone before intranasal inoculation with 1.5 × 106 Aspergillus fumigatus 293 conidia. ABLC or L-AMB was administered in daily intravenous doses (1, 5, or 10 mg/kg of body weight), starting 12 h after infection and continuing until day 5. At predetermined times (0, 24, 72, and 120 h), mice were euthanized, and lungs were harvested for determinations of lung fungal burdens (quantitative PCR) and total AMB lung tissue concentrations. Both ABLC and L-AMB were effective at reducing lung fungal burdens at doses of ≥5 mg/kg/day. Clearance of A. fumigatus during the first 24 h was associated with AMB tissue concentrations of >4 μg/g. At 5 mg/kg/day, ABLC produced a more rapid fungal clearance than did L-AMB, but at the end of therapy, fungal burden reductions were similar for both formulations and were not improved with higher dosages. These data suggest that ABLC delivers active AMB to the lung more rapidly than does L-AMB, resulting in faster Aspergillus clearance in an experimental model of IPA. However, pharmacodynamic differences between the two formulations were less apparent when mice were dosed at 10 mg/kg/day.

scholarly journals Inhaled amphotericin B lipid complex for prophylaxis against COVID-19-associated invasive pulmonary aspergillosis

2021 ◽  
Author(s):  
María Cruz Soriano ◽  
Gabriela Narváez-Chávez ◽  
Marina López-Olivencia ◽  
Jesús Fortún ◽  
Raúl de Pablo
Keyword(s):  
Amphotericin B ◽  
Invasive Pulmonary Aspergillosis ◽  
Pulmonary Aspergillosis ◽  
Lipid Complex ◽  
Amphotericin B Lipid Complex

scholarly journals Antifungal Agents for the Treatment of Systemic Fungal Infections in Children

2010 ◽  
Vol 21 (4) ◽  
pp. e116-e121 ◽  
Author(s):  
UD Allen
Keyword(s):  
Combination Therapy ◽  
Amphotericin B ◽  
Antifungal Therapy ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Invasive Pulmonary Aspergillosis ◽  
Fungal Diseases ◽  
Pulmonary Aspergillosis ◽  
Amphotericin B Deoxycholate ◽  
Systemic Antifungal Therapy

Traditionally, the mainstay of systemic antifungal therapy has been amphotericin B deoxycholate (conventional amphotericin B). Newer agents have been developed to fulfill special niches and to compete with conventional amphotericin B by virtue of having more favourable toxicity profiles. Some agents have displaced conventional amphotericin B for the treatment of specific fungal diseases. For example, voriconazole has emerged as the preferred treatment for invasive pulmonary aspergillosis. This notwithstanding, conventional amphotericin B remains a useful agent for the treatment of paediatric fungal infections. Knowledge of the characteristics of the newer agents is important, given the increasing numbers of patients who are being treated with these drugs. Efforts need to be directed at research aimed at generating paediatric data where these are lacking. The antifungal agents herein described are most often used as monotherapy regimens because there is no uniform consensus on the value of combination therapy, except for specific scenarios.

scholarly journals A Pharmacokinetic Study of Amphotericin B Lipid Complex Injection (Abelcet) in Patients with Definite or Probable Systemic Fungal Infections

2000 ◽  
Vol 44 (10) ◽  
pp. 2900-2902 ◽  
Author(s):  
Adedayo Adedoyin ◽  
Christine E. Swenson ◽  
Lois E. Bolcsak ◽  
Andrzej Hellmann ◽  
Danuta Radowska ◽  
...  
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Volume Of Distribution ◽  
Lipid Complex ◽  
Systemic Fungal Infection ◽  
Elimination Half ◽  
Amphotericin B Lipid Complex ◽  
Pharmacokinetic Evaluation

ABSTRACT This study describes a pharmacokinetic evaluation of amphotericin B (AMB) lipid complex injection (ABLC or Abelcet) in 17 patients with systemic fungal infection administered 5 mg/kg of body weight/day by infusion for 10 to 17 days. The results showed that AMB exhibited multiexponential disposition with high clearance, large volume of distribution at steady state, and long apparent elimination half-life but no evidence of accumulation in the blood after multiple daily doses. The results confirm previous observations and further reinforce the suggestion that ABLC may exist as a depot in the tissues from which free AMB is slowly released to limit exposure.

Two-year Longitudinal Evaluation of Amphotericin B Lipid Complex Injection in a Tertiary Care Medical Center

2000 ◽  
Vol 35 (2) ◽  
pp. 176-181 ◽  
Author(s):  
Leanne D. Kennedy ◽  
Julie F. Connelly ◽  
Kevin M. Kuzma
Keyword(s):  
Serum Creatinine ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Tertiary Care ◽  
Serum Creatinine Concentration ◽  
Creatinine Concentration ◽  
Lipid Complex ◽  
Tertiary Care Medical Center ◽  
Amphotericin B Lipid Complex ◽  
The Mean

A 2-year concurrent drug use evaluation was conducted in 156 patients to determine whether Abelcet (amphotericin B lipid complex injection) was being prescribed according to institution-approved guidelines and to characterize the patient population receiving Abelcet. Eighty-nine patients (57%) had fungal infections documented by chest x-ray, computed tomography, or fungal cultures. Sixty-seven (43%) had clinically suspected fungal infections. The Abelcet mean dose by weight was 5 mg/kg/day (actual body weight). Seventy-one patients (46%) met the established guidelines for use; 85 (54%) did not. Premedication was given to 64% of the patients; only 15 patients (10%) experienced documented fever and chills. A total of 72 patients (46%) died during therapy. Of the 75 patients who completed therapy in the hospital, 41 were switched to conventional amphotericin B, fluconazole, or itraconazole following a decrease in serum creatinine concentration, and 34 did not receive further antifungal therapy. The mean length of Abelcet therapy was 11 days. The mean increase in serum creatinine concentration at discontinuation of therapy was 0.2 mg/dL. Continued monitoring of Abelcet use was recommended and established guidelines were reaffirmed. Hydration with normal saline before and after dosing was suggested to help improve renal function, and dopamine was recommended to increase renal blood flow.

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