Efficacy of Nebulized Liposomal Amphotericin B in Treatment of Experimental Pulmonary Aspergillosis

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.Pulmonary disease is the most frequent form of invasive aspergillosis (4), a fungal infection of growing incidence among immunocompromised patients (4), chiefly caused by Aspergillus fumigatus and associated with high mortality rates (10), despite a therapeutic arsenal that has been broadened with the approval of new drugs (5,7,15). To improve the poor results obtained with current treatment regimens, the potential usefulness of methods which may increase the concentration of amphotericin B (AMB) at the infectious focus, including its use by nebulization, has been suggested (8,16,19).The efficacy of nebulized deoxycholate AMB or liposomal AMB was compared to that of conventional intravenous (i.v.) dosages of both formulations, using a murine model of invasive pulmonary aspergillosis (IPA). The potential benefits of inhalation plus i.v. administration were also explored. This experimental protocol was approved by the Ethics Committee of Vall d'Hebron Hospitals.Female Wistar rats (180 to 200 g; Harland Iberica, Spain), fed with a low-protein diet, were immunosuppressed with 125 mg of subcutaneous cortisone acetate (Sigma Chemical Co., St. Louis, MO) per kg of body weight three times per week, from 14 days before infection to the end of the experiment (11).On day 0, animals were intratracheally challenged with 0.3 ml of a conidial suspension prepared from a 1-week-old subculture on Sabouraud dextrose agar of a clinical isolate of A. fumigatus (AF19/68). Conidia were counted in a hemocytometer and adjusted to 8 ϫ 10 6 cells/ml in sterile saline. Intravenous treatments were administered through a central venous catheter (11). Aerosols were generated by a CR60 compressor (Medic-Aid Ltd., West Sussex, United Kingdom; flow rate, 10 liter/min) attached to a Nebulizer II Oxinova (Carburos Metálicos, Barcelona, Spain) and were led through a nose-only exposure inhalation chamber (Panlab, Spain) over a 60-min period. The total dosage of AMB administered to each animal was calculated with the following formula: the total dosage ϭ the chamber concentration of AMB (mg/liter) ϫ the minute volume (liter/min) ϫ the duration of exposition (min) ϫ the animal's weight (kg Ϫ1 ) (1). The minute volume is equal to the body weight 0.75 (grams) ϫ 0.00254 (6). Animals were randomized to receive 5% dextrose i.v. Surviving rats were sacrificed 24 h after the last dose of treatment. All animals were aseptically dissected. Lungs were weighed and homogenized in sterile distilled water, and aliquots were serially diluted and plated onto Sabouraud dextrose agar for colony counts. Lung homogenates were processed for chitin assay, as des...

In Vivo Efficacy of Aerosolized Nanostructured ItraconazoleFormulations for Prevention of Invasive Pulmonary Aspergillosis

“…In contrast, peak lung ITZ concentrations for aerosolized EPAS (25.9 g/g) and SFL (5.3 g/g) were substantially higher than concentrations achieved with SOL (1.5 g/g) and remained detectable for greater than 10 h following aerosolized administration of these formulations ( Table 1 (2,6,19). However, decreased in vitro activity and clinical failures with the use of amphotericin B have been reported for both A. flavus and A. terreus (1,9,15,22).…”

Liposome as nanocarrier: Site targeted delivery in lung cancer

“…Gavalda et al [76] studied the aptitude of remedial aerosolized amphotericin-B in a steroid-immune compromised murine model of attacking pulmonary aspergillosis. They compared a murine model of invasive pulmonary aspergillosis (IPA), for the competence of nebulized deoxycholate-amphotericin-B or liposomal AMB and then the banal intravenous (i.v.)…”

“…For the treatment of IPA, they investigated the efficiency of nebulized AMB. Gavalda et al [76] concluded that for the cure of experimental disturbing IPA, AMB is a valuable method, with more apposite domino effect attained with nebulized-L amphotericin-B (NL-AMB) than with nebulized deoxycholate-amphotericin-B (ND-AMB). In the lungs, the suitable concentrations of both ND-AMB and NL-AMB were seen, though with liposomal formulation concentrations were perchance elevated.…”

Liposomes prolong the therapeutic effect of anti-asthmatic medication via pulmonary delivery

“…These can be either liquid, [8][9][10][11][12][13][14] solid, 14,15 or gaseous formulations. Over the years, liposomes have received widespread attention as a pulmonary drug delivery system, 8,16 providing an attractive means for noninvasive delivery and sustained release of drugs for treating chronic diseases, such as asthma and diabetes.…”