Comparative Efficacies of Four Amphotericin B Formulations—Fungizone, Amphotec (Amphocil), AmBisome, and Abelcet—against Systemic Murine Aspergillosis

Abstract

We compared various amphotericin B formulations (no treatment or 0.8 mg of Fungizone [conventional deoxycholate amphotericin B] per kg of body weight, or 0.8, 4, or 8 mg of Amphocil, AmBisome, or Abelcet per kg of body weight) for treatment of systemic murine aspergillosis. In two studies, all formulations prolonged survival, with the results for AmBisome nearly equivalent to those for Fungizone; Amphocil and Abelcet were less effective or equivalent depending on the severity of infection. No survivors were cured in both kidneys and brain, but each formulation showed efficacy, especially in the kidneys. Although higher doses could be given, no lipid-based formulation showed consistent superiority over Fungizone or over each other.In spite of present therapeutic options, the mortality rate from invasive aspergillosis is high (13)(14)(15). Despite the introduction of newer agents into the therapy of aspergillosis, conventional deoxycholate-formulated amphotericin B (AMB; Fungizone) remains a principal therapeutic and comparator in clinical trials. However, its well-described toxicities can limit its usefulness (19).The following lipid-carried formulations of AMB have reduced toxicities (20,24,30): Amphotec (Amphocil [ABCD]; Intermune, Inc., Burlingame, Calif.), a discoidal complex of cholesteryl sulfate and AMB (21, 22); AmBisome (AmBi; Gilead Sciences, Foster City, Calif.), a true unilamellar liposome (1, 33); and Abelcet (ABLC; Enzon, Fairfield, N.J.), a ribbon form of dimyristoyl phosphatidyl choline and dimyristoyl phosphatidyl glycerol with AMB (27, 35). Each formulation has been reported to have efficacy against aspergillosis equal to or better than that of conventional AMB (3,4,18,25,29,32). However, no studies comparing the four formulations against aspergillosis have been done. Systemic model. Murine models of systemic aspergillosis were established in 6-week-old female CD-1 mice (average weight, 24.2 g) by intravenous injection of 8 ϫ 10 6 (high inoculum) or 3.6 ϫ 10 6 (low inoculum) conidia of Aspergillus fumigatus isolate 10AF (16, 23). Therapy began 1 day after infection, with groups of 10 or 11 mice receiving either no treatment, 0.8 mg of conventional AMB per kg of body weight (a dose just below toxicity in this model), or 0.8, 4, or 8 mg of ABCD, AmBi, or ABLC per kg. All dosages were based on an equivalent number of milligrams of AMB per kilogram of body weight. Four doses were administered intravenously every other day, as AMB has a long half-life in all four preparations (4, 21, 30, 33).Deaths were tallied through 9 days of infection. All surviving mice were then euthanatized by CO 2 asphyxia, and the number of CFU of A. fumigatus in the brain and kidneys was determined by quantitative plating of organ homogenates (16, 23); the dilution procedures eliminated drug carryover.Statistics. Evaluation of survival was done by using a logrank test and a comparison of the number of CFU by a MannWhitney U test. For the quantification of CFU burdens, to ensure that death was considered as a worse outcome t...

Pharmacodynamics and Dose-Response Relationships of Liposomal Amphotericin B against Different Azole-Resistant Aspergillus fumigatus Isolates in a Murine Model of Disseminated Aspergillosis

“…These results are similar to the present results, as the maximum effect (100% survival) was reached at a dose of 4 or 16 mg/kg for all isolates. Our observations are also in keeping with previously published experimental studies of aspergillosis (18,19,(36)(37)(38)(39)(40). Leenders et al reported that in a pulmonary aspergillosis infection in rats, L-AmB monotherapy at 5 and 10 mg/kg was effective in preventing dissemination from the lungs to the kidneys, liver, and spleen (36).…”

NAC is associated with additional alleviation of lung injury induced by invasive pulmonary aspergillosis in a neutropenic model

“…Murine models of aspergillosis have been used extensively in the study of antifungal drug efficacy [25][26][27][28] . Intratracheal inoculation best mimics the natural route of infection in humans, in whom the lung is the primary target organ following conidia inhalation, especially during immunosuppression [29,30] .…”

Pharmacokinetic-Pharmacodynamic Comparison of Amphotericin B (AMB) and Two Lipid-Associated AMB Preparations, Liposomal AMB and AMB Lipid Complex, in Murine Candidiasis Models

“…However, it is generally accepted that the lipid formulations of AMB are not as potent as conventional AMB on an mg/kg basis. Most clinical trials and current dosing conventions with each of the lipid preparations use doses 4-to 10-fold in excess of those for amphotericin B deoxycholate (1,8,9,10,18,24,25). However, few studies have performed systematic analyses to define the relative in vivo potencies of these compounds to discern if these dose escalations are optimal.…”