Efficacy of Liposomal Amphotericin B with Prolonged Circulation in Blood in Treatment of Severe Pulmonary Aspergillosis in Leukopenic Rats

Els W. M. Van Etten; Lorna E. T. Stearne-Cullen; Marian T. Ten Kate; Irma A. J. M. Bakker-Woudenberg

doi:10.1128/AAC.44.3.540-545.2000

DOI: 10.1128/AAC.44.3.540-545.2000

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Fig. 1.
Effects of a single dose (a) or double doses (b) of PEG-AMB-LIP versus multiple doses of AMB desoxycholate (c) on survival of persistently leukopenic rats with pulmonary aspergillosis (Kaplan-Meier plot). Leukopenic rats were inoculated in the left lobe of the lung with 2 × 10⁴A. fumigatusconidia at time zero. Groups of 15 animals each were treated intravenously with PEG-AMB-LIP as a single dose of 10 mg of AMB/kg (■), a double dose (given every 72 h) of 10 mg of AMB/kg/dose (⧫) or a double dose (given every 72 h) of 14 mg of AMB/kg/dose (▴); AMB desoxycholate was administered for 10 consecutive days at 1 mg of AMB/kg/dose (●). Controls were treated with placebo liposomes (▵) or 5% glucose (○) or were left untreated (▿). Treatment was started 30 h after fungal inoculation, at which time mycelial growth was firmly established. ⧣, P ≤ 0.05; and ∗, P ≤ 0.005, versus untreated or placebo-treated rats.
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Fig. 2.
Effects of a single dose (a) or double doses (b) PEG-AMB-LIP versus multiple doses of AMB desoxycholate (c) on survival of temporarily leukopenic rats with pulmonary aspergillosis (Kaplan-Meier plot). For explanation of symbols and panels, see the legend to Fig. 1.

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Table 1.

Effects of a single dose or double doses of PEG-AMB-LIP versus multiple doses of AMB desoxycholate on presence of viableA. fumigatus in the left lung and dissemination to the right lung and liver at the time of death in persistently or temporarily leukopenic rats^a

Treatment^b	Daily dose of AMB (mg/kg)	No. of doses (dosing interval [h])	No. of culture-positive organs^c/total no. of rats^d
			Left lung		Right lung		Liver
			P	T	P	T	P	T
Untreated			15/15	15/15	14/15	12/15	10/15	9/15
PEG-AMB-LIP	10	1	15/15	15/15	13/15	12/15	1/15^e	2/15^f
PEG-AMB-LIP	10	2 (72)	15/15	15/15	9/15	8/15	0/15^e	0/15^e
PEG-AMB-LIP	14	2 (72)	15/15	15/15	9/15	8/15	0/15^e	0/15^e
AMB desoxycholate	1	10 (24)	15/15	15/15	9/15^f	6/15^e	1/15^e	1/15^e
Placebo liposomes		2 (72)	15/15	15/15	12/15	12/15	11/15	8/15
Placebo (glucose)		10 (24)	15/15	15/15	15/15	14/15	10/15	8/15

↵a Leukopenic rats were inoculated in the left lung at time zero with 2 × 10⁴A. fumigatus conidia.
↵b PEG-AMB-LIP, AMB desoxycholate, or placebo treatment was administered intravenously.
↵c Effect of treatment was determined by postmortem cultures.
↵d P, persistent leukopenia; T, temporary leukopenia.
↵e P ≤ 0.005 versus placebo treatment.
↵f P ≤ 0.05 versus placebo treatment.