JAC Advance Access originally published online on April 20, 2006
Journal of Antimicrobial Chemotherapy 2006 57(6):1153-1160; doi:10.1093/jac/dkl141
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Amphotericin B tissue distribution in autopsy material after treatment with liposomal amphotericin B and amphotericin B colloidal dispersion
1 Clinical Pharmacokinetics Unit, Laboratory of Inflammation Research, Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical School Anichstrasse 35, A-6020 Innsbruck, Austria 2 Inflammation Research Unit, Laboratory of Inflammation Research, Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical School Anichstrasse 35, A-6020 Innsbruck, Austria 3 Intensive Care Unit, Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical School Anichstrasse 35, A-6020 Innsbruck, Austria 4 Infectious Diseases Unit, Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical School Anichstrasse 35, A-6020 Innsbruck, Austria
*Correspondence address. Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical School, Anichstrasse 35, A-6020 Innsbruck, Austria. Tel: +43-512-504-81389; Fax: + 43-512-504-24199; E-mail: romuald.bellmann{at}uibk.ac.at
Received 8 December 2005; returned 5 February 2006; revised 17 March 2006; accepted 22 March 2006
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Abstract |
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Objectives: Tissue concentrations of amphotericin B were determined in autopsy material of patients who had been treated with liposomal amphotericin B or amphotericin B colloidal dispersion (colloidal amphotericin B) for suspected or proven invasive fungal infection.
Patients and methods: Amphotericin B tissue levels were measured in liver, spleen, lung, kidney, and myocardial and brain tissue of 20 patients who had been treated with lipid-formulated amphotericin B, before they died from multi-organ failure. Seven patients had been treated with liposomal amphotericin B (AmBisome®) and thirteen with colloidal amphotericin B (Amphocil®). Tissue samples were obtained during routine autopsy, homogenized and extracted with methanol. Amphotericin B concentrations were measured using HPLC after purification by solid phase extraction.
Results: The highest amphotericin B levels were found in liver and spleen, followed by kidney, lung, myocardium and brain. In the lung higher amphotericin B concentrations were found after treatment with amphotericin B colloidal dispersion than after therapy with liposomal amphotericin B.
Conclusions: The choice of lipid formulation may influence amphotericin B penetration into the lung.
Keywords: antimycotics , lipid-formulated amphotericin B , tissue penetration , lung concentration , invasive fungal infections
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Introduction |
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Invasive mycoses are a major threat for immunocompromised patients. Amphotericin B was introduced in therapy almost 50 years ago.1 Until now it is the standard drug for proven or suspected invasive fungal infections.2 Since its clinical use is limited by nephrotoxicity and infusion-related side effects, less toxic lipid formulations have been developed. Three of these lipid formulations are commercially available: liposomal amphotericin B (AmBisome®), amphotericin B colloidal dispersion (colloidal amphotericin B, Amphocil®) and amphotericin B lipid complex (Abelcet®). Liposomal amphotericin B consists of spherical liposomes, 45–80 nm in size with an aqueous core. The bilayer membrane forming these liposomes comprises hydrogenated soy phosphatidylcholine, cholesterol, distearoylphosphatidylglycerol and amphotericin B.3,4 The particles of amphotericin B colloidal dispersion are disc-like structures of
75–170 nm in diameter containing amphotericin B as a cholesteryl sulphate complex.3,5,6 The lipid formulations of amphotericin B display remarkable differences in their plasma pharmacokinetics.4,5,7–9 These differences may be attributed to the physico-chemical diversity of the lipid moieties, whereas pharmacokinetic behaviour of the liberated amphotericin B fraction is independent from the administered formulation. Whether these differences have any impact on clinical efficacy is still a matter of discussion.2,9–12 The antimycotic activity in vivo, however, probably depends also on the amphotericin B concentration at the site of infection. Liposomes have been shown to accumulate in vivo at sites of fungal infection and to interact with fungal cells.4 Tissue or fungal phospholipases are hypothesized to be involved in cleavage of amphotericin B from its lipid encapsulation at the target site.6,13 Data on amphotericin B tissue distribution during treatment with lipid-formulated amphotericin B, however, are sparse and are mainly derived from animal experiments, where considerable inter-species differences have been observed.7,14,15 Therefore, the present study was set out to investigate amphotericin B penetration into various human tissues using autopsy samples obtained from patients who died during treatment with liposomal or colloidal amphotericin B. |
Patients and methods |
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The study was approved by the local Ethics Committee (The Ethics Committee's protocol number ‘Studienkennzahl’ UN 1969, Amendment 1, AM 1969). Tissue samples from liver, spleen, lung, kidney, myocardium and brain were taken during routine autopsies of 20 patients who had been given liposomal or colloidal amphotericin B for proven or suspected invasive mycoses within the last 72 h before they died. Therapy with amphotericin B deoxycholate had been contraindicated in all 20 patients because of impaired renal function. Demographic data and diagnoses are listed in Table 1. Routine laboratory values at the first and the last day of amphotericin B treatment are displayed in Table 2. A total of 7 patients had been treated with liposomal amphotericin B and 13 patients with amphotericin B colloidal dispersion. The daily dose was 3.48 ± 0.81 mg/kg (mean ± SD) in the liposomal amphotericin B group and 4.60 ± 0.83 mg/kg in the colloidal amphotericin B group. The cumulative dose was 2739.29 ± 3754.24 mg (mean ± SD) and 3350.00 ± 4211.48 mg, respectively. Liposomal amphotericin B (AmBisome®,Gilead, San Dimas, CA, USA) and colloidal amphotericin B (Amphocil®, Torrex Chiesi, Vienna, Austria) were dissolved as recommended by the manufacturers, diluted in 500 mL of 5% dextrose and administered intravenously over 4 h. The mean time between last infusion and death was 16 ± 13 h in liposomal amphotericin B-treated patients and 36 ± 21 h in colloidal amphotericin B-treated patients (P = 0.027). Autopsies were performed at the Institute of Pathology, Innsbruck Medical School. Small cubes of
2 g wet tissue weight were cut out from liver, spleen, lung, myocardium, kidney and different cerebral areas (cortex, hippocampus, caudate nucleus, brainstem and cerebellum). Tissue samples were put in 50 mL polypropylene tubes (Falcon®, Becton Dickinson Labware Europe, Le Pont De Claix, France), placed on ice, weighed, frozen and kept at –80°C until they were further processed. Tissue samples were defrosted at room temperature and homogenized with a tissue homogenizer (Ultraturrax T25®, IKA-Labortechnik, Staufen, Germany). For amphotericin B extraction from tissue the method described by Ramaswamy et al.16 was used with some modifications. Homogenized tissue (1 g) was mixed with 2 mL of pure methanol (Methanol, LiChrosolv®, gradient grade for liquid chromatography, Merck) and shaken by vortex (Vortex VF®, IKA-Labortechnik, Staufen, Germany) for 3 min. Subsequently, the samples were centrifuged at 2000 g (3500 rpm) at 10°C for 15 min. The clear supernatant was further purified for HPLC analysis: 0.5 mL of it was put on a solid phase extraction (SPE) column (Bond Elut-C18, Varian, Vösendorf, Austria) which had been pre-rinsed with 1 mL of pure methanol and subsequently with 1 mL of 45% methanol. Afterwards, another 500 µL of 45% methanol was added and the column was centrifuged for 2 min at 250 g (2000 rpm) in a table centrifuge. Amphotericin B was eluted with 60% acetonitrile (Acetonitrile, LiChrosolv®, hypergrade for liquid chromatography, Merck). The column was centrifuged for another 2 min at 250 g (2000 rpm). Of the eluate 300 µL was diluted with 150 µL of water (Water, gradient HPLC grade, Scharlau) and transferred to HPLC vials. HPLC analysis was performed as described previously.17 The detection limit was 0.005 µg/g. The concentrations were assessed by means of a linear standard-curve (r between 0.995 and 0.9998), obtained by standards comprising calf or pork tissue (liver, spleen, lung, kidney, myocardium and brain) spiked with amphotericin B. Tissue was treated with ultraturrax for 3 min until a homogeneous mash was obtained. Spiking was performed by adding 10, 5, 2.5, 1, 0.5 and 0.25 µg/g of conventional amphotericin B ‘BMS’ (Bristol-Myers Squibb GesmbH, Vienna) to animal tissues. Subsequently, the samples were thoroughly mixed to ensure that amphotericin B was evenly distributed. Homogenization with ultraturrax and the use of organic solvents during the extraction procedure result in complete disruption of cell structures.18,19 Therefore, of course, no separate quantification of concentrations in intra- and extracellular compartments is possible. Reproducibility of amphotericin B quantification was investigated by assessing inter- and intraday variability in animal tissue samples spiked with conventional amphotericin B or amphotericin B lipid formulations. The intraday precision was determined using five animal tissue samples (calf and pork) of any corresponding tissue spiked with amphotericin B at concentrations of 10.00 and 0.25 µg/g as well as using five samples spiked with 5.00 and 0.50 µg/g of liposomal amphotericin B and amphotericin B colloidal dispersion, respectively. The extraction procedure and measurement was performed as described above and was repeated five times for each sample on the same day. Results were calculated as relative standard deviation. The intraday precision was 15.24% for liver spiked with 10 µg/g amphotericin B and 3.13% for liver spiked with 0.25 µg/g, 10.97% and 19.50% for lung spiked with the same concentrations, 9.29% and 12.46% for spleen, 4.37% and 5.76% for kidney, 5.68% and 3.72% for myocardium, 5.18% and 8.01% for brain, and 0.09% and 0.70% for plasma samples. In lung tissue spiked with amphotericin B lipid formulations (5.00 and 0.50 µg/g), intraday precision was 0.6% and 1.2%, respectively, for liposomal amphotericin B and 0.8% and 0.9%, respectively, for amphotericin B colloidal dispersion. Interday precision was assessed on three different days by analysis of four concentrations (5.00, 2.50, 1.00 and 0.50 µg/g conventional amphotericin B, liposomal amphotericin B and amphotericin B colloidal dispersion). In lung tissue interday precision was between 0 and 1.2% for both amphotericin B lipid formulations and between 0.2 and 0.4% for conventional amphotericin B. For interday precision the mean relative standard deviation was 2.16%. The amphotericin B recovery was determined for four concentrations (5.00, 2.50, 1.00 and 0.50 µg/g) in liver, spleen and kidney. It was found to be 55.17 ± 4.10% (mean ± SD).
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Statistical significance of the differences between liposomal and colloidal amphotericin B-treated patients was analysed by Mann-Whitney U-test. A P value of <0.05 was considered to be statistically significant. Correlation between amphotericin B tissue concentration and cumulative dose, daily dose and the interval between last amphotericin B administration and death of the patient was assessed by linear regression. Calculations were performed using Statistica 5.1–1997® (StatSoft, Inc., Tulsa, USA).
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Results |
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The highest amphotericin B concentrations were found in the liver [102.81 ± 68.72 µg/g (mean ± SD) in the liposomal amphotericin B group and 94.42 ± 60.17 µg/g in the colloidal amphotericin B group] and in the spleen (60.32 ± 29.75 µg/g and 81.34 ± 57.97 µg/g, respectively), followed by concentrations in kidney (11.89 ± 12.77 µg/g and 36.77 ± 33.22 µg/g) and lung, where amphotericin B concentrations were 11.63 ± 7.70 µg/g in the liposomal amphotericin B group and 32.62 ± 22.52 µg/g in the colloidal amphotericin B group. Tissue levels in myocardium and brain tissue were low. In myocardium amphotericin B levels of 3.18 ± 3.18 µg/g in the liposomal amphotericin B group and 6.21 ± 5.10 µg/g in the colloidal amphotericin B group were found. In cerebral cortex amphotericin B concentrations of 0.98 ± 0.75 µg/g and 1.39 ± 0.77 µg/g were detected. Mean amphotericin B concentrations in liver, spleen, myocardium and brain were similar in both treatment groups. In lung and kidney mean amphotericin B tissue concentrations of colloidal amphotericin B-treated patients exceeded those of liposomal amphotericin B-treated patients by a factor of three. The differences were significant (P = 0.010 for lung, P = 0.018 for kidney). After treatment with liposomal amphotericin B, amphotericin B concentrations and cumulative doses correlated in spleen (R = 0.88, P = 0.009), in kidney (R = 0.96, P = 0.002), in myocardium (R = 0.96, P = 0.003) and in cerebral cortex (R = 0.91, P = 0.004), but not in liver and lung (Figure 1). In the colloidal amphotericin B group no correlation between tissue levels and cumulative dose was found. Besides cerebral cortex, hippocampus, caudate nucleus, brainstem and cerebellum were investigated. There were no significant differences found in amphotericin B concentrations between the two treatment groups in any parts of the brain (mean 1.51 ± 0.33 µg/g after liposomal amphotericin B treatment and 1.57 ± 0.20 µg/g after amphotericin B colloidal dispersion treatment).
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Discussion |
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Both lipid formulations, liposomal and colloidal amphotericin B, displayed high penetration into liver and spleen. Amphotericin B levels were intermediate in lung and kidney and low in myocardium and brain. Lung concentrations of colloidal amphotericin B-treated patients exceeded those of the liposomal amphotericin B-treated patients significantly. Also in kidney significantly higher amphotericin B concentrations were reached after treatment with colloidal than after liposomal amphotericin B. This may suggest a higher nephrotoxicity of amphotericin colloidal dispersion. Nephrotoxicity of liposomal amphotericin B and amphotericin B colloidal dispersion has been compared with that of conventional amphotericin B in several studies. Both formulations are clearly less nephrotoxic than conventional amphotericin B.7,20–24 The incidence of doubling in serum creatinine while being treated with conventional amphotericin B (0.6 mg/kg) is about twice as high as during treatment with lipid-formulated amphotericin B (3–6 mg/kg).21–23 Thus, nephrotoxicity of liposomal amphotericin B and amphotericin B colloidal dispersion appears to be similar. Interpretation of our data on kidney penetration is limited by the lack of kidney samples in Patient 5, who had received a total dosage of 8850 mg of liposomal amphotericin B. Thus, in kidney mean amphotericin B levels have been achieved by a mean cumulative dose of only 1721 mg of liposomal amphotericin B (i.e. about 50% of the mean cumulative colloidal amphotericin B dose).
Due to the longer residence time of the small bilaminar liposomes of liposomal amphotericin B, plasma amphotericin B levels are much higher in patients on treatment with liposomal amphotericin B than in those on amphotericin B colloidal dispersion.5,6,8 Colloidal amphotericin B displays a higher plasma clearance and a larger volume of distribution in comparison with liposomal amphotericin B, because the larger disc-like particles formed by colloidal amphotericin B are rapidly taken up by peripheral tissues, particularly by cells of the reticulo-endothelial system.25,26 Amphotericin B tissue distribution displays high variability, even within the same species. In rats Wang et al.27 found a mean amphotericin B concentration of 10.6 µg/g in liver, 24.8 µg/g in spleen and 5.2 µg/g in kidney 24 h after administration of 1 mg/kg of conventional amphotericin B, while Fielding and colleagues measured 2.4 µg/g in liver, 5.7 µg/g in spleen and only 1.5 µg/g in kidney under very similar conditions.28 Inter-species variability has been demonstrated for dog and rat: 24 h after treatment with 1 mg/kg of liposomal amphotericin B the mean lung concentration was 3.00 µg/g in dog and 0.53 µg/g in rat.15,29 On the other hand, tissue concentrations in rats after long-term administration of 5 mg/kg liposomal amphotericin B are in good agreement with our data: highest amphotericin B concentrations were found in liver (347.00 µg/g) and spleen (396.10 µg/g), followed by lung (10.35 µg/g) and kidney (7.10 µg/g). Amphotericin B concentration in brain was also very low (0.30 µg/g).30 Two studies on amphotericin B distribution in human tissue after therapy with conventional amphotericin B confirmed amphotericin B accumulation in liver and spleen.31,32 Mean amphotericin B lung concentrations in these two studies were 11.29 and 5.29 µg/g, respectively, which is comparable with our results obtained in the liposomal amphotericin B group (11.63 µg/g). In the kidney, concentrations were also similar to our results in the liposomal amphotericin B group (11.89 ± 12.77 µg/g). In myocardium and brain tissue amphotericin B concentrations were below 3.70 µg/g.31,32 After administration of lipid-formulated amphotericin B, levels of amphotericin B in human autopsy samples have been measured in two small studies so far: three patients had been given liposomal amphotericin B33 and three patients amphotericin B lipid complex.34 Amphotericin B lung concentrations of liposomal amphotericin B-treated patients (cumulative dose 820–3428 mg, mean = 1716 mg) were 0.55–45.39 µg/g (mean = 16.83 µg/g)33 and 222–1019 µg/g (mean = 491 µg/g) after treatment with amphotericin B lipid complex (cumulative dose 1200–22 200 mg, mean = 8300 mg).34 For colloidal amphotericin B, to our knowledge, no data on penetration into human tissue have been available so far. Recently, Demartini et al.35 investigated amphotericin B lung penetration after a single dose of 1.5 mg/kg of liposomal amphotericin B in samples derived from surgery of lung cancer. In the study, 24 h after administration, amphotericin B lung concentration was 2.58 µg/g, which is in good agreement with the level of 3.83 µg/g, measured in our Patient 4 after a single dose of 2.5 mg/kg of liposomal amphotericin B. Enhanced plasma levels and lung penetration of liposomal amphotericin B were reported in graft failure after liver transplantation.36 In our study population Patients 1, 4, 10, 12, 13, 15 and 18 had suffered from advanced liver cirrhosis. In Patient 1 the highest amphotericin B lung concentration within the liposomal amphotericin B group (21.00 µg/g) was measured after a cumulative dose of only 300 mg of liposomal amphotericin B. In the colloidal amphotericin B group, patients suffering from liver cirrhosis had obtained a mean cumulative dose of 1450 mg, yielding 41.52 µg/g of amphotericin B in the lung. In patients without liver failure who had obtained a mean cumulative dose of 5121.43 mg of colloidal amphotericin B, mean amphotericin B lung concentration reached only 28.13 µg/g. This difference, however, was not significant. In the liposomal amphotericin B treatment group, mean lung concentrations in patients with liver failure were similar to those without liver dysfunction (12.42 and 11.32 µg/g, respectively). The mean cumulative dose in patients with liver failure, however, was much lower (225 versus 3745 mg). Thus, our data support the hypothesis of enhanced amphotericin B lung penetration in patients with impaired liver function. A correlation between cumulative doses and tissue concentrations can be anticipated from principle considerations and previous studies. In autopsy studies performed in samples derived from patients on conventional amphotericin B, tissue concentrations appeared to increase with higher cumulative doses.31,32 A correlation between dose and tissue levels was also found in animal experiments, e.g. in a study by Fielding et al.28 The reason for the lack of correlation in our patients on amphotericin B colloidal dispersion remains unknown. As shown in Figure 1, a correlation between amphotericin B tissue levels and cumulative dose was found only for liposomal amphotericin B treatment in spleen, kidney, myocardium and cerebral cortex. Besides cumulative dose, however, a multitude of patho-physiological changes in the critically ill patients (e.g. changes in perfusion, use of vasopressors, oedema, extracorporeal circulation) may influence drug concentrations at the target site.
Since we performed amphotericin B measurements in autopsy material, no simultaneous assessment of plasma amphotericin B was possible. Therefore the penetration ratios could not be calculated. Agonal or post-mortem changes in amphotericin B tissue levels caused e.g. by autolytic processes cannot be ruled out completely. Amphotericin B, however, is stable at 4°C for at least 24 h.37,38 There is even no loss or degradation of amphotericin B during storage for 35 days at 4°C.39 In plasma, liberated amphotericin B (i.e. free and plasma protein bound amphotericin B) and lipid-formulated amphotericin B (liposomal or colloidal amphotericin B) can be separated by SPE.12,17,40 Amphotericin B extraction from tissue, however, requires organic solvents such as methanol that destroy the non-covalent bonds between amphotericin B and the lipid particles, thus precluding a separate quantification of liberated and lipid-formulated drug. The duration of treatment and the cumulative doses were highly variable in both treatment groups and there was also a difference in mean cumulative dose between the two groups: it was 2739.29 mg in the liposomal amphotericin B group and 3350.00 in the colloidal amphotericin B group (i.e. 22% higher in the colloidal amphotericin B group, difference not significant). This may have contributed to the slightly higher tissue levels measured after colloidal amphotericin B treatment in spleen, myocardium and brain. In the lung, however, mean amphotericin B concentrations differed by 300%, which is probably not the result of a 22% difference in cumulative dose. The mean interval between the last amphotericin B administration and the death of the patient was also different in both treatment groups. It was 16 h in the liposomal amphotericin B group and 36 h in the colloidal amphotericin B group (P = 0.027). After a single dose of liposomal amphotericin B, lung concentrations of amphotericin B have been shown to rise over 24 h after infusion.35 In our setting, however, approximate steady state conditions can be supposed, since mean treatment duration was 10 days in the liposomal amphotericin B group and 9 days in the colloidal amphotericin B group.
Since the lung is a major target for invasive fungal infections,41,42 amphotericin B lung penetration is of particular clinical relevance. In all patients, who had been on therapy for more than 1 day, amphotericin B lung concentrations were above MIC90 values reported for most Aspergillus species (1–2 mg/L) and Candida species (0.25–2 mg/L).43 Whether the difference in mean amphotericin B lung concentrations after liposomal and colloidal amphotericin B therapy will influence clinical outcome in pulmonary mycoses is unknown. No head to head comparison of liposomal and colloidal amphotericin B has been performed so far. Efficacy of liposomal amphotericin B has been compared with that of amphotericin B deoxycholate44–46 and with that of amphotericin B lipid complex47,48 in suspected and proven invasive fungal infections. No superiority of either of the two formulations could be detected.6,11,39 Clinical efficacy of colloidal amphotericin B has been proven in two randomized double-blinded trials.22,23
In conclusion, the choice of the lipid formulation may influence amphotericin B lung penetration. After treatment with colloidal amphotericin B higher amphotericin B concentrations in lung tissue could be achieved than after treatment with liposomal amphotericin B. Whether this will have any impact on clinical efficacy in pulmonary mycoses has to be investigated in further studies addressing clinical endpoints.
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We obtained financial support from Torrex Chiesi, Vienna, Austria (salary support for H. V. and S. W.).
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Present address. Department of Internal Medicine, General Hospital of Bolzano, Bolzano, Italy 
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Acknowledgements |
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We are in debt of Gregor Mikuz, Hans Maier, Hermann Rogatsch, Bettina Zelger, Patrizia Moser, Christian Ensinger, Consolato Sergi, Jens Krugmann, Sylvia Stadlmann, Georg Schäfer, Thomas Brunhuber, Alexandar Tzankov, Andrea Brunner, Martina Hager and Irmgard Verdorfer from the Institute of Pathology, Innsbruck Medical School, for providing the tissue samples. We thank Torrex Chiesi Pharma, Vienna, Austria, for the financial support.
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