JAC Advance Access originally published online on July 28, 2008
Journal of Antimicrobial Chemotherapy 2008 62(5):1163-1164; doi:10.1093/jac/dkn306
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Research letters |
Levels of amphotericin B lipid formulations in ascites
Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria
* Corresponding author. Tel: +43-512-504-81389; Fax: +43-512-504-24199; E-mail: romuald.bellmann{at}i-med.ac.at
Keywords: ascitic fluid , polyene antifungals , clinical pharmacokinetics , target-site penetration, lipid formulations , peritoneal fluid
Recently, van der Voort et al.1 assessed the intraperitoneal levels of amphotericin B (AMB) during treatment with AMB deoxycholate (AMB dc) in critically ill patients with Candida peritonitis. Median intraperitoneal levels of AMB amounted to 0.12 mg/L. In 43%, AMB was not detectable in the peritoneal fluid. Especially in critically ill patients, the use of conventional AMB is limited by its nephrotoxicity. Liposomal amphotericin B (LAMB), amphotericin B colloidal dispersion (ABCD) and amphotericin B lipid complex (ABLC) have been developed to improve therapeutic safety. These AMB lipid formulations exhibit different composition, structure and particle size, which is reflected in different pharmacokinetic behaviour in plasma and tissue.2,3
We determined AMB levels in five ascitic specimens from three critically ill patients who were on treatment with LAMB (first sample of Patient 3), ABCD (two patients) or ABLC (second sample of Patient 3) for suspected invasive fungal infection. The study was approved by the local Ethics Committee. Demographic and clinical characteristics of the patients are shown in Table 1. LAMB (AmBisome®, Gilead, San Dimas, CA, USA), ABCD (Amphocil®, Torrex Chiesi, Vienna, Austria) and ABLC (Abelcet®, Zeneus Pharma, Munich, Germany) were administered intravenously at standard doses of 3–5 mg/kg body weight once a day over 4 h. Aliquots of ascitic fluid were taken at therapeutic paracentesis. The lipid-formulated fraction and the liberated AMB fraction were separated by C18 solid-phase extraction, as described previously (with modifications for ascites).4 AMB was quantified by reversed-phase HPLC, using a LiChrosorb-RP-8 column, UV detection (
= 405 nm) and acetonitrile/methanol/0.010 M NaH2PO4 buffer (41:10:49, by vol.) as the mobile phase.4
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AMB was detectable in all samples from ascites. Ascites concentrations are displayed in Table 1. Mean total AMB levels in ascites amounted to 0.27 ± 0.05 mg/L. Very low concentrations of the lipid-formulated fraction were measured (0.05 ± 0.05 mg/L).
Sufficient antimycotic concentrations at the site of infection are considered to be necessary for clinical response. Fungal peritonitis is mainly caused by Candida spp., less frequently by Aspergillus spp., Fusarium and Zygomycetes, especially in patients on peritoneal dialysis. The MIC of AMB has been reported to range from 0.125 to 1 mg/L for Candida spp.5 Candida peritonitis has been reported to be an independent risk factor for the mortality in intensive care patients; however, antifungal therapy with fluconazole and/or AMB dc did not reduce the mortality rate.6 In contrast to the patients reported by van der Voort et al., none of our patients suffered from peritonitis. Ascites was due to portal hypertension. The serum-to-ascites albumin gradient was >1.1 g/dL in all ascitic fluid samples (from 2.6 to 7.0 g/dL). The highest cell count was reached in sample B of Patient 2 (150 cells/µL). In Patient 2, an increased antimycotic concentration was detected after a prolonged period of ABCD treatment (cumulative dose at the first sampling was 1050 versus 3450 mg at the second sampling). Compared with AMB dc, the lipid formulations achieved higher concentrations in ascites.1 Although AMB dc and lipid formulations were administered at standard doses (1 and 3–5 mg/kg/day, respectively), a direct comparison between the two studies is hampered by some differences in the study designs, such as different treatment durations and cumulative doses, different administration (continuous versus over 4 h) and different patient conditions (inflamed versus normal peritoneum). After treatment with AMB lipid formulations, AMB concentrations reached substantially lower values in peritoneal fluid than previously measured in plasma, liver, spleen, lung or kidney.2,3 As simultaneous plasma levels were not determined in our patients, the penetration ratio cannot be calculated. Since only three patients were assessed and the cumulative doses and the intervals between last administration and paracentesis were different, a comparison between the three lipid formulations is not possible. By the separation of lipid-formulated and liberated AMB, we could show that almost exclusively the liberated AMB penetrates into peritoneal fluid (0.22 ± 0.09 mg/L liberated AMB of 0.27 ± 0.05 mg/L total AMB). However, in the inflamed peritoneum, the penetration rate may be altered. Nonetheless, in peritonitis, it is unlikely that medical therapy with AMB lipid formulations will be effective due to insufficient target-site penetration. Surgical interventions including the removal of the catheter in continuous ambulatory peritoneal dialysis are recommended by the Infectious Diseases Society of America.
In conclusion, after administration of AMB lipid formulations AMB levels in ascites were higher than after treatment with conventional AMB, but were similar to or even lower than the MIC for the most relevant pathogens. This may increase the risk of treatment failure in fungal peritonitis.
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Funding |
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 Top Funding Transparency declarationsReferences |
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This study was supported by the Tiroler Wissenschaftsfonds (Tyrolian Scientific Fund) and Torrex Chiesi, Vienna, Austria.
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Transparency declarations |
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TopFundingTransparency declarationsReferences |
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S. W., M. J. and R. B. have received research support from Torrex-Chiesi. S. W. and R. B. have also received research support from Pfizer Inc. All other authors have none to declare.
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Acknowledgements |
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We thank the Tiroler Wissenschaftsfonds and Torrex-Chiesi, Austria for support.
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References |
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TopFundingTransparency declarationsReferences |
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1 van der Voort PH, Boerma EC, Yska JP. Serum and intraperitoneal levels of amphotericin B and flucytosine during intravenous treatment of critically ill patients with Candida peritonitis. J Antimicrob Chemother (2007) 59:952–6.
2 Bellmann R, Egger P, Wiedermann CJ. Differences in pharmacokinetics of amphotericin B lipid formulations despite clinical equivalence. Clin Infect Dis (2003) 36:1500–1.[CrossRef][Web of Science][Medline]
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Vogelsinger H, Weiler S, Djanani A, et al. Amphotericin B tissue distribution in autopsy material after treatment with liposomal amphotericin B and amphotericin B colloidal dispersion. J Antimicrob Chemother (2006) 57:1153–60.
4 Egger P, Bellmann R, Wiedermann CJ. Determination of amphotericin B, liposomal amphotericin B, and amphotericin B colloidal dispersion in plasma by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl (2001) 760:307–13.[CrossRef][Medline]
5 Rex JH, Pfaller MA, Barry AL, et al. Antifungal susceptibility testing of isolates from a randomized, multicenter trial of fluconazole versus amphotericin B as treatment of nonneutropenic patients with candidemia. NIAID Mycoses Study Group and the Candidemia Study Group. Antimicrob Agents Chemother (1995) 39:40–4.[Abstract]
6 Montravers P, Dupont H, Gauzit R, et al. Candida as a risk factor for mortality in peritonitis. Crit Care Med (2006) 34:646–52.[CrossRef][Web of Science][Medline]
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