Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter January 25, 2023

C-reactive protein interacts with amphotericin B liposomes and its potential clinical consequences

  • Joris R. Delanghe ORCID logo EMAIL logo , Jonas Himpe , Jerina Boelens , Dominique Benoit , Bram Gadeyne , Marijn M. Speeckaert and Frederick Verbeke

Abstract

Objectives

Amphotericin B (AmB) is the gold standard for treating invasive fungal infections. New liposomal-containing AmB formulations have been developed to improve efficacy and tolerability. Serum/plasma C-reactive protein (CRP) values are widely used for monitoring infections and inflammation. CRP shows a high affinity to phosphocholine and it aggregates structures bearing this ligand, e.g. phosphocholine-containing liposomes. Therefore, we studied the interaction between CRP and phosphocholine-containing liposomal AmB preparations in vivo and in vitro.

Methods

CRP was prepared by affinity chromatography. Liposomal AmB (L-AmB, AmBisome®) was spiked (final concentrations of L-AmB: 150 mg/L) to CRP-containing serum (final CRP concentration: 300 mg/L). Following the addition of L-AmB, complex formation was monitored turbidimetrically. The size of CRP-L-AmB complexes was assessed using gel filtration. CRP was monitored in patients receiving either L-Amb or AmB lipid complex (ABLC).

Results

Following addition of L-AmB to CRP-containing plasma, turbidimetry showed an increase in absorbance. These results were confirmed by gel permeation chromatography. Similarly, in vivo effects were observed following intravenous administration of AmBisome®: a decline in CRP values was observed. In patients receiving L-Amb, decline of CRP concentration was faster than in patients receiving ABLC.

Conclusions

In vitro experiments are suggestive of a complexation between CRP and liposomes in plasma. Interpretation of CRP values following administration of AmBisome® might be impaired due to this complexation. In vivo formation of complexes between liposomes and CRP might contribute, or even lead, to intravascular microembolisation. Similar effects have been described following the administration of Intralipid® and other phosphocholine-containing liposomes.


Corresponding author: Prof. Dr. Joris R. Delanghe, Department of Diagnostic Sciences, Ghent University, De Pintelaan 185, B 9000, Ghent, Belgium, Phone: ++ 32 9 332 2956, Fax: ++ 32 9 332 3659, E-mail:

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: The local Institutional Review Board deemed the study exempt from review.

References

1. Adler-Moore, JP, Proffitt, RT. Amphotericin B lipid preparations: what are the differences? Clin Microbiol Infect 2008;14:5–36. https://doi.org/10.1111/j.1469-0691.2008.01979.x.Search in Google Scholar PubMed

2. Hamill, RJ, Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs 2013;73:919–34. https://doi.org/10.1007/s40265-013-0069-4.Search in Google Scholar PubMed

3. Adler-moore, JP, Proffitt, RT. Development, characterization, efficacy and mode of action of AmBisome, A unilamellar liposomal formulation of amphotericin B. J Liposome Res 1993;3:429–50. https://doi.org/10.3109/08982109309150729.Search in Google Scholar

4. Fujii, G, Chang, JE, Coley, T, Steere, B. The formation of amphotericin B ion channels in lipid bilayers. Biochemistry 1997;36:4959–68. https://doi.org/10.1021/bi962894z.Search in Google Scholar PubMed

5. Janoff, AS, Boni, LT, Popescu, MC, Minchey, SR, Cullis, PR, Madden, TD, et al.. Unusual lipid structures selectively reduce the toxicity of amphotericin B. Proc Natl Acad Sci USA 1988;85:6122–6. https://doi.org/10.1073/pnas.85.16.6122.Search in Google Scholar PubMed PubMed Central

6. Guo, LSS, Fielding, RM, Lasic, DD, Hamilton, RL, Mufson, D. Novel antifungal drug delivery: stable amphotericin B-cholesteryl sulfate discs. Int J Pharm 1991;75:45–54. https://doi.org/10.1016/0378-5173(91)90249-N.Search in Google Scholar

7. Hulman, G. Fat macroglobule formation from chylomicrons and non-traumatic fat embolism. Clin Chim Acta 1988;177:173–8. https://doi.org/10.1016/0009-8981(88)90139-8.Search in Google Scholar PubMed

8. Zagara, G, Scaravilli, P, Locati, L, Seveso, M. C-reactive protein and serum agglutination in vivo of intravenous fat emulsions. Lancet 1989;1:733. https://doi.org/10.1016/s0140-6736(89)92254-x.Search in Google Scholar PubMed

9. Rowe, IR, Soutar, AK, Pepys, MB. Agglutination of intravenous lipid emulsion (‘Intralipid’) and plasma lipoproteins by C-reactive protein. Clin Exp Immunol 1986;66:241–7.Search in Google Scholar

10. Tuckwell, KR. MIMS Annual., Sydney, Australia, n.d. Intralipid. Pharmacia and UpJohn product information. MIMS Annual 1997;19:1110–1.Search in Google Scholar

11. Hulman, G, Pearson, HJ, Fraser, I, Bell, PR. Agglutination of intralipid by serum. Lancet 1983;1:985–6. https://doi.org/10.1016/s0140-6736(83)92105-0.Search in Google Scholar PubMed

12. Tugirimana, P, Speeckaert, MM, Fiers, T, De Buyzere, ML, Kint, J, Benoit, D, et al.. Agglutination of intravenously administered phosphatidylcholine-containing lipid emulsions with serum C-reactive protein. Nutr Clin Pract 2013;28:253–9. https://doi.org/10.1177/0884533612474040.Search in Google Scholar PubMed

13. Volanakis, JE, Clements, WL, Schrohenloher, RE. C-reactive protein: purification by affinity chromatography and physicochemical characterization. J Immunol Methods 1978;23:285–95. https://doi.org/10.1016/0022-1759(78)90203-X.Search in Google Scholar

14. Tugirimana, PL, Holderbeke, AL, Kint, JA, Delanghe, JR. A new turbidimetric method for assaying serum C-reactive protein based on phosphocholine interaction. Clin Chem Lab Med 2009;47:1417–22. https://doi.org/10.1515/CCLM.2009.312.Search in Google Scholar PubMed

15. Pepys, MB, Hirschfield, GM. C-reactive protein: a critical update. J Clin Invest 2003;111:1805–12. https://doi.org/10.1172/JCI18921.Search in Google Scholar PubMed PubMed Central

16. Bellmann, R. Pharmacodynamics and pharmacokinetics of antifungals for treatment of invasive aspergillosis, Curr Pharmaceut Des 2013;19:3629–47. https://doi.org/10.2174/13816128113199990332.Search in Google Scholar PubMed

17. Christofilopoulou, S, Charvalos, E, Petrikkos, G. Could procalcitonin be a predictive biological marker in systemic fungal infections? Study of 14 cases. Eur J Intern Med 2002;13:493–5. https://doi.org/10.1016/s0953-6205(02)00160-7.Search in Google Scholar PubMed

18. Tolentino, LF, Tsai, SF, Witt, MD, French, SW. Fatal fat embolism following amphotericin B lipid complex injection. Exp Mol Pathol 2004;77:246–8. https://doi.org/10.1016/j.yexmp.2004.07.001.Search in Google Scholar PubMed

Received: 2022-11-26
Accepted: 2023-01-13
Published Online: 2023-01-25
Published in Print: 2023-05-25

© 2023 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 29.3.2024 from https://www.degruyter.com/document/doi/10.1515/cclm-2022-1213/html
Scroll to top button