Immunomodulatory Effects of Tigecycline in Balb/C Mice

Open access

Abstract

Tigecycline is a glycylcycline antibiotic approved by the FDA for the treatment of complicated infections. Despite its effectiveness, the FDA announced a warning of increasing mortality associated with its use. There is, however, no clear explanation for this side effect. Previous reports found a possible effect of tigecycline on leukocyte proliferation and proinflammatory cytokine release. We t herefore i nvestigated the effect of tigecycline on the immune components and response in Balb/c mice in vivo and in vitro. It was found that tigecycline enhanced lymphocyte proliferation and significantly increased cellular infiltration within the footpad, as based on DTH testing, but reduced the hemagglutination titer. In splenocyte cultures, tigecycline suppressed splenocyte proliferation with IC50 3-5 mmol L-1, significantly increased IL-2 secretion and reduced IL-17 secretion in a dose dependent mode. In conclusion, tigecycline is safe at therapeutic and sub-therapeutic doses, but it could still have an immunomodulatory effect at higher doses. Use of higher doses of tigecycline requires further investigation.

1. International Conference of Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Immunotoxicity Studies for Human Pharmaceuticals S8, Current Step 4 version; Geneva, September 2005, https://www.ich.org/filadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S8/Step4/S8/Guideline.pdf; last access date April 05, 2018.

2. United State Office of Technology Assesment, Identifying and Controlling Immunotoxic Substances: Background Paper, OTA-BP-BA-75, US Government Printing Office, Washington (DC), April 1991.

3. C.-S. Lee and Y. Doi, Therapy of infections due to carbapenem-resistant gram-negative pathogens, Infect. Chemother. 46 (2014) 149-164; https://doi.org/10.3947/ic.2014.46.3.149

4. T. M. Wyeth, Product Monograph Tygacil®Tigecycline for Injection, Pfizer Canada Inc, Kirkland (Quebec), Canada, 2014, pp. 10-12.

5. G. Bucaneve, A. Micozzi, M. Picardi, S. Ballanti, N. Cascavilla, P. Salutari, G. Specchia, R. Fanci, M. Luppi, L. Cudillo, R. Cantaffa, G. Milone, M. Bocchia, G. Martinelli, M. Offidani, A. Chierichini, F. Fabbiano, G. Quarta, V. Primon, B. Martino, A. Manna, E. Zuffa, A. Ferrari, G. Gentile, R. Foa and A. Del Favero, Results of a multicenter, controlled, randomized clinical trial evaluating the combination of piperacillin/tazobactam and tigecycline in high-risk hematologic patients with cancer with febrile neutropenia, J. Clin. Oncol. 32 (2014) 1463-1471; https://doi.org/10.1200/jco.2013.51.6963

6. N. Maximova, D. Zanon, F. Verzegnassi and M. Granzotto, Neutrophils engraftment delay during tigecycline treatment in 2 bone marrow-transplanted patients, J. Pediatr. Hematol. Oncol. 35 (2013) e33-e37; https://doi.org/10.1097/MPH.0b013e318279eec2

7. Q. Zhang, S. Zhou and J. Zhou, Tigecycline treatment causes a decrease in fibrinogen levels, Antimicrob. Agents Chemother. 59 (2015) 1650-1655; https://doi.org/10.1128/aac.04305-14

8. Food and Drug Administeration, FDA Safety Communication: Increased Risk of Death with Tygacil (Tigecycline) Compared to Other Antibiotics Used to Treat Similar Infections, Silver Spring (MD), USA 2010; https://fda.gov/Drug/DrugSafety/ucm223470.htm; last access date June 20, 2018

9. R. Cockeran, N. D. Mutepe, A. J. Theron, G. R. Tintinger, H. C. Steel, P. I. Stivaktas, G. A. Richards, C. Feldman and R. Anderson, Calcium-dependent potentiation of the pro-inflammatory functions of human neutrophils by tigecycline in vitro, J. Antimicrob. Chemother. 67 (2012) 130-137; https://doi.org/10.1093/jac/dkr441

10. A. Naess, H. Andreeva and S. Sornes, Tigecycline attenuates polymorphonuclear leukocyte (PMN) receptors but not functions, Acta Pharm. 61 (2011) 297-302; https://doi.org/10.2478/v10007-011-0024-4

11. C. M. Salvatore, C. Techasaensiri, C. Tagliabue, K. Katz, N. Leos, A. M. Gomez, G. H. McCracken and R. D. Hardy, Tigecycline t herapy significantly reduces t he concentrations of i nflammatory pulmonary cytokines and chemokines in a murine model of Mycoplasma pneumoniae pneumonia, Antimicrob. Agents Chemother. 53 (2009) 1546-1551; https://doi.org/10.1128/aac.00979-08

12. S. Pichereau, J. J. Moran, M. S. Hayney, S. K. Shukla, G. Sakoulas and W. E. Rose, Concentrationdependent effects of antimicrobials on Staphylococcus aureus toxin-mediated cytokine production from peripheral blood mononuclear cells, J. Antimicrob. Chemother. 67 (2012) 123-129; https://doi.org/10.1093/jac/dkr417

13. R. Saliba, L. Paasch and A. El Solh, Tigecycline attenuates staphylococcal superantigen-induced T-cell proliferation and production of cytokines and chemokines, Immunopharmacol. Immunotoxicol. 31 (2009) 583-588; https://doi.org/10.3109/08923970902838672

14. F. Traunmuller, C. Thallinger, J. Hausdorfer, C. Lambers, S. Tzaneva, T. Kampitsch, G. Endler and C. Joukhadar, Tigecycline has no effect on cytokine release in an ex vivo endotoxin model of human whole blood, Int. J. Antimicrob. Agents. 33 (2009) 583-586; https://doi.org/10.1016/j.ijantimicag.2008.11.008

15. M. K. Mohammad, I. M. Al-Masri, M. O. Taha, M. A. Al-Ghussein, H. S. Alkhatib, S. Najjar and Y. Bustanji, Olanzapine inhibits glycogen synthase kinase-3beta: an investigation by docking simulation and experimental validation, Eur. J. Pharmacol. 584 (2008) 185-191; https://doi.org/10.1016/j.ejphar.2008.01.019

16. Committee for the Update of the Guide for the Care and Use of Laboratory Animals, National Research Council of the National Academies, Guide for the Care and Use of Laboratory Animals, 8th ed.; Washington DC, 2011, https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf; last access date June 22, 2018.

17. N. Kasbekar, Tigecycline: a new glycylcycline antimicrobial agent, Am. J. Health Syst. Pharm. 63 (2006) 1235-1243; https://doi.org/10.2146/ajhp050487

18. Y. Abdelrahman, M. Fararjeh, W. Abdel-Razeq, M. K. Mohammad and Y. Bustanji, Assessment of possible immunotoxicity of the antipsychotic drug clozapine, J. Pharm. Parmacol. 66 (2014) 378-386;https://doi.org/10.1111/jphp.12150

19. M. Fararjeh, M. K. Mohammad, Y. Bustanji, H. Alkhatib and S. Abdalla, Evaluation of immunosuppression induced by metronidazole in Balb/c mice and human peripheral blood lymphocytes, Int. Immunopharmacol. 8 (2008) 341-350; https://doi.org/10.1016/j.intimp.2007.10.018

20. D. D. Dietz, K. M. Abdo, J. K. Haseman, S. L. Eustis and J. E. Huff, Comparative toxicity and carcinogenicity studies of tetracycline and oxytetracycline in rats and mice, Fundam. Appl. Toxicol. 17 (1991) 335-346.

21. J. M. Korth-Bradley, S. M. Troy, K. Matschke, G. Muralidharan, R. J. Fruncillo, J. L. Speth and D. G. Raible, Tigecycline pharmacokinetics in subjects with various degrees of renal function, J. Clin. Pharmacol. 52 (2012) 1379-1387; https://doi.org/10.1177/0091270011416938

22. J. Rello, Pharmacokinetics, pharmacodynamics, safety and tolerability of tigecycline, J. Chemother. 17 (Suppl. 1) (2005) 12-22; https://doi.org/10.1179/joc.2005.17.Supplement-1.12.

23. M. Shinkai, M. O. Henke and B. K. Rubin, Macrolide antibiotics as immunomodulatory medications: proposed mechanisms of action, Pharmacol. Ther. 117 (2008) 393-405; https://doi.org/10.1016/j.pharmthera.2007.11.001

24. S. Farhath, P. Vijaya and M. Vimal, Immunomodulatory activity of geranial, geranial acetate, gingerol, and eugenol essential oils: evidence for humoral and cell-mediated responses, Avicenna J. Phytomed. 3 (2013) 224-230

25. G. A. Pankey, Tigecycline, J. Antimicrob. Chemother. 56 (2005) 470-480.

26. M. Schwarz, R. Sunder-Plassmann, A. Cerwenka, W. F. Pickl and W. Holter, [Regulation of cytokine production by human T-lymphocytes in allergic immune response], Wien Klin. Wochenschr. 105 (1993) 672-676.

27. N. Y. A. Hemdan, A. M. Abu El-Saad and U. Sack, The role of T helper (TH)17 cells as a doubleedged sword in the interplay of infection and autoimmunity with a focus on xenobiotic-induced immunomodulation, Clin. Dev. Immunol. 2013 (2013) Article ID 374769 (13 pages); https://doi.org/10.1155/2013/374769

28. P. Miossec and J. K. Kolls, Targeting IL-17 and TH17 cells in chronic inflammation, Nat. Rev. Drug Discov. 11 (2012) 763-776; https://doi.org/10.1038/nrd3794

29. R. Joks and H. G. Durkin, Non-antibiotic properties of tetracyclines as anti-allergy and asthma drugs, Pharmacol. Res. 64 (2011) 602-609; https://doi.org/10.1016/j.phrs.2011.04.001

30. T. Polhill, G. Y. Zhang, M. Hu, A. Sawyer, J. J. Zhou, M. Saito, K. E. Webster, Y. Wang, Y. Wang, S. T. Grey, J. Sprent, D. C. Harris, S. I. Alexander and Y. M. Wang, IL-2/IL-2Ab complexes induce regulatory T cell expansion and protect against proteinuric CKD, J. Am. Soc. Nephrol. 23 (2012) 1303-1308; https://doi.org/10.1681/asn.2011111130

31. M. Mizui, T. Koga, L. A. Lieberman, J. Beltran, N. Yoshida, M. C. Johnson, R. Tisch and G. C. Tsokos, IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4-CD8- IL- 17-producing T cells, J. Immunol. 193 (2014) 2168-2177; https://doi.org/10.4049/jimmunol.1400977

Acta Pharmaceutica

The Journal of Croatian Pharmaceutical Society

Journal Information


IMPACT FACTOR 2017: 1.071
5-year IMPACT FACTOR: 1.623

CiteScore 2017: 1.46

SCImago Journal Rank (SJR) 2017: 0.362
Source Normalized Impact per Paper (SNIP) 2017: 0.642

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 107 107 33
PDF Downloads 52 52 17