Advertisement

Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

Oral administration of azithromycin ameliorates trypanosomosis in Trypanosoma congolense-infected mice

Abstract

Animal trypanosomosis is a devastating parasitic disease that is of economic importance to livestock production. The infection includes animal African trypanosomosis, surra, and dourine. The treatment is based solely on few compounds that were discovered decades ago and which are associated with severe toxicity. Furthermore, it is likely that the parasite has developed resistance towards them. Thus, there is an urgent need for new, accessible, and less toxic drugs. Azithromycin is an antibiotic with documented efficacy against Toxoplasma, Babesia, and Plasmodium. The current study investigated its effects against animal trypanosomes. An in vitro system was used to determine the trypanocidal effects of azithromycin against Trypanosoma congolense, Trypanosoma brucei brucei, and Trypanosoma evansi, and cytotoxicity in Madin-Darby bovine kidney (MDBK) and NIH 3T3 cells. Furthermore, the trypanocidal effects of azithromycin were investigated in T. congolense-infected mice. In vitro, azithromycin had an IC50 of 0.19 ± 0.17; 3.69 ± 2.26; 1.81 ± 1.82 μg/mL against T. congolense, T. b. brucei, and T. evansi, respectively. No cytotoxic effects were observed in MDBK and NIH 3T3 cells. The efficacy of orally administered azithromycin was investigated in short-term and long-term treatment protocols. Although the short-term treatment protocol showed no curative effects, the survival rate of the mice was significantly prolonged (p < 0.001) in comparison to the control group. The long-term treatment yielded satisfying curative effects with doses of 300 and 400 mg/kg achieving 80 and 100% survival, respectively. In conclusion, long-term oral azithromycin treatment has trypanocidal effects against T. congolense.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Birkenheuer AJ, Levy MG, Breitschwerdt EB (2004) Efficacy of combined atovaquone and azithromycin for therapy of chronic Babesia gibsoni (Asian genotype) infections in dogs. J Vet Intern Med 18(4):494–498

  2. Blais J, Garneau V, Chamberland S (1993) Inhibition of Toxoplasma gondii protein synthesis by azithromycin. Antimicrob Agents Chemother 37(8):1701–1703

  3. Boonleang J, Panrat K, Tantana C, Krittathanmakul S, Jintapakorn W (2007) Bioavailability and pharmacokinetic comparison between generic and branded azithromycin capsule: a randomized, double-blind, 2-way crossover in healthy male thai volunteers. Clin Ther 29(4):703–710

  4. Bushra R, Aslam N, Khan AY (2011) Food-drug interactions. Oman Med J 26(2):77–83

  5. Chico RM, Pittrof R, Greenwood B, Chandramohan D (2008) Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy. Malar J 7:255

  6. Clausen PH, Bauer B, Zessin KH, Diall O, Bocoum Z, Sidibe I, Affognon H, Waibel H, Grace D, Randolph T (2010) Preventing and containing trypanocide resistance in the cotton zone of West Africa. Transbound Emerg Dis 57(1–2):28–32

  7. d’leteren GDM, Authié E, Wissocq N, Murray M (1998) Trypanotolerance, an option for sustainable livestock production in areas at risk from trypanosomosis. Rev Sci Tech Off Int Epiz 17(1):154–175

  8. Desquesnes M, Dargantes A, Lai DH, Lun ZR, Holzmuller P, Jittapalapong S (2013) Trypanosoma evansi and surra: a review and perspectives on transmission, epidemiology and control, impact, and zoonotic aspects. Biomed Res Int 2013:321237

  9. Dorfman MS, Wagner RS, Jamison T, Bell B, Stroman DW (2008) The pharmacodynamic properties of azithromycin in a kinetics-of-kill model and implications for bacterial conjunctivitis treatment. Adv Ther 25(3):208–217

  10. Foulds G, Luke DR, Teng R, Willavize SA, Friedman H, Curatolo WJ (1996) The absence of an effect of food on the bioavailability of azithromycin administered as tablets, sachet or suspension. J Antimicrob Chemother 37:37–44

  11. Hirumi H, Hirumi K (1991) In vitro cultivation of Trypanosoma congolense bloodstream forms in the absence of feeder cell layers. Parasitology 102(2):225–236

  12. Jaiswal AK, Sudan V, Verma N, Verma AK (2015) Insight into trypanosomiasis in animals: various approaches for its diagnosis, treatment and control: a review. Asian J Anim Sci 9(5):172–186

  13. Lisulo M, Sugimoto C, Kajino K, Hayashida K, Mudenda M, Moonga L, Ndebe J, Nzala S, Namangala B (2014) Determination of the prevalence of Africa trypanosome species in indigenous dogs of Mambwe district, eastern Zambia, by loop-mediated isothermal amplification. Parasit Vectors 2014(7):19–25

  14. Lou J, Chu G, Zhou G, Jiang J, Huang F, Xu J, Zheng S, Jiang W, Lu Y, Li X, Chen Z, He J (2010) Comparison between two kinds of cigarette smoke condensates (CSCs) of the cytogenotoxicity and protein expression in a human B-cell lymphoblastoid cell line using CCK-8 assay, comet assay and protein microarray. Mutat Res 697(1–2):55–59

  15. Morrison LJ, Vezza L, Rowan T, Hope JC (2016) Animal African trypanosomiasis: time to increase focus on clinically relevant parasite and host species. Trends Parasitol 32(8):599–607

  16. Mwai O, Hanotte O, Kwon YJ, Cho S (2015) African indigenous cattle: unique genetic resources in a rapidly changing world. Asian-Australas J Anim Sci 28(7):911–921

  17. Parasuraman S (2011) Toxicological screening. J Pharmacol Pharmacother 2(2):74–79

  18. Parnham MJ, Erakovic Haber V, Giamarellos-Bourboulis EJ, Perletti G, Verleden GM, Vos R (2014) Azithromycin: mechanisms of action and their relevance for clinical applications. Pharmacol Ther 143(2):225–245

  19. Steverding D (2010) The development of drugs for treatment of sleeping sickness: a historical review. Parasit Vectors 3(15):9

  20. Suganuma K, Allamanda P, Hakimi H, Zhou M, Angeles JM, Kawazu SI, Inoue N (2014) Establishment of ATP-based luciferase viability assay in 96-well plate for Trypanosoma congolense. J Vet Med Sci 76(11):1437–1441

  21. Vreysen MJB, Saleh K, Mramba F, Parker A, Feldmann U, Dyck VA, Msangi A, Bouyer J (2014) Sterile insects to enhance agricultural development: the case of sustainable tsetse eradication on Unguja island, Zanzibar, using an area-wide integrated pest management approach. PLOs Negl Trop Dis 8(5):e2857

  22. Watier-Grillot S, Herder S, Marie JL, Cuny G, Davoust B (2013) Chemoprophylaxis and treatment of African canine trypanosomosis in French military working dogs: a retrospective study. Vet Parasitol 194(1):1–8

  23. Weyermann J, Lochmann D, Zimmer A (2005) A practical note on the use of cytotoxicity assays. Int J Pharm 288(2):369–376

  24. Wilson DW, Goodman CD, Sleebs BE, Weiss GE, de Jong NW, Angrisano F, Langer C, Baum J, Crabb BS, Gilson PR, McFadden GI, Beeson JG (2015) Macrolides rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium falciparum. BMC Biol 13:52

  25. Yaro M, Munyard KA, Stear MJ, Groth DM (2016) Combatting African Animal Trypanosomiasis (AAT) in livestock: the potential role of trypanotolerance. Vet Parasitol 225:43–52

  26. Zuckerman JM (2004) Macrolides and ketolides: azithromycin, clarithromycin, telithromycin. Infect Dis Clin N Am 18(3):621–649

Download references

Acknowledgements

The authors would like to express their gratitude to the Ministry of Education, Culture, Sports, Science and Technology (MEXT) for the financial support granted to this study, which was conducted at Obihiro University of Agriculture and Veterinary Medicine in the National Research Center for Protozoan Diseases. This study was also financially supported by grants from the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 16K18793 (Grants-in-Aid for Young Scientists [B]), the “International Collaborative Research Program for Tackling the NTD (Neglected Tropical Disease) Challenges in African Countries” from the Japan Agency for Medical Research and Development (AMED), and the AMED/JICA SATREPS.

Author information

Correspondence to Noboru Inoue.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of Obihiro University of Agriculture and Veterinary Medicine, Japan, animal committee (approval nos. 28-129 and 28-169).

Electronic supplementary material

ESM. 1

(PDF 283 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Molefe, N.I., Yamasaki, S., Macalanda, A.M.C. et al. Oral administration of azithromycin ameliorates trypanosomosis in Trypanosoma congolense-infected mice. Parasitol Res 116, 2407–2415 (2017). https://doi.org/10.1007/s00436-017-5542-7

Download citation

Keywords

  • Animal trypanosomosis
  • Azithromycin
  • Oral administration
  • Trypanosoma congolense