Tropical Animal Health and Production

, Volume 51, Issue 8, pp 2603–2610 | Cite as

The effects of Mannheimia haemolytica and albendazole on marbofloxacin pharmacokinetics in lambs

  • Feray AltanEmail author
  • Duygu Neval Sayin Ipek
  • Orhan Corum
  • Simten Yesilmen Alp
  • Polat Ipek
  • Kamil Uney
Regular Articles


The study aimed to define the effects of M. haemolytica and a single oral dose of albendazole on the single-dose pharmacokinetics of marbofloxacin in lambs. The pharmacokinetic–pharmacodynamic integration of marbofloxacin was applied to describe a 3 mg/kg intramuscular dose in lambs. The 6 healthy and 12 naturally infected with M. haemolytica lambs (Akkaraman, males weighing 10–15 kg and aged 2–3 months) were used in this study. In the marbofloxacin group, 6 healthy lambs received marbofloxacin. In the albendazole group after 2 weeks washout period, the same animals received marbofloxacin on 1 h after albendazole. In the diseased marbofloxacin group, 6 lambs naturally infected with M. haemolytica received marbofloxacin. In the diseased albendazole group, 6 lambs naturally infected with M. haemolytica received marbofloxacin on 1 h after albendazole. The marbofloxacin and albendazole were administered each as a single dose of 3 mg/kg intramuscular and 7.5 mg/kg oral, respectively, in the respective groups. Plasma concentration of marbofloxacin was measured with HPLC-UV and pharmacokinetic parameters were analyzed by non-compartmental model. Albendazole did not change the pharmacokinetic profiles of marbofloxacin in healthy and diseased lambs. However, M. haemolytica affected the pharmacokinetics of marbofloxacin in diseased lambs, AUC0–24/MIC90 ratio was not found to be higher than 125, but Cmax/MIC90 ratios was found to be higher than 10 for an MIC value of 0.25 μg/mL in all groups. The marbofloxacin dose described in this study may not be effective for the treatment of infections due to M. haemolytica in lambs, with MIC ≤ 0.25 μg/mL.


Albendazole Lamb Mannheimia haemolytica Marbofloxacin Pharmacokinetics 



This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Thanks are due to Ceva Animal Health Inc., Turkey, for supplying MB pure substance. Abstract presented form at the WVAC 2018 - 34th World Veterinary Association Congress Barcelona, Spain, May 2018.

Compliance with ethical standards

Competing interests

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

Animal experiments were carried out under the approval protocol of the Ethics Committee of the Dicle University Animal Experiments (Diyarbakir, Turkey, permit No 28/2014), which is in adherence with the Rules for the Working Procedures and Principles of the Ethical Committees of Animal Experiments and Animal Protection Act.


  1. Abo El-Sooud, K., 2003. Influence of albendazole on the disposition kinetics and milk antimicrobial equivalent activity of enrofloxacin in lactating goats Pharmacological Research, 48, 389–395PubMedGoogle Scholar
  2. Aliabadi, F.S. and Lees, P., 2002. Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbofloxacin in calf serum, exudate and transudate. Journal of veterinary pharmacology and therapeutics, 25, 161–74PubMedGoogle Scholar
  3. Alomar, M.J., 2014. Factors affecting the development of adverse drug reactions (Review article)Google Scholar
  4. Altan, F., Corum, O., Corum, D.D., Atik, O. and Uney, K., 2018. Pharmacokinetics and bioavailability of marbofloxacin in lambs following administration of intravenous, intramuscular and subcutaneous Small Ruminant Research, 159, 5–10Google Scholar
  5. Ambrose, P.G., Bhavnani, S.M., Rubino, C.M., Louie, A., Gumbo, T., Forrest, A. and Drusano, G.L., 2007. Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America, 44, 79–86Google Scholar
  6. Atef, M., El-Gendi, A.Y.I., Amer, A.M. and El-Aty, A.M.A., 2010. Effect of three anthelmentics on disposition kinetics of florfenicol in goats Food and Chemical Toxicology, 48, 3340–3344PubMedGoogle Scholar
  7. Balikci, E., Kizil, O., Karapinar, T., Karahan, M., Ozdemir, H. and Dabak, M., 2008. Efficacy of marbofloxacin for naturally occurring contagious caprine pleuropneumonia Small Ruminant Research, 77, 75–79Google Scholar
  8. Bapiro, T.E., Andersson, T.B., Otter, C., Hasler, J.A. and Masimirembwa, C.M., 2002. Cytochrome P450 1A1/2 induction by antiparasitic drugs: dose-dependent increase in ethoxyresorufin O-deethylase activity and mRNA caused by quinine, primaquine and albendazole in HepG2 cells. European Journal of Clinical Pharmacology, 58, 537–542PubMedGoogle Scholar
  9. Bell, S., 2008. Respiratory disease in sheep: 1. Differential diagnosis and epidemiology. In Practice, 30, 200–207Google Scholar
  10. Blot, S.I., Pea, F. and Lipman, J., 2014. The effect of pathophysiology on pharmacokinetics in the critically ill patient — Concepts appraised by the example of antimicrobial agents Advanced Drug Delivery Reviews, 77, 3–11PubMedGoogle Scholar
  11. Brogden, K.A., Lehmkuhl, H.D. and Cutlip, R.C., 1998. Pasteurella haemolytica complicated respiratory infections in sheep and goats Veterinary Research, 29, 233–254PubMedGoogle Scholar
  12. Brown, S.A., 1996. Fluoroquinolones in animal health J Vet Pharmacol Ther, 19, 1–14PubMedGoogle Scholar
  13. Bryskier, A. and Chantot, J.-F., 1995. Classification and Structure-Activity Relationships of Fluoroquinolones Drugs, 49, 16–28PubMedGoogle Scholar
  14. Calbo, E., Alsina, M., Rodríguez-Carballeira, M., Lite, J. and Garau, J., 2008. Systemic expression of cytokine production in patients with severe pneumococcal pneumonia: Effects of treatment with a β-lactam versus a fluoroquinolone Antimicrobial Agents and Chemotherapy, 52, 2395–2402PubMedPubMedCentralGoogle Scholar
  15. Campbell, W.C., 1990. Benzimidazoles: veterinary uses. Parasitology today (Personal ed.), 6, 130–133PubMedGoogle Scholar
  16. Cohen, R., 2006. Approaches to reduce antibiotic resistance in the community. The Pediatric infectious disease journal, 25, 977–980PubMedGoogle Scholar
  17. Craig, W.A., 1998. State-of-the-Art Clinical Article: Pharmacokinetic/Pharmacodynamic Parameters: Rationale for Antibacterial Dosing of Mice and Men Clinical Infectious Diseases, 26, 1–10PubMedGoogle Scholar
  18. Dorey, L., Pelligand, L. and Lees, P., 2017. Prediction of marbofloxacin dosage for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida by pharmacokinetic/pharmacodynamic modelling BMC Veterinary Research, 13, 209–219PubMedPubMedCentralGoogle Scholar
  19. Drusano, G.L., 2007. Pharmacokinetics and Pharmacodynamics of Antimicrobials Clinical Infectious Diseases, 45, 89–95Google Scholar
  20. Elmas, M., Yazar, E., Uney, K., Er Karabacak A., and Traş, B., 2008. Pharmacokinetics of enrofloxacin and flunixin meglumine and interactions between both drugs after intravenous co-administration in healthy and endotoxaemic rabbits Veterinary Journal, 177, 418–424Google Scholar
  21. Escobar-Garcia, D., Camacho-Carranza, R., Pérez, I., Dorado, V., Arriaga-Alba, M. and Espinosa-Aguirre, J.J., 2001. S9 induction by the combined treatment with cyclohexanol and albendazole Mutagenesis, 16, 523–528PubMedGoogle Scholar
  22. Fitton, A., 1992. The Quinolones: An Overview of their Pharmacology Clinical Pharmacokinetics, 22, 1–11PubMedGoogle Scholar
  23. Giacomini, K.M., Huang, S.-M., Tweedie, D.J., Benet, L.Z., Brouwer, K.L.R., Chu, X., Dahlin, A., Evers, R., Fischer, V., Hillgren, K.M., Hoffmaster, K.A., Ishikawa, T., Keppler, D., Kim, R.B., Lee, C.A., Niemi, M., Polli, J.W., Sugiyama, Y., Swaan, P.W., Ware, J.A., Wright, S.H., Wah Yee, S., Zamek-Gliszczynski, M.J. and Zhang, L., 2010. Membrane transporters in drug development Nature Reviews Drug Discovery, 9, 215–236PubMedGoogle Scholar
  24. Greko, C., Finn, M., Franklin, A. and Bengtsson, B., 2003. Pharmacokinetic/pharmacodynamic relationship of danofloxacin agaisnt Mannheimia haemolytica in a tissue-cage model in calves Journal of Antimicrobial Chemotherapy, 52, 253–257PubMedGoogle Scholar
  25. Ito, K., Iwatsubo, T., Kanamitsu, S., Ueda, K., Suzuki, H. and Sugiyama, Y., 1998. Prediction of pharmacokinetic alterations caused by drug-drug interactions: metabolic interaction in the liver. Pharmacological reviews, 50, 387–412PubMedGoogle Scholar
  26. Jacobs, M.R., 2001. Optimisation of antimicrobial therapy using pharmacokinetic and pharmacodynamic parameters. Clinical Microbiology and Infection, 7(11), 589–596.PubMedGoogle Scholar
  27. Kroemer, S., Galland, D., Guérin-Faublée, V., Giboin, H. and Woehrlé-Fontaine, F., 2012. Survey of marbofloxacin susceptibility of bacteria isolated from cattle with respiratory disease and mastitis in Europe. The Veterinary record, 170(2), 53PubMedGoogle Scholar
  28. Kumar, S., Kumar, S., Kumar, V., Singh, K.K. and Roy, B.K., 2009. Pharmacokinetic studies of levofloxacin after oral administration in healthy and febrile cow calves Veterinary Research Communications, 33, 887–893PubMedGoogle Scholar
  29. MacFaddin, J., 2000. Biochemical Tests for the Identification of Aerobic Bacteria Clinical Microbiology Procedures Handbook, 3rd Edition, 503–642Google Scholar
  30. Mahmood, A., Grice, J.E., Roberts, M.S. and Prow, T.W., 2013. Feasibility of multiphoton microscopy-based quantification of antibiotic uptake into neutrophil granulocytes. Journal of biomedical optics, 18(7), 076003–1-6PubMedGoogle Scholar
  31. Martin, W.B., 1996. Respiratory infections of sheep. Comparative immunology, microbiology and infectious diseases, 19, 171–179PubMedGoogle Scholar
  32. McKellar, Q.A., Sanchez Bruni, S.F. and Jones, D.G., 2004. Pharmacokinetic/pharmacodynamic relationships of antimicrobial drugs used in veterinary medicine. Journal of veterinary pharmacology and therapeutics, 27, 503–514PubMedGoogle Scholar
  33. Morgan, E.T., 2009. Impact of Infectious and Inflammatory Disease on Cytochrome P450 – Mediated Drug Metabolism and Pharmacokinetics Nature, 85, 434–438Google Scholar
  34. Palleria, C., Di Paolo, A., Giofrè, C., Caglioti, C., Leuzzi, G., Siniscalchi, A., De Sarro, G. and Gallelli, L., 2013. Pharmacokinetic drug-drug interaction and their implication in clinical managementGoogle Scholar
  35. Papich, M.G., 2014. Pharmacokinetic–pharmacodynamic (PK–PD) modeling and the rational selection of dosage regimes for the prudent use of antimicrobial drugs Veterinary Microbiology, 171, 480–486PubMedGoogle Scholar
  36. Papich, M.G., 2017. Ciprofloxacin Pharmacokinetics in Clinical Canine Patients Journal of Veterinary Internal Medicine, 31(5), 1508–1513PubMedPubMedCentralGoogle Scholar
  37. Pomorska-Mól, M. and Pejsak, Z., 2015. Effect of therapeutic doses of enrofloxacin on circulating lymphocyte subpopulations in pigs Bulletin of the Veterinary Institute in Pulawy, 59(2), 287–293Google Scholar
  38. Potter, T., Illambas, J., Pelligand, L., Rycroft, A. and Lees, P., 2013. Pharmacokinetic and pharmacodynamic integration and modelling of marbofloxacin in calves for Mannheimia haemolytica and Pasteurella multocida Veterinary Journal, 195, 53–58Google Scholar
  39. Real, R., Egido, E., Pérez, M., González-Lobato, L., Barrera, B., Prieto, J.G., Alvarez, A.I. and Merino, G., 2011. Involvement of breast cancer resistance protein (BCRP/ABCG2) in the secretion of danofloxacin into milk: interaction with ivermectin. Journal of veterinary pharmacology and therapeutics, 34, 313–321PubMedGoogle Scholar
  40. Redondo, E., Gázquez, A., García, A., Vadillo, S. and Masot, A.J., 2011. Dominant expression of interleukin-8 vs interleukin-1β and tumour necrosis factor alpha in lungs of lambs experimentally infected with Mannheimia haemolytica New Zealand Veterinary Journal, 59, 225–232PubMedGoogle Scholar
  41. Rougier, S., Vouldoukis, I., Fournel, S., Pérès, S. and Woehrlé, F., 2008. Efficacy of different treatment regimens of marbofloxacin in canine visceral leishmaniosis: A pilot study Veterinary Parasitology, 153, 244–254PubMedGoogle Scholar
  42. Schneider, M., Thomas, V., Boisrame, B. and Deleforge, J., 1996. Pharmacokinetics of marbofloxacin in dogs after oral and parenteral administration Journal of Veterinary Pharmacology and Therapeutics, 19, 56–61PubMedGoogle Scholar
  43. Sidhu, P.K., Landoni, M.F., Aliabadi, F.S. and Lees, P., 2010. PK-PD integration and modeling of marbofloxacin in sheep. Research in veterinary science, 88, 134–141PubMedGoogle Scholar
  44. Sidhu, P.K., Landoni, M.F., Aliabadi, M.H.S., Toutain, P.L. and Lees, P., 2011. Pharmacokinetic and pharmacodynamic modelling of marbofloxacin administered alone and in combination with tolfenamic acid in calves. Journal of veterinary pharmacology and therapeutics, 34, 376–387PubMedGoogle Scholar
  45. Skoufos, J., Christodoulopoulos, G., Fragkou, I.A., Tzora, A., Gougoulis, D.A., Orfanou, D.C., Tsiolaki, K. and Fthenakis, G.C., 2007. Efficacy of marbofloxacin against respiratory infections of lambs Small Ruminant Research, 71, 304–309Google Scholar
  46. Taburet, A.-M., Tollier, C. and Richard, C., 1990. The Effect of Respiratory Disorders on Clinical Pharmacokinetic Variables Clinical Pharmacokinetics, 19, 462–490PubMedGoogle Scholar
  47. Thomas, E., Caldow, G.L., Borell, D. and Davot, J.L., 2001. A field comparison of the efficacy and tolerance of marbofloxacin in the treatment of bovine respiratory disease Journal of Veterinary Pharmacology and Therapeutics, 24, 353–358PubMedGoogle Scholar
  48. Toutain, P.L., Del Castillo, J.R.E. and Bousquet-Mélou, A., 2002. The pharmacokinetic-pharmacodynamic approach to a rational dosage regimen for antibiotics. Research in Veterinary Science, 73(2), 105–114PubMedGoogle Scholar
  49. Voigt, K., Brügmann, M., Huber, K., Dewar, P., Cousens, C., Hall, M., Sharp, J.M. and Ganter, M., 2007. PCR examination of bronchoalveolar lavage samples is a useful tool in pre-clinical diagnosis of ovine pulmonary adenocarcinoma (Jaagsiekte) Research in Veterinary Science, 83, 419–427PubMedGoogle Scholar

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© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and Toxicology, Faculty of Veterinary MedicineUniversity of DicleDiyarbakirTurkey
  2. 2.Department of Parasitology, Faculty of Veterinary MedicineUniversity of DicleDiyarbakirTurkey
  3. 3.Department of Pharmacology and Toxicology, Faculty of Veterinary MedicineUniversity of KastamonuKastamonuTurkey
  4. 4.Department of Microbiology, Faculty of Veterinary MedicineUniversity of DicleDiyarbakirTurkey
  5. 5.Department of Physiology, Faculty of Veterinary MedicineUniversity of DicleDiyarbakirTurkey
  6. 6.Department of Pharmacology and Toxicology, Faculty of Veterinary MedicineUniversity of SelcukKonyaTurkey

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