Campylobacter jejuni is a small (width, 0.2 to 0.9 μm; length, 0.2 to 5.0 μm), spiral, gramnegative, non–spore-forming bacterium that is vigorously motile owing to a polar flagellum at 1 or both ends.1 Campylobacter species are a leading cause of reproductive losses in sheep, with abortion rates that range from 5% to 50% in infected flocks.2–4 Historically, Campylobacter-induced abortions in sheep were primarily associated with Campylobacter fetus ssp fetus and to a lesser extent with Campylobacter jejuni.1,3 However, over the past few decades, C jejuni has replaced C fetus ssp fetus as the predominant cause of abortion in sheep in the United States. This etiologic species shift appears to be primarily driven by the expansion of a hypervirulent, tetracycline-resistant C jejuni clone, termed the SA clone. The SA clone is currently responsible for 93% of C jejuni abortions in sheep in the midwestern United States.1,2
During outbreaks of Campylobacter-induced abortions in sheep, antimicrobials may be administered in the feed to facilitate treating large numbers of animals over an extended period of time. In the United States, the only feed-grade antimicrobial currently approved by the FDA for the prevention or treatment of Campylobacter-induced abortion in sheep is chlortetracycline at a rate of 80 mg/sheep/day.5 Pharmacokinetic studies5,6 indicate that feeding chlortetracycline to sheep at the FDA-approved dose, or at an even higher dose (500 mg/sheep/day), results in drug concentrations that are presumed to be subtherapeutic in the plasma of pregnant ewes and are generally undetectable in fetal tissues and amniotic fluid. Moreover, most recent C jejuni isolates obtained from US sheep are resistant to tetracycline, largely owing to the presence of the tet(O) gene,2,7,8 Thus, for sheep flocks, administration of chlortetracycline via the feed is unlikely to be effective during abortion outbreaks caused by C jejuni.
Results of susceptibility testing for C jejuni isolates cultured from field cases of SAs indicate that most are susceptible to macrolides, including tulathromycin, azithromycin, telithromycin, and erythromycin.2,7,8 Tulathromycin is a recently developed, semi-synthetic, triamilide macrolide.9 The benefits of treating sheep with tulathromycin include its ease of administration (SC injection), wide volume of distribution, low therapeutic concentrations, and long terminal half-life, which ranges from 60 to 140 hours across domestic species.9 The mean ± SD apparent elimination half-life of tulathromycin is 110.8 ± 20.9 hours in pregnant ewes.10 The protracted duration of action for tulathromycin following a single injection to pregnant ewes might be protective during an abortion outbreak caused by C jejuni. Additionally, tulathromycin administration to pregnant ewes results in detectable concentrations of the drug in fetal plasma and amniotic fluid that persist for days.10
To our knowledge, the only experimental model for C jejuni-induced abortion in sheep involves IV inoculation of the bacterium.11,a Most pregnant ewes will abort 3 to 12 days after IV administration of C jejuni.11,a Characteristics of experimental C jejuni-induced abortions in sheep include suppurative metritis, placentitis with numerous intralesional bacterial colonies, and the isolation of large numbers of the bacterium from uterine, placental, and fetal tissues.11,a However, that experimental model represents a particularly aggressive C jejuni challenge to pregnant ewes and is associated with some adverse effects. In a small proportion of ewes, IV inoculation of C jejuni can cause severe endotoxemia, which may necessitate euthanasia within 24 hours after injection.a Other ewes may develop vaginal bleeding or abort within 24 to 48 hours after C jejuni inoculation owing to the effects of the bacterial endotoxin on the fetus and placenta.a The purpose of the study reported here was to evaluate the efficacy of tulathromycin for the prevention of abortion in pregnant ewes when administered within 24 hours after experimental inoculation with C jejuni.
Supported by USDA APHIS Cooperative Agreement AP17VSSPRS00G002. The funding source did not have any involvement in the study design, data analysis and interpretation, or writing and publication of the manuscript.
Dr. Ocal was supported by the International Postdoctoral Research Scholarship Program 2219 (No. 1059B191700841) of the Scientific and Technological Research Council of Turkey.
Lashley V, Yaeger M, Sahin O, Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, Iowa: Unpublished data, 2019.
Tenderfoot flooring system, Tandem Products Inc, Minneapolis, Minn.
Teklad 7060, Envigo, Huntingdon, England.
Draxxin (tulathromycin concentration, 100 mg/mL), Zoetis Inc, Kalamazoo, Mich.
Oxoid Microbiology Products, Thermo Fisher Scientific, Waltham, Mass.
2. Sahin O, Plummer PJ, Jordan DM, et al. Emergence of a tetracycline-resistant Campylobacter jejuni clone associated with outbreaks of ovine abortion in the United States. J Clin Microbiol 2008;46:1663–1671.
5. Washburn K, Fajt VR, Plummer PJ, et al. Pharmacokinetics of oral chlortetracycline in nonpregnant adult ewes. J Vet Pharmacol Ther 2014;37:607–610.
6. Washburn K, Fajt VR, Plummer PJ, et al. Pharmacokinetics of chlortetracycline in maternal plasma and in fetal tissues following oral administration to pregnant ewes. J Vet Pharmacol Ther 2018;41:218–223.
7. Sahin O, Fitzgerald C, Stroika S, et al. Molecular evidence for zoonotic transmission of an emergent, highly pathogenic Campylobacter jejuni clone in the United States. J Clin Microbiol 2012;50:680–687.
8. Wu Z, Sippy R, Sahin O, et al. Genetic diversity and antimicrobial susceptibility of Campylobacter jejuni isolates associated with sheep abortion in the United States and Great Britain. J Clin Microbiol 2014;52:1853–1861.
9. Villarino N, Brown SA, Martín-Jiménez T. The role of the macrolide tulathromycin in veterinary medicine. Vet J 2013;198:352–357.
10. MacKay EE, Washburn KE, Padgett AL, et al. Pharmacokinetics of tulathromycin in fetal sheep and pregnant ewes. J Vet Pharmacol Ther 2019;42:373–379
12. Luo Y, Sahin O, Dai L, et al. Development of a loop-mediated isothermal amplification assay for rapid, sensitive and specific detection of a Campylobacter jejuni clone. J Vet Med Sci 2012;74:591–596.
13. AVMA. AVMA guidelines for the euthanasia of animals: 2013 edition. Available at: www.avma.org/KB/Policies/Documents/euthanasia.pdf. Accessed Oct 19, 2019.
14. Elbehiry A, Marzouk E, Hamada M, et al. Application of MALDI-TOF MS fingerprinting as a quick tool for identification and clustering of foodborne pathogens isolated from food products. New Microbiol 2017;40:269–278.
15. Ávila TV, Bastos Pereira AL, De Oliveira Christoff A, et al. Hepatic effects of flunixin-meglumin in LPS-induced sepsis. Fundam Clin Pharmacol 2010;24:759–769.
16. Sargison N. Campylobacteriosis. In: Sheep flock health: a planned approach. Oxford, England: Blackwell Publishing Inc, 2008;57–59.
17. Checkley SL, Campbell JR, Chirino-Trejo M, et al. Associations between antimicrobial use and the prevalence of antimicrobial resistance in fecal Escherichia coli from feedlot cattle in western Canada. Can Vet J 2010;51:853–861.
18. Liu D, Liu W, Lv Z, et al. Emerging erm(B)-mediated macrolide resistance associated with novel multidrug resistance genomic islands in Campylobacter. Antimicrob Agents Chemother 2019; 63:e00153–19.