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Vet Comp Orthop Traumatol 2021; 34(04): 287-293
DOI: 10.1055/s-0041-1726083
Original Research

The Concentration of Metronidazole in the Distal Interphalangeal Joint following Intravenous Regional Limb Perfusion via the Cephalic Vein in Standing Horses

Kajsa Gustafsson 
1   Department of Large Animal Medicine and Surgery, Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and Environment, the Hebrew University of Jerusalem, Rehovot, Israel
,
Amos J. Tatz
1   Department of Large Animal Medicine and Surgery, Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and Environment, the Hebrew University of Jerusalem, Rehovot, Israel
,
Roee Dahan
1   Department of Large Animal Medicine and Surgery, Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and Environment, the Hebrew University of Jerusalem, Rehovot, Israel
,
Malka Britzi
2   National Residue Control Laboratory, Kimron Veterinary Institute, Beit Dagan, Israel
,
Stefan Soback
2   National Residue Control Laboratory, Kimron Veterinary Institute, Beit Dagan, Israel
,
Wiessam Abu Ahmad
3   Braun School of Public Health and Community Medicine, Hebrew University-Hadassah Braun School of Public Health and Community Medicine, Jerusalem, Israel
,
Hagar Prince
1   Department of Large Animal Medicine and Surgery, Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and Environment, the Hebrew University of Jerusalem, Rehovot, Israel
,
Gal Kelmer
1   Department of Large Animal Medicine and Surgery, Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and Environment, the Hebrew University of Jerusalem, Rehovot, Israel
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Abstract

Objective The aim of this study was to determine the concentration of metronidazole in the distal interphalangeal joint (DIPJ) of the thoracic limb after administering metronidazole to standing horses by intravenous regional limb perfusion (IVRLP).

Methods Eleven healthy horses had a wide rubber tourniquet applied to the proximal aspect of the antebrachium for 0.5 hours and 500 mg of metronidazole diluted in physiologic saline solution to a total volume of 108 mL was administered by cephalic IVRLP. Synovial fluid samples were collected from the DIPJ before perfusion and at 0.25, 0.5, 2, 12 and 24 hours. Blood samples were obtained at the same time points for serum analysis. Concentrations of metronidazole were determined by liquid chromatography/tandem mass spectrometry.

Results Four horses were excluded due to low synovial fluid concentrations and not completing the full tourniquet application time. The C max in the synovial fluid was 327 ± 208 µg/mL, and the t max was 26 ± 7 minutes. Only the concentrations of metronidazole at time points 0.25 and 0.5 hours were significantly different (p < 0.001) from synovial concentration before perfusion. The serum C max was 1.78 ± 0.93 µg/mL, and the t max was 76 ± 52min.

Conclusion Metronidazole administered by IVRLP reached high concentrations in the synovial fluid at 0.5 hours. However, the concentrations rapidly decreased below the minimum inhibitory concentration of potential target pathogens. Effectiveness of metronidazole administered by IVRLP as a sole therapy against anaerobic infections of synovial structures of the distal limb cannot be determined by a pharmacokinetic study. However, the present study serves as the basis for future carefully planned clinical trials.

Keywords

metronidazole - equine - intravenous regional limb perfusion - synovial fluid - distal interphalangeal joint

Note

The study was presented in part at the ECVS and ACVS annual scientific meetings 2019.


Author's Contributions

K.G. contributed to all parts of the study. A.J.T., R.D., H.P. and G.K. contributed to the conception of study, study design, acquisition of data and preparation and approval of the manuscript. M.B. and S.S. contributed to the acquisition of data, data analysis and interpretation and preparation and approval of the manuscript. W.A.A. contributed to data analysis ad interpretation and preparation and approval of the final manuscript.


Supplementary Material



Publication History

Received: 13 March 2020

Accepted: 26 January 2021

Article published online:
12 May 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Richardson G, O'Brien T, Pascoe J, Meagher D. Puncture wounds of the navicular bursa in 38 horses: a retrospective study. Vet Surg 1986; 15: 156-160
    CrossrefPubMedGoogle Scholar
  • 2 Smith M. Penetrating injuries of the foot. Equine Vet Educ 2013; 25: 422-431
    CrossrefPubMedGoogle Scholar
  • 3 Findley JA, Pinchbeck GL, Milner PI. et al. Outcome of horses with synovial structure involvement following solar foot penetrations in four UK veterinary hospitals: 95 cases. Equine Vet J 2014; 46 (03) 352-357
    CrossrefPubMedGoogle Scholar
  • 4 Honnas CM, Crabill MR, Mackie JT, Yarbrough TB, Schumacher J. Use of autogenous cancellous bone grafting in the treatment of septic navicular bursitis and distal sesamoid osteomyelitis in horses. J Am Vet Med Assoc 1995; 206 (08) 1191-1194
    PubMedGoogle Scholar
  • 5 Wright IM, Phillips TJ, Walmsley JP. Endoscopy of the navicular bursa: a new technique for the treatment of contaminated and septic bursae. Equine Vet J 1999; 31 (01) 5-11
    CrossrefPubMedGoogle Scholar
  • 6 Moore RM, Schneider RK, Kowalski J, Bramlage LR, Mecklenburg LM, Kohn CW. Antimicrobial susceptibility of bacterial isolates from 233 horses with musculoskeletal infection during 1979-1989. Equine Vet J 1992; 24 (06) 450-456
    CrossrefPubMedGoogle Scholar
  • 7 Green SL, Little CB, Baird JD, Tremblay RR, Smith-Maxie LL. Tetanus in the horse: a review of 20 cases (1970 to 1990). J Vet Intern Med 1994; 8 (02) 128-132
    CrossrefPubMedGoogle Scholar
  • 8 Ovesen AL, Riihimäki M, Båverud V, Pringle M. Antimicrobial Susceptibility of Bacteroides spp. from clinical samples from horses. J Equine Vet Sci 2016; 45: 46-52
    CrossrefPubMedGoogle Scholar
  • 9 Dumoulin M, Pille F, van den Abeele AM. et al. Use of blood culture medium enrichment for synovial fluid culture in horses: a comparison of different culture methods. Equine Vet J 2010; 42 (06) 541-546
    CrossrefPubMedGoogle Scholar
  • 10 Baggot JD, Wilson WD, Hietala S. Clinical pharmacokinetics of metronidazole in horses. J Vet Pharmacol Ther 1988; 11 (04) 417-420
    CrossrefPubMedGoogle Scholar
  • 11 Plumb DC. Metronidazole. Accessed February 12, 2021 at: https://www.plumbsveterinarydrugs.com/#!/monograph/qwJQlPmivi
    Google Scholar
  • 12 Steinman A, Gips M, Lavy E, Sinay I, Soback S. Pharmacokinetics of metronidazole in horses after intravenous, rectal and oral administration. J Vet Pharmacol Ther 2000; 23 (06) 353-357
    CrossrefPubMedGoogle Scholar
  • 13 Nagy E, Urbán E, Nord CE. ESCMID Study Group on Antimicrobial Resistance in Anaerobic Bacteria. Antimicrobial susceptibility of Bacteroides fragilis group isolates in Europe: 20 years of experience. Clin Microbiol Infect 2011; 17 (03) 371-379
    CrossrefPubMedGoogle Scholar
  • 14 Mayorga M, Rodríguez-Cavallini E, López-Ureña D, Barquero-Calvo E, Quesada-Gómez C. Identification and antimicrobial susceptibility of obligate anaerobic bacteria from clinical samples of animal origin. Anaerobe 2015; 36: 19-24
    CrossrefPubMedGoogle Scholar
  • 15 Båverud V, Gustafsson A, Franklin A, Aspán A, Gunnarsson A. Clostridium difficile: prevalence in horses and environment, and antimicrobial susceptibility. Equine Vet J 2003; 35 (05) 465-471
    CrossrefPubMedGoogle Scholar
  • 16 http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_9.0_Breakpoint_Tables.pdf 2020 .07.31. Accessed February 12, 2021
  • 17 Kelmer G. Regional limb perfusion in horses. Vet Rec 2016; 178 (23) 581-584
    CrossrefPubMedGoogle Scholar
  • 18 Cruz AM, Rubio-Martinez L, Dowling T. New antimicrobials, systemic distribution, and local methods of antimicrobial delivery in horses. Vet Clin North Am Equine Pract 2006; 22 (02) 297-322 , vii–viii
    CrossrefPubMedGoogle Scholar
  • 19 Rubio-Martínez LM, Cruz AM. Antimicrobial regional limb perfusion in horses. J Am Vet Med Assoc 2006; 228 (05) 706-712 , 655
    CrossrefPubMedGoogle Scholar
  • 20 Moyer W, Schumacher J, Schumacher J. A Guide to Equine Joint Injection and Regional Anesthesia. Yardley, PA: Veterinary Learning Systems; 2007
    Google Scholar
  • 21 Wilson D, Hartmann F, Carter V, Klohnen A, MacWilliams P. Comparison of three preoperative skin preparation techniques in ponies. Equine Vet Educ 2011; 23: 462-465
    CrossrefPubMedGoogle Scholar
  • 22 Britzi M, Gross M, Lavy E, Soback S, Steinman A. Bioavailability and pharmacokinetics of metronidazole in fed and fasted horses. J Vet Pharmacol Ther 2010; 33 (05) 511-514
    CrossrefPubMedGoogle Scholar
  • 23 Oreff GL, Tatz AJ, Dahan R. et al. Pharmacokinetics of ceftazidime after regional limb perfusion in standing horses. Vet Surg 2017; 46 (08) 1120-1125
    CrossrefPubMedGoogle Scholar
  • 24 Zantingh AJ, Schwark WS, Fubini SL, Watts AE. Accumulation of amikacin in synovial fluid after regional limb perfusion of amikacin sulfate alone and in combination with ticarcillin/clavulanate in horses. Vet Surg 2014; 43 (03) 282-288
    CrossrefPubMedGoogle Scholar
  • 25 Pille F, De Baere S, Ceelen L. et al. Synovial fluid and plasma concentrations of ceftiofur after regional intravenous perfusion in the horse. Vet Surg 2005; 34 (06) 610-617
    CrossrefPubMedGoogle Scholar
  • 26 Dahan R, Oreff GL, Tatz AJ, Raz T, Britzi M, Kelmer G. Pharmacokinetics of regional limb perfusion using a combination of amikacin and penicillin in standing horses. Can Vet J 2019; 60 (03) 294-299
    PubMedGoogle Scholar
  • 27 McKellar QA, Sanchez Bruni SF, Jones DG. Pharmacokinetic/pharmacodynamic relationships of antimicrobial drugs used in veterinary medicine. J Vet Pharmacol Ther 2004; 27 (06) 503-514
    CrossrefPubMedGoogle Scholar
  • 28 Lavoie GY, Bergeron MG. Influence of four modes of administration on penetration of aztreonam, cefuroxime, and ampicillin into interstitial fluid and fibrin clots and on in vivo efficacy against Haemophilus influenzae. Antimicrob Agents Chemother 1985; 28 (03) 404-412
    CrossrefPubMedGoogle Scholar
  • 29 Nix DE, Tyrrell R, Müller M. Pharmacodynamics of metronidazole determined by a time-kill assay for Trichomonas vaginalis. Antimicrob Agents Chemother 1995; 39 (08) 1848-1852
    CrossrefPubMedGoogle Scholar
  • 30 Child J, Chen X, Mistry RD. et al. Pharmacokinetic and pharmacodynamic properties of metronidazole in pediatric patients with acute appendicitis: a prospective study. J Pediatric Infect Dis Soc 2019; 8 (04) 297-302
    CrossrefPubMedGoogle Scholar
  • 31 Morales-León F, von Plessing-Rossel C, Villa-Zapata L. et al. [Pharmacokinetics/pharmacodynamic (PK/PD) evaluation of a short course of oral administration of metronidazole for the management of infections caused by Bacteroides fragilis]. Rev Chilena Infectol 2015; 32 (02) 135-141
    CrossrefPubMedGoogle Scholar
  • 32 Kelmer G, Hayes ME. Regional limb perfusion with erythromycin for treatment of septic physitis and arthritis caused by Rhodococcus equi. Vet Rec 2009; 165 (10) 291-292
    CrossrefPubMedGoogle Scholar
  • 33 Finsterbusch A, Argaman M, Sacks T. Bone and joint perfusion with antibiotics in the treatment of experimental staphylococcal infection in rabbits. J Bone Joint Surg Am 1970; 52 (07) 1424-1432
    CrossrefPubMedGoogle Scholar
  • 34 Fiorello CV, Beagley J, Citino SB. Antibiotic intravenous regional perfusion for successful resolution of distal limb infections: two cases. J Zoo Wildl Med 2008; 39 (03) 438-444
    CrossrefPubMedGoogle Scholar
  • 35 Sattar MA, Sankey MG, Cawley MI, Kaye CM, Holt JE. The penetration of metronidazole into synovial fluid. Postgrad Med J 1982; 58 (675) 20-24
    CrossrefPubMedGoogle Scholar
  • 36 George WL, Kirby BD, Sutter VL, Wheeler LA, Mulligan ME, Finegold SM. Intravenous metronidazole for treatment of infections involving anaerobic bacteria. Antimicrob Agents Chemother 1982; 21 (03) 441-449
    CrossrefPubMedGoogle Scholar
  • 37 Lallemand E, Trencart P, Tahier C, Dron F, Paulin A, Tessier C. Pharmacokinetics, pharmacodynamics and local tolerance at injection site of marbofloxacin administered by regional intravenous limb perfusion in standing horses. Vet Surg 2013; 42 (06) 649-657
    CrossrefPubMedGoogle Scholar
  • 38 Kilcoyne I, Nieto JE, Knych HK, Dechant JE. Time required to achieve maximum concentration of amikacin in synovial fluid of the distal interphalangeal joint after intravenous regional limb perfusion in horses. Am J Vet Res 2018; 79 (03) 282-286
    CrossrefPubMedGoogle Scholar
  • 39 Kelmer G, Martin-Jimenez T, Saxton AM, Catasus C, Elliot SB, Lakritz J. Evaluation of regional limb perfusion with erythromycin using the saphenous, cephalic, or palmar digital veins in standing horses. J Vet Pharmacol Ther 2013; 36 (05) 434-440
    CrossrefPubMedGoogle Scholar
  • 40 Rubio-Martínez LM, López-Sanromán J, Cruz AM, Santos M, Andrés MS, Román FS. Evaluation of safety and pharmacokinetics of vancomycin after intravenous regional limb perfusion in horses. Am J Vet Res 2005; 66 (12) 2107-2113
    CrossrefPubMedGoogle Scholar
  • 41 Roquet I, Hendrick S, Carmalt JL. The effect of blood contamination on equine synovial fluid analysis. Vet Comp Orthop Traumatol 2012; 25 (06) 460-465
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Coleman MM, Peng PW, Regan JM, Chan VW, Hendler AL. Quantitative comparison of leakage under the tourniquet in forearm versus conventional intravenous regional anesthesia. Anesth Analg 1999; 89 (06) 1482-1486
    CrossrefPubMedGoogle Scholar
  • 43 Parra-Sanchez A, Lugo J, Boothe DM. et al. Pharmacokinetics and pharmacodynamics of enrofloxacin and a low dose of amikacin administered via regional intravenous limb perfusion in standing horses. Am J Vet Res 2006; 67 (10) 1687-1695
    CrossrefPubMedGoogle Scholar
  • 44 Robinson CS, Timofte D, Singer ER, Rimmington L, Rubio-Martínez LM. Prevalence and antimicrobial susceptibility of bacterial isolates from horses with synovial sepsis: a cross-sectional study of 95 cases. Vet J 2016; 216: 117-121
    CrossrefPubMedGoogle Scholar