FREE SHIPPING over $40
OVER 10000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Frontiers in microbiology2023; 14; 1282949; doi: 10.3389/fmicb.2023.1282949

Pharmacokinetic-pharmacodynamic cutoff values for benzylpenicillin in horses to support the establishment of clinical breakpoints for benzylpenicillin antimicrobial susceptibility testing in horses.

Abstract: The aim of this international project was to establish a species-specific Clinical Breakpoint for interpretation of Antimicrobial Susceptibility Testing of benzylpenicillin (BP) in horses. Unassigned: A population pharmacokinetic model of BP disposition was developed to compute PK/PD cutoff values of BP for different formulations that are commonly used in equine medicine around the world (France, Sweden, USA and Japan). Investigated substances were potassium BP, sodium BP, procaine BP, a combination of procaine BP and benzathine BP and penethamate, a prodrug of BP. Data were collected from 40 horses that provided 63 rich profiles of BP corresponding to a total of 1022 individual BP plasma concentrations. Unassigned: A 3-compartment disposition model was selected. For each of these formulations, the PK/PD cutoff was estimated for different dosage regimens using Monte Carlo simulations. The AUC/MIC or T>MIC were calculated with a free BP fraction set at 0.4. For AUC/MIC, a target value of 72 h (for a 72h treatment) was considered. For T>MIC, efficacy was assumed when free plasma concentrations were above the explored MIC (0.0625-2 mg/L) for 30 or 40 % of the dosing interval. For continuous infusion, a T>MIC of 90 % was considered. It was shown that a PK/PD cutoff of 0.25 mg/L can be achieved in 90 % of horses with routine regimen (typically 22,000 IU/kg or 12.4 mg/kg per day) with IM procaine BP once a day (France, Japan, Sweden but not USA1) and with IM sodium BP at 14.07 mg/kg, twice a day or IV sodium BP infusion of 12.4 mg/kg per day. In contrast, penethamate and the combination of procaine BP and benzathine BP were unable to achieve this PK/PD cutoff not even an MIC of 0.125 mg/L. Unassigned: The PK/PD cutoff of 0.25 mg/L is one dilution lower than the clinical breakpoint released by the CLSI (0.5 mg/ L). From our simulations, the CLSI clinical breakpoint can be achieved with IM procaine BP twice a day at 22,000 IU i.e. 12.4 mg/kg.
Copyright © 2023 Lallemand, Bousquet-Mélou, Chapuis, Davis, Ferran, Kukanich, Kuroda, Lacroix, Minamijima, Olsén, Pelligand, Portugal, Roques, Santschi, Wilson and Toutain.
Get Full Text
Publication Date: 2023-10-25 PubMed ID: 37954237PubMed Central: PMC10634207DOI: 10.3389/fmicb.2023.1282949Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research aims to establish horse-specific clinical breakpoint guidelines for the interpretation of antimicrobial susceptibility tests for Benzylpenicillin (BP), a commonly used antibiotic in equine medicine. The study used samples from 40 horses to develop a pharmacokinetic model, determining optimal dosage regimens for various BP formulations, resulting in a pharmacokinetic/pharmacodynamic (PK/PD) cutoff value of 0.25mg/L for most formulations except for Penethamate and a combination of Procaine BP and Benzathine BP.

Background and Aim

  • The study aimed to create a clinical breakpoint value specifically for horses when using the antibiotic BP. This value aids vets in understanding how susceptible a horse’s bacterial infection might be to BP, thus informing its course of treatment.

Methodology

  • A 3-compartment pharmacokinetic model was constructed to better understand how BP is metabolized in horses. For this, plasma concentrations of BP from 40 horses were collected, resulting in 1022 individual data points.
  • The research team then used this model to calculate what they refer to as the PK/PD cutoff – a threshold at which the drug shows effectiveness – for various BP derivatives and dosages.
  • During the estimations, a couple of metrics called AUC/MIC and T>MIC were considered. These metrics relate to the time a drug stays in the body above the minimum level required to inhibit bacterial growth.
  • In terms of dosages, a regimen typically of 22,000 IU/kg or 12.4 mg/kg per day was considered, injected via intramuscular (IM) or intravenous (IV) routes depending on the formulation.

Findings

  • The study concluded that a PK/PD cutoff of 0.25 mg/L was achievable in 90% of the horses on the investigated dosing regimens for most formulations, except for Penethamate and the mix of Procaine BP and Benzathine BP.
  • The recommended clinical breakpoint from the Clinical and Laboratory Standards Institute (CLSI) is 0.5 mg/L, which is higher than the cutoff found in this research. Nevertheless, simulations from this research suggested that the CLSI breakpoint may be achievable with a Procaine BP dose delivered twice daily.

Implications

  • This study fills a crucial gap in veterinary pharmacology, providing valuable data specific to horses and the metabolism of BP. This can help in making informed decisions in treating horses with bacterial infections.
  • The species-specific clinical breakpoint developed here complements the general guidelines offered by the CLSI and can result in more refined and effective treatment strategies.

Cite This Article

APA
Lallemand EA, Bousquet-Mélou A, Chapuis L, Davis J, Ferran AA, Kukanich B, Kuroda T, Lacroix MZ, Minamijima Y, Olsén L, Pelligand L, Portugal FR, Roques BB, Santschi EM, Wilson KE, Toutain PL. (2023). Pharmacokinetic-pharmacodynamic cutoff values for benzylpenicillin in horses to support the establishment of clinical breakpoints for benzylpenicillin antimicrobial susceptibility testing in horses. Front Microbiol, 14, 1282949. https://doi.org/10.3389/fmicb.2023.1282949

Publication

Frontiers in microbiology
ISSN: 1664-302X
NlmUniqueID: 101548977
Country: Switzerland
Language: English
Volume: 14
Pages: 1282949
PII: 1282949

Researcher Affiliations

Lallemand, Elodie A
  • INTHERES, Université de Toulouse, INRAE, ENVT, Toulouse, France.
Bousquet-Mélou, Alain
  • INTHERES, Université de Toulouse, INRAE, ENVT, Toulouse, France.
Chapuis, Laura
  • INTHERES, Université de Toulouse, INRAE, ENVT, Toulouse, France.
Davis, Jennifer
  • Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, United States.
Ferran, Aude A
  • INTHERES, Université de Toulouse, INRAE, ENVT, Toulouse, France.
Kukanich, Butch
  • Department of Anatomy and Physiology, Kansas State University, Manhattan, KS, United States.
Kuroda, Taisuke
  • Clinical Veterinary Medicine Division, Equine Research Institute, Japan Racing Association, Shimotsuke, Japan.
Lacroix, Marlène Z
  • INTHERES, Université de Toulouse, INRAE, ENVT, Toulouse, France.
Minamijima, Yohei
  • Drug Analysis Department, Laboratory of Racing Chemistry, Utsunomiya, Japan.
Olsén, Lena
  • Division of Pharmacology and Toxicology, Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Pelligand, Ludovic
  • Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, United Kingdom.
Portugal, Felipe Ramon
  • INTHERES, Université de Toulouse, INRAE, ENVT, Toulouse, France.
Roques, Béatrice B
  • INTHERES, Université de Toulouse, INRAE, ENVT, Toulouse, France.
Santschi, Elizabeth M
  • Department of Clinical Sciences, Kansas State University, Manhattan, KS, United States.
Wilson, Katherine E
  • Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, United States.
Toutain, Pierre-Louis
  • INTHERES, Université de Toulouse, INRAE, ENVT, Toulouse, France.
  • Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, United Kingdom.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

This article includes 42 references
  1. Anonymous. Penethamate (hydroiodide); summary report 2. The European Agency for the evaluation of Medicinal products .
  2. Anonymous. European committee on antimicrobial susceptibility testing. Benzylpenicillin: Rationale for the clinical breakpoints, version 1.0, 2010. .
  3. Anonymous. Reflection paper on the use of aminopenicillins and their beta-lactamase inhibitor combinations in animals in the European Union: Development of resistance and impact on human and animal health. European Medicines Agency .
  4. Anonymous. The United States committee on antimicrobial susceptibility testing (USCAST) Breakpoint tables for interpretation of MIC and zone diameter results. Version 7.0, 2021. The United States Committee on Antimicrobial Susceptibility Testing .
    pmc: PMC6985752pubmed: 31767718
  5. Burnham K. P., Anderson D. R.. Multimodel inference: understanding AIC and BIC in model selection. Sociol. Methods Res. 33, 261–304.
    doi: 10.1177/0049124104268644google scholar: lookup
  6. Byon W., Fletcher C. V., Brundage R. C.. Impact of censoring data below an arbitrary quantification limit on structural model misspecification. J. Pharmacokinet. Pharmacodyn. 35, 101–116.
    doi: 10.1007/s10928-007-9078-9pubmed: 17963024google scholar: lookup
  7. Choi S.-K., Hwang J.-Y., Park C.-S., Cho G.-J.. Frequencies and antimicrobial susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) isolated from horses in South Korea. TOASJ 12, 148–155.
    doi: 10.2174/1874331501812010148google scholar: lookup
  8. De Briyne N., Atkinson J., Pokludová L., Borriello S. P.. Antibiotics used most commonly to treat animals in Europe. Vet. Rec. 175:325.
    doi: 10.1136/vr.102462pmc: PMC4215272pubmed: 24899065google scholar: lookup
  9. Dubois A., Bertrand J., Mentré F.. Mathematical expressions of the pharmacokinetic and Pharmacodynamic models implemented in the PFIM software. .
  10. Dürr A.. Comparison of the pharmacokinetics of penicillin G and ampicillin in the horse. Res. Vet. Sci. 20, 24–29.
    doi: 10.1016/S0034-5288(18)33474-Xpubmed: 1257624google scholar: lookup
  11. Firth E. C., Nouws J. F., Driessens F., Schmaetz P., Peperkamp K., Klein W. R.. Effect of the injection site on the pharmacokinetics of procaine penicillin G in horses. Am. J. Vet. Res. 47, 2380–2384.
    pubmed: 3789498
  12. Food and Drug Administration. Guidance for industry; population Pharmacokinetics. U.S. Department of Health and Human Services Food and Drug Administration; Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER) .
  13. Gartlan W. A., Rahman S., Reti K.. Benzathine penicillin. StatPearls Treasure Island (FL): StatPearls Publishing LLC.
    pubmed: 29939545
  14. Horspool L. J., McKellar Q. A.. Disposition of penicillin G sodium following intravenous and oral administration to Equidae. Br. Vet. J. 151, 401–412.
    doi: 10.1016/s0007-1935(95)80129-4pubmed: 7552196google scholar: lookup
  15. Hughes L. A., Pinchbeck G., Callaby R., Dawson S., Clegg P., Williams N.. Antimicrobial prescribing practice in UK equine veterinary practice. Equine Vet. J. 45, 141–147.
    doi: 10.1111/j.2042-3306.2012.00602.xpubmed: 22994559google scholar: lookup
  16. Kass R. E., Raftery A. E.. Bayes Factors. J. Am. Stat. Assoc. 90, 773–795.
    doi: 10.1080/01621459.1995.10476572google scholar: lookup
  17. Knych H. K., Magdesian K. G.. Equine antimicrobial therapy: current and past issues facing practitioners. J. Vet. Pharmacol. Therap. 44, 270–279.
    doi: 10.1111/jvp.12964pubmed: 33650183google scholar: lookup
  18. Kuroda T., Minamijima Y., Niwa H., Tamura N., Mita H., Fukuda K.. Rational dosage regimens for cephalothin and cefazolin using pharmacokinetics and pharmacodynamics analysis in healthy horses. Equine Vet. J. 53, 1239–1249.
    doi: 10.1111/evj.13406pmc: PMC8518962pubmed: 33341979google scholar: lookup
  19. Li M., Gehring R., Lin Z., Riviere J.. A framework for meta-analysis of veterinary drug pharmacokinetic data using mixed effect modeling. J. Pharm. Sci. 104, 1230–1239.
    doi: 10.1002/jps.24341pubmed: 25641543google scholar: lookup
  20. Love D. N., Rose R. J., Martin I. C. A., Bailey M.. Serum concentrations of penicillin in the horse after administration of a variety of penicillin preparations. Equine Vet. J. 15, 43–48.
    doi: 10.1111/j.2042-3306.1983.tb01700.xpubmed: 6825648google scholar: lookup
  21. Maddox T. W., Clegg P. D., Diggle P. J., Wedley A. L., Dawson S., Pinchbeck G. L.. Cross-sectional study of antimicrobial-resistant bacteria in horses. Part 1: prevalence of antimicrobial-resistant Escherichia coli and methicillin-resistant Staphylococcus aureus: prevalence of antimicrobial-resistant bacteria in horses. Equine Vet. J. 44, 289–296.
    doi: 10.1111/j.2042-3306.2011.00441.xpubmed: 21848534google scholar: lookup
  22. Magdesian K. G.. Chapter 33 - Update on Antimicrobial Selection and Use. Robinson’s Current Therapy in Equine Medicine (Seventh Edition) 144–149.
  23. Nielsen E. I., Cars O., Friberg L. E.. Pharmacokinetic/Pharmacodynamic (PK/PD) indices of antibiotics predicted by a Semimechanistic PKPD model: a step toward model-based dose optimization. Antimicrob. Agents Chemother. 55, 4619–4630.
    doi: 10.1128/AAC.00182-11pmc: PMC3186970pubmed: 21807983google scholar: lookup
  24. Nielsen I. L., Jacobs K. A., Huntington P. J., Chapman C. B., Lloyd K. C.. Adverse reaction to procaine penicillin G in horses. Aust. Vet. J. 65, 181–185.
    doi: 10.1111/j.1751-0813.1988.tb14296.xpubmed: 3415617google scholar: lookup
  25. Olsén L., Bremer H., Olofsson K., Bröjer J., Bondesson U., Bergh A.. Intramuscular administration of sodium benzylpenicillin in horses as an alternative to procaine benzylpenicillin. Res. Vet. Sci. 95, 212–218.
    doi: 10.1016/j.rvsc.2013.01.019pubmed: 23419937google scholar: lookup
  26. Olsén L., Ingvast-Larsson C., Broström H., Larsson P., Tjälve H.. Clinical signs and etiology of adverse reactions to procaine benzylpenicillin and sodium/potassium benzylpenicillin in horses. J. Vet. Pharmacol. Ther. 30, 201–207.
    doi: 10.1111/j.1365-2885.2007.00851.xpubmed: 17472651google scholar: lookup
  27. Olsén L., Olsan A., Ingvast-Larsson C.. Synovial and plasma concentrations of benzylpenicillin after intravenous administration of sodium benzylpenicillin in horses. J. Vet. Pharmacol. Ther. 134–135.
  28. Papich M. G., Korsrud G. O., Boison J. O., Yates W. D., MacNeil J. D., Janzen E. D.. Disposition of penicillin G after administration of benzathine penicillin G, or a combination of benzathine penicillin G and procaine penicillin G in cattle. Am. J. Vet. Res. 55, 825–830.
    pubmed: 7944023
  29. Rey J. F., Laffont C. M., Croubels S., de Backer P., Zemirline C., Bousquet E.. Use of Monte Carlo simulation to determine pharmacodynamic cutoffs of amoxicillin to establish a breakpoint for antimicrobial susceptibility testing in pigs. Am. J. Vet. Res. 75, 124–131.
    doi: 10.2460/ajvr.75.2.124pubmed: 24471748google scholar: lookup
  30. Schoemaker R. C., Cohen A. F.. Estimating impossible curves using NONMEM. Br. J. Clin. Pharmacol. 42, 283–290.
    doi: 10.1046/j.1365-2125.1996.04231.xpmc: PMC2042675pubmed: 8877017google scholar: lookup
  31. Tjälve H.. Adverse reactions to veterinary drugs reported in Sweden during 1991-1995. J. Vet. Pharmacol. Ther. 20, 105–110.
    doi: 10.1046/j.1365-2885.1997.00050.xpubmed: 9131536google scholar: lookup
  32. Tobin T., Blake J. W.. A review of the pharmacology, pharmacokinetics and behavioral effects of procaine in thoroughbred horses. Br. J. Sports Med. 10, 109–116.
    doi: 10.1136/bjsm.10.3.109pmc: PMC1859703pubmed: 1000155google scholar: lookup
  33. Toutain P.-L., Bousquet-Mélou A., Damborg P., Ferran A. A., Mevius D., Pelligand L.. En route towards European clinical breakpoints for veterinary antimicrobial susceptibility testing: a position paper explaining the VetCAST approach. Front. Microbiol. 8:2344.
    doi: 10.3389/fmicb.2017.02344pmc: PMC5736858pubmed: 29326661google scholar: lookup
  34. Toutain P.-L., Bousquet-Mélou A., Martinez M.. AUC/MIC: a PK/PD index for antibiotics with a time dimension or simply a dimensionless scoring factor?. J. Antimicrob. Chemother. 60, 1185–1188.
    doi: 10.1093/jac/dkm360pubmed: 17932075google scholar: lookup
  35. Toutain P., Gandia P., Pelligand L., Ferran A. A., Lees P., Bousquet-Mélou A.. Biased computation of probability of target attainment for antimicrobial drugs. CPT Pharmacom. Syst. Pharm. 12, 681–689.
    doi: 10.1002/psp4.12929pmc: PMC10196429pubmed: 37025064google scholar: lookup
  36. Toutain P., Pelligand L., Lees P., Bousquet-Mélou A., Ferran A. A., Turnidge J. D.. The pharmacokinetic/pharmacodynamic paradigm for antimicrobial drugs in veterinary medicine: recent advances and critical appraisal. J. Vet. Pharmacol. Therap. 44, 172–200.
    doi: 10.1111/jvp.12917pubmed: 33089523google scholar: lookup
  37. Toutain P.-L., Sidhu P. K., Lees P., Rassouli A., Pelligand L.. VetCAST method for determination of the pharmacokinetic-Pharmacodynamic cut-off values of a long-acting formulation of Florfenicol to support clinical breakpoints for Florfenicol antimicrobial susceptibility testing in cattle. Front. Microbiol. 10:1310.
    doi: 10.3389/fmicb.2019.01310pmc: PMC6581757pubmed: 31244816google scholar: lookup
  38. Turnidge J. D., Martinez M. N.. Proposed method for estimating clinical cut-off (COCL) values: an attempt to address challenges encountered when setting clinical breakpoints for veterinary antimicrobial agents. Vet. J. 228, 33–37.
    doi: 10.1016/j.tvjl.2017.10.004pubmed: 29153105google scholar: lookup
  39. Wayne P.. CLSI Performance standards for antimicrobial disk and dilution susceptibility tests for bacteria isolated from animals4th ed. CLSI supplement VET08. Clinical and laboratory Standard Institut .
  40. Weese J. S., Baptiste K. E., Baverud V., Toutain P.-L.. Guidelines for antimicrobial use in horses. Guide to antimicrobial use in animals 161–182.
  41. Wilson K. E., Bogers S. H., Council-Troche R. M., Davis J. L.. Potassium penicillin and gentamicin pharmacokinetics in healthy conscious and anesthetized horses. Vet. Surg. 52, 87–97.
    doi: 10.1111/vsu.13896pubmed: 36286077google scholar: lookup
  42. Younkin J. T., Santschi E. M., Kukanich B., Lubbers B. V., Warner M.. Evaluation of plasma concentration after intravenous and intramuscular penicillin administration over 24 hr in healthy adult horses. J. Vet. Pharmacol. Therap. 42, 239–242.
    doi: 10.1111/jvp.12730pubmed: 30387161google scholar: lookup

Citations

This article has been cited 6 times.
  1. Guillot M, Mespoulhes-Rivière C, Bousquet-Mélou A, Lacroix MZ, Roques BB, Lallemand EA. Pharmacokinetics, pharmacodynamics, and local tolerance at injection site of penicillin and gentamicin administered by intravenous regional limb perfusion in standing horses: comparison between weightbearing and flexed limbs. BMC Vet Res 2025 Nov 7;21(1):650.
    doi: 10.1186/s12917-025-04936-0pubmed: 41204239google scholar: lookup
  2. Damborg P, Allerton F, Bousquet-Mélou A, Britt C, Cagnardi P, Carmo LP, Cvetkovikj I, Erhard M, Heuvelink A, Jessen LR, Overesch G, Pelligand L, Gómez Raja J, Scahill K, Timofte D, Vale AP, Veldman K, Broens EM. ENOVAT: the European Network for Optimization of Veterinary Antimicrobial Treatment. Open Res Eur 2024;4:170.
    doi: 10.12688/openreseurope.18016.2pubmed: 39247170google scholar: lookup
  3. Temmerman R, Berlamont H, El Garch F, Rose M, Simjee S, Meschi S, de Jong A. Antimicrobial Susceptibility of Canine and Feline Urinary Tract Infection Pathogens Isolated from Animals with Clinical Signs in European Veterinary Practices during the Period 2013-2018. Antibiotics (Basel) 2024 May 28;13(6).
    doi: 10.3390/antibiotics13060500pubmed: 38927167google scholar: lookup
  4. Ferran AA, Roques BB, Chapuis L, Kuroda T, Lacroix MZ, Toutain PL, Bousquet-Melou A, Lallemand EA. Predicted efficacy and tolerance of different dosage regimens of benzylpenicillin in horses based on a pharmacokinetic study with three IM formulations and one IV formulation. Front Vet Sci 2024;11:1409266.
    doi: 10.3389/fvets.2024.1409266pubmed: 38881781google scholar: lookup
  5. Toutain PL. Why the racing industry and equestrian disciplines need to implement population pharmacokinetics: To learn, explain, summarize, harmonize, and individualize. Drug Test Anal 2025 Feb;17(2):250-258.
    doi: 10.1002/dta.3706pubmed: 38685692google scholar: lookup
  6. Kuroda T, Minamijima Y, Niwa H, Mita H, Tamura N, Fukuda K, Toutain PL, Ohta M. Pharmacokinetics/pharmacodynamics cut-off determination for fosfomycin using Monte Carlo simulation in healthy horses. J Vet Med Sci 2024 Apr 10;86(4):413-420.
    doi: 10.1292/jvms.23-0476pubmed: 38346727google scholar: lookup
Subscribe to our newsletter
Join 100,127 horse owners like you who receive our email updates on horse health and nutrition.