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Home / Equine Research Bank / Equine Vet J / Synergistic combinations of clarithromycin with doxycycline ...
Equine veterinary journal2021; doi: 10.1111/evj.13508

Synergistic combinations of clarithromycin with doxycycline or minocycline reduce the emergence of antimicrobial resistance in Rhodococcus equi.

Abstract: The alarming increase in rifampin and macrolide resistance among Rhodococcus equi isolates highlights the need to identify alternative therapeutic options that can effectively control rhodococcosis in foals while limiting the further development of drug resistance. Objective: To evaluate bacterial killing, antibiotic synergism and mutant prevention concentrations (MPCs) of clarithromycin alone and in combination with doxycycline, minocycline or rifampin against clinical isolates of R equi. Methods: In vitro experiments. Methods: Bacterial time-kill, fractional inhibitory concentration (checkerboard) and mutant prevention concentration assays were evaluated in four clarithromycin- and rifampin-susceptible (Cla /Rif ) and two clarithromycin- and rifampin-resistant (Cla /Rif ) R equi clinical strains. Results: In this study evaluating a limited number of isolates, combinations of clarithromycin with doxycycline or minocycline, but not with rifampin, were generally synergistic in both Cla /Rif and Cla /Rif strains as determined by checkerboard testing. In time-kill assays, all antibiotics, both alone and in combination, reduced viable Cla /Rif R equi by more than 3 log10 at 24 hours compared with control cultures without antibiotics. Combinations of clarithromycin with doxycycline, minocycline or rifampin induced significantly lower MPC values compared with the individual antimicrobials alone for all Cla /Rif R equi strains, resulting in a narrower mutant selection window (MSW). However, clarithromycin/rifampin combination did not markedly decrease MPCs of the individual antimicrobials in Cla /Rif R equi isolates, and the observed decrease in MPCs for doxycycline or minocycline did not generally differ when combined with clarithromycin. Conclusions: The number of analysed R equi isolates was limited. In vitro outcomes require clinical confirmation. Conclusions: Dual therapy combinations consisting of clarithromycin with doxycycline or minocycline merit consideration as a treatment protocol against R equi in foals due to in vitro synergy. These combination therapies may also minimise the emergence of antimicrobial resistance in cases of rhodococcosis.
© 2021 EVJ Ltd.
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Publication Date: 2021-09-04 PubMed ID: 34480367DOI: 10.1111/evj.13508Google Scholar: Lookup
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  • 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 paper explores the use of antibiotic combinations to decrease resistance and increase effectiveness in treating rhodococcosis, a bacterial infection in young horses, or foals.

Objective of Research

  • The objective of this study was to assess the efficacy of a combination of antibiotics, specifically clarithromycin, doxycycline, minocycline and rifampin, in terms of helping combat bacterial infection from Rhodococcus equi, limiting antibiotic resistance, and considering their potential as a therapeutic option for foals suffering from rhodococcosis.

Methodology

  • The research work was carried out through in vitro experiments, focused on bacterial time-kill, fractional inhibitory concentration and mutant prevention concentration assays.
  • These investigations were tested on a series of R equi clinical strains. Four of these strains were susceptible to clarithromycin and rifampin (Cla/Rif), and two were resistant to the same antibiotics.

Findings

  • The results illustrated that when clarithromycin was used in combination with either doxycycline or minocycline, there was generally a greater synergistic impact against both clarithromycin/rifampin susceptible and resistant R equi strains.
  • When the antibiotics were used separately or in combination during time-kill assays, they eliminated a significant number of viable clarithromycin/rifampin susceptible R equi bacteria within 24 hours.
  • Combinations of clarithromycin with doxycycline, minocycline, or rifampin resulted in significantly lower mutant prevention concentration (MPC) values compared to the individual antibiotics; this indicates a reduced probability for the development of antibiotic-resistant mutants.

Concluding Remarks

  • The results of the study indicate that dual therapies of clarithromycin, plus either doxycycline or minocycline, may be potent treatments for R equi in foals due to demonstrated in-vitro synergy.
  • Furthermore, these proposed combination therapies may also potentially help in reducing the emergence of antimicrobial resistance in rhodococcosis cases.
  • However, these conclusions need to be supplemented with more extensive studies, considering the limited number of analyzed R equi isolates in this study, as well as the need for actual clinical experimentation to corroborate the in vitro findings.

Cite This Article

APA
Erol E, Shaffer CL, Lubbers BV. (2021). Synergistic combinations of clarithromycin with doxycycline or minocycline reduce the emergence of antimicrobial resistance in Rhodococcus equi. Equine Vet J. https://doi.org/10.1111/evj.13508

Publication

Equine veterinary journal
ISSN: 2042-3306
NlmUniqueID: 0173320
Country: United States
Language: English

Researcher Affiliations

Erol, Erdal
  • Department of Veterinary Science and the Veterinary Diagnostic Laboratory, University of Kentucky, Lexington, KY, USA.
Shaffer, Carrie L
  • Department of Veterinary Science and the Gluck Equine Research Center, University of Kentucky, Lexington, KY, USA.
Lubbers, Brian V
  • Department of Clinical Sciences, Kansas State University, Manhattan, KS, USA.

Grant Funding

  • AG-6395-C-17-0027 / U.S. Department of Agriculture
  • 1015612 / U.S. Department of Agriculture

References

This article includes 39 references
  1. Prescott JF. Rhodococcus equi: an animal and human pathogen.. Clin Microbiol Rev 1991;4:20-34.
  2. Hondalus MK, Mosser DM. Survival and replication of Rhodococcus equi in macrophages.. Infect Immun 1994;62:4167-75.
  3. Vázquez-Boland JA, Giguère S, Hapeshi A, MacArthur I, Anastasi E, Valero-Rello A. Rhodococcus equi: the many facets of a pathogenic actinomycete.. Vet Microbiol 2013;167:9-33.
  4. Reuss SM, Chaffin MK, Cohen ND. Extrapulmonary disorders associated with Rhodococcus equi infection in foals: 150 cases (1987-2007).. J Am Vet Med Assoc 2009;235:855-63.
  5. Nordmann P, Ronco E. In-vitro antimicrobial susceptibility of Rhodococcus equi.. J Antimicrob Chemother 1992;29:383-393.
  6. Jacks SS, Giguère S, Nguyen A. In vitro susceptibilities of Rhodococcus equi and other common equine pathogens to azithromycin, clarithromycin, and 20 other antimicrobials.. Antimicrob Agents Chemother 2003;47:1742-5.
  7. Giguère S, Lee EA, Guldbech KM, Berghaus LJ. In vitro synergy, pharmacodynamics, and postantibiotic effect of 11 antimicrobial agents against Rhodococcus equi.. Vet Microbiol 2012;160:207-13.
  8. Burton AJ, Giguère S, Berghaus LJ, Hondalus MK. Activity of clarithromycin or rifampin alone or in combination against experimental Rhodococcus equi infection in mice.. Antimicrob Agents Chemother 2015;59:3633-6.
  9. Hillidge CJ. Use of erythromycin-rifampin combination in treatment of Rhodococcus equi pneumonia.. Vet Microbiol 1987;14:337-42.
  10. Sweeney CR, Sweeney RW, Divers TJ. Rhodococcus equi pneumonia in 48 foals: response to antimicrobial therapy.. Vet Microbiol 1987;14:329-36.
  11. Berghaus LJ, Giguère S, Guldbech K. Mutant prevention concentration and mutant selection window for 10 antimicrobial agents against Rhodococcus equi.. Vet Microbiol 2013;166:670-5.
  12. Burton AJ, Giguère S, Sturgill TL, Berghaus LJ, Slovis NM, Whitman JL. Macrolide- and rifampin-resistant Rhodococcus equi on a horse breeding farm, Kentucky, USA.. Emerg Infect Dis 2013;19:282-5.
  13. Huber L, Giguère S, Cohen ND, Slovis NM, Hanafi A, Schuckert A. Prevalence and risk factors associated with emergence of Rhodococcus equi resistance to macrolides and rifampicin in horse-breeding farms in Kentucky, USA.. Vet Microbiol 2019;235:243-7.
  14. Erol E, Locke S, Saied A, Cruz Penn MJ, Smith J, Fortner J. Antimicrobial susceptibility patterns of Rhodococcus equi from necropsied foals with rhodococcosis.. Vet Microbiol 2020.
    doi: 10.1016/j.vetmic.2019.108568google scholar: lookup
  15. Peters J, Eggers K, Oswald S, Block W, Lütjohann D, Lämmer M. Clarithromycin is absorbed by an intestinal uptake mechanism that is sensitive to major inhibition by rifampicin: results of a short-term drug interaction study in foals.. Drug Metab Dispos 2012;40:522-8.
  16. Venner M, Peters J, Höhensteiger N, Schock B, Bornhorst A, Grube M. Concentration of the macrolide antibiotic tulathromycin in broncho-alveolar cells is influenced by comedication of rifampicin in foals.. Naunyn Schmiedebergs Arch Pharmacol 2010;38:161-9.
  17. Giguère S. Treatment of infections caused by Rhodococcus equi.. Vet Clin North Am Equine Pract 2017;33:67-85.
  18. Peters J, Block W, Oswald S, Freyer J, Grube M, Kroemer HK. Oral absorption of clarithromycin is nearly abolished by chronic comedication of rifampin in foals.. Drug Metab Dispos 2011;39:1643-9.
  19. Fines M, Pronost S, Maillard K, Taouji S, Leclercq R. Characterization of mutations in the rpoB gene associated with rifampin resistance in Rhodococcus equi isolated from foals.. J Clin Microbiol 2001;39:2784-7.
  20. Anastasi E, Giguère S, Berghaus LJ, Hondalus MK, Willingham-Lane JM, MacArthur I. Novel transferable erm(46) determinant responsible for emerging macrolide resistance in Rhodococcus equi.. J Antimicrob Chemother 2015;70:3184-90.
  21. Álvarez-Narváez S, Giguère S, Anastasi E, Hearn J, Scortti M, Vázquez-Boland JA. Clonal confinement of a highly mobile resistance element driven by combination therapy in Rhodococcus equi.. MBio 2019;10.
    doi: 10.1128/mbio.02260-19google scholar: lookup
  22. Yamshchikov AV, Schuetz A, Lyon GM. Rhodococcus equi infection.. Lancet Infect Dis 2010;10:350-9.
  23. Collignon PJ, Conly JM, Andremont A, McEwen SA, Aidara-Kane A, World Health Organization Advisory Group, Bogotá Meeting on Integrated Surveillance of Antimicrobial Resistance (WHO-AGISAR), Agerso Y, Andremont A, Collignon P, Conly J, Dang Ninh T, Donado-Godoy P, Fedorka-Cray P, Fernandez H, Galas M, Irwin R, Karp B, Matar G, McDermott P, McEwen S, Mitema E, Reid-Smith R, Scott HM, Singh R, DeWaal CS, Stelling J, Toleman M, Watanabe H, Woo GJ. World Health Organization ranking of antimicrobials according to their importance in human medicine: a critical step for developing risk management strategies to control antimicrobial resistance from food animal production.. Clin Infect Dis 2016;15:1087-93.
  24. Haworth CS, Banks J, Capstick T, Fisher AJ, Gorsuch T, Laurenson IF, Leitch A, Loebinger MR, Milburn HJ, Nightingale M, Ormerod P, Shingadia D, Smith D, Whitehead N, Wilson R, Floto RA. British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).. Thorax 72 (Suppl. 2), ii1-ii64.
  25. Berghaus LJ, Giguère S, Guldbech K, Warner E, Ugorji U, Berghaus RD. Comparison of Etest, disk diffusion, and broth macrodilution for in vitro susceptibility testing of Rhodococcus equi.. J Clin Microbiol 2015;53:314-8.
  26. Wetzig M, Venner M, Giguère S. Efficacy of the combination of doxycycline and azithromycin for the treatment of foals with mild to moderate bronchopneumonia.. Equine Vet J 2019;52:613-9.
  27. Clinical Laboratory Standard Institute. Methods for Antimicrobial Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria Isolated from Animals-1st edn.. CLSI document VET06. Wayne, PA: Clinical Laboratory Standard Institute.
  28. Riesenberg A, Feßler AT, Erol E, Prenger-Berninghoff E, Stamm I, Böse R. MICs of 32 antimicrobial agents for Rhodococcus equi isolates of animal origin.. J Antimicrob Chemother 2014;69:1045-9.
  29. Pillai SK, Moellering RC, Eliopoulos GM. Antimicrobial combinations.. In: Lorian V, editor. Antibiotics in laboratory medicine. Philadelphia: Lippincott, Williams and Wilkins; 2005. pp. 365-440.
  30. Suarez-Mier G, Giguère S, Lee EA. Pulmonary disposition of erythromycin, azithromycin, and clarithromycin in foals.. J Vet Pharmacol Ther 2007;30:109-15.
  31. Womble A, Giguère S, Lee EA. Pharmacokinetics of oral doxycycline and concentrations in body fluids and bronchoalveolar cells of foals.. J Vet Pharmacol Ther 2007;30:187-93.
  32. Schnabel LV, Papich MG, Divers TJ, Altier C, Aprea MS, McCarre TM. Pharmacokinetics and distribution of minocycline in mature horses after oral administration of multiple doses and comparison with minimum inhibitory concentrations.. Equine Vet J 2012;44:453-8.
  33. Drlica K. The mutant selection window and antimicrobial resistance.. J Antimicrob Chemother 2003;52:11-7.
  34. Huber L, Giguère S, Slovis NM, Carter CN, Barr BS, Cohen ND. Emergence of Resistance to Macrolides and Rifampin in Clinical Isolates of Rhodococcus equi from Foals in Central Kentucky, 1995 to 2017.. Antimicrob Agents Chemother 2019;63.
  35. Álvarez-Narváez S, Berghaus LJ, Morris ERA, Willingham-Lane JM, Slovis NM, Giguère S. A common practice of widespread antimicrobial use in horse production promotes multi-drug resistance.. Sci Rep 2020;10:911.
  36. Huber L, Giguère S, Hart KA, Slovis NM, Greiter ME, Dailey CA. Association between antimicrobial treatment of subclinical pneumonia in foals and selection of macrolide- and rifampicin-resistant Rhodococcus equi strains at horse-breeding farms in central Kentucky.. J Am Vet Med Assoc 2021;258:648-53.
  37. Álvarez-Narváez S, Giguère S, Berghaus LJ, Dailey C, Vázquez-Boland JA. Horizontal spread of Rhodococcus equi macrolide resistance plasmid pRErm46 across environmental Actinobacteria.. Appl Environ Microbiol 2020.
  38. Takai S, Takeda K, Nakano Y, Karasawa T, Furugoori J, Sasaki Y. Emergence of rifampin-resistant Rhodococcus equi in an infected foal.. J Clin Microbiol 1997;35:1904-8.
  39. Zhao X, Drlica K. Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies.. Clin Infect Dis 2001;33:S147-56.

Citations

This article has been cited 5 times.
  1. Baptiste KE, Kyvsgaard NC, Ahmed MO, Damborg P, Dowling PM. Is Rifampin (Rifampicin) Essential for the Treatment of Rhodococcus equi Infections in Foals? A Critical Review of the Role of Rifampin. J Vet Pharmacol Ther 2025 Sep;48(5):345-358.
    doi: 10.1111/jvp.70007pubmed: 40552784google scholar: lookup
  2. Huguet AS, Gourbeyre O, Bernand A, Philibert C, Bousquet-Melou A, Lallemand EA, Ferran AA. Comparative bactericidal activity of four macrolides alone and combined with rifampicin or doxycycline against Rhodococcus equi at concentrations achievable in foals. Front Pharmacol 2024;15:1458496.
    doi: 10.3389/fphar.2024.1458496pubmed: 39624843google scholar: lookup
  3. Kabir A, Lamichhane B, Habib T, Adams A, El-Sheikh Ali H, Slovis NM, Troedsson MHT, Helmy YA. Antimicrobial Resistance in Equines: A Growing Threat to Horse Health and Beyond-A Comprehensive Review. Antibiotics (Basel) 2024 Jul 29;13(8).
    doi: 10.3390/antibiotics13080713pubmed: 39200013google scholar: lookup
  4. Alvarez Narvaez S, Sanchez S. Exploring the Accessory Genome of Multidrug-Resistant Rhodococcus equi Clone 2287. Antibiotics (Basel) 2023 Nov 17;12(11).
    doi: 10.3390/antibiotics12111631pubmed: 37998833google scholar: lookup
  5. Rakowska A, Czopowicz M, Bereznowski A, Witkowski L. Investigation of the relationship between pulmonary lesions based on lung ultrasound and respiratory clinical signs in foals with suspected pulmonary rhodococcosis. Sci Rep 2023 Nov 8;13(1):19401.
    doi: 10.1038/s41598-023-46833-2pubmed: 37938262google scholar: lookup
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