1887

Abstract

The antibacterial activity and selection of resistant bacteria, along with mechanisms of fluoroquinolone resistance, were investigated by integrating the static [MIC or mutant-prevention concentration (MPC)] and dynamic model approaches using isolates from diseased dogs. Using the dynamic models, selected strains and enrofloxacin and marbofloxacin at a range of simulated area under concentration–time curve over a 24 h interval (AUC)/MIC ratios were investigated. Our results indicated increasing losses in susceptibility of upon continuous exposure to enrofloxacin and marbofloxacin . This effect was transferable to other fluoroquinolones, as well as to structurally unrelated drugs. Our results also confirmed an AUC/MIC (AUC/MPC)-dependent antibacterial activity and selection of resistant mutants, in which maximum losses in fluoroquinolone susceptibility occurred at simulated AUC/MIC ratios of 40–60. AUC/MPC ratios of 39 (enrofloxacin) and 32 (marbofloxacin) were considered protective against the selection of resistant mutants of . Integrating our MIC and MPC data with published pharmacokinetic information in dogs revealed a better effect of the conventional dosing regimen of marbofloxacin than that of enrofloxacin in restricting the selection of resistant mutants of Target mutations, especially at codon 83 (serine to leucine) of , and overexpression of efflux pumps contributed to resistance development in both clinically resistant and -selected mutants of . We also report here a previously undescribed mutation at codon 116 of in two laboratory-derived resistant mutants of . Additional studies would determine the exact role of this mutation in fluoroquinolone susceptibility, as well as establish the importance of our findings in the clinical setting.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.028654-0
2011-10-01
2020-01-21
Loading full text...

Full text loading...

/deliver/fulltext/jmm/60/10/1512.html?itemId=/content/journal/jmm/10.1099/jmm.0.028654-0&mimeType=html&fmt=ahah

References

  1. Ball K. R. , Rubin J. E. , Chirino-Trejo M. , Dowling P. M. . ( 2008; ). Antimicrobial resistance and prevalence of canine uropathogens at the Western College of Veterinary Medicine Veterinary Teaching Hospital, 2002–2007. . Can Vet J 49:, 985–990.[PubMed]
    [Google Scholar]
  2. Blondeau J. M. , Zhao X. , Hansen G. , Drlica K. . ( 2001; ). Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae . . Antimicrob Agents Chemother 45:, 433–438. [CrossRef] [PubMed]
    [Google Scholar]
  3. Booth D. M. . ( 2001; ). Treatment of bacterial infections. . In Small Animal Veterinary Pharmacology and Therapeutics, pp. 175–221. Edited by Booth D. M. . . Philadelphia, PA:: W. B. Saunders;.
    [Google Scholar]
  4. Boothe D. M. , Boeckh A. , Simpson R. B. , Dubose K. . ( 2006; ). Comparison of pharmacodynamic and pharmacokinetic indices of efficacy for 5 fluoroquinolones toward pathogens of dogs and cats. . J Vet Intern Med 20:, 1297–1306. [CrossRef] [PubMed]
    [Google Scholar]
  5. CLSI ( 2002; ). Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals, 2nd edn. Approved Standard M31–A2. Wayne, PA: Clinical and Laboratory Standards Institute.
  6. Cohn L. A. , Gary A. T. , Fales W. H. , Madsen R. W. . ( 2003; ). Trends in fluoroquinolone resistance of bacteria isolated from canine urinary tracts. . J Vet Diagn Invest 15:, 338–343. [CrossRef] [PubMed]
    [Google Scholar]
  7. Craigmill A. L. , Riviere J. E. , Webb A. I. . ( 2006; ). Tabulation of FARAD Comparative and Veterinary Pharmacokinetic Data, pp. 719–859. Ames, IA:: Wiley-Blackwell;.
    [Google Scholar]
  8. Dong Y. , Zhao X. , Kreiswirth B. N. , Drlica K. . ( 2000; ). Mutant prevention concentration as a measure of antibiotic potency: studies with clinical isolates of Mycobacterium tuberculosis . . Antimicrob Agents Chemother 44:, 2581–2584. [CrossRef] [PubMed]
    [Google Scholar]
  9. Drlica K. , Zhao X. . ( 2007; ). Mutant selection window hypothesis updated. . Clin Infect Dis 44:, 681–688. [CrossRef] [PubMed]
    [Google Scholar]
  10. Firsov A. A. , Lubenko I. Y. , Vostrov S. N. , Kononenko O. V. , Zinner S. H. , Portnoy Y. A. . ( 2000; ). Comparative pharmacodynamics of moxifloxacin and levofloxacin in an in vitro dynamic model: prediction of the equivalent AUC/MIC breakpoints and equiefficient doses. . J Antimicrob Chemother 46:, 725–732. [CrossRef] [PubMed]
    [Google Scholar]
  11. Firsov A. A. , Zinner S. H. , Lubenko I. Y. , Portnoy Y. A. , Vostrov S. N. . ( 2002; ). Simulated in vitro quinolone pharmacodynamics at clinically achievable AUC/MIC ratios: advantage of I E over other integral parameters. . Chemotherapy 48:, 275–279.[CrossRef]
    [Google Scholar]
  12. Firsov A. A. , Vostrov S. N. , Lubenko I. Y. , Arzamastsev A. P. , Portnoy Y. A. , Zinner S. H. . ( 2004; ). ABT492 and levofloxacin: comparison of their pharmacodynamics and their abilities to prevent the selection of resistant Staphylococcus aureus in an in vitro dynamic model. . J Antimicrob Chemother 54:, 178–186. [CrossRef] [PubMed]
    [Google Scholar]
  13. Frazier D. L. , Thompson L. L. , Trettien A. , Evans E. I. . ( 2000; ). Comparison of fluoroquinolone pharmacokinetic parameters after treatment with marbofloxacin, enrofloxacin, and difloxacin in dogs. . J Vet Pharmacol Ther 23:, 293–302. [CrossRef] [PubMed]
    [Google Scholar]
  14. Gebru E. , Lee J. S. , Chang Z. Q. , Hwang M. H. , Cheng H. , Park S. C. . ( 2009; ). Integration of pharmacokinetic and pharmacodynamic indices of orbifloxacin in beagle dogs after a single intravenous and intramuscular administration. . Antimicrob Agents Chemother 53:, 3024–3029. [CrossRef] [PubMed]
    [Google Scholar]
  15. Grobbel M. , Lübke-Becker A. , Wieler L. H. , Froyman R. , Friederichs S. , Filios S. . ( 2007; ). Comparative quantification of the in vitro activity of veterinary fluoroquinolones. . Vet Microbiol 124:, 73–81. [CrossRef] [PubMed]
    [Google Scholar]
  16. Heinen E. . ( 2002; ). Comparative serum pharmacokinetics of the fluoroquinolones enrofloxacin, difloxacin, marbofloxacin, and orbifloxacin in dogs after single oral administration. . J Vet Pharmacol Ther 25:, 1–5. [CrossRef] [PubMed]
    [Google Scholar]
  17. Ince D. , Hooper D. C. . ( 2001; ). Mechanisms and frequency of resistance to gatifloxacin in comparison to AM-1121 and ciprofloxacin in Staphylococcus aureus . . Antimicrob Agents Chemother 45:, 2755–2764. [CrossRef] [PubMed]
    [Google Scholar]
  18. Isenberg H. D. . ( 1995; ). Identification methods: aerobic bacteriology. . In Clinical Microbiology Procedures Handbook, pp. 1.19.1–1.19.58. Washington, DC:: American Society for Microbiology;.
    [Google Scholar]
  19. Johnson J. R. , Kuskowski M. A. , Owens K. , Clabots C. , Singer R. S. . ( 2009; ). Virulence genotypes and phylogenetic background of fluoroquinolone-resistant and susceptible Escherichia coli urine isolates from dogs with urinary tract infection. . Vet Microbiol 136:, 108–114. [CrossRef] [PubMed]
    [Google Scholar]
  20. Litster A. , Moss S. , Honnery M. , Rees B. , Edingloh M. , Trott D. . ( 2007; ). Clinical efficacy and palatability of pradofloxacin 2.5 % oral suspension for the treatment of bacterial lower urinary tract infections in cats. . J Vet Intern Med 21:, 990–995. [CrossRef] [PubMed]
    [Google Scholar]
  21. Martinez M. , McDermott P. , Walker R. . ( 2006; ). Pharmacology of the fluoroquinolones: a perspective for the use in domestic animals. . Vet J 172:, 10–28. [CrossRef] [PubMed]
    [Google Scholar]
  22. Minh Vien L. T. , Baker S. , Phuong Thao L. T. , Phuong Tu L. T. , Thu Thuy C. , Thu Nga T. T. , Minh Hoang N. V. , Campbell J. I. , Minh Yen L. et al. ( 2009; ). High prevalence of plasmid-mediated quinolone resistance determinants in commensal members of the Enterobacteriaceae in Ho Chi Minh City, Vietnam. . J Med Microbiol 58:, 1585–1592. [CrossRef] [PubMed]
    [Google Scholar]
  23. Mueller R. S. , Stephan B. . ( 2007; ). Pradofloxacin in the treatment of canine deep pyoderma: a multicentred, blinded, randomized parallel trial. . Vet Dermatol 18:, 144–151. [CrossRef] [PubMed]
    [Google Scholar]
  24. Mueller M. , de la Peña A. , Derendorf H. . ( 2004; ). Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: kill curves versus MIC. . Antimicrob Agents Chemother 48:, 369–377. [CrossRef] [PubMed]
    [Google Scholar]
  25. Ng E. Y. , Trucksis M. , Hooper D. C. . ( 1996; ). Quinolone resistance mutations in topoisomerase IV: relationship to the flqA locus and genetic evidence that topoisomerase IV is the primary target and DNA gyrase is the secondary target of fluoroquinolones in Staphylococcus aureus . . Antimicrob Agents Chemother 40:, 1881–1888.[PubMed]
    [Google Scholar]
  26. Olofsson S. K. , Marcusson L. L. , Komp Lindgren P. , Hughes D. , Cars O. . ( 2006; ). Selection of ciprofloxacin resistance in Escherichia coli in an in vitro kinetic model: relation between drug exposure and mutant prevention concentration. . J Antimicrob Chemother 57:, 1116–1121. [CrossRef] [PubMed]
    [Google Scholar]
  27. Oram M. , Fisher L. M. . ( 1991; ). 4-Quinolone resistance mutations in the DNA gyrase of Escherichia coli clinical isolates identified by using the polymerase chain reaction. . Antimicrob Agents Chemother 35:, 387–389.[PubMed] [CrossRef]
    [Google Scholar]
  28. Pasquali F. , Manfreda G. . ( 2007; ). Mutant prevention concentration of ciprofloxacin and enrofloxacin against Escherichia coli, Salmonella typhimurium and Pseudomonas aeruginosa . . Vet Microbiol 119:, 304–310. [CrossRef] [PubMed]
    [Google Scholar]
  29. Peterson M. L. , Hovde L. B. , Wright D. H. , Brown G. H. , Hoang A. D. , Rotschafer J. C. . ( 2002; ). Pharmacodynamics of trovafloxacin and levofloxacin against Bacteroides fragilis in an in vitro pharmacodynamic model. . Antimicrob Agents Chemother 46:, 203–210. [CrossRef] [PubMed]
    [Google Scholar]
  30. Platell J. L. , Cobbold R. N. , Johnson J. R. , Trott D. J. . ( 2010; ). Clonal group distribution of fluoroquinolone-resistant Escherichia coli among humans and companion animals in Australia. . J Antimicrob Chemother 65:, 1936–1938. [CrossRef] [PubMed]
    [Google Scholar]
  31. Poole K. . ( 2000; ). Efflux-mediated resistance to fluoroquinolones in Gram-negative bacteria. . Antimicrob Agents Chemother 44:, 2233–2241. [CrossRef] [PubMed]
    [Google Scholar]
  32. Roberts J. A. , Kruger P. , Paterson D. L. , Lipman J. . ( 2008; ). Antibiotic resistance – what’s dosing got to do with it?. Crit Care Med 36:, 2433–2440. [CrossRef] [PubMed]
    [Google Scholar]
  33. Ruiz J. . ( 2003; ). Mechanisms of resistance to quinolones: target alterations, decreased accumulation and DNA gyrase protection. . J Antimicrob Chemother 51:, 1109–1117. [CrossRef] [PubMed]
    [Google Scholar]
  34. Rybak M. J. . ( 2006; ). Pharmacodynamics: relation to antimicrobial resistance. . Am J Med 119: (Suppl. 1), S37–S44. [CrossRef] [PubMed]
    [Google Scholar]
  35. Tejedor M. T. , Martín J. L. , Navia M. , Freixes J. , Vila J. . ( 2003; ). Mechanisms of fluoroquinolone resistance in Pseudomonas aeruginosa isolates from canine infections. . Vet Microbiol 94:, 295–301. [CrossRef] [PubMed]
    [Google Scholar]
  36. Vila J. , Ruiz J. , Goñi P. , De Anta M. T. . ( 1996; ). Detection of mutations in parC in quinolone-resistant clinical isolates of Escherichia coli . . Antimicrob Agents Chemother 40:, 491–493.[PubMed]
    [Google Scholar]
  37. Vostrov S. N. , Kononenko O. V. , Lubenko I. Y. , Zinner S. H. , Firsov A. A. . ( 2000; ). Comparative pharmacodynamics of gatifloxacin and ciprofloxacin in an in vitro dynamic model: prediction of equiefficient doses and the breakpoints of the area under the curve/MIC ratio. . Antimicrob Agents Chemother 44:, 879–884. [CrossRef] [PubMed]
    [Google Scholar]
  38. Walker R. D. . ( 2000; ). The use of fluoroquinolones for companion animal antimicrobial therapy. . Aust Vet J 78:, 84–90. [CrossRef] [PubMed]
    [Google Scholar]
  39. Wang A. , Yang Y. , Lu Q. , Wang Y. , Chen Y. , Deng L. , Ding H. , Deng Q. , Zhang H. et al. ( 2008; ). Presence of qnr gene in Escherichia coli and Klebsiella pneumoniae resistant to ciprofloxacin isolated from pediatric patients in China. . BMC Infect Dis 8:, 68. [CrossRef] [PubMed]
    [Google Scholar]
  40. Wetzstein H. G. . ( 2005; ). Comparative mutant prevention concentrations of pradofloxacin and other veterinary fluoroquinolones indicate differing potentials in preventing selection of resistance. . Antimicrob Agents Chemother 49:, 4166–4173. [CrossRef] [PubMed]
    [Google Scholar]
  41. Zinner S. H. , Lubenko I. Y. , Gilbert D. , Simmons K. , Zhao X. , Drlica K. , Firsov A. A. . ( 2003; ). Emergence of resistant Streptococcus pneumoniae in an in vitro dynamic model that simulates moxifloxacin concentrations inside and outside the mutant selection window: related changes in susceptibility, resistance frequency and bacterial killing. . J Antimicrob Chemother 52:, 616–622. [CrossRef] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.028654-0
Loading
/content/journal/jmm/10.1099/jmm.0.028654-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error