Low Propensity of Gatifloxacin-BAK Combination to Select for Fluoroquinolone Resistance Among Methicillin-Resistant Staphylococcus aureus

1
Low Propensity of Gatifloxacin-BAK Combination to
Select for Fluoroquinolone Resistance Among
Methicillin-Resistant Staphylococcus aureus
Christine Hesje, BSc Joseph M. Blondeau, PhD
Department of Clinical Microbiology, Royal
University Hospital and the Departments of
Microbiology and Immunology and Pathology,
University of Saskatchewan, Saskatoon,
Saskatchewan, Canada
2
Financial Disclosures

• Study supported by an unrestricted educational
  grant from Allergan, Inc.
• Christine Hesje and Joseph Blondeau have no
  financial interests in any product mentioned in
  this study

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INTRODUCTION

• Staphylococcus aureus is a common cause of ocular
  infections
• Methicillin-resistant S aureus (MRSA) strains are
  now prevalent in both the hospital and community
  settings1
• Co-resistance of MRSA to third-generation
  fluoroquinolones is well known2
• The fourth-generation fluoroquinolone
  gatifloxacin has a reduced probability of
  resistance because 2 mutations are necessary for
  resistance to develop3
• Older fluoroquinolones develop resistance with
  only 1 mutation

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Purpose

• The ability of an antibiotic to overcome
  antimicrobial resistance can be evaluated using
  the mutant prevention concentration (MPC)4,5
• MPC is defined as the drug concentration that
  prevents the growth of the most resistant
  first-step mutants in a large heterogeneous
  bacterial population
• In vitro potency of the gatifloxacin commercial
  formulation has been evaluated with the active
  ingredient alone
• Commercial formulation of gatifloxacin (Zymar
  Allergan Inc. Irvine, CA) contains 0.005
  benzalkonium chloride (BAK) as a preservative6
• Recent studies from our laboratory demonstrated
  that the presence of BAK increases antimicrobial
  activity of gatifloxacin7
• The purpose of this study was to determine the
  minimal inhibitory concentration (MIC) and MPC
  values of gatifloxacin, BAK, and the
  gatifloxacin-BAK combination against clinical
  isolates of MRSA

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METHODS

• Seventeen clinical isolates of MRSA were tested
• MIC testing
• Bacteria (105 colony-forming units CFU/mL) were
  inoculated in Mueller-Hinton broth containing
  2-fold concentration increments of the test
  agents
• The lowest concentration that prevented growth of
  90 of bacteria was recorded as the MIC90
• MPC testing
• Bacteria (1010 CFU/mL) were inoculated onto agar
  plates in the presence of increasing
  concentrations of the test agents
• The lowest drug concentration preventing
  bacterial growth was recorded as the MPC
• The range of gatifloxacin concentrations tested
  was from 8 µg/mL to lt 0.004 µg/mL

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RESULTS
The MIC90 of Gatifloxacin, BAK, and the
Gatifloxacin-BAK Combination Against Clinical
Isolates of MRSA
4.0
3.1
3.0
0.125
MIC90 (µg/mL)
lt 0.004
Gatifloxacin
BAK
Gatifloxacin-BAKCombination
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RESULTS
The MPC of Gatifloxacin, BAK, and the
Gatifloxacin-BAK Combination Against Clinical
Isolates of MRSA
6a
4
MPC (µg/mL)
lt 0.004b
Gatifloxacin
BAK
Gatifloxacin-BAKCombination
aRanged from 6 to 10 µg/mL. bThe concentration of
BAK was 10 µg/mL.
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CONCLUSIONS

• The combination of gatifloxacin and BAK was
  highly active against MRSA in vitro
• The MIC of the gatifloxacin-BAK combination was
  over 30-fold and 775-fold lower than the MIC of
  gatifloxacin and BAK alone, respectively
• The MPC of the gatifloxacin-BAK combination was
  at least 1000-fold and 1500-fold lower than the
  MPC of gatifloxacin and BAK alone, respectively
• These findings suggest that Zymar may have low
  propensity to select for fluoroquinolone-resistant
  MRSA

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REFERENCES

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