Transcript Staphylococcus aureus

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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
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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 < 0.004 µg/mL
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RESULTS
The MIC90 of Gatifloxacin, BAK, and the GatifloxacinBAK Combination Against Clinical Isolates of MRSA
4.0
3.1
MIC90 (µg/mL)
0.2
3.0
0.125
0.1
< 0.004
0
Gatifloxacin
BAK
Gatifloxacin-BAK
Combination
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RESULTS
The MPC of Gatifloxacin, BAK, and the GatifloxacinBAK Combination Against Clinical Isolates of MRSA
6a
MPC (µg/mL)
6
5
≥4
4
3
2
1
< 0.004b
0
Gatifloxacin
aRanged
bThe
from 6 to 10 µg/mL.
concentration of BAK was 10 µg/mL.
BAK
Gatifloxacin-BAK
Combination
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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 775fold 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
REFERENCES
1. Blomquist PH. Methicillin-resistant Staphylococcus aureus infections of the
eye and orbit. Trans Am Ophthalmol Soc. 2006;104:322-345.
2. Marangon FB, Miller D, Muallem MS, Romano AC, Alfonso EC. Ciprofloxacin
and levofloxacin resistance among methicillin-sensitive Staphylococcus
aureus isolates from keratitis and conjunctivitis. Am J Ophthalmol.
2004;137(3):453-458.
3. Hooper DC. Mechanisms of action and resistance of older and newer
fluoroquinolones. Clin Infect Dis. 2000;31 (suppl 2):S24-S28.
4. Hansen G, Blondeau JM. Mutant prevention concentrations as a strategy to
minimize antimicrobial resistance: a timely concept but will its acceptance be
too late? Therapy. 2005;2:61-66.
5. Blondeau JM, Zhao X, Hansen GT, Drlica K. Mutant prevention
concentrations (MPC) of fluoroquinolones for clinical isolates of
Streptococcus pneumoniae. Antimicrob Agents Chemother. 2001;45(2):433438.
6. ZYMAR® [package insert]. Irvine, CA: Allergan, Inc.; 2004.
7. Blondeau JM, Borsos S, Hesje CK. Antimicrobial efficacy of gatifloxacin and
moxifloxacin with and without benzalkonium chloride compared with
ciprofloxacin and levofloxacin against methicillin-resistant Staphylococcus
aureus. J Chemother. 2007;19(2):146-151.
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