Abstract 507 Resistance Patterns of Methicillin- and Mupirocin-resistant S. aureus from Correspondence: S. Bouchillon IHMA Uncomplicated Skin and Skin Structure Infections (SSSIs) in the United States 2122 Palmer Drive Schaumburg IL 60173 from March 2004–March 2005; Retapamulin Surveillance Study USA Tel: +1 615 599 8429 Fax: +1 847 303 5601 S. Bouchillon,1 B. Johnson,1 T. Stevens,1 D. Hoban,1 J. Johnson,1 N. Scangarella,2 R. Shawar2 E-mail: [email protected] 1International Health Management Associates, Schaumburg, IL, USA; 2GlaxoSmithKline, Collegeville, PA, USA Abstract
guidelines4 for retapamulin and 14 comparators in dried broth
Table 1. MIC (µg/mL) Summary for Retapamulin Activity against 994 S. aureus Isolates Table 2. MIC (µg/mL) Summary for Retapamulin and Comparators against S. aureus Isolates by Recovered from SSSIs Resistant Phenotype
microdilution panels (Trek Diagnostic Systems Ltd, West Sussex, UK). Background: Retapamulin is a novel semi-synthetic pleuromutilin currently in
Comparator antimicrobial agents included: amoxicillin-clavulanic acid,
development as a topical antimicrobial for the treatment of skin and skin
bacitracin, ceftriaxone, cephalothin, clindamycin, cloxacillin,
structure infections (SSSIs). The mode of action for pleuromutilin is unique and
shows no cross-resistance to other classes of antibiotics and is fully active against
erythromycin, fusidic acid, gentamicin, linezolid, mupirocin,
skin bacterial isolates carrying resistance determinants to established agents
including β-lactams, macrolides, quinolones, fusidic acid and mupirocin.
All study organisms were clinical isolates collected and frozen at -70°C
Methods: Clinical isolates of Staphylococcus aureus were collected from 9 sites
from March 2004 to March 2005 from 9 sites in the USA. All isolates
in the United States during 2004 and 2005. All isolates were sent to the central
were obtained from uncomplicated SSSI, primarily from infections
laboratory for testing, identification confirmation and confirmation of oxacillin
Mupirocin-resistant and methicillin-susceptible (42)
resistance. Organisms were frozen at -70°C prior to evaluation. Susceptibility
seen in community settings. Isolates were obtained from both adult
Mupirocin-resistant and methicillin-resistant (61)
testing was performed using broth microdilution panels. Quality controls were
and pediatric patients with one isolate per patient.
performed each day of testing following Clinical and Laboratory Standards
Phenotypes were determined by the in vitro susceptibility of the respective antimicrobial agent against the
Organism collection, transport, confirmation of organism
corresponding organism as defined in CLSI document M100-S15 unless otherwise noted;6 methicillin = oxacillin
Institute (CLSI; formerly the National Committee for Clinical Laboratory Standards
identification, antimicrobial susceptibility testing, as well as
[NCCLS]) guidelines. Results: A total of 994 S. aureus isolates were collected of
bMupirocin susceptibility breakpoints (≤4 µg/mL susceptible; ≥8 µg/mL resistant) as defined by Finlay et al.7
construction and management of a centralized database, were
which 416 or 41.9% were determined to be methicillin-resistant (MRSA).
Mupirocin-resistance (MURMRSA) was detected in 61/416 or 14.7% of all MRSAs.
coordinated by International Health Management Associates, Inc.
Retapamulin MIC s against MRSA/MURMRSA isolates is 0.12/0.12 µg/mL. The same
isolates exhibited MIC s (expressed in µg/mL) of >64/>64 for neomycin; 0.5/1
A total of 994 S. aureus isolates were collected from patients in
for fusidic acid; >128/>128 for bacitracin; >32/>32 for erythromycin; 32/32 for
hospital and community settings and tested. Of these, 416 (41.9%)
tetracycline; 2/2 for linezolid; 32/32 for cephalothin; 4/8 for gentamicin; and
were methicillin-resistant, 103 (10.4%) were mupirocin-resistant and
16/16 for amoxicillin/clavulanic acid. Conclusions: Retapamulin demonstrated
Phenotype was determined by the susceptibility of S. aureus to oxacillin as defined in CLSI document M100-S15.6
bPhenotype was determined by the susceptibility of S. aureus to mupirocin as defined by Finlay et al.7
greater activity against methicillin- and mupirocin-resistant S. aureus isolates than
61 (6.1%) were methicillin- and mupirocin-resistant. These rates may
cInterpretive criteria of compounds defined in CLSI document M100-S15 where available; mupirocin susceptibility
current commonly used topical and oral antimicrobial agents in the treatment
be somewhat higher than those observed in routine clinical practice
(≤4 µg/mL susceptible; ≥8 µg/mL resistant) defined in Finlay et al.;7 fusidic acid susceptibility (≤1 µg/mL susceptible;
as surveillance studies only reflect data from patients for whom a
4 µg/mL resistant) defined in Toma and Barriault;8 Note: β-lactams reported as resistant for MRSA in accordance
culture and susceptibility testing were performed.
dAmoxicillin/clavulanic acid was tested in a 2:1 ratio; MICs are reported based on the amoxicillin concentration. Introduction
Mueller-Hinton broth (Sensititre®, Cleveland, OH, USA) was used for
Retapamulin (SB-275833; Figure 1), a novel derivative of the pleuromutilin
The trays were incubated at 35°C in ambient air for 16–20 h before
class of antimicrobials, is currently in development for the topical treatment of
a variety of Gram positive pathogens associated with secondarily infected
Quality control testing was performed each day of testing as specified
traumatic lesions and dermatoses. The pleuromutilins are potent inhibitors of
by the CLSI using the following isolates: S. aureus ATCC 29213 and
protein synthesis in bacteria through the interference of peptide bond
S. aureus ATCC 25923. In addition, quality control ranges previously
formation by binding to the peptidyl transferase center of the 50S ribosomal
determined for retapamulin were used as a control.5
subunit.1 Due to the unique pleuromutilin mode of action, retapamulin shows
no target specific cross-resistance to other classes of antibacterials.
ranges were determined for all antimicrobial agents tested.
Mupirocin is a topical antimicrobial commonly used in the treatment of
Interpretive criteria and resistant phenotypes to the corresponding
Phenotypes were determined by the susceptibility of S. aureus to oxacillin as defined in CLSI document
uncomplicated skin infections and also nasal decolonization of methicillin-
antimicrobial agent were defined according to CLSI breakpoints6 or
resistant Staphylococcus aureus (MRSA). Mupirocin activity against MRSA has
the literature (mupirocin7 and fusidic acid8 only). Methicillin-resistance
decreased since the advent of mupirocin-resistant S. aureus and is linked to
was based upon oxacillin screening agar.
Figure 2. Cumulative Inhibition (%) at Each MIC (µg/mL) for Retapamulin and Comparators
increased usage and exposure to the drug.2,3 Due to a rise in drug resistance
against 416 Methicillin-resistanta S. aureus Isolates from the USA
and the potential for reduced effectiveness of existing treatments, there is anincreased need for new antibiotics with activity against drug-resistant
organisms. This study looked at the in vitro activity of retapamulin against a
geographically diverse population of MRSA and mupirocin-resistant S. aureus
The activity of retapamulin and comparator antimicrobials is presented
from uncomplicated skin and skin structure infections (SSSI) in the USA.
in Tables 1 and 2 and Figures 2–4.
aPhenotypes were determined by the susceptibility of S. aureus to oxacillin as defined in the CLSI document
M100-S15,6 and mupirocin as defined by Finlay et al.7
Materials and Methods Conclusions Figure 4. Cumulative Inhibition (%) at Each MIC (µg/mL) for Retapamulin and Comparators against 61 Mupirocin-resistant/Methicillin-resistanta S. aureus Isolates from the USA
MIC endpoints were determined by broth microdilution and interpreted
Retapamulin demonstrated excellent in vitro activity against
according to Clinical and Laboratory Standards Institute (CLSI, formerly
methicillin-resistant, mupirocin-resistant, and mupirocin-
the National Committee for Clinical Laboratory Standards [NCCLS])
resistant/methicillin-resistant S. aureus isolates from uncomplicated
values at least 8-fold lower than those of any
Schlunzen F, Pyetan E, Fucini P, et al. Inhibition of peptide bond formation by pleuromutilins: the structure of
comparator in this study including linezolid, mupirocin, and fusidic
the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin. Mol Microbiol 2004; 54:
Walker ES, Vasquez JE, Dula R, et al. Mupirocin-resistant, methicillin-resistant Staphylococcus aureus: does
mupirocin remain effective? Infect Control Hosp Epidemiol 2003; 24: 342–346.
Walker ES, Levy F, Shorman M, et al. A decline in mupirocin resistance in methicillin-resistant Staphylococcus
Against all 994 S. aureus isolates tested, retapamulin was the most
aureus accompanied administrative control of prescriptions. J Clin Microbiol 2004; 42: 2792–2795.
CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved
potent agent in vitro and inhibited all S. aureus isolates at a MIC of
Standard 6th Edition. Document M7-A6. Wayne, PA, USA; CLSI, 2005.
≤0.5 µg/mL, including methicillin-resistant, mupirocin-resistant, and
Jones RN. SB-275833, An Investigational Topical Agent: Quality Control Studies for the MIC (M7-A6) Method. Document on file, UH2004/00009/00, GlaxoSmithKline, Collegeville, PA, USA, 2005.
CLSI. Performance Standards for Antimicrobial Susceptibility Testing, in Document M100-S15. Wayne, PA, USA:
Retapamulin’s retention of potent in vitro activity against S. aureus
Finlay JE, Miller LA, Poupard JA. Interpretive criteria for testing susceptibility of staphylococci to mupirocin. Antimicrob Agents Chemother 1997; 41: 1137–1139.
strains resistant to one or more of the agents commonly used in the
Toma E, Barriault D. Antimicrobial activity of fusidic acid and disk diffusion susceptibility testing criteria
treatment of SSSIs could potentially provide a useful option for
for Gram-positive cocci. J Clin Microbiol 1995; 33: 1712–1715.
aPhenotypes were determined by the susceptibility of S. aureus to mupirocin as defined by Finlay et al.7
Clinical trial data is needed to assess the clinical significance of these
Figure 3. Cumulative Inhibition (%) at Each MIC (µg/mL) for Retapamulin and Comparators Figure 1. Chemical Structure of Retapamulin against 103 Mupirocin-resistanta S. aureus Isolates from the USA
This study was sponsored by a grant from GlaxoSmithKline Pharmaceuticals.
Presented at 43rd IDSA, October 6–9 2005, San Francisco, CA, USA
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