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Correspondence:
Abstract 1900
In Vitro Activity of Retapamulin and Comparators
D. Sahm
Focus Bio-Inova
(F-2052)
13665 Dulles Technology Drive
against 1690 Recent Gram-Positive Clinical Isolates
Suite 200
Herndon, VA 20171
Tel: +1 703 480 2500
Fax: +1 703 480 2654
D. Draghi,1 N. Scangarella,2 R. Shawar2 & D. Sahm1
E-mail: dsahm@focusbioinova.com
1Focus Bio-Inova, Herndon, VA, USA; 2GlaxoSmithKline Pharmaceuticals, Collegeville, PA, USA.
Abstract
however, some of the organisms tested, not typically associated with Table 3. In Vitro Activity of Retapamulin and Comparator Antimicrobials
points were read visually and MICs were interpreted as susceptible, SSSIs, were derived from other specimen sources (Table 1). intermediate, or resistant using the 2004 CLSI M100-S14 published Background: Retapamulin (SB-275833) is the first pleuromutilin formulated as a
breakpoints, where available.2 VISA and VRSA isolates were tested topical antibacterial for treating skin and skin structure infections (SSSIs). It has The following comparator antibacterial agents were tested: bacitracin, in triplicate using fresh broth microdilution panels prepared at Focus a unique mode of action and shows no target-specific cross-resistance to other cephalothin, ciprofloxacin, erythromycin, gentamicin, mupirocin, antibacterial classes. The aim of this study was to assess the in vitro activity of retapamulin and other antibacterial agents against clinical isolates from Gram- positive bacterial species commonly associated with SSSIs. Methods: MICs of
In addition to the isolates described, 11 vancomycin-intermediate retapamulin, bacitracin, cephalothin, ciprofloxacin, erythromycin, gentamicin, (VISA; vancomycin MICs = 8 µg/mL) and 2 vancomycin-resistant (VRSA; mupirocin, oxacillin and penicillin were determined by broth microdilution ● Retapamulin maintained a high level of activity (based on MIC ) vancomycin MICs >32 µg/mL) isolates were selected from the Network according to the Clinical and Laboratory Standards Institute (CLSI, formerly the against all key Gram-positive species associated with skin infections.
National Committee for Clinical Laboratory Standards [NCCLS]) methodology. on Antimicrobial Resistance in Staphylococcus aureus (NARSA) isolate This level of activity did not appear to be impacted by the A total of 1690 recent clinical isolates (1998–2004) from the USA and Europe repository based on their vancomycin MIC as reported by NARSA. The organism’s resistance phenotypes to other drug classes (Table 2).
were selected for testing, the majority of which were chosen from SSSI sources. following comparator agents were tested against the VISA and VRSA ● For S. aureus, Streptococcus pyogenes, Staphylococcus saprophyticus Results: The MIC
isolates: fusidic acid, moxifloxacin and mupirocin.
and other coagulase-negative staphylococci, retapamulin exhibited Susceptibility testing
the comparator agents (for S. aureus, retapamulin and mupirocin exhibited the same MIC ). For Streptococcus agalactiae and viridans Isolates were tested by broth microdilution at Focus Bio-Inova central group streptococci, retapamulin activity was greater than that of laboratory (Herndon, VA, USA). Testing was done using commercially comparators and equal to that of penicillin (Table 3).
prepared frozen broth microdilution panels (TREK Diagnostic Systems, ● With regard to specific S. aureus-resistant phenotypes, retapamulin Inc., Cleveland, OH, USA) according to Clinical and Laboratory Standards activity was maintained regardless of the methicillin status of the Institute (CLSI, formerly National Committee for Clinical Laboratory isolates tested. In contrast, the activity of several comparators was Standards [NCCLS]) standard methodology (M7-A6).1 Inhibition end- ● Similarly, retapamulin exhibited strong in vitro activity against all RE, retapamulin; BA, bacitracin, CE, cephalothin; CI, ciprofloxacin; ER, erythromycin; GE, gentamicin; Table 1. Breakdown of Organisms by Specimen Source
the VISA and VRSA strains tested (Table 5).
MU, mupirocin; OX, oxacillin; PE, penicillin.
Conclusion: On the basis of MIC s, retapamulin had the most potent in vitro
Conclusions
profile against staphylococci and streptococci. With the exception of Bacillus spp., the in vitro activity of retapamulin indicates potential in the treatment of SSSIs ● Retapamulin exhibited promising activity against clinically relevant caused by these Gram-positive organisms.
Gram-positive organisms associated with SSSIs and this in vitro activity was not impacted by resistance to other antimicrobial Introduction
● These in vitro findings strongly support retapamulin’s clinical Staphylococcal, streptococcal and facultative aerobic Gram-positive potential. Clinical trial data are required in order to assess its organisms are of serious concern for clinicians treating skin and soft tissue infections. Resistance to currently marketed antibacterial agents is S. saprophyticus (100) Retapamulin Acknowledgements
rising for patients with these types of infections. Retapamulin (Figure 1, SB-275833) is the first, novel, semi-synthetic pleuromutilin, representing This study was sponsored by a grant from GlaxoSmithKline a new class of antibacterial agent, which has been formulated as a topical antibacterial for the treatment of skin and skin structure Table 2. Overall Summary of Retapamulin In Vitro Activity
infections (SSSIs). It inhibits protein synthesis by interacting at a unique References
site on the 50S ribosomal subunit and shows no target-specific cross- National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests resistance to other antibacterial classes. The aim of this study was to for Bacteria that Grow Aerobically, Approved Standard, 6th Edition. M7-A6. Wayne, PA, USA: NCCLS, 2003.
National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility assess the in vitro activity of retapamulin and other antibacterial agents Testing, 14th Informational Supplement. M100-S14. Wayne, PA, USA: NCCLS, 2004.
against clinical isolates from Gram-positive bacterial species, some of Table 4. Comparative In Vitro Activity of Retapamulin and Comparators against
which are commonly associated with SSSIs. Methicillin-susceptible and Methicillin-resistant S. aureus
Bacterial isolates and antimicrobials
In total, 1690 recent clinical isolates (1998–2004) from the USA and Europe were selected for testing. All isolates were consecutively collected and only one isolate per patient was tested. Isolates were chosen from skin and skin structure specimen sources where possible; Table 5. Comparative In Vitro Activity of Retapamulin and Comparators against
VISA and VRSA
aCephalothin was tested to predict the activity of cephalexin.
Figure 1. Chemical Structure of Retapamulin
aMIC and MIC not reported for isolate subsets with n<10.
bNCCLS interpretations are unavailable to determine percent resistant.
Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, 16–19 December 2005, Washington, DC, USA

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