Correspondence: Abstract 2338 B. Johnson In Vitro Activity of Retapamulin (SB-275833), a Novel Topical Antimicrobial, against 3721 Gram-Positive IHMA (F-2050) 2122 Palmer Drive Schaumburg Isolates Associated with Skin and Skin Structure Infections (SSSIs) From 17 Sites in North America IL 60173 USA 1 1 1 1 2 2 1 1 Tel: +1 847 303 5003 B. Johnson, A. Jordan, S. Bouchillon, D. Hoban, N. Scangarella, R. Shawar, J. Johnson & R. Badal Fax: +1 847 303 5601 1International Health Management Associates, Schaumburg, IL, USA; 2GlaxoSmithKline, Collegeville, PA, USA E-mail: [email protected] Table 3. MIC (µg/mL) Summary for Retapamulin and Comparators against S. aureus from Table 6. MIC (µg/mL) Summary For Retapamulin and Comparators against Viridans Revised Abstract Materials and Methods North America (n = 1182) Streptococci from North America (n = 471) Background: Retapamulin is a novel pleuromutilin currently in development as a topical G MIC endpoints were determined by broth microdilution according to MIC (µg/mL) MIC (µg/mL) antimicrobial for the treatment of skin and skin structure infections (SSSIs) that shows no Clinical and Laboratory Standards Institute (CLSI) guidelines3 for retapamulin a a Compound %Sus %Int %Res Range MIC50 MIC90 Compound %Sus %Int %Res Range MIC50 MIC90 target specific cross-resistance to other classes of antibiotics and exhibits a unique mode of and 14 comparators in customized dried broth microdilution panels (Trek action. Methods: A total of 3721 clinical isolates of staphylococci (Staphylococcus aureus and Retapamulin NA NA NA 0.015–0.5 0.06 0.12 Retapamulin NA NA NA 0.004–0.5 0.06 0.25 Diagnostic Systems Ltd, West Sussex, UK). Comparator antimicrobial agents coagulase-negative staphylococci, including Staphylococcus epidermidis), Streptococcus pyogenes, Amoxicillin- 61.1 0 38.9 0.12–>32 1 16 Amoxicillin- NA NA NA ≤0.015–8 0.12 1 Clavulanic acidb Streptococcus agalactiae, and viridans streptococci were collected from 17 sites in North America included: amoxicillin-clavulanic acid, bacitracin, ceftriaxone, cephalothin, Clavulanic acidb Bacitracin NA NA NA 0.25–>128 32 128 during 2004–2005. A total of 14 antimicrobials were compared with retapamulin. All isolates clindamycin, cloxacillin, erythromycin, fusidic acid, gentamicin, linezolid, Bacitracin NA NA NA ≤0.06–>128 >128 >128 were sent to the central laboratory for confirmation of identification and testing. Susceptibility mupirocin, neomycin, penicillin, and tetracycline. Ceftriaxone 92.8 2.3 4.9 ≤0.015–>64 0.12 1 Ceftriaxone 58.2 4.3 37.5 1–>64 4 32 Cephalothin NA NA NA ≤0.03–128 0.5 2 testing was performed by the central laboratory using broth microdilution panels and quality G All study organisms were clinical isolates collected and frozen at -70°C from Cephalothin 62.7 0.3 37.1 0.12–256 1 8 Clindamycin 86.0 1.1 13.0 ≤0.015–>32 0.03 8 controls were performed each day of testing following Clinical and Laboratory Standards March 2004 to March 2005 from Canada, Mexico, and the USA (Table 1). Clindamycin 75.1 2.4 22.5 0.03–>32 0.12 >32 Cloxacillin NA NA NA 0.03–>32 2 8 Institute (CLSI) guidelines. Results: Results were as follows: All isolates were obtained from SSSIs. Isolates were obtained from both adult Cloxacillin NA NA NA 0.12–>32 0.5 2 Erythromycin 42.3 2.3 55.4 ≤0.015–>32 1 >32 and paediatric patients with one isolate per patient. Erythromycin 35.3 6.9 57.8 0.06–>32 32 >32 Fusidic acid NA NA NA 0.06–>32 16 32 G Organism collection, transport, confirmation of organism identification, Fusidic acid 93.2 2.5 4.2 0.03–16 0.12 1 Gentamicin NA NA NA 0.06–32 4 16 Antimicrobial MIC90 (µg/mL) Linezolid 100 0 0 0.25–2 1 1 antimicrobial susceptibility testing, as well as construction and management Gentamicin 93.3 2.8 3.9 ≤0.03–>64 0.25 2 Mupirocin NA NA NA 0.06–>256 0.5 2 S. aureus Coagulase- S. pyogenes S. agalactiae viridans of a centralized database, were coordinated by International Health (n = 1182) negative (n = 1164) (n = 462) streptococci Linezolid 100 0 0 0.5–4 2 4 Neomycin NA NA NA 0.12–>64 32 >64 staphylococci (n = 471) Management Associates, Inc. (IHMA, Schaumburg, IL, USA). Mupirocin 90.9 0 9.1 0.06–>256 0.25 4 Penicillin 59.4 38.6 1.9 ≤0.015–>32 0.12 0.5 (n = 442) G Mueller–Hinton broth (Sensititre®, Cleveland, OH, USA) was used for all Neomycin NA NA NA ≤0.03–>64 2 64 Tetracycline 48.4 3.6 48.0 0.12–>32 4 >32 Staphylococcus species. Fresh lysed horse blood (Hemostat Laboratories, Penicillin 7.4 0 92.6 ≤0.015–>32 8 32 Retapamulin 0.12 0.06 0.06 0.06 0.25 aInterpretive criteria of compounds defined in the CLSI document M100-S15 where available. Amoxicillin- 16 8 0.12 0.25 1 Dixon, CA, USA) was added to the Mueller–Hinton broth to make the 3% Tetracycline 82.7 3.6 13.7 0.12–>32 0.5 16 bAmoxicillin/clavulanic acid was tested in a 2:1 ratio; MICs are reported based on the amoxicillin concentration. lysed horse blood broth used for MIC testing of all Streptococcus species. Sus, susceptible; Int, intermediate; Res, resistant; NA, not available. Clavulanic acid aInterpretive criteria of compounds defined in the CLSI document M100-S15 (2005) where available; mupirocin Bacitracin >128 >128 64 128 128 G The trays were incubated at 35°C in ambient air for 16–20 h before reading susceptibility defined by Finlay et al.;6 fusidic acid susceptibility defined by Toma and Barriault;7 Note:β-lactams are Ceftriaxone 32 32 0.12 0.12 1 the MIC endpoints. reported as resistant for MRSA in accordance with current CLSI guidelines. Table 7. MIC (µg/mL) Summary for Retapamulin and Comparators against S. agalactiae Cephalothin 8 4 0.25 0.5 2 bAmoxicillin/clavulanic acid was tested in a 2:1 ratio; MICs are reported based on the amoxicillin concentration. G Quality control testing was performed each day of testing as specified by the Sus, susceptible; Int, intermediate; Res, resistant; NA, not available. From North America (n = 462) Clindamycin >32 >32 0.25 32 8 CLSI using the following ATCC strains: S. aureus ATCC 29213, S. aureus ATCC Cloxacillin 2 16 0.5 2 8 MIC (µg/mL) 25923, Enterococcus faecalis ATCC 29212, Streptococcus pneumoniae ATCC Erythromycin >32 >32 2 32 >32 a Table 4. MIC (µg/mL) Summary for Retapamulin and Comparators against Compound %Sus %Int %Res Range MIC50 MIC90 Fusidic acid 1 8 8 16 32 49619, and Escherichia coli ATCC 25922. In addition, quality control ranges Coagulase-negative Staphylococci from North America (n = 442) Retapamulin NA NA NA 0.008–0.25 0.03 0.06 Gentamicin 2 16 16 32 16 previously determined for retapamulin were used as a control.4 Amoxicillin- NA NA NA ≤0.015–1 0.12 0.25 Linezolid 4 2 1 1 1 The total number of isolates, MIC (µg/mL), MIC (µg/mL) and MIC ranges MIC (µg/mL) G 50 90 Clavulanic acidb Mupirocin 4 >256 0.5 1 2 a were determined for all antimicrobial agents tested. Interpretive criteria and Compound %Sus %Int %Res Range MIC50 MIC90 Bacitracin NA NA NA 2–>128 128 128 Neomycin 64 16 64 >64 >64 resistant phenotypes to the corresponding antimicrobial agent were defined Retapamulin NA NA NA ≤0.002–0.5 0.06 0.06 Ceftriaxone 99.8 0 0.2 ≤0.015–1 0.06 0.12 Penicillin 32 16 0.06 0.12 0.5 5 Cephalothin NA NA NA ≤0.03–2 0.25 0.5 according to CLSI breakpoints or the literature (mupirocin and fusidic acid). Amoxicillin- 40.3 0 59.7 ≤0.015–32 1 8 Tetracycline 16 >32 16 >32 >32 Clindamycin 83.3 1.7 14.9 ≤0.015–>32 0.06 32 Methicillin-resistance was based upon oxacillin screening agar. Clavulanic acidb Cloxacillin NA NA NA 0.12–4 2 2 Bacitracin NA NA NA 0.25–>128 128 >128 Erythromycin 59.7 1.9 38.3 ≤0.015–>32 0.06 32 Conclusion: Retapamulin demonstrated excellent in vitro activity against staphylococci, Ceftriaxone 37.1 5.0 57.9 0.5–>64 8 32 Fusidic acid NA NA NA 0.5–>32 8 16 S. pyogenes, S. agalactiae, and viridans streptococci isolates as demonstrated by the lowest Results Cephalothin 42.1 0 57.9 ≤0.03–64 1 4 Gentamicin NA NA NA 1–>64 16 32 MIC compared with that of topical and oral antimicrobial agents commonly used in the Clindamycin 61.1 2.7 36.2 ≤0.015–>32 0.12 >32 Linezolid 100 0 0 0.5–2 1 1 90 The results are shown in Tables 2–7. treatment of uncomplicated SSSIs. Cloxacillin NA NA NA 0.06–>32 1 16 Mupirocin NA NA NA 0.12–256 1 1 Neomycin NA NA NA 0.06–>64 64 >64 Erythromycin 24.4 3.8 71.7 ≤0.015–>32 >32 >32 Penicillin 98.9 0 1.1 ≤0.015–4 0.06 0.12 Fusidic acid 82.8 1.8 15.4 ≤0.015–>32 0.12 8 Table 1. Geographic Distribution of Isolates Tetracycline 13.9 1.3 84.8 0.12–>32 32 >32 Introduction Gentamicin 73.5 13.8 12.7 ≤0.03–>64 0.12 16 Country Sites Total Isolates (n) % Total Linezolid 100 0 0 0.25–4 1 2 aInterpretive criteria of compounds defined in the CLSI document M100-S15 where available.