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Antimicrobial Agents and Chemotherapy, May 2006, p. 1727-1730, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1727-1730.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Activity of Retapamulin against Streptococcus pyogenes and Staphylococcus aureus Evaluated by Agar Dilution, Microdilution, E-Test, and Disk Diffusion Methodologies

Glenn A. Pankuch,^1* Gengrong Lin,¹ Dianne B. Hoellman,¹ Caryn E. Good,² Michael R. Jacobs,² and Peter C. Appelbaum¹

Department of Pathology, Hershey Medical Center, Hershey, Pennsylvania 17033,¹ Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106²

Received 30 August 2005/ Returned for modification 9 November 2005/ Accepted 22 February 2006

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The in vitro activity of retapamulin against 106 Staphylococcus aureus isolates and 109 Streptococcus pyogenes isolates was evaluated by the agar dilution, broth microdilution, E-test, and disk diffusion methodologies. Where possible, the tests were performed by using the CLSI methodology. The results of agar dilution, broth microdilution, and E-test (all with incubation in ambient air) for S. aureus yielded similar MICs, in the range of 0.03 to 0.25 µg/ml. These values corresponded to zone diameters between 25 and 33 mm by the use of a 2-µg retapamulin disk. Overall, 99% of the agar dilution results and 95% of E-test results for S. aureus were within ±1 dilution of the microdilution results. For S. pyogenes, the MICs obtained by the agar and broth microdilution methods (both after incubation in ambient air) were in the range of 0.008 to 0.03 µg/ml, and E-test MICs (with incubation in ambient air) were 0.016 to 0.06 µg/ml. For S. pyogenes, 100% of the agar dilution MIC results were within ±1 dilution of the broth microdilution results. E-test MICs (after incubation in ambient air) were within ±1 and ±2 dilutions of the broth microdilution results for 76% and 99% of the isolates, respectively. E-test MICs for S. pyogenes strains in CO₂ were up to 4 dilutions higher than those in ambient air. Therefore, it is recommended that when retapamulin MICs are determined by E-test, incubation be done in ambient air and not in CO₂, due to the adverse effect of CO₂ on the activity of this compound. Diffusion zones (with incubation in CO₂) for S. pyogenes were 18 to 24 mm. Retapamulin MICs for all strains by all methods (with incubation in ambient air) were 0.25 µg/ml. These results demonstrate that S. pyogenes (including macrolide-resistant strains) and S. aureus (including methicillin-resistant and vancomycin-nonsusceptible strains) are inhibited by very low concentrations of retapamulin and that all four testing methods are satisfactory for use for susceptibility testing.

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The causative organisms of skin and soft tissue infections are usually Staphylococcus aureus, Streptococcus pyogenes, or a combination of these two organisms. S. aureus strains are becoming increasingly drug resistant. Methicillin resistance commonly occurs in both nosocomial and community-acquired infections, and nosocomially acquired methicillin-resistant strains are also usually quinolone resistant (1, 9, 20, 21, 24). Vancomycin-intermediate S. aureus (VISA) have recently been isolated, first in Japan and subsequently all over the world (10). Three vancomycin-resistant S. aureus (VRSA) strains carrying vanA have been reported in the literature (3, 4, 22), with an additional two strains reported in Michigan (J. T. Rudrick and D. M. Sievert, personal communications). Although S. pyogenes retains its original susceptibility to penicillin G, macrolide resistance is increasingly being encountered in this species (2, 14, 16).

Topical agents such as mupirocin and fusidic acid have been established as topical treatments for skin and soft tissue infections. There are no approved CLSI or FDA breakpoints for topical agents, and there is difficulty in assessing the pharmacokinetic and pharmacodynamic parameters for these agents to establish their breakpoints. Despite the latter problems, susceptibility testing should be performed for topical agents in order to monitor changes in susceptibility patterns, as decreases in susceptibility due to the development of resistance could potentially lead to poorer clinical outcomes (5, 6, 21).

Pleuromutilins, a new class of antimicrobials currently available for veterinary use, have not yet been exploited for use in humans. These compounds have a novel mode of action (with a predominantly L3 ribosomal target site) and show no target-specific cross-resistance with currently available antibacterial agents (7, 8, 11, 12). Retapamulin (SB-275833) (Fig. 1) is a semisynthetic pleuromutilin analog being developed for topical use and has excellent in vitro activity against gram-positive bacteria and some gram-negative bacteria (such as Haemophilus influenzae and Moraxella catarrhalis) (B. Johnson, A. Jordan, S. Bouchillon, D. Hoban, N. Scangarella, R. Shawar, and J. Johnson, Abstr. 105th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-2050, 2005; L. McCloskey, R. Zonis, J. Brosky, S. Biswas, J. Pizzollo, C. Jakielaszek, D. Payne, and S. Rittenhouse, Abstr. 105th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-2055, 2005).

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FIG. 1. Structure of retapamulin. Me, methyl.

One of the factors upon which the clinical applicability of this compound should be based is the results of laboratory testing. This study used four standard susceptibility testing methodologies to test the in vitro activity of retapamulin against 106 S. aureus strains and 109 S. pyogenes strains with different susceptibility phenotypes.

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Bacteria and antibiotics. A total of 106 S. aureus strains and 109 S. pyogenes strains (collected during the past 3 years from various laboratories in and outside the United States) were tested. All strains were identified by standard methods (15). The 106 S. aureus strains comprised 53 methicillin-susceptible strains and 53 methicillin-resistant strains; the latter included 6 VISA strains and the 3 published VRSA strains. The 109 S. pyogenes comprised 51 macrolide-susceptible organisms and 58 macrolide-resistant organisms. The cultures were stored at –70°C in double-strength skim milk (Difco Laboratories, Detroit, MI). Retapamulin susceptibility powder, E-test strips, and disks (2 µg) were obtained from GlaxoSmithKline Laboratories, Collegeville, PA. Retapamulin powder was dissolved in dimethyl sulfoxide and was further diluted in 10% ß-cyclodextrin.

Agar dilution MICs. Agar dilution MICs (17, 18) were determined on Mueller-Hinton agar (Difco), which was supplemented with 5% sheep blood for S. pyogenes. Inocula were prepared by suspending the growth from overnight cultures on blood agar plates in sterile saline to a turbidity of a 0.5 McFarland standard. Final inocula contained 10⁴ CFU/spot. Plates were inoculated with a Steers replicator with 3-mm inoculating pins and were incubated overnight at 35°C in ambient air. The lowest concentration of antibiotic resulting in no growth was read as the MIC. A subset of 55 S. aureus strains (27 methicillin-susceptible strains and 28 methicillin-resistant strains, including the 6 VISA and 3 VRSA strains) was also tested for their susceptibilities to vancomycin (a drug unaffected by CO₂) and retapamulin by agar dilution in ambient air and CO₂.

Broth microdilution MICs. Retapamulin MICs (17, 18) were determined by the method recommended by the CLSI (formerly the National Committee for Clinical Laboratory Standards) by using cation-adjusted Mueller-Hinton broth (Difco Laboratories), which was supplemented with 5% lysed horse blood for S. pyogenes. Suspensions with a turbidity equivalent to that of a 0.5 McFarland standard were prepared by suspending the growth from overnight cultures on blood agar plates in 2 ml of sterile saline. The suspensions were further diluted 1:10 to obtain a final inoculum of 5 x 10⁵ CFU/ml. The trays were incubated overnight in ambient air at 35°C.

E-test MICs. Mueller-Hinton agar plates, which were supplemented with 5% sheep blood for S. pyogenes, were inoculated with a 0.5 McFarland suspension harvested from overnight growth on blood plates; and retapamulin E-test strips (AB Biodisk, Solna, Sweden) were placed on each plate. After overnight incubation at 35°C in ambient air or CO₂ (S. pyogenes) or in ambient air only (S. aureus), the MICs of all strains were read where the ellipse of growth inhibition intersected the strip. To control for growth by using a drug unaffected by CO₂ (as described above), all S. pyogenes strains were tested for vancomycin susceptibility in ambient air and CO₂. A subset of 55 S. aureus strains (as described above) was also tested for their susceptibilities to vancomycin and retapamulin by E-test in ambient air and CO₂.

Disk diffusion. Disk diffusion was performed by the standard CLSI methodology (18) by using Mueller-Hinton agar plates, which were supplemented with 5% sheep blood for group A streptococci, inoculated with a 0.5 McFarland standard; 2-µg SB 275833 disks (BBL Microbiology Systems, Cockeysville, MD) were placed on plates. After overnight incubation at 35°C in ambient air only (S. aureus) or CO₂ (S. pyogenes), the diameters of the inhibition zones were measured with calipers.

Quality control strains and original inocula. Quality control strains were included in each run, as recommended by the CLSI (18), and consisted of Streptococcus pneumoniae ATCC 49619, Staphylococcus aureus ATCC 29213, and Staphylococcus aureus ATCC 25923. Any isolate for which the retapamulin MIC was >1.0 µg/ml was retested to determine the actual MIC endpoint. Testing was performed on the same day, with the same culture used for the start-up inoculum used for all four methods. S. aureus ATCC 29213 was tested seven times by microdilution, five times by agar dilution, six times by E-test, and seven times by disk diffusion. S. aureus ATCC 25923 was tested two times by microdilution, four times by agar dilution, four times by E-test, and five times by disk diffusion. S. pneumoniae ATCC 49619 was tested six times by microdilution, five times by agar dilution, once by E-test in ambient air, seven times by E-test in CO₂, and six times by disk diffusion.

Interpretation of results. Provisional microbiologically based retapamulin breakpoints of 2 µg/ml (susceptible), 4 µg/ml (intermediate), and 8 µg/ml (resistant) were derived from frequency distributions and scattergrams (S.D. Brown and M. M. Traczewski, Abstr. 105th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-2065, 2005). Essential agreement was defined as the MIC by one method being within ±1 log₂ dilution of the MIC by the broth microdilution method (which was taken as the reference method).

Data analysis. Data were summarized descriptively by determining the geometric mean MICs, the MICs at which 50% of isolates are inhibited (MIC₅₀s), and the MIC₉₀s. Essential agreement was determined by calculating the proportion of agreement of the results of the test MIC methods (agar dilution and E-test) with those of the indicated MIC reference method; agreement of MICs within 1 doubling dilution was considered good, and trends in a positive or a negative direction were noted.

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The retapamulin MICs and the disk diffusion diameters obtained for each of the quality control strains, with results taken from five to seven replicates of each strain, are presented in Table 1. All three methods of MIC determination gave excellent agreement for both S. aureus quality control strains, with MICs in the range of 0.06 to 0.125 µg/ml by all test methods. By contrast, E-test MICs for S. pneumoniae ATCC 49619 incubated under 5% CO₂ (according to the manufacturer's recommendations) were 2 to 3 dilutions higher than those obtained by broth microdilution and agar dilution (both with incubation in ambient air). All quality control results were within the proposed quality control ranges for retapamulin (19).

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TABLE 1. Retapamulin MICs for quality control strainsa

The retapamulin MICs for S. aureus and S. pyogenes obtained by all three methods are presented in Table 2. The results of the agreement of the retapamulin MICs obtained by the agar dilution and E-test methods compared to those obtained by the reference methods and the geometric mean MICs are presented in Table 3. An excellent correlation of the results of all three methods when incubation was in ambient air was obtained for the S. aureus strains, with MICs varying between 0.016 and 0.25 µg/ml for all strains, irrespective of their phenotypes, and with geometric mean MICs varying between 0.072 and 0.11 µg/ml. Overall, there was 99% essential agreement between the agar dilution results and the microdilution MICs and 95% essential agreement between E-test results and the microdilution MICs. The disk diffusion zone diameter values (with incubation in ambient air) ranged from 25 to 33 mm. Because the MICs of all strains clustered tightly in a narrow range, no attempt was made to perform regression analyses between the disk diameters and the MICs. The effect of the atmosphere used was assessed for a subset of S. aureus isolates tested by E-test and agar dilution in ambient air and CO₂. Only 9.1% and 21.8% of the retapamulin MIC results from incubation in CO₂ were within ±1 dilution of those obtained from incubation in ambient air for agar dilution and E-test, respectively, and the geometric mean MICs were higher with incubation in CO₂ than with incubation in air (0.48 to 0.56 µg/ml) (Table 3). All vancomycin MICs from agar dilution and E-tests incubated in CO₂ were within 1 dilution of those obtained from tests incubated in ambient air (data not shown).

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TABLE 2. Retapamulin MICs obtained by four susceptibility test methodsa

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TABLE 3. Agreement of Retapamulin MIC results obtained by agar dilution and E-test methods compared to those obtained by reference methoda

For the S. pyogenes strains, the MICs obtained by microdilution and agar dilution incubated in ambient air correlated very well, ranging from 0.008 to 0.03 µg/ml, with geometric mean MICs varying between 0.017 and 0.024 µg/ml and with 100% essential agreement. The results of E-test with incubation in ambient air showed a geometric mean MIC of 0.038 µg/ml and gave essential agreement for 83/109 strains (76.1%), with 99% agreement within 2 dilutions compared to the MICs obtained by broth microdilution. By contrast, the geometric mean MIC of retapamulin against S. pyogenes by E-test incubated in CO₂ was 0.12 µg/ml and showed 0% essential agreement compared to the MICs obtained by broth microdilution. The MICs were up to 4 dilutions higher, varying between 0.06 and 0.25 µg/ml. All strains of S. pyogenes incubated in air yielded sufficient growth for accurate interpretation of E-test results; and all MICs for vancomycin from E-tests incubated in CO₂ were within 1 dilution of those obtained from E-tests incubated in ambient air (data not shown). For both S. aureus and S. pyogenes as well as all three quality control strains, the E-test zone intersects were clearly demarcated and easy to interpret. The disk diffusion zone diameters (with incubation in CO₂) for retapamulin against S. pyogenes varied between 18 and 24 mm. Regression analyses of the zone diameters were not done for S. pyogenes for the same reason stated above for S. aureus. Since all strains were considered susceptible when a provisional susceptibility breakpoint of 2 µg/ml was used, these zones probably represent the range for susceptible isolates.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Our results confirm the excellent in vitro activity of retapamulin against all S. aureus and S. pyogenes strains, irrespective of their phenotype. All MIC and disk diffusion quality control results were within the proposed ranges for retapamulin (19). Retapamulin MICs were unimodal, and all retapamulin MICs were 0.25 µg/ml against all strains by all three MIC testing methodologies when incubation was in ambient air. For S. aureus, the correlation of the results between agar dilution and microdilution MIC methods in ambient air (as recommended by the CLSI) was excellent, as was the correlation between E-test and agar and microdilution MICs when incubation was in ambient air. For S. pyogenes, the results of the agar dilution and microdilution tests, both with incubation in ambient air, yielded excellent correlations, which were within 1 dilution; the results of E-tests were within 2 dilutions of those of the broth microdilution method. E-tests incubated in CO₂ for S. pyogenes gave retapamulin MICs which were up to fourfold higher than those obtained in ambient air, with the highest MIC being 0.25 µg/ml. Similar findings were obtained for the S. pneumoniae ATCC 49619 quality control strain and the subset of S. aureus isolates tested by agar dilution and E-test in ambient air and CO₂. Therefore, our results show that incubation in CO₂ results in an elevation of MICs of retapamulin against both S. pyogenes and S. aureus. The same effect was not seen for vancomycin, a compound known not to be affected by CO₂, for either species or for any of the testing methods (23), thereby illustrating that the differences in retapamulin MICs were not due to insufficient growth of the organism in ambient air. The reason for the effect of CO₂ on retamapulin susceptibility testing is unknown but may be related to factors such as the lower pH resulting from incubation in a CO₂-containing atmosphere. The E-test manufacturer generally recommends incubation in CO₂ for fastidious organisms. However, for certain compounds, the manufacturer indicates that incubation in ambient air may be specified. Given the results of this study, we recommend that retapamulin E-test strips be incubated in ambient air for S. pyogenes, provided that sufficient growth is obtained from the clinical isolate in the absence of CO₂. No adjustment is needed for S. aureus, as the E-test manufacturer recommends incubation in ambient air for this and other nonfastidious organisms.

Recent descriptions of the alarming spread of toxin-producing S. aureus strains in the community mandate treatment with a drug with a mechanism unrelated to those of ß-lactams and glycopeptides for the treatment of skin and soft tissue infections in individuals at risk of such infections (e.g., football players and others participating in contact sports or where towels or whirlpool baths and saunas are shared) (13). Clinical studies are necessary to determine if topical application of retapamulin holds promise in this regard.

 
This study was supported by a grant from GlaxoSmithKline Laboratories.

We thank Focus Technologies (Herndon, VA) for provision of VISA and two of the three VRSA strains.

 
* Corresponding author. Mailing address: Department of Pathology, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033. Phone: (717) 531-5113. Fax: (717) 531-7953. E-mail: pappelbaum{at}psu.edu.

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Antimicrobial Agents and Chemotherapy, May 2006, p. 1727-1730, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1727-1730.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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