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Antimicrobial Agents and Chemotherapy, December 2005, p. 5182-5184, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.5182-5184.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Antipneumococcal Activity of Dalbavancin Compared to Other Agents

Gengrong Lin, Kathy Smith, Lois M. Ednie, and Peter C. Appelbaum*

Department of Pathology, Hershey Medical Center, Hershey, Pennsylvania 17033

Received 19 July 2005/ Returned for modification 12 September 2005/ Accepted 23 September 2005


   ABSTRACT
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Against 307 pneumococci of various resistotypes, dalbavancin MICs were 0.008 to 0.125 µg/ml. All strains were susceptible to vancomycin, teicoplanin, linezolid, and quinupristin-dalfopristin. Dalbavancin at 2x MIC was bactericidal against all 10 pneumococci tested after 24 h. Vancomycin and teicoplanin killed 10 and 8 strains, respectively, at 2x MIC after 24 h.


   TEXT
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The incidence of drug-resistant pneumococci has increased worldwide (11, 12). In the United States, a 1997 survey reported that 50.4% of 1,476 clinical isolates were penicillin nonsusceptible (11). Worldwide between 1998 and 2000 the incidence of pneumococci for which drug MICs were ≥2 µg/ml was 18.2%, and the incidence of erythromycin resistance was 24.6% (12). A recent paper testing 1,817 United States pneumococci isolated between 2002 and 2003 reported an incidence of 34.2% penicillin G nonsusceptibility (6), so rates of pneumococcal ß-lactam resistance in the United States may be decreasing. Levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin have greater antipneumococcal activity than ciprofloxacin and ofloxacin (5, 11, 12, 22, 24). Although the overall worldwide rate of pneumococcal fluoroquinolone resistance appears stable at <1% (6), several reports have noted a worrisome trend toward quinolone resistance (4, 10).

Dalbavancin is a lipoglycopeptide with a half-life of approximately 8 days in humans and has activity against gram-positive organisms (1, 2, 7, 8, 13-15, 17, 21, 23). In this study, we used MICs to test activity of dalbavancin, vancomycin, teicoplanin, linezolid, quinupristin-dalfopristin, amoxicillin, ceftriaxone, imipenem, levofloxacin, and azithromycin against 307 pneumococci of differing resistotypes. Activity of the above drugs against 10 pneumococci was also studied by time-kill.

Pneumococci comprised 106 penicillin-susceptible, 96 penicillin-intermediate, and 105 penicillin-resistant strains; 163 strains were azithromycin susceptible, 1 was azithromycin intermediate, and 143 were azithromycin resistant. Additionally, 30 strains with levofloxacin MICs of ≥4.0 µg/ml were tested. Ten strains were analyzed by time-kill: three penicillin-susceptible, three penicillin-intermediate, four penicillin-resistant, four azithromycin-resistant, and two quinolone-resistant strains. The four strains with azithromycin MICs of >64 µg/ml and two strains with levofloxacin MICs of 16.0 to 32.0 µg/ml were not tested by time-kill.

Dalbavancin powder was obtained from Vicuron Pharmaceuticals, King of Prussia, PA, and other antimicrobials were from respective manufacturers. For all drugs except dalbavancin, MICs were determined by standard agar dilution (5, 20, 22, 24). Because the agar dilution MIC is being standardized for dalbavancin (B. P. Goldstein, personal communication), microdilution MICs (18) with dry-format trays (TREK Diagnostics, Cleveland, OH) were used. Standard quality control strains (18) were included in each run. Strains used for time-kill studies also had MICs determined using the broth macrodilution method (18).

For time-kills, previously reported techniques were used (19, 24). Only initial inocula of 5 x 105 to 5 x 106 CFU/ml were acceptable (19, 24). Viability counts were as described previously, and colony counts were performed on plates yielding 30 to 300 colonies. The lower limit of sensitivity of colony counts was 300 CFU/ml (19, 24). Time-kill assays were analyzed by determining the number of strains with a {Delta}log10 CFU/milliliter of –1, –2, and –3 at 3, 6, 12, and 24 h compared to counts at time zero. Bactericidal activity was considered a reduction of the original inoculum by ≥3 log10 CFU/ml (99.9%) (19, 24).

MICs are presented in Table 1. Dalbavancin had potent activity against all pneumococci, with MICs of 0.008 to 0.125 µg/ml. Vancomycin and teicoplanin were potent, with MICs of 0.03 to 0.5 µg/ml and 0.03 to 0.25 µg/ml, respectively. Linezolid inhibited all strains at ≤2.0 µg/ml, and quinupristin-dalfopristin inhibited all strains at ≤1.0 µg/ml. ß-Lactam and azithromycin MICs paralleled those of penicillin G. Except for 30 strains chosen for their quinolone resistance phenotype, strains were susceptible to levofloxacin, with MICs of ≤2.0 µg/ml.


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  		TABLE 1. MICs (in micrograms/milliliter) of dalbavancin and comparators against 307 pneumococcal strains enriched for isolates with specific resistance traitsa

 
Broth macrodilution MICs of strains tested by time-kill are listed in Table 2, and time-kills are listed in Table 3. Dalbavancin was bactericidal to the extent of at least 3 logs at 2x MIC after 24 h against all 10 strains and against 8 strains at MIC. By comparison, vancomycin and teicoplanin were bactericidal by 3 logs at 2x MIC after 24 h against 10 and 8 strains, respectively. Linezolid was mainly bacteriostatic and quinupristin-dalfopristin was bactericidal against all 10 strains at 2x MIC after 24 h, with significant killing at earlier periods. ß-Lactams were bactericidal against 9 or 10 strains at 2x MIC after 24 h. Levofloxacin was bactericidal against all eight quinolone-susceptible strains at 2x MIC after 24 h, and azithromycin was bactericidal against five of six macrolide-susceptible strains at 2x MIC after 24 h.


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  		TABLE 2. Broth macrodilution MICs (in micrograms/milliliter) of dalbavancin and comparators for 10 strains tested by time-killa

 

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  		TABLE 3. Time-kill results

 
Dalbavancin is a semisynthetic derivative of the teicoplanin-like glycopeptide A40926 and is more active in vitro against staphylococci than teicoplanin and vancomycin. Against streptococci, dalbavancin has activity comparable to teicoplanin but better than vancomycin (1, 2, 13, 15, 23). In a study of >6,000 isolates, Streit et al., using CLSI broth microdilution methodology, showed excellent dalbavancin activity against all gram-positives except vanA enterococci (23), with a MIC range against 1,396 drug-susceptible and -resistant pneumococci of ≤0.015 to 0.25 µg/ml. Similarly, in our study all strains tested had dalbavancin MICs between 0.008 and 0.125 µg/ml. Our vancomycin agar dilution MICs were very similar to those reported by Streit et al. in broth, with 50% minimum inhibitory concentration (MIC50) and MIC90s of 0.25 and 0.5 µg/ml, respectively, by both methods. Jones and coworkers demonstrated bactericidal activity of dalbavancin against S. pneumoniae ATCC 49619 at 4x MIC after 24 h, but exact methodology was not provided (13). In our study, dalbavancin kinetics were similar to those of vancomycin and teicoplanin, i.e., relatively slow compared to those of ß-lactams and levofloxacin. We have found dalbavancin to be bactericidal after 24 h at 2x MIC against Staphylococcus aureus strains, including the Hershey vancomycin-resistant S. aureus, with cidality against eight strains at MIC (15). MICs and time-kills for other compounds were consistent with previous studies (3, 5, 9, 11, 12, 16, 20, 22, 24).

Against anaerobic gram-positive species and corynebacteria and using agar dilution, dalbavancin had MICs of ≤2.0 µg/ml against all species except Clostridium clostridioforme and lactobacilli (8). Dalbavancin agar MICs are higher than those in broth for reasons that are under investigation (8, 15). However, our results of broth macrodilution MIC assays in strains tested by time-kill were similar to those obtained using prepared dry-format trays.

Due to its half-life of ca. 8 days, dalbavancin is under investigation as a once-weekly-dose drug (7). A recent study has shown that two doses of dalbavancin administered 1 week apart is effective in treatment of complicated gram-positive skin and soft-tissue infections (21), and Lefort et al. have reported that a single dose of dalbavancin was active against S. aureus with or without reduced glycopeptide susceptibility in an adult rabbit endocarditis model (14).

Our results indicate a potential place for dalbavancin in therapy of drug-susceptible and -resistant pneumococcal infections. Clinical trials will be necessary in order to validate this hypothesis.


   ACKNOWLEDGMENTS
 
This study was supported by a grant from Vicuron Pharmaceuticals, King of Prussia, PA.


   FOOTNOTES
 
* 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. Back


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Antimicrobial Agents and Chemotherapy, December 2005, p. 5182-5184, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.5182-5184.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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