This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wootton, M.
Right arrow Articles by Walsh, T. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wootton, M.
Right arrow Articles by Walsh, T. R.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, December 2006, p. 4195-4197, Vol. 50, No. 12
0066-4804/06/$08.00+0     doi:10.1128/AAC.00678-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Comparative Bactericidal Activities of Daptomycin and Vancomycin against Glycopeptide-Intermediate Staphylococcus aureus (GISA) and Heterogeneous GISA Isolates{triangledown}

Mandy Wootton,1,2* Alasdair P. MacGowan,2 and Timothy R. Walsh1,{dagger}

Bristol Centre for Antimicrobial Research and Evaluation (BCARE), Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, United Kingdom,1 BCARE, Southmead Hospital, North Bristol NHS Trust, Bristol BS10 5NB, United Kingdom2

Received 2 June 2006/ Returned for modification 7 July 2006/ Accepted 6 October 2006


arrow
ABSTRACT
 
Staphylococcus aureus strains from the U.S. SENTRY Antimicrobial Surveillance Program, 2002-2003, glycopeptide-intermediate S. aureus (GISA) strains, and heterogeneous GISA (hGISA) strains were used to compare bactericidal activities of daptomycin and vancomycin using MICs and minimum bactericidal concentrations. Glycopeptide-susceptible S. aureus and hGISA strains were further studied by using time-kill curves. For all isolates, the daptomycin MIC50 and MIC90 are four times lower and the log drops in viable counts at 6 h and 24 h are significantly greater than those for vancomycin.


arrow
TEXT
 
Staphylococcus aureus is an important cause of serious infections in both hospitals and the community and is particularly efficient at developing resistance to antimicrobial agents (9). In the United States, the proportion of nosocomial intensive care unit S. aureus infections due to methicillin-resistant Staphylococcus aureus (MRSA) is now >50%, and infections caused by MRSA are associated with a longer hospital stay, more antibiotic administration, and higher costs (11, 3). Until recently, glycopeptides were believed to have retained activity against all S. aureus strains, and therefore, the spread of MRSA has led to increased usage of glycopeptides and hence increased selective pressure for the development of resistance (7, 14). Although the isolation of glycopeptide-intermediate S. aureus (GISA) is rare, there seems to be a more widespread prevalence of heterogeneous GISA (hGISA) (8, 17). Consequently, we are now faced with growing problems of reduced susceptibility in S. aureus (both homogeneous and heterogeneous) and the need of alternatives for treatment.

Daptomycin has recently demonstrated significantly better bactericidal activity than vancomycin against S. aureus and enterococci (15, 16) and has activity against a small number of glycopeptide-intermediate S. aureus strains and vancomycin-resistant enterococcus (1). Daptomycin is an acidic lipopeptide with a mode of action requiring calcium (2).

The aim of this study was to compare bactericidal activities of daptomycin and vancomycin against a range of glycopeptide-susceptible and intermediately resistant Staphylococcus aureus strains. Accordingly, MICs and minimum bactericidal concentrations (MBCs) were determined for four phenotypes (methicillin-susceptible S. aureus/glycopeptide-susceptible S. aureus [MSSA/GSSA], MRSA/GSSA, hGISA/MRSA, and GISA/MRSA), and time-kill curves were used to compare bactericidal activities of both antimicrobials against the more prevalent hGISA and GSSA/MRSA isolates. Daptomycin and vancomycin MICs and MBCs were determined for 11 methicillin-susceptible and glycopeptide-susceptible S. aureus isolates (from the SENTRY program, 2002-2003), 95 MRSA/GSSA isolates (SENTRY program, 2002-2003), 55 hGISA/MRSA isolates (4 isolates from the SENTRY program, 2002-2003, and 51 from BCARE), and 15 GISA/MRSA isolates (BCARE) using a standard CLSI (formerly NCCLS) broth microdilution technique (10). Bactericidal activities of vancomycin and daptomycin were also investigated for 10 GSSA and 10 hGISA strains using standard time-kill-curve techniques (6). Strains were divided according to phenotype using the previously described population analysis profile-area under the curve method (18). MICs were determined using standard CLSI broth microdilution methodology with Mueller-Hinton Broth (MHB) alone for vancomycin and MHB with an adjusted Ca2+ concentration (50 mg/liter) for daptomycin. Antimicrobials were used in a log 2 dilution series from 0.06 to 64 mg/liter for daptomycin and from 0.25 to 16 mg/liter for vancomycin. Inocula were prepared from direct colony suspension, and microtiter plates were inoculated with 105 CFU/ml. Plates were incubated in air at 37°C for 18 h. The MIC was defined as the lowest concentration of an antimicrobial agent that prevents visible growth of a microorganism in a broth dilution susceptibility test. MBCs were determined by subculture of 100 µl of well contents on blood agar with incubation of plates in air at 37°C for 18 h. The MBC was defined as the lowest concentration of an antimicrobial agent that reduces the initial viable count by 99.9%.

Time-kill experiments were performed using MHB alone for vancomycin and Ca2+-supplemented MHB for daptomycin with a 106-CFU/ml inoculum. Drug concentrations used were 2x and 4x the MIC of the organism tested plus an antibiotic-free control. Samples were collected at 0, 1, 2, 4, 6, and 24 h and viable counts plotted versus antibiotic concentrations. Log drops in viable counts at 6 h and 24 h were calculated, and the bactericidal effect was defined as a ≥3 log10 CFU/ml decrease of the initial inoculum after 6 h and 24 h.

The in vitro activities of daptomycin and vancomycin against all phenotypes tested are shown in Tables 1 and 2. Daptomycin MICs were higher for hGISA and GISA strains than for GSSA strains. This suggests that daptomycin MICs increase with increasing vancomycin MICs, with a GISA daptomycin mean MIC of 0.91 compared to 0.48 for hGISA strains and 0.31/0.30 for GSSA strains. However, daptomycin MIC50s and MIC90s were four times lower than those for vancomycin for all phenotypes tested (Table 1). The daptomycin mean MIC was four times lower than the vancomycin mean MIC for all phenotypes tested. MBCs at which 50% and 90% of the strains tested were killed (MBC50s and MBC90s) for daptomycin were 8 and 16 times lower than those for vancomycin for all phenotypes, including hGISA and GISA strains. Daptomycin MBC/MIC ratios were significantly lower than vancomycin MBC/MIC ratios for all phenotypes (Table 2).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Activities of daptomycin and vancomycin against a collection of S. aureus strains with various vancomycin susceptibilities


View this table:
[in this window]
[in a new window]
  		TABLE 2. MBCs for daptomycin and vancomycin against a collection of S. aureus strains with various vancomycin susceptibilities

In time-kill curve studies, the 10 GSSA strains used had vancomycin MICs ranging from 0.5 to 1 mg/liter and daptomycin MICs ranging from 0.12 to 1 mg/liter, while 10 hGISA strains had vancomycin MICs ranging from 1 to 4 mg/liter and daptomycin MICs ranging from 0.12 to 2 mg/liter. The mean log drop (6 h) in viable counts of GSSA with daptomycin at 2x or 4x MIC was 2.9 or 2.4 times greater than that for vancomycin (Table 3). At 24 h, the mean log drop in viable counts of GSSA for daptomycin at 2x or 4x MIC was 2.6 or 2.2 times greater than that for vancomycin. With hGISA, the mean log drop (6 h) in viable counts for daptomycin at 2x or 4x MIC was 2.5 or 2.5 times greater than that for vancomycin (Table 3). At 24 h, the mean log drop in viable counts of hGISA for daptomycin at 2x or 4x MIC was 1.9 or 1.7 times greater than that for vancomycin. In all cases, the log drops in viable counts at 2x and 4x MIC were significantly greater for daptomycin than for vancomycin (P = <0.001).


View this table:
[in this window]
[in a new window]
  		TABLE 3. Log drop in viable count at 6 h or 24 h for 10 GSSA and 10 hGISA strains using vancomycin or daptomycin at 2x or 4x MICa

At 6 h, daptomycin was bactericidal (≥3-log drop) for 50% of GSSA strains at 2x MIC and for 70% of GSSA strains at 4x MIC compared with no GSSA strains at both 2x and 4x MIC for vancomycin. With hGISA, daptomycin was bactericidal at 6 h for 30% of strains at 2x MIC and 60% of strains at 4x MIC compared with 10% of strains at both 2x and 4x MICs for vancomycin. At 24 h, daptomycin was bactericidal for 70% of GSSA strains at 2x MIC and 90% of strains at 4x MIC compared with 10% of GSSA strain at 4x MIC for vancomycin. For hGISA, daptomycin was bactericidal at 24 h for 100% of strains at both 2x and 4x MIC compared with 20% of strains at 2x MIC and 80% of strains at 4x MIC for vancomycin.

Bactericidal activity is probably essential for effective treatment of high-bacterial-density infections, such as bacterial endocarditis and serious infections in immunocompromised patients (5). In addition, the emergence of reduced susceptibility to glycopeptides and in particular the more highly prevalent hGISA has increased pressure for effective treatment options. In this study, MIC/MBC data confirm those of previous studies, which show higher daptomycin MICs for some strains with reduced susceptibility to vancomycin (4, 13). This suggests that the development of heterogeneous vancomycin resistance and more specifically the thickening of the bacterial cell wall may act as a barrier to the large daptomycin molecule (4). However, bactericidal activity, as determined by MBC50s, MBC90s, and MBC/MIC ratios, shows that daptomycin is considerably more bactericidal than vancomycin against glycopeptide-susceptible, hGISA, and GISA strains. Time-kill curves also clearly show that daptomycin is significantly more bactericidal for each strain, especially at 6 h, than vancomycin for both GSSA and hGISA. Daptomycin was also bactericidal against one daptomycin-resistant hGISA strain (MIC of 2 mg/liter). These data confirm that daptomycin shows bactericidal activity against hGISA and suggest that the bactericidal activity of daptomycin is affected little by the decreased vancomycin susceptibility seen with hGISA (12).

In summary, the data presented here show that despite the slightly raised MICs seen for strains with reduced susceptibility to vancomycin, daptomycin has greater bactericidal activity than vancomycin for hGISA and GISA and can be considered a valid alternative to vancomycin in the treatment of infections caused by MRSA, hGISA, or GISA.


arrow
ACKNOWLEDGMENTS
 
We thank the providers of all strains, including the SENTRY Antimicrobial Surveillance Program.

We thank Cubist for financial support.


arrow
FOOTNOTES
 
* Corresponding author. Present address: Specialist Antimicrobial Chemotherapy Unit, NPHS Microbiology Cardiff, University Hospital Wales, Heath Park, Cardiff CF14 4XW, United Kingdom. Phone: 44 02920 746581. Fax: 44 02920 744130. E-mail: mandy.wootton{at}nphs.wales.nhs.uk. Back

{triangledown} Published ahead of print on 16 October 2006. Back

{dagger} Present address: School of Medicine, Department of Medical Microbiology, Cardiff University, Heath Park, Cardiff CF14 4XW, United Kingdom. Back


arrow
REFERENCES
 
    1
  1. Akins, R. L., and M. J. Rybak. 2001. Bactericidal activities of two daptomycin regimens against clinical strains of glycopeptide intermediate-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations. Antimicrob. Agents Chemother. 45:454-459.[Abstract/Free Full Text]
    2. 2
  2. Carpenter, C. F., and H. F. Chambers. 2004. Daptomycin: another novel agent for treating infections due to drug-resistant Gram-positive pathogens. Clin. Infect. Dis. 38:994-1000.[CrossRef][Medline]
    3. 3
  3. Cosgrove, S. E., Y. Qi, K. S. Kaye, S. Harbarth, A. W. Karchmer, and Y. Carmeli. 2005. The impact of methicillin resistance in Staphylococcus aureus bacteremia on patient outcomes: mortality, length of stay, and hospital charges. Infect. Control Hosp. Epidemiol. 26:166-174.[CrossRef][Medline]
    4. 4
  4. Cui, L., E. Tominaga, H. M. Neoh, and K. Hiramatsu. 2006. Correlation between reduced daptomycin susceptibility and vancomycin resistance in vancomycin-intermediate Staphylococcus aureus. Antimicrob. Agents Chemother. 50:1079-1082.[Abstract/Free Full Text]
    5. 5
  5. DeGirolami, P. C., and G. Eliopoulos. 1989. Antimicrobial susceptibility tests and their role in therapeutic drug monitoring. Clin. Lab. Med. 7:499-513.
    6. 6
  6. Eliopoulos, G. M., and R. C. Moellering, Jr. 1996. Antimicrobial combinations, p. 330-396. In V. Lorian (ed.), Antibiotics in laboratory medicine, 4th ed. The Williams & Wilkins Co., Baltimore, Md.
    7. 7
  7. Hiramatsu, K., N. Aritaka, H. Hanaki, S. Kawasaki, Y. Hosoda, S. Hori, Y. Fukuchi, and I. Kobayashi. 1997. Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin. Lancet 350:1670-1673.[CrossRef][Medline]
    8. 8
  8. Howe, R. A., A. Monk, M. Wootton, T. R. Walsh, and M. C. Enright. 2004. Vancomycin susceptibility within methicillin-resistant Staphylococcus aureus lineages. Emerg. Infect. Dis. 10:855-857.[Medline]
    9. 9
  9. Lowy, F. D. 2003. Antimicrobial resistance: the example of Staphylococcus aureus. J. Clin. Investig. 111:1265-1273.[CrossRef][Medline]
    10. 10
  10. National Committee for Clinical Laboratory Standards. 2003. Performance standards for antimicrobial susceptibility testing, M100-S13. National Committee for Clinical Laboratory Standards Wayne, Pa.
    11. 11
  11. National Nosocomial Infections Surveillance System. 2004. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am. J. Infect. Control 32:470-485.[CrossRef][Medline]
    12. 12
  12. Sader, H. S., T. R. Fritsche, and R. N. Jones. 2006. Daptomycin bactericidal activity and correlation between disk and broth microdilution method results in testing of Staphylococcus aureus strains with decreased susceptibility to vancomycin. Antimicrob. Agents Chemother. 50:2330-2336.[Abstract/Free Full Text]
    13. 13
  13. Sakoulas, G., J. Alder, C. Thauvin-Eliopoulos, R. C. Moellering, and G. M. Eliopoulos. 2006. Induction of daptomycin heterogeneous susceptibility in Staphylococcus aureus by exposure to vancomycin. Antimicrob. Agents Chemother. 50:1581-1585.[Abstract/Free Full Text]
    14. 14
  14. Sievert, D. M., M. L. Boulton, G. Stoltman, D. Johnson, M. G. Stobierski, F. P. Downes, P. A. Somsel, and J. T. Rudrik. 2002. Staphylococcus aureus resistant to vancomycin. Morb. Mortal. Wkly. Rep. 51:565-567.[Medline]
    15. 15
  15. Silverman, J. A., N. Oliver, T. Andrew, and T. Li. 2001. Resistance studies with daptomycin. Antimicrob. Agents Chemother. 45:1799-1802.[Abstract/Free Full Text]
    16. 16
  16. Tally, F. P., M. Zeckel, M. M. Wasilewski, C. Carini, C. L. Berman, G. L. Drusano, and F. B. Oleson, Jr. 1999 Daptomycin: a novel agent for Gram-positive infections. Expert Opin. Investig. Drugs 8:1223-1228.[CrossRef][Medline]
    17. 17
  17. Walsh, T. R., and R. A. Howe. 2002. The prevalence and mechanisms of vancomycin resistance in Staphylococcus aureus. Annu. Rev. Microbiol. 56:657-675.[CrossRef][Medline]
    18. 18
  18. Wootton, M., R. A. Howe, R. Hillman, T. R. Walsh, P. M. Bennett, and A. P. MacGowan. 2001. A modified population analysis profile (PAP) method to detect Staphylococcus aureus with decreased susceptibility to vancomycin in a U.K. hospital. J. Antimicrob. Chemother. 47:399-403.[Abstract/Free Full Text]

Antimicrobial Agents and Chemotherapy, December 2006, p. 4195-4197, Vol. 50, No. 12
0066-4804/06/$08.00+0     doi:10.1128/AAC.00678-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Traczewski, M. M., Katz, B. D., Steenbergen, J. N., Brown, S. D. (2009). Inhibitory and Bactericidal Activities of Daptomycin, Vancomycin, and Teicoplanin against Methicillin-Resistant Staphylococcus aureus Isolates Collected from 1985 to 2007. Antimicrob. Agents Chemother. 53: 1735-1738 [Abstract] [Full Text]  
  • Leonard, S. N., Rybak, M. J. (2009). Evaluation of vancomycin and daptomycin against methicillin-resistant Staphylococcus aureus and heterogeneously vancomycin-intermediate S. aureus in an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations. J Antimicrob Chemother 63: 155-160 [Abstract] [Full Text]  
  • Kosowska-Shick, K., Ednie, L. M., McGhee, P., Smith, K., Todd, C. D., Wehler, A., Appelbaum, P. C. (2008). Incidence and Characteristics of Vancomycin Nonsusceptible Strains of Methicillin-Resistant Staphylococcus aureus at Hershey Medical Center. Antimicrob. Agents Chemother. 52: 4510-4513 [Abstract] [Full Text]  
  • Rose, W. E., Leonard, S. N., Rybak, M. J. (2008). Evaluation of Daptomycin Pharmacodynamics and Resistance at Various Dosage Regimens against Staphylococcus aureus Isolates with Reduced Susceptibilities to Daptomycin in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations. Antimicrob. Agents Chemother. 52: 3061-3067 [Abstract] [Full Text]  
  • Rose, W. E., Leonard, S. N., Sakoulas, G., Kaatz, G. W., Zervos, M. J., Sheth, A., Carpenter, C. F., Rybak, M. J. (2008). Daptomycin Activity against Staphylococcus aureus following Vancomycin Exposure in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations. Antimicrob. Agents Chemother. 52: 831-836 [Abstract] [Full Text]  
  • Muthaiyan, A., Silverman, J. A., Jayaswal, R. K., Wilkinson, B. J. (2008). Transcriptional Profiling Reveals that Daptomycin Induces the Staphylococcus aureus Cell Wall Stress Stimulon and Genes Responsive to Membrane Depolarization. Antimicrob. Agents Chemother. 52: 980-990 [Abstract] [Full Text]  
  • Jones, T., Yeaman, M. R., Sakoulas, G., Yang, S.-J., Proctor, R. A., Sahl, H.-G., Schrenzel, J., Xiong, Y. Q., Bayer, A. S. (2008). Failures in Clinical Treatment of Staphylococcus aureus Infection with Daptomycin Are Associated with Alterations in Surface Charge, Membrane Phospholipid Asymmetry, and Drug Binding. Antimicrob. Agents Chemother. 52: 269-278 [Abstract] [Full Text]  

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wootton, M.
Right arrow Articles by Walsh, T. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wootton, M.
Right arrow Articles by Walsh, T. R.

Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»