Cubist Pharmaceuticals, Inc., 65 Hayden Avenue, Lexington, MA 02421, USA
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Abstract |
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Keywords: MRSA , cSSSI , vancomycin
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Introduction |
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To date, three vancomycin-resistant S. aureus strains (VRSA) have been isolated in the United States.811 Both the Pennsylvania and the New York strains were isolated from patients not on vancomycin therapy.9,12 Therefore, the need for new potent antimicrobial agents with MRSA activity is essential.
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Mechanism of action |
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The unique structure of daptomycin consists of a 13-member amino acid cyclic lipopeptide with a decanoyl side-chain (Figure 1). This distinctive structure confers a novel mechanism of action.22 The proposed mechanism involves insertion of the lipophilic daptomycin tail into the bacterial cell membrane, causing rapid membrane depolarization and a potassium ion efflux. This is followed by arrest of DNA, RNA and protein synthesis resulting in bacterial cell death (Figure 2).2224 The bactericidal effect of daptomycin is rapid with greater than 99.9% of both MRSA and MSSA bacteria dead in less than 1 h.25,26 This rapid cell death does not result in rapid bacterial cell lysis.24 Daptomycin also remains bactericidal (99.9% kill within 24 h) against stationary phase cultures of both MSSA and MRSA present at high density (109 cfu) in a simulated endocardial vegetation model.27
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Microbiology |
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Resistance |
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Pharmacology |
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Pre-clinical studies |
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Clinical studies |
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Conclusions |
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References |
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2 . Stefani, S. & Varaldo, P. E. (2003). Epidemiology of methicillin-resistant staphylococci in Europe. Clinical Microbiology and Infection 9, 117986.[CrossRef][ISI][Medline]
3
.
Fluit, A. C., Wielders, C. L., Verhoef, J. et al. (2001). Epidemiology and susceptibility of 3,051 Staphylococcus aureus isolates from 25 university hospitals participating in the European SENTRY study. Journal of Clinical Microbiology 39, 372732.
4
.
Cui, L., Ma, X., Sato, K. et al. (2003). Cell wall thickening is a common feature of vancomycin resistance in Staphylococcus aureus. Journal of Clinical Microbiology 41, 514.
5
.
Verdier, I., Reverdy, M. E., Etienne, J. et al. (2004). Staphylococcus aureus isolates with reduced susceptibility to glycopeptides belong to accessory gene regulator group I or II. Antimicrobial Agents and Chemotherapy 48, 10247.
6 . Sakoulas, G., Eliopoulos, G. M., Moellering, R. C. et al. (2003). Staphylococcus aureus accessory gene regulator (agr) group II: is there a relationship to the development of intermediate-level glycopeptide resistance? Journal of Infectious Diseases 187, 92938.[CrossRef][ISI][Medline]
7
.
Adhikari, R. P., Scales, G. C., Kobayashi, K. et al. (2004). Vancomycin-induced deletion of the methicillin resistance gene mecA in Staphylococcus aureus. Journal of Antimicrobial Chemotherapy 54, 3603.
8 . Centers for Disease Control and Prevention. (2002). Staphylococcus aureus resistant to vancomycinUnited States, 2002. In Morbidity and Mortality Weekly Report, pp. 5657.
9 . Centers for Disease Control and Prevention. (2002). Public Health Dispatch: vancomycin-resistant Staphylococcus aureusPennsylvania, 2002. In Morbidity and Mortality Weekly Report 902.
10 . Centers for Disease Control and Prevention. (2004). Brief report: vancomycin-resistant Staphylococcus aureusNew York, 2004. In Morbidity and Mortality Weekly Report 322.
11 . Mutnick, A. H., Biedenbach, D. J. & Jones, R. N. (2003). Geographic variations and trends in antimicrobial resistance among Enterococcus faecalis and Enterococcus faecium in the SENTRY Antimicrobial Surveillance Program (19972000). Diagnostic Microbiology and Infectious Disease 46, 638.[CrossRef][ISI][Medline]
12 . Kacica, M. A., Scott, C., Johnson, G. et al. (2004). Vancomycin-resistant Staphylococcus aureus (VRSA) in a resident of a long-term care facility (LTCF). In Program and Abstracts of the 42nd Annual Meeting of the Infectious Diseases Society of America, Boston, MA, USA. Abstract 530, p. 143. Infectious Diseases Society of America, Alexandria, VA, USA.
13
.
Barry, A. L., Fuchs, P. C. & Brown, S. D. (2001). In vitro activities of daptomycin against 2,789 clinical isolates from 11 North American medical centers. Antimicrobial Agents and Chemotherapy 45, 191922.
14
.
Critchley, I. A., Draghi, D. C., Sahm, D. F. et al. (2003). Activity of daptomycin against susceptible and multidrug-resistant Gram-positive pathogens collected in the SECURE study (Europe) during 20002001. Journal of Antimicrobial Chemotherapy 51, 63949.
15 . Fluit, A. C., Schmitz, F. J., Verhoef, J. et al. (2004). Daptomycin in vitro susceptibility in European Gram-positive clinical isolates. International Journal of Antimicrobial Agents 24, 5966.[CrossRef][ISI][Medline]
16
.
Fluit, A. C., Schmitz, F. J., Verhoef, J. et al. (2004). In vitro activity of daptomycin against Gram-positive European clinical isolates with defined resistance determinants. Antimicrobial Agents and Chemotherapy 48, 100711.
17
.
Petersen, P. J., Bradford, P. A., Weiss, W. J. et al. (2002). In vitro and in vivo activities of tigecycline (GAR-936), daptomycin, and comparative antimicrobial agents against glycopeptide-intermediate Staphylococcus aureus and other resistant gram-positive pathogens. Antimicrobial Agents and Chemotherapy 46, 2595601.
18
.
Richter, S. S., Kealey, D. E., Murray, C. T. et al. (2003). The in vitro activity of daptomycin against Staphylococcus aureus and Enterococcus species. Journal of Antimicrobial Chemotherapy 52, 1237.
19
.
Rybak, M. J., Hershberger, E., Moldovan, T. et al. (2000). In vitro activities of daptomycin, vancomycin, linezolid, and quinupristindalfopristin against staphylococci and enterococci, including vancomycin-intermediate and -resistant strains. Antimicrobial Agents and Chemotherapy 44, 10626.
20
.
Snydman, D. R., Jacobus, N. V., McDermott, L. A. et al. (2000). Comparative in vitro activities of daptomycin and vancomycin against resistant Gram-positive pathogens. Antimicrobial Agents and Chemotherapy 44, 344750.
21
.
Streit, J. M., Jones, R. N. & Sader, H. S. (2004). Daptomycin activity and spectrum: a worldwide sample of 6737 clinical Gram-positive organisms. Journal of Antimicrobial Chemotherapy 53, 66974.
22
.
Silverman, J. A., Perlmutter, N. G. & Shapiro, H. M. (2003). Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 47, 253844.
23 . Canepari, P., Boaretti, M., del Mar Lleo, M. et al. (1990). Lipoteichoic acid as a new target for activity of antibiotics: mode of action of daptomycin (LY146032). Antimicrobial Agents and Chemotherapy 34, 12206.[ISI][Medline]
24 . Silverman, J., Harris, B., Cotroneo, N., et al. (2003). Daptomycin (DAP) treatment induces membrane and cell wall alterations in Staphylococcus aureus. In Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL. Abstract C12135, p. 103. American Society for Microbiology, Washington, DC, USA.
25
.
Cha, R. & Rybak, M. J. (2004). Influence of protein binding under controlled conditions on the bactericidal activity of daptomycin in an in vitro pharmacodynamic model. Journal of Antimicrobial Chemotherapy 54, 25962.
26
.
Fuchs, P. C., Barry, A. L. & Brown, S. D. (2002). In vitro bactericidal activity of daptomycin against staphylococci. Journal of Antimicrobial Chemotherapy 49, 46770.
27 . Tedesco, K. L. & Rybak, M. J. (2003). Impact of high inoculum Staphylococcus aureus on the activities of nafcillin (NAF), vancomycin (VAN), linezolid (LZD), gentamicin (GEN), and daptomycin (DAP) in an in vitro pharmacodynamic model (IVD). In Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL. Abstract A-1151, p. 14. American Society for Microbiology, Washington, DC, USA.
28
.
Goldstein, E. J., Citron, D. M., Merriam, C. V. et al. (2003). In vitro activities of daptomycin, vancomycin, quinupristindalfopristin, linezolid, and five other antimicrobials against 307 gram-positive anaerobic and 31 Corynebacterium clinical isolates. Antimicrobial Agents and Chemotherapy 47, 33741.
29
.
Rand, K. H. & Houck, H. (2004). Daptomycin synergy with rifampicin and ampicillin against vancomycin-resistant enterococci. Journal of Antimicrobial Chemotherapy 53, 5302.
30
.
Silverman, J. A., Oliver, N., Andrew, T. et al. (2001). Resistance studies with daptomycin. Antimicrobial Agents and Chemotherapy 45, 1799802.
31
.
Oleson, F. B., Jr, Berman, C. L., Kirkpatrick, J. B. et al. (2000). Once-daily dosing in dogs optimizes daptomycin safety. Antimicrobial Agents and Chemotherapy 44, 294853.
32
.
Safdar, N., Andes, D. & Craig, W. A. (2004). In vivo pharmacodynamic activity of daptomycin. Antimicrobial Agents and Chemotherapy 48, 638.
33
.
Cottagnoud, P., Pfister, M., Acosta, F. et al. (2004). Daptomycin is highly efficacious against penicillin-resistant and penicillin- and quinolone-resistant pneumococci in experimental meningitis. Antimicrobial Agents and Chemotherapy 48, 392833.
34 . Arbeit, R. D., Maki, D., Tally, F. P. et al. (2004). The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clinical Infectious Diseases 38, 167381.[CrossRef][ISI][Medline]
35
.
Alder, J., Li, T., Yu, D. et al. (2003). Analysis of daptomycin efficacy and breakpoint standards in a murine model of Enterococcus faecalis and Enterococcus faecium renal infection. Antimicrobial Agents and Chemotherapy 47, 35616.
36
.
Cha, R., Grucz, R. G., Jr & Rybak, M. J. (2003). Daptomycin doseeffect relationship against resistant gram-positive organisms. Antimicrobial Agents and Chemotherapy 47, 1598603.
37
.
Dandekar, P. K., Tessier, P. R., Williams, P. et al. (2003). Pharmacodynamic profile of daptomycin against Enterococcus species and methicillin-resistant Staphylococcus aureus in a murine thigh infection model. Journal of Antimicrobial Chemotherapy 52, 40511.
38 . Kaatz, G. W., Seo, S. M., Reddy, V. N. et al. (1990). Daptomycin compared with teicoplanin and vancomycin for therapy of experimental Staphylococcus aureus endocarditis. Antimicrobial Agents and Chemotherapy 34, 20815.[ISI][Medline]
39
.
Louie, A., Kaw, P., Liu, W. et al. (2001). Pharmacodynamics of daptomycin in a murine thigh model of Staphylococcus aureus infection. Antimicrobial Agents and Chemotherapy 45, 84551.
40 . Mader, J. T. & Adams, K. (1989). Comparative evaluation of daptomycin (LY146032) and vancomycin in the treatment of experimental methicillin-resistant Staphylococcus aureus osteomyelitis in rabbits. Antimicrobial Agents and Chemotherapy 33, 68992.[ISI][Medline]
41 . Smith, K., Cobbs, G., Dill, R. et al. (1990). Daptomycin versus vancomycin treatment for Staphylococcus aureus bacteremia in a murine model. Chemotherapy 36, 42834.[ISI][Medline]
42
.
Wise, R., Gee, T., Andrews, J. M. et al. (2002). Pharmacokinetics and inflammatory fluid penetration of intravenous daptomycin in volunteers. Antimicrobial Agents and Chemotherapy 46, 313.
43 . Michiels, M. J. & Bergeron, M. G. (1996). Differential increased survival of staphylococci and limited ultrastructural changes in the core of infected fibrin clots after daptomycin administration. Antimicrobial Agents and Chemotherapy 40, 20311.[Abstract]
44
.
Vaudaux, P., Francois, P., Bisognano, C. et al. (2003). Comparative efficacy of daptomycin and vancomycin in the therapy of experimental foreign body infection due to Staphylococcus aureus. Journal of Antimicrobial Chemotherapy 52, 8995.
45 . Alder, J., Arbeit, R., Eisenstein, B., et al. (2004). Pulmonary epithelial lining fluid (ELF) as a privileged site: daptomycin in pulmonary infections. In International Congress of Infectious Diseases, Cancun, Mexico. 11th ICID Abstracts, Abstract 60.005, p. S195. International Society for Infectious Diseases, Brighton, UK.