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. 1997 Jun;41(6):1307–1312. doi: 10.1128/aac.41.6.1307

Pharmacodynamic evaluation of a new glycopeptide, LY333328, and in vitro activity against Staphylococcus aureus and Enterococcus faecium.

R C Mercier 1, H H Houlihan 1, M J Rybak 1
PMCID: PMC163905  PMID: 9174189

Abstract

The objectives of the present study were to compare the in vitro activity of LY333328 (LY) to that of vancomycin (V) alone and in combination with gentamicin (G) and rifampin (R) against methicillin-resistant Staphylococcus aureus (MRSA) and V-resistant Enterococcus faecium (VREF), by using the killing curve methods. In addition, the effect of the inoculum size and protein on LY's activity was evaluated by using MICs and killing curves. MICs, MBCs, and killing curves were determined with supplemented Mueller-Hinton broth (B), B with albumin (4 g/dl) (A), and B with 50% pooled human serum (S). For MRSA, time to 99.9% killing after exposure to LY at four times the MIC (4x MIC) was achieved at 0.5 +/- 0 h (mean +/- standard deviation) and was significantly faster than that by V (8.54 +/- 0.10 h; P = 0.001). Against VREF, LY decreased the inoculum by 2.2 log10 CFU/ml at 24 h (P = 0.002). With a large inoculum of MRSA, the activity of LY and V at 4x MIC was decreased compared to that with the standard inoculum (P = 0.0003) and regrowth occurred at 24 h. The reduction in the number of CFU per milliliter at 24 h to 2 log10 CFU/ml was restored by increasing the LY concentration to at least 16x MIC. At 24 h, the combinations of LY and G, LY and R, LY and V, and V and G were better than either LY or V alone against a large inoculum of MRSA (P = 0.0002). LY and G achieved 99.9% killing at 1.01 +/- 0.03 h and was more rapid (P < 0.007) than all the other regimens studied except for V and G, which achieved 99.9% killing at 3.59 +/- 0.01 h. Killing curves determined with different media against a standard inoculum of MRSA did not demonstrate a significant difference between LY and V at 24 h. Time to 99.9% killing was more rapid with LY than with V in B, A, and S (P = 0.0002). Times to 99.9% killing by LY in B, A, and S were not significantly different from each other. Against VREF, LY killed better than V in B, A, or S at 24 h (P = 0.0002). LY in B was more active than LY in A or S (P = 0.0002). LY is a new potent glycopeptide with a unique activity profile. It has a greater activity than that of V against MRSA and has activity against VREF. LY demonstrated synergism in combination with gentamicin against MRSA. LY was affected by large inoculum sizes and proteins in time-kill studies. However, the effect was compensated for by increasing the drug concentration to 16x MIC.

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Selected References

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  1. Bailey E. M., Rybak M. J., Kaatz G. W. Comparative effect of protein binding on the killing activities of teicoplanin and vancomycin. Antimicrob Agents Chemother. 1991 Jun;35(6):1089–1092. doi: 10.1128/aac.35.6.1089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bayer A. S. Infective endocarditis. Clin Infect Dis. 1993 Sep;17(3):313–322. doi: 10.1093/clinids/17.3.313. [DOI] [PubMed] [Google Scholar]
  3. Chambers H. F., Kennedy S. Effects of dosage, peak and trough concentrations in serum, protein binding, and bactericidal rate on efficacy of teicoplanin in a rabbit model of endocarditis. Antimicrob Agents Chemother. 1990 Apr;34(4):510–514. doi: 10.1128/aac.34.4.510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Craig W. A., Ebert S. C. Killing and regrowth of bacteria in vitro: a review. Scand J Infect Dis Suppl. 1990;74:63–70. [PubMed] [Google Scholar]
  5. Faville R. J., Jr, Zaske D. E., Kaplan E. L., Crossley K., Sabath L. D., Quie P. G. Staphylococcus aureus endocarditis. Combined therapy with vancomycin and rifampin. JAMA. 1978 Oct 27;240(18):1963–1965. doi: 10.1001/jama.240.18.1963. [DOI] [PubMed] [Google Scholar]
  6. Gopal V., Bisno A. L., Silverblatt F. J. Failure of vancomycin treatment in Staphylococcus aureus endocarditis. In vivo and in vitro observations. JAMA. 1976 Oct 4;236(14):1604–1606. [PubMed] [Google Scholar]
  7. Jacoby G. A., Archer G. L. New mechanisms of bacterial resistance to antimicrobial agents. N Engl J Med. 1991 Feb 28;324(9):601–612. doi: 10.1056/NEJM199102283240906. [DOI] [PubMed] [Google Scholar]
  8. Kang S. L., Rybak M. J. Comparative in vitro activities of LY191145, a new glycopeptide, and vancomycin against Staphylococcus aureus and Staphylococcus-infected fibrin clots. Antimicrob Agents Chemother. 1995 Dec;39(12):2832–2834. doi: 10.1128/aac.39.12.2832. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Lamp K. C., Rybak M. J., Bailey E. M., Kaatz G. W. In vitro pharmacodynamic effects of concentration, pH, and growth phase on serum bactericidal activities of daptomycin and vancomycin. Antimicrob Agents Chemother. 1992 Dec;36(12):2709–2714. doi: 10.1128/aac.36.12.2709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lamp K. C., Rybak M. J. Teicoplanin and daptomycin bactericidal activities in the presence of albumin or serum under controlled conditions of pH and ionized calcium. Antimicrob Agents Chemother. 1993 Mar;37(3):605–609. doi: 10.1128/aac.37.3.605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Levine D. P., Fromm B. S., Reddy B. R. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med. 1991 Nov 1;115(9):674–680. doi: 10.7326/0003-4819-115-9-674. [DOI] [PubMed] [Google Scholar]
  12. Massanari R. M., Donta S. T. The efficacy of rifampin as adjunctive therapy in selected cases of staphylococcal endocarditis. Chest. 1978 Mar;73(3):371–375. doi: 10.1378/chest.73.3.371. [DOI] [PubMed] [Google Scholar]
  13. McGrath B. J., Kang S. L., Kaatz G. W., Rybak M. J. Bactericidal activities of teicoplanin, vancomycin, and gentamicin alone and in combination against Staphylococcus aureus in an in vitro pharmacodynamic model of endocarditis. Antimicrob Agents Chemother. 1994 Sep;38(9):2034–2040. doi: 10.1128/aac.38.9.2034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mobarakai N., Quale J. M., Landman D. Bactericidal activities of peptide antibiotics against multidrug-resistant Enterococcus faecium. Antimicrob Agents Chemother. 1994 Feb;38(2):385–387. doi: 10.1128/aac.38.2.385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Moellering R. C., Jr Emergence of Enterococcus as a significant pathogen. Clin Infect Dis. 1992 Jun;14(6):1173–1176. doi: 10.1093/clinids/14.6.1173. [DOI] [PubMed] [Google Scholar]
  16. Mulazimoglu L., Drenning S. D., Muder R. R. Vancomycin-gentamicin synergism revisited: effect of gentamicin susceptibility of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1996 Jun;40(6):1534–1535. doi: 10.1128/aac.40.6.1534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nagarajan R. Structure-activity relationships of vancomycin-type glycopeptide antibiotics. J Antibiot (Tokyo) 1993 Aug;46(8):1181–1195. doi: 10.7164/antibiotics.46.1181. [DOI] [PubMed] [Google Scholar]
  18. Reymann M. T., Holley H. P., Jr, Cobbs C. G. Persistent bacteremia in staphylococcal endocarditis. Am J Med. 1978 Nov;65(5):729–737. doi: 10.1016/0002-9343(78)90790-8. [DOI] [PubMed] [Google Scholar]
  19. Small P. M., Chambers H. F. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother. 1990 Jun;34(6):1227–1231. doi: 10.1128/aac.34.6.1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Spera R. V., Jr, Farber B. F. Multiply-resistant Enterococcus faecium. The nosocomial pathogen of the 1990s. JAMA. 1992 Nov 11;268(18):2563–2564. [PubMed] [Google Scholar]
  21. Stanley D., McGrath B. J., Lamp K. C., Rybak M. J. Effect of human serum on killing activity of vancomycin and teicoplanin against Staphylococcus aureus. Pharmacotherapy. 1994 Jan-Feb;14(1):35–39. doi: 10.1002/j.1875-9114.1994.tb02786.x. [DOI] [PubMed] [Google Scholar]
  22. Tailor S. A., Bailey E. M., Rybak M. J. Enterococcus, an emerging pathogen. Ann Pharmacother. 1993 Oct;27(10):1231–1242. doi: 10.1177/106002809302701014. [DOI] [PubMed] [Google Scholar]
  23. Watanakunakorn C., Tisone J. C. Synergism between vancomycin and gentamicin or tobramycin for methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains. Antimicrob Agents Chemother. 1982 Nov;22(5):903–905. doi: 10.1128/aac.22.5.903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. de Lencastre H., de Jonge B. L., Matthews P. R., Tomasz A. Molecular aspects of methicillin resistance in Staphylococcus aureus. J Antimicrob Chemother. 1994 Jan;33(1):7–24. doi: 10.1093/jac/33.1.7. [DOI] [PubMed] [Google Scholar]

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