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. 1997 Jun;41(6):1359–1363. doi: 10.1128/aac.41.6.1359

Pharmacodynamics of RP 59500 (quinupristin-dalfopristin) administered by intermittent versus continuous infusion against Staphylococcus aureus-infected fibrin-platelet clots in an in vitro infection model.

M J Rybak 1, H H Houlihan 1, R C Mercier 1, G W Kaatz 1
PMCID: PMC163915  PMID: 9174199

Abstract

We evaluated the bactericidal activity of RP 59500 (quinupristin-dalfopristin) against fibrin-platelet clots (FPC) infected with two clinical isolates of Staphylococcus aureus, one constitutively erythromycin and methicillin resistant (S. aureus AW7) and one erythromycin and methicillin susceptible (S. aureus 1199), in an in vitro pharmacodynamic infection model. RP 59500 was administered by continuous infusion (peak steady-state concentration of 6 microg/ml) or intermittent infusion (simulated regimens of 7.5 mg/kg of body weight every 6 h (q6h) q8h, and q12h. FPCs were infected with S. aureus to achieve an initial bacterial density of 10(9) CFU/g. Model experiments were run in duplicate over 72 h. Two FPCs were removed from each model at 0, 12, 24, 36, 48, and 72 h, and the bacterial densities (in CFU per gram) were determined and compared to those of growth control experiments. Additional samples were also removed from the model over the 72-h period for pharmacokinetic evaluation. All regimens significantly (P < or = 0.01) decreased bacterial densities in the infected FPCs for both isolates compared to growth controls. This occurred even though MBCs were equal to or greater than the RP 59500 concentrations achieved in the models. There were no significant differences found between the dosing frequencies and levels of killing when examining each isolate separately. However, examination of the residual bacterial densities (CFU per gram at 72 h) and visual inspection of the overall killing effect (killing curve plots over 72 h) clearly demonstrated a more favorable bactericidal activity against 1199 than against the AW7 isolate. This was most apparent when the q8h and the q12h AW7 regimens were compared to all 1199 treatment regimens by measuring the 72-h bacterial densities (P < or = 0.01). Killing (99.9%) was not achieved against the AW7 isolate. However, a 99.9% kill was demonstrated for all dosing regimens against the 1199 isolate. The area under the concentration-time curve from 0 to 24 h was found to be significantly correlated with reduction in bacterial density for the AW7 isolate (r = 0.74, P = 0.04). No resistance was detected during any experiment for either isolate. RP 59500 efficacy against constitutively erythromycin- and methicillin-resistant S. aureus may be improved by increasing organism exposure to RP 59500 as a function of dosing frequency.

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Selected References

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  1. Barrière J. C., Bouanchaud D. H., Paris J. M., Rolin O., Harris N. V., Smith C. Antimicrobial activity against Staphylococcus aureus of semisynthetic injectable streptogramins: RP 59500 and related compounds. J Antimicrob Chemother. 1992 Jul;30 (Suppl A):1–8. doi: 10.1093/jac/30.suppl_a.1. [DOI] [PubMed] [Google Scholar]
  2. Brumfitt W., Hamilton-Miller J. M., Shah S. In-vitro activity of RP 59500, a new semisynthetic streptogramin antibiotic, against gram-positive bacteria. J Antimicrob Chemother. 1992 Jul;30 (Suppl A):29–37. doi: 10.1093/jac/30.suppl_a.29. [DOI] [PubMed] [Google Scholar]
  3. Chant C., Rybak M. J. Quinupristin/dalfopristin (RP 59500): a new streptogramin antibiotic. Ann Pharmacother. 1995 Oct;29(10):1022–1027. doi: 10.1177/106002809502901013. [DOI] [PubMed] [Google Scholar]
  4. Cremieux A. C., Carbon C. Pharmacokinetic and pharmacodynamic requirements for antibiotic therapy of experimental endocarditis. Antimicrob Agents Chemother. 1992 Oct;36(10):2069–2074. doi: 10.1128/aac.36.10.2069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Entenza J. M., Drugeon H., Glauser M. P., Moreillon P. Treatment of experimental endocarditis due to erythromycin-susceptible or -resistant methicillin-resistant Staphylococcus aureus with RP 59500. Antimicrob Agents Chemother. 1995 Jul;39(7):1419–1424. doi: 10.1128/aac.39.7.1419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Etienne S. D., Montay G., Le Liboux A., Frydman A., Garaud J. J. A phase I, double-blind, placebo-controlled study of the tolerance and pharmacokinetic behaviour of RP 59500. J Antimicrob Chemother. 1992 Jul;30 (Suppl A):123–131. doi: 10.1093/jac/30.suppl_a.123. [DOI] [PubMed] [Google Scholar]
  7. Fantin B., Leclercq R., Merlé Y., Saint-Julien L., Veyrat C., Duval J., Carbon C. Critical influence of resistance to streptogramin B-type antibiotics on activity of RP 59500 (quinupristin-dalfopristin) in experimental endocarditis due to Staphylococcus aureus. Antimicrob Agents Chemother. 1995 Feb;39(2):400–405. doi: 10.1128/aac.39.2.400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fass R. J. In vitro activity of RP 59500, a semisynthetic injectable pristinamycin, against staphylococci, streptococci, and enterococci. Antimicrob Agents Chemother. 1991 Mar;35(3):553–559. doi: 10.1128/aac.35.3.553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kang S. L., Rybak M. J. Pharmacodynamics of RP 59500 alone and in combination with vancomycin against Staphylococcus aureus in an in vitro-infected fibrin clot model. Antimicrob Agents Chemother. 1995 Jul;39(7):1505–1511. doi: 10.1128/aac.39.7.1505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Leclercq R., Courvalin P. Intrinsic and unusual resistance to macrolide, lincosamide, and streptogramin antibiotics in bacteria. Antimicrob Agents Chemother. 1991 Jul;35(7):1273–1276. doi: 10.1128/aac.35.7.1273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Leclercq R., Nantas L., Soussy C. J., Duval J. Activity of RP 59500, a new parenteral semisynthetic streptogramin, against staphylococci with various mechanisms of resistance to macrolide-lincosamide-streptogramin antibiotics. J Antimicrob Chemother. 1992 Jul;30 (Suppl A):67–75. doi: 10.1093/jac/30.suppl_a.67. [DOI] [PubMed] [Google Scholar]
  12. Lorian V., Amaral L., Fernandes F. RP 59500 postantibiotic effect defined by bacterial ultrastructure. Drugs Exp Clin Res. 1995;21(3):125–128. [PubMed] [Google Scholar]
  13. Low D. E. Quinupristin/dalfopristin: spectrum of activity, pharmacokinetics, and initial clinical experience. Microb Drug Resist. 1995 Fall;1(3):223–234. doi: 10.1089/mdr.1995.1.223. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Nougayrede A., Berthaud N., Bouanchaud D. H. Post-antibiotic effects of RP 59500 with Staphylococcus aureus. J Antimicrob Chemother. 1992 Jul;30 (Suppl A):101–106. doi: 10.1093/jac/30.suppl_a.101. [DOI] [PubMed] [Google Scholar]
  16. Rocci M. L., Jr, Jusko W. J. LAGRAN program for area and moments in pharmacokinetic analysis. Comput Programs Biomed. 1983 Jun;16(3):203–216. doi: 10.1016/0010-468x(83)90082-x. [DOI] [PubMed] [Google Scholar]
  17. Sanchez M. L., Flint K. K., Jones R. N. Occurrence of macrolide-lincosamide-streptogramin resistances among staphylococcal clinical isolates at a university medical center. Is false susceptibility to new macrolides and clindamycin a contemporary clinical and in vitro testing problem? Diagn Microbiol Infect Dis. 1993 Mar-Apr;16(3):205–213. doi: 10.1016/0732-8893(93)90111-j. [DOI] [PubMed] [Google Scholar]
  18. Siedentop K. H., Harris D. M., Ham K., Sanchez B. Extended experimental and preliminary surgical findings with autologous fibrin tissue adhesive made from patients own blood. Laryngoscope. 1986 Oct;96(10):1062–1064. doi: 10.1288/00005537-198610000-00003. [DOI] [PubMed] [Google Scholar]
  19. Simon H. J., Yin E. J. Microbioassay of antimicrobial agents. Appl Microbiol. 1970 Apr;19(4):573–579. doi: 10.1128/am.19.4.573-579.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Thompson D. F., Letassy N. A., Thompson G. D. Fibrin glue: a review of its preparation, efficacy, and adverse effects as a topical hemostat. Drug Intell Clin Pharm. 1988 Dec;22(12):946–952. doi: 10.1177/106002808802201203. [DOI] [PubMed] [Google Scholar]

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