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. 1997 Nov;41(11):2497–2501. doi: 10.1128/aac.41.11.2497

Pharmacodynamics of vancomycin alone and in combination with gentamicin at various dosing intervals against methicillin-resistant Staphylococcus aureus-infected fibrin-platelet clots in an in vitro infection model.

H H Houlihan 1, R C Mercier 1, M J Rybak 1
PMCID: PMC164151  PMID: 9371356

Abstract

We compared the pharmacodynamic activities of vancomycin with or without gentamicin in an in vitro infection model with methicilin-resistant Staphylococcus aureus-infected fibrin-platelet clots. Infected fibrin-platelet clots (FPCs) were prepared with human cryoprecipitate, human platelets, thrombin, and the organism (approximately 10[9] CFU of MRSA-494/g) and were suspended with monofilament line in an infection model capable of simulating human pharmacokinetics. Antibiotics were bolused to simulate vancomycin regimens of 2 g every 24 h (q24h), 1 g q12h, 500 mg q6h, and continuous infusion (steady-state concentration of 20 microg/ml) and gentamicin regimens of 1.5 mg/kg of body weight q12h and 5 mg/kg once daily (q.d.). Model experiments were performed in duplicate over 72 h. FPCs were removed from the models in quadruplicate at 0, 8, 24, 32, 48, 72 h, weighed, homogenized, diluted, and plated to determine colony counts. The inoculum density at 72 h was used to compare bactericidal activities between the regimens. All regimens containing vancomycin significantly decreased the bacterial inoculum compared to the growth control (P < 0.001). Vancomycin monotherapy regimens were similar in bacterial kill regardless of dosing frequency. The addition of gentamicin (either q12h or q.d.) significantly improved the bactericidal activity of the vancomycin q6h, q12h, and q24h regimens (P < 0.001). The greatest reduction in bacterial density at 72 h (P < 0.001) and the most rapid rate of kill (time to 99.9% killing) were achieved with the regimen consisting of 2 g of vancomycin q24h plus gentamicin (q.d. or q12h).

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Selected References

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  1. Ackerman B. H., Vannier A. M., Eudy E. B. Analysis of vancomycin time-kill studies with Staphylococcus species by using a curve stripping program to describe the relationship between concentration and pharmacodynamic response. Antimicrob Agents Chemother. 1992 Aug;36(8):1766–1769. doi: 10.1128/aac.36.8.1766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bates R. D., Nahata M. C. Once-daily administration of aminoglycosides. Ann Pharmacother. 1994 Jun;28(6):757–766. doi: 10.1177/106002809402800614. [DOI] [PubMed] [Google Scholar]
  3. Blaser J. In-vitro model for simultaneous simulation of the serum kinetics of two drugs with different half-lives. J Antimicrob Chemother. 1985 Jan;15 (Suppl A):125–130. doi: 10.1093/jac/15.suppl_a.125. [DOI] [PubMed] [Google Scholar]
  4. Cremieux A. C., Maziere B., Vallois J. M., Ottaviani M., Azancot A., Raffoul H., Bouvet A., Pocidalo J. J., Carbon C. Evaluation of antibiotic diffusion into cardiac vegetations by quantitative autoradiography. J Infect Dis. 1989 May;159(5):938–944. doi: 10.1093/infdis/159.5.938. [DOI] [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. Francioli P. B., Glauser M. P. Synergistic activity of ceftriaxone combined with netilmicin administered once daily for treatment of experimental streptococcal endocarditis. Antimicrob Agents Chemother. 1993 Feb;37(2):207–212. doi: 10.1128/aac.37.2.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Garrison M. W., Rotschafer J. C., Crossley K. B. Suboptimal effect of daptomycin in the treatment of bacteremias. South Med J. 1989 Nov;82(11):1414–1415. doi: 10.1097/00007611-198911000-00018. [DOI] [PubMed] [Google Scholar]
  8. Gavaldà J., Cardona P. J., Almirante B., Capdevila J. A., Laguarda M., Pou L., Crespo E., Pigrau C., Pahissa A. Treatment of experimental endocarditis due to Enterococcus faecalis using once-daily dosing regimen of gentamicin plus simulated profiles of ampicillin in human serum. Antimicrob Agents Chemother. 1996 Jan;40(1):173–178. doi: 10.1128/aac.40.1.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gavaldà J., Pahissa A., Almirante B., Laguarda M., Crespo E., Pou L., Fernández F. Effect of gentamicin dosing interval on therapy of viridans streptococcal experimental endocarditis with gentamicin plus penicillin. Antimicrob Agents Chemother. 1995 Sep;39(9):2098–2103. doi: 10.1128/aac.39.9.2098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Geraci J. E., Hermans P. E. Vancomycin. Mayo Clin Proc. 1983 Feb;58(2):88–91. [PubMed] [Google Scholar]
  11. Gilbert D. N., Wood C. A., Kimbrough R. C. Failure of treatment with teicoplanin at 6 milligrams/kilogram/day in patients with Staphylococcus aureus intravascular infection. The Infectious Diseases Consortium of Oregon. Antimicrob Agents Chemother. 1991 Jan;35(1):79–87. doi: 10.1128/aac.35.1.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hatala R., Dinh T., Cook D. J. Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis. Ann Intern Med. 1996 Apr 15;124(8):717–725. doi: 10.7326/0003-4819-124-8-199604150-00003. [DOI] [PubMed] [Google Scholar]
  13. Kaatz G. W., Seo S. M., Barriere S. L., Albrecht L. M., Rybak M. J. Development of resistance to fleroxacin during therapy of experimental methicillin-susceptible Staphylococcus aureus endocarditis. Antimicrob Agents Chemother. 1991 Aug;35(8):1547–1550. doi: 10.1128/aac.35.8.1547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kaatz G. W., Seo S. M., Dorman N. J., Lerner S. A. Emergence of teicoplanin resistance during therapy of Staphylococcus aureus endocarditis. J Infect Dis. 1990 Jul;162(1):103–108. doi: 10.1093/infdis/162.1.103. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Leport C., Perronne C., Massip P., Canton P., Leclercq P., Bernard E., Lutun P., Garaud J. J., Vilde J. L. Evaluation of teicoplanin for treatment of endocarditis caused by gram-positive cocci in 20 patients. Antimicrob Agents Chemother. 1989 Jun;33(6):871–876. doi: 10.1128/aac.33.6.871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. 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]
  20. Palmer S. M., Rybak M. J. Pharmacodynamics of once- or twice-daily levofloxacin versus vancomycin, with or without rifampin, against Staphylococcus aureus in an in vitro model with infected platelet-fibrin clots. Antimicrob Agents Chemother. 1996 Mar;40(3):701–705. doi: 10.1128/aac.40.3.701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Perdikaris G., Giamarellou H., Pefanis A., Donta I., Karayiannakos P. Vancomycin or vancomycin plus netilmicin for methicillin- and gentamicin-resistant Staphylococcus aureus aortic valve experimental endocarditis. Antimicrob Agents Chemother. 1995 Oct;39(10):2289–2294. doi: 10.1128/aac.39.10.2289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Rotschafer J. C., Rybak M. J. Single daily dosing of aminoglycosides: a commentary. Ann Pharmacother. 1994 Jun;28(6):797–801. doi: 10.1177/106002809402800618. [DOI] [PubMed] [Google Scholar]
  24. Rybak M. J., Albrecht L. M., Boike S. C., Chandrasekar P. H. Nephrotoxicity of vancomycin, alone and with an aminoglycoside. J Antimicrob Chemother. 1990 Apr;25(4):679–687. doi: 10.1093/jac/25.4.679. [DOI] [PubMed] [Google Scholar]
  25. Rybak M. J., Bailey E. M., Lamp K. C., Kaatz G. W. Pharmacokinetics and bactericidal rates of daptomycin and vancomycin in intravenous drug abusers being treated for gram-positive endocarditis and bacteremia. Antimicrob Agents Chemother. 1992 May;36(5):1109–1114. doi: 10.1128/aac.36.5.1109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rybak M. J., Lerner S. A., Levine D. P., Albrecht L. M., McNeil P. L., Thompson G. A., Kenny M. T., Yuh L. Teicoplanin pharmacokinetics in intravenous drug abusers being treated for bacterial endocarditis. Antimicrob Agents Chemother. 1991 Apr;35(4):696–700. doi: 10.1128/aac.35.4.696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. 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]
  29. Tuazon C. U., Lin M. Y., Sheagren J. N. In vitro activity of rifampin alone and in combination with nafcillin and Vancomycin against pathogenic strains of Staphylococcus aureus. Antimicrob Agents Chemother. 1978 May;13(5):759–761. doi: 10.1128/aac.13.5.759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Watanakunakorm C., Glotzbecker C. Enhancement of the effects of anti-staphylococcal antibiotics by aminoglycosides. Antimicrob Agents Chemother. 1974 Dec;6(6):802–806. doi: 10.1128/aac.6.6.802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Watanakunakorn C., Guerriero J. C. Interaction between vancomycin and rifampin against Staphylococcus aureus. Antimicrob Agents Chemother. 1981 Jun;19(6):1089–1091. doi: 10.1128/aac.19.6.1089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]

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