Clinical Pharmacokinetics

, Volume 43, Issue 13, pp 925–942 | Cite as

Pharmacodynamics of Vancomycin and Other Antimicrobials in Patients with Staphylococcus aureus Lower Respiratory Tract Infections

  • Pamela A. Moise-Broder
  • Alan Forrest
  • Mary C. Birmingham
  • Jerome J. SchentagEmail author
Original Research Article



Vancomycin is commonly used to treat staphylococcal infections, but there has not been a definitive analysis of the pharmacokinetics of this antibacterial in relation to minimum inhibitory concentration (MIC) that could be used to determine a target pharmacodynamic index for treatment optimisation.


To clarify relationships between vancomycin dosage, serum concentration, MIC and antimicrobial activity by using data gathered from a therapeutic monitoring environment that observes failures in some cases.


We investigated all patients with a Staphylococcus aureus lower respiratory tract infection at a 300-bed teaching hospital in the US during a 1-year period. Clinical and pharmacokinetic information was used to determine the following: (i) whether steady-state 24-hour area under the concentration-time curve (AUC24) divided by the MIC (AUC24/MIC) values for vancomycin could be precisely calculated with a software program; (ii) whether the percentage of time vancomycin serum concentrations were above the MIC (%Time>MIC) was an important determinant of vancomycin response; (iii) whether the time to bacterial eradication differed as the AUC24/MIC value increased; (iv) whether the time to bacterial eradication for vancomycin differed compared with other antibacterials at the same AUC24/MIC value; and (v) whether a relationship existed between time to bacterial eradication and time to significant clinical improvement of pneumonia symptoms.


The median age of the 108 patients studied was 74 (range 32–93) years. Measured vancomycin AUC24/MIC values were precisely predicted with the A.U.I.C. calculator in a subset of our patients (r2 = 0.935). Clinical and bacteriological response to vancomycin therapy was superior in patients with higher (≥400) AUC24/MIC values (p = 0.0046), but no relationship was identified between vancomycin %Time>MIC and infection response. Bacterial eradication of S. aureus (both methicillin-susceptible and methicillin-resistant) occurred more rapidly (p = 0.0402) with vancomycin when a threshold AUC24/MIC value was reached. S. aureus killing rates were slower with vancomycin than with other antistaphylococcal antibacterials (p = 0.002). There was a significant relationship (p < 0.0001) between time to bacterial eradication and the time to substantial improvement in pneumonia score.


Vancomycin AUC24/MIC values predict time-related clinical and bacteriological outcomes for patients with lower respiratory tract infections caused by methicillin-resistant S. aureus.


Minimum Inhibitory Concentration Vancomycin Lower Respiratory Tract Infection Bacterial Eradication Vancomycin Dosage 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No financial support was obtained for the preparation of this article. The authors have no conflicts of interest directly relevant to the content of this study.


  1. 1.
    Forrest A, Nix DE, Ballow CH, et al. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993; 37(5): 1073–81PubMedCrossRefGoogle Scholar
  2. 2.
    Highet VS, Forrest A, Ballow CH, et al. Antibiotic dosing issues in lower respiratory tract infection: population-derived area under inhibitory curve is predictive of efficacy. J Antimicrob Chemother 1999; 43 Suppl. A: 55–63PubMedCrossRefGoogle Scholar
  3. 3.
    Schentag JJ, Nix DE, Adelman MH. Mathematical examination of dual individualization principles (I): relationships between AUC above MIC and area under the inhibitory curve for cefmenoxime, ciprofloxacin, and tobramycin. DICP 1991; 25(10): 1050–7PubMedGoogle Scholar
  4. 4.
    Goss TF, Forrest A, Nix DE, et al. Mathematical examination of dual individualization principles (II): the rate of bacterial eradication at the same area under the inhibitory curve is more rapid for ciprofloxacin than for cefmenoxime. Ann Pharmacother 1994; 28(7–8): 863–8PubMedGoogle Scholar
  5. 5.
    Schentag JJ. Pharmacokinetic and pharmacodynamic predictors of antimicrobial efficacy: moxifloxacin and Streptococcus pneumoniae. J Chemother 2002; 14 Suppl. 2: 13–21PubMedGoogle Scholar
  6. 6.
    Schentag JJ. Antimicrobial management strategies for Grampositive bacterial resistance in the intensive care unit. Crit Care Med 2001; 29 (4 Suppl.): N100–7PubMedCrossRefGoogle Scholar
  7. 7.
    Schentag JJ, Meagher AK, Forrest A. Fluoroquinolone AUIC break points and the link to bacterial killing rates (Pt 2): human trials. Ann Pharmacother 2003; 37(10): 1478–88PubMedCrossRefGoogle Scholar
  8. 8.
    Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26(1): 1–10PubMedCrossRefGoogle Scholar
  9. 9.
    Moellering RC. Monitoring serum vancomycin levels: climbing the mountain because it is there [published erratum appears in Clin Infect Dis 1994 Aug; 19 (2): 379]. Clin Infect Dis 1994; 18(4): 544–6PubMedCrossRefGoogle Scholar
  10. 10.
    Kralovicova K, Spanik S, Halko J, et al. Do vancomycin serum levels predict failures of vancomycin therapy or nephrotoxicity in cancer patients? J Chemother 1997; 9(6): 420–6PubMedGoogle Scholar
  11. 11.
    Burnie J, Matthews R, Jiman-Fatami A, et al. Analysis of 42 cases of septicemia caused by an epidemic strain of methicillin-resistant Staphylococcus aureus: evidence of resistance to vancomycin. Clin Infect Dis 2000; 31(3): 684–9PubMedCrossRefGoogle Scholar
  12. 12.
    Tenover FC, Lancaster MV, Hill BC, et al. Characterization of staphylococci with reduced susceptibilities to vancomycin and other glycopeptides [published erratum appears in J Clin Microbiol 1998 Jul; 36 (7): 2167]. J Clin Microbiol 1998; 36(4): 1020–7PubMedGoogle Scholar
  13. 13.
    National Nosocomial Infections Surveillance (NNIS) System Report. Data summary from January 1990 to May 1999. Issued June 1999. Am J Infect Control 1999; 27: 520–32CrossRefGoogle Scholar
  14. 14.
    Lowy FD. Staphylococcus aureus infections. N Engl J Med 1998; 339(8): 520–32PubMedCrossRefGoogle Scholar
  15. 15.
    Panlilio AL, Culver DH, Gaynes RP, et al. Methicillin-resistant Staphylococcus aureus in U.S. hospitals, 1975–1991. Infect Control Hosp Epidemiol 1992; 13(10): 582–6PubMedCrossRefGoogle Scholar
  16. 16.
    Atkinson BA, Lorian V. Antimicrobial agent susceptibility patterns of bacteria in hospitals from 1971 to 1982. J Clin Microbiol 1984; 20(4): 791–6PubMedGoogle Scholar
  17. 17.
    Ploy MC, Grelaud C, Martin C, et al. First clinical isolate of vancomycin-intermediate Staphylococcus aureus in a French hospital [letter]. Lancet 1998; 351(9110): 1212PubMedCrossRefGoogle Scholar
  18. 18.
    McManus J. Vancomycin resistant staphyiococcus reported in Hong Kong. BMJ 1999; 318(7184): 626PubMedCrossRefGoogle Scholar
  19. 19.
    Sieradzki K, Roberts RB, Haber SW, et al. The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection. N Engl J Med 1999; 340(7): 517–23PubMedCrossRefGoogle Scholar
  20. 20.
    Sieradzki K, Tomasz A. Gradual alterations in cell wall structure and metabolism in vancomycin-resistant mutants of Staphylococcus aureus. J Bacteriol 1999; 181(24): 7566–70PubMedGoogle Scholar
  21. 21.
    Hiramatsu K, Hanaki H. Glycopeptide resistance in staphylococci. Curr Opin Infect Dis 1998; 11: 653–8PubMedCrossRefGoogle Scholar
  22. 22.
    Hiramatsu K, Hanaki H, Ino T, et al. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility [letter]. J Antimicrob Chemother 1997; 40(1): 135–6PubMedCrossRefGoogle Scholar
  23. 23.
    Smith TL, Pearson ML, Wilcox KR, et al. Emergence of vancomycin resistance in Staphylococcus aureus. Glycopeptide-Intermediate Staphylococcus aureus Working Group. N Engl J Med 1999; 340(7): 493–501PubMedCrossRefGoogle Scholar
  24. 24.
    Rotun SS, McMath V, Schoonmaker DJ, et al. Staphyiococcus aureus with reduced susceptibility to vancomycin isolated from a patient with fatal bacteremia. Emerg Infect Dis 1999; 5(1): 147–9PubMedCrossRefGoogle Scholar
  25. 25.
    Moise PA, Schentag JJ. Vancomycin treatment failures in Staphyiococcus aureus lower respiratory tract infections. Int J Antimicrob Agents 2000; 16 Suppl. 1: S31–4PubMedCrossRefGoogle Scholar
  26. 26.
    Rubinstein E, Cammarata S, Oliphant T, et al. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis 2001; 32(3): 402–12PubMedCrossRefGoogle Scholar
  27. 27.
    Drew RH, Perfect JR, Srinath L, et al. Treatment of methicillin-resistant Staphylococcus aureus infections with quinupristindalfopristin in patients intolerant of or failing prior therapy. For the Synercid Emergency-Use Study Group. J Antimicrob Chemother 2000; 46(5): 775–84PubMedCrossRefGoogle Scholar
  28. 28.
    Wysocki M, Delateur F, Faurisson F, et al. Continuous versus intermittent infusion of vancomycin in severe staphylococcal infections: prospective multicenter randomized study. Antimicrob Agents Chemother 2001; 45(9): 2460–7PubMedCrossRefGoogle Scholar
  29. 29.
    Fridkin SK, Hageman J, McDougal LK, et al. Epidemiological and microbiological characterization of infections caused by Staphylococcus aureus with reduced susceptibility to vancomycin, United States, 1997–2001. Clin Infect Dis 2003; 36(4): 429–39PubMedCrossRefGoogle Scholar
  30. 30.
    Cosgrove SE, Sakoulas G, Perencevich EN, et al. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 2003; 36(1): 53–9PubMedCrossRefGoogle Scholar
  31. 31.
    Stevens DL, Herr D, Lampiris H, et al. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2002; 34(11): 1481–90PubMedCrossRefGoogle Scholar
  32. 32.
    Johnson JR. Linezolid versus vancomycin for methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2003; 36(2): 236–7PubMedCrossRefGoogle Scholar
  33. 33.
    Nichols RL, Graham DR, Barriere SL, et al. Treatment of hospitalized patients with complicated gram-positive skin and skin structure infections: two randomized, multicentre studies of quinupristin/dalfopristin versus cefazolin, oxacillin or vancomycin. Synercid Skin and Skin Structure Infection Group. J Antimicrob Chemother 1999; 44(2): 263–73PubMedCrossRefGoogle Scholar
  34. 34.
    Moise PA, Forrest A, Bhavnani SM, et al. Area under the inhibitory curve and a pneumonia scoring system for predicting outcomes of vancomycin therapy for respiratory infections by Staphylococcus aureus. Am J Health Syst Pharm 2000; 57 Suppl. 2: S4–9PubMedGoogle Scholar
  35. 35.
    ASHP. Correction on AUIC and a pneumonia scoring system for predicting outcomes of vancomycin therapy for respiratory infections caused by Staphylococcus aureus. Am J Health Syst Pharm 2001; 58: 78Google Scholar
  36. 36.
    Center for Drug Evaluation and Research. Evaluating clinical studies of antimicrobials in the division of anti-infective drug products. FDA draft guidance [online]. Available from URL: [Accessed 2004 Aug 9]
  37. 37.
    Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13(10): 818–29PubMedCrossRefGoogle Scholar
  38. 38.
    Luzier A, Goss TF, Cumbo TJ, et al. Mathematical examination of dual individualization principles (III): development of a scoring system for pneumonia staging and quantitation of response to antibiotics: results in cefmenoxime-treated patients. Ann Pharmacother 1992; 26(11): 1358–65PubMedGoogle Scholar
  39. 39.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16(1): 31–41PubMedCrossRefGoogle Scholar
  40. 40.
    Amsden GW, Ballow CH, Schentag JJ. Population pharmacokinetic methods to optimise antibiotic effects. Drug Invest 1993; 5: 256–68CrossRefGoogle Scholar
  41. 41.
    Rodvold KA, Blum RA, Fischer JH, et al. Vancomycin pharmacokinetics in patients with various degrees of renal function. Antimicrob Agents Chemother 1988; 32(6): 848–52PubMedCrossRefGoogle Scholar
  42. 42.
    Mouton JW, Dudley MN, Cars O, et al. Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs. Int J Antimicrob Agents 2002; 19(4): 355–88PubMedCrossRefGoogle Scholar
  43. 43.
    Hyatt JM, McKinnon PS, Zimmer GS, et al. The importance of pharmacokinetic/pharmacodynamic urrogate markers to outcome: focus on antibacterial agents. Clin Pharmacokinet 1995; 28(2): 143–60PubMedCrossRefGoogle Scholar
  44. 44.
    Rotschafer JC, Crossley K, Zaske DE, et al. Pharmacokinetics of vancomycin: observations in 28 patients and dosage recommendations. Antimicrob Agents Chemother 1982; 22(3): 391–4PubMedCrossRefGoogle Scholar
  45. 45.
    Healy DP, Polk RE, Garson ML, et al. Comparison of steadystate pharmacokinetics of two dosage regimens of vancomycin in normal volunteers. Antimicrob Agents Chemother 1987; 31(3): 393–7PubMedCrossRefGoogle Scholar
  46. 46.
    Golper TA, Noonan HM, Elzinga L, et al. Vancomycin pharmacokinetics, renal handling, and nonrenal clearances in normal human subjects. Clin Pharmacol Ther 1988; 43(5): 565–70PubMedCrossRefGoogle Scholar
  47. 47.
    Sgarabotto D, Cusinato R, Name E, et al. Synercid plus vancomycin for the treatment of severe methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci infections: evaluation of 5 cases. Scand J Infect Dis 2002; 34(2): 122–6PubMedCrossRefGoogle Scholar
  48. 48.
    Watanakunakorn C, Guerriero JC. Interaction between vancomycin and rifampin against Staphylococcus aureus. Antimicrob Agents Chemother 1981; 19(6): 1089–91PubMedCrossRefGoogle Scholar
  49. 49.
    Tuazon CU, Lin MY, Sheagren JN. In vitro activity of rifampin alone and in combination with nafcillin and vancomycin against pathogenic strains of Staphylococcus aureus. Antimicrob Agents Chemother 1978; 13(5): 759–61PubMedCrossRefGoogle Scholar
  50. 50.
    Faville Jr RJ, Zaske DE, Kaplan EL, et al. Staphylococcus aureus endocarditis: combined therapy with vancomycin and rifampin. JAMA 1978; 240(18): 1963–5PubMedCrossRefGoogle Scholar
  51. 51.
    Massanari RM, Donta ST. The efficacy of rifampin as adjunctive therapy in selected cases of staphylococcal endocarditis. Chest 1978; 73(3): 371–5PubMedCrossRefGoogle Scholar
  52. 52.
    Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991; 115(9): 674–80PubMedGoogle Scholar
  53. 53.
    McGrath BJ, Kang SL, Kaatz GW, et al. 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; 38(9): 2034–40PubMedCrossRefGoogle Scholar
  54. 54.
    Watanakunakorn C, Tisone JC. Synergism between vancomycin and gentamicin or tobramycin for methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains. Antimicrob Agents Chemother 1982; 22(5): 903–5PubMedCrossRefGoogle Scholar
  55. 55.
    Houlihan HH, Mercier RC, Rybak MJ. 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. Antimicrob Agents Chemother 1997; 41(11): 2497–501PubMedGoogle Scholar
  56. 56.
    Mouton JW, van Ogtrop ML, Andes D, et al. Use of pharmacodynamic indices to predict efficacy of combination therapy in vivo. Antimicrob Agents Chemother 1999; 43(10): 2473–8PubMedGoogle Scholar
  57. 57.
    Hyatt JM, Luzier AB, Forrest A, et al. Modeling the response of pneumonia to antimicrobial therapy. Antimicrob Agents Chemother 1997; 41(6): 1269–74PubMedGoogle Scholar
  58. 58.
    Zokufa HZ, Rodvold KA, Blum RA, et al. Simulation of vancomycin peak and trough concentrations using five dosing methods in 37 patients. Pharmacotherapy 1989; 9(1): 10–6PubMedGoogle Scholar
  59. 59.
    Klepser ME, Kang SL, McGrath BJ. Influence of vancomycin serum concentration on the outcome of gram-positive infections [abstract]. Program and abstracts of the American College of Clinical Pharmacy Annual Winter Meeting; 1994 Feb 6–9; San DiegoGoogle Scholar
  60. 60.
    Garrod LP, Lambert HP, O’Grady F. Various antibacterial agents. 4th ed. London: Churchill Livingstone, 1973Google Scholar
  61. 61.
    Geraci JE. Vancomycin. Mayo Clin Proc 1977; 52(10): 631–4PubMedGoogle Scholar
  62. 62.
    Rello J, Torres A, Ricart M, et al. Ventilator-associated pneumonia by Staphylococcus aureus: comparison of methicillin resistant and methicillin-sensitive episodes. Am J Respir Crit Care Med 1994; 150 (6 Pt 1): 1545–9PubMedGoogle Scholar
  63. 63.
    Gonzalez C, Rubio M, Romero-Vivas J, et al. Bacteremic pneumonia due to Staphylococcus aureus: a comparison of disease caused by methicillin-resistant and methicillin-susceptible organisms. Clin Infect Dis 1999; 29(5): 1171–7PubMedCrossRefGoogle Scholar
  64. 64.
    Schentag JJ. Clinical significance of antibiotic tissue penetration. Clin Pharmacokinet 1989; 16 Suppl. 1: 25–31PubMedCrossRefGoogle Scholar
  65. 65.
    Nix DE, Goodwin SD, Peloquin CA, et al. Antibiotic tissue penetration and its relevance: models of tissue penetration and their meaning. Antimicrob Agents Chemother 1991; 35(10): 1947–52PubMedCrossRefGoogle Scholar
  66. 66.
    Nix DE, Goodwin SD, Peloquin CA, et al. Antibiotic tissue penetration and its relevance: impact of tissue penetration on infection response. Antimicrob Agents Chemother 1991; 35(10): 1953–9PubMedCrossRefGoogle Scholar
  67. 67.
    Matzke GR. Vancomycin. In: Evans WE, Schentag JJ, Jusko WJ, editors. Applied pharmacokinetics, principles of drug monitoring. Vancouver (WA): Applied Therapeutics Inc., 1992: 15.1–15.30Google Scholar
  68. 68.
    Ackerman BH, Berg HG, Strate RG, et al. Comparison of radioimmunoassay and fluorescent polarization immunoassay for quantitative determination of vancomycin concentrations in serum. J Clin Microbiol 1983; 18(4): 994–5PubMedGoogle Scholar
  69. 69.
    Zokufa HZ, Solem LD, Rodvold KA, et al. The influence of serum albumin and alpha 1-acid glycoprotein on vancomycin protein binding in patients with burn injuries. J Burn Care Rehabil 1989; 10(5): 425–8PubMedCrossRefGoogle Scholar
  70. 70.
    Moellering RC, Linden PK, Reinhardt J, et al. The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium. Synercid Emergency-Use Study Group. J Antimicrob Chemother 1999; 44(2): 251–61PubMedCrossRefGoogle Scholar
  71. 71.
    Birmingham MC, Rayner CR, Meagher AK, et al. Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-use program. Clin Infect Dis 2003; 36(2): 159–68PubMedCrossRefGoogle Scholar
  72. 72.
    Moise PA, Forrest A, Birmingham MC, et al. The efficacy and safety of linezolid as treatment for Staphylococcus aureus infections in compassionate use patients who are intolerant of, or who have failed to respond to, vancomycin. J Antimicrob Chemother 2002; 50(6): 1017–26PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Pamela A. Moise-Broder
    • 1
  • Alan Forrest
    • 1
    • 2
  • Mary C. Birmingham
    • 1
  • Jerome J. Schentag
    • 1
    • 2
    Email author
  1. 1.CPL AssociatesLLCAmherstUSA
  2. 2.University at Buffalo School of Pharmacy and Pharmaceutical SciencesBuffaloUSA

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