, Volume 66, Issue 1, pp 1–14 | Cite as

Optimising Dosing Strategies of Antibacterials Utilising Pharmacodynamic Principles

Impact on the Development of Resistance
  • C. Andrew DeRyke
  • Su Young Lee
  • Joseph L. Kuti
  • David P. NicolauEmail author
Current Opinion


Evolving antimicrobial resistance is of global concern. The impact of decreased susceptibility to current antibacterials coupled with the decline in the marketing of new agents with novel mechanisms of action places a tremendous burden on clinicians to appropriately use available agents. Optimising antibacterial dose administration through the use of pharmacodynamic principles can aid clinicians in accomplishing this task more effectively. Methods to achieve this include: continuous or prolonged infusion, or the use of smaller doses administered more frequently for the time-dependent β-lactam agents; or higher, less frequent dose administration of the concentration-dependent aminoglycosides and fluoroquinolones. Pharmacodynamic breakpoints, which are predictive of clinical and/or microbiological success in the treatment of infection, have been determined for many classes of antibacterials, including the fluoroquinolones, aminoglycosides and β-lactams. Although surpassing these values may predict efficacy, it may not prevent the development of resistance. Recent studies seek to determine the pharmacodynamic breakpoints that prevent the development of resistance. Numerous studies to this point have determined these values in fluoroquinolones in both Gram-positive and Gram-negative bacteria. However, among the other antibacterial classes, there is a lack of sufficient data. Additionally, a new term, the mutant prevention concentration, has been based on the concentrations above which resistance is unlikely to occur. Future work is needed to fully characterise these target concentrations that prevent resistance.


Minimum Inhibitory Concentration Fluoroquinolones Levofloxacin Meropenem Moxifloxacin 
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 sources of funding were used in the preparation of this article. The authors have no conflicts of interest to disclose that are directly relevant to the preparation of this review.


  1. 1.
    Clark NM, Patterson J, Lynch JP. Antimicrobial resistance among gram-negative organisms in the intensive care unit. Curr Opin Crit Care 2003; 9: 413–23PubMedCrossRefGoogle Scholar
  2. 2.
    Bad bugs, no drugs. Statement from the Infectious Disease Society of America, 2004 Jul [online]. Available from URL: [Accessed 2005 Jul 24]
  3. 3.
    Drusano GL. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev Microbiol 2004; 2: 289–300PubMedCrossRefGoogle Scholar
  4. 4.
    Deshpande LM, Fritsche TR, Jones RN. Molecular epidemiology of selected multidrug-resistant bacteria: a global report from the SENTRY Antimicrobial Surveillance Program. Diagn Microbiol Infect Dis 2004; 49: 231–6PubMedCrossRefGoogle Scholar
  5. 5.
    National Nosocomial Infections Surveillance (NNIS) system report, data summary from January 1992 through June 2003, issued August 2003. Am J Infect Control 2003; 31: 481-98Google Scholar
  6. 6.
    Karlowsky JA, Thornsberry C, Jones ME, et al. Factors associated with relative rates of antimicrobial resistance among Streptococcus pneumoniae in the United States: results from the TRUST Surveillance Program (1998–2002). Clin Infect Dis 2003; 36: 963–70PubMedCrossRefGoogle Scholar
  7. 7.
    Chen DK, McGeer A, de Azavedo JC, et al. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada: Canadian Bacterial Surveillance Network. N Engl J Med 1999; 341: 233–9PubMedCrossRefGoogle Scholar
  8. 8.
    Ho PL, Que TL, Tsang DN, et al. Emergence of fluoroquinolone resistance among multiply resistant strains of Streptococcus pneumoniae in Hong Kong. Antimicrob Agents Chemother 1999; 43: 1310–3PubMedGoogle Scholar
  9. 9.
    Anderson KB, Tan JS, File TM, et al. Emergence of levofloxacin-resistant pneumococci in immunocompromised adults after therapy for community-acquired pneumonia. Clin Infect Dis 2003; 37: 376–81PubMedCrossRefGoogle Scholar
  10. 10.
    Davidson R, Cavalcanti R, Brunton JL, et al. Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002; 346: 747–50PubMedCrossRefGoogle Scholar
  11. 11.
    Biedenbach DJ, Moet GJ, Jones RN. Occurrence and antimicrobial resistance pattern comparisons among bloodstream infection isolates from the SENTRY Antimicrobial Surveillance Program (1997–2002). Diagn Microbiol Infect Dis 2004; 50: 59–69PubMedCrossRefGoogle Scholar
  12. 12.
    Obritsch MD, Fish DN, MacLaren R, et al. National surveillance of antimicrobial resistance in Pseudomonas aeruginosa isolates obtained from intensive care unit patients from 1993 to 2002. Antimicrob Agents Chemother 2004; 48: 4606–10PubMedCrossRefGoogle Scholar
  13. 13.
    Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis 2002; 34: 634–40PubMedCrossRefGoogle Scholar
  14. 14.
    Neuhauser MM, Weinstein RA, Rydman R, et al. Antibiotic resistance among gram-negative bacilli in US intensive care units: implications for fluoroquinolone use. JAMA 2003; 289: 885–8PubMedCrossRefGoogle Scholar
  15. 15.
    Chow JW, Fine MJ, Shlaes DM, et al. Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med 1991; 115: 585–90PubMedGoogle Scholar
  16. 16.
    Owens RC, Ambrose PG. Pharmacodynamics of quinolones. In: Nightingale CH, Marakawa T, Ambrose PG, editors. Antimicrobial pharmacodynamics in theory and clinical practice. New York: Marcel Dekker Inc., 2002: 155–76Google Scholar
  17. 17.
    Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26: 1–10PubMedCrossRefGoogle Scholar
  18. 18.
    Deziel-Evans LM, Murphy JE, Job ML. Correlation of pharmacokinetic indices with therapeutic outcome in patients receiving aminoglycosides. Clin Pharm 1986; 5: 319–24PubMedGoogle Scholar
  19. 19.
    Kashuba AD, Bertino JS, Nafziger AN. Dosing of aminoglycosides to rapidly attain pharmacodynamic goals and hasten therapeutic response by using individualized pharmacokinetic monitoring of patients with pneumonia caused by gram-negative organisms. Antimicrob Agents Chemother 1998; 42: 1842–4PubMedGoogle Scholar
  20. 20.
    Kashuba AD, Nafziger AN, Drusano GL, et al. Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria. Antimicrob Agents Chemother 1999; 43: 623–9PubMedGoogle Scholar
  21. 21.
    Prins JM, Buller HR, Kuijper EJ, et al. Once-daily gentamicin versus once-daily netilmicin in patients with serious infections: a randomized clinical trial. J Antimicrob Chemother 1994; 33: 823–35PubMedCrossRefGoogle Scholar
  22. 22.
    Prins JM, Buller HR, Kuijper EJ, et al. Once versus thrice daily gentamicin in patients with serious infections. Lancet 1993; 341: 335–9PubMedCrossRefGoogle Scholar
  23. 23.
    Rozdzinski E, Kern WV, Reichle A, et al. Once-daily versus thrice-daily dosing of netilmicin in combination with beta-lactam antibiotics as empirical therapy for febrile neutropenic patients. J Antimicrob Chemother 1993; 31: 585–98PubMedCrossRefGoogle Scholar
  24. 24.
    Marik PE, Lipman J, Kobilski S, et al. A prospective randomized study comparing once-versus twice-daily amikacin dosing in critically ill adult and paediatric patients. J Antimicrob Chemother 1991; 28: 753–64PubMedCrossRefGoogle Scholar
  25. 25.
    Nicolau DP, Wu AH, Finocchiaro S, et al. Once-daily aminoglycoside dosing: impact on requests and costs for therapeutic drug monitoring. Ther Drug Monit 1996; 18: 263–6PubMedCrossRefGoogle Scholar
  26. 26.
    Preston SL, Drusano GL, Berman AL, et al. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA 1998; 279: 125–9PubMedCrossRefGoogle Scholar
  27. 27.
    Forrest A, Nix DE, Ballow CH, et al. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993; 37: 1073–81PubMedCrossRefGoogle Scholar
  28. 28.
    Drusano GL, Preston SL, Fowler C, et al. Relationship between fluoroquinolone area under the curve: minimum inhibitory concentration ratio and the probability of eradication of the infecting pathogen, in patients with nosocomial pneumonia. J Infect Dis 2004; 189: 1590–7PubMedCrossRefGoogle Scholar
  29. 29.
    Ambrose PG, Grasela DM, Grasela TH, et al. Pharmacodynamics of fluoroquinolones against Streptococcus pneumoniae in patients with community-acquired respiratory tract infections. Antimicrob Agents Chemother 2001; 45: 2793–7PubMedCrossRefGoogle Scholar
  30. 30.
    Lim S, Bast D, McGeer A, et al. Antimicrobial susceptibility breakpoints and first-step parC mutations in Streptococcus pneumoniae: redefining fluoroquinolone resistance. Emerg Infect Dis 2003; 9: 833–7PubMedCrossRefGoogle Scholar
  31. 31.
    Allen GP, Kaatz GW, Rybak MJ. Activities of mutant prevention concentration-targeted moxifloxacin and levofloxacin against Streptococcus pneumoniae in an in vitro pharmacodynamic model. Antimicrob Agents Chemother 2003; 47: 2606–14PubMedCrossRefGoogle Scholar
  32. 32.
    Smith HJ, Walters M, Hisanaga T, et al. Mutant prevention concentrations for single-step fluoroquinolone-resistant mutants of wild-type, efflux-positive, or ParC or GyrA mutation-containing Streptococcus pneumoniae isolates. Antimicrob Agents Chemother 2004; 48: 3954–8PubMedCrossRefGoogle Scholar
  33. 33.
    Drusano GL. Prevention of resistance: a goal for dose selection for antimicrobial agents. Clin Infect Dis 2003; 36: S42–50PubMedCrossRefGoogle Scholar
  34. 34.
    Turnidge JD. The pharmacodynamics of beta-lactams. Clin Infect Dis 1998; 27: 10–22PubMedCrossRefGoogle Scholar
  35. 35.
    Schentag JJ, Smith IL, Swanson DJ, et al. Role for dual individualization with cefmenoxime. Am J Med 1984; 77: 43–50PubMedGoogle Scholar
  36. 36.
    Dagan R, Klugman KP, Craig WA, et al. Evidence to support the rationale that bacterial eradication in respiratory tract infection is an important aim of antimicrobial therapy. J Antimicrob Chemother 2001; 47: 129–40PubMedCrossRefGoogle Scholar
  37. 37.
    Tarn VH, McKinnon PS, Akins RL, et al. Pharmacodynamics of cefepime in patients with Gram-negative infections. J Antimicrob Chemother 2002; 50: 425–8CrossRefGoogle Scholar
  38. 38.
    Lee SY, Kuti JK, Nicolau DP. Cefepime pharmacodynamics in patients with extended spectrum beta lactamases (ESBL) and non-ESBL infections [abstract no. A-1151]. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2005 Dec 16–19; Washington, DCGoogle Scholar
  39. 39.
    Nicolau DP, McNabb J, Lacy MK, et al. Continuous versus intermittent administration of ceftazidime in intensive care unit patients with nosocomial pneumonia. Int J Antimicrob Agents 2001; 17: 497–504PubMedCrossRefGoogle Scholar
  40. 40.
    Grant EM, Kuti JL, Nicolau DP, et al. Clinical efficacy and pharmacoeconomics of a continuous-infusion piperacillintazobactam program in a large community teaching hospital. Pharmacotherapy 2002; 22: 471–83PubMedCrossRefGoogle Scholar
  41. 41.
    Thalhammer F, Traunmuller F, El Menyawi I, et al. Continuous infusion versus intermittent administration of meropenem in critically ill patients. J Antimicrob Chemother 1999; 43: 523–7PubMedCrossRefGoogle Scholar
  42. 42.
    Krueger WA, Bulitta J, Kinzig-Schippers M, et al. Evaluation by Monte Carlo simulation of the pharmacokinetics of two doses of meropenem administered intermittently or as a continuous infusion in healthy volunteers. Antimicrob Agents Chemother 2005; 49: 1881–9PubMedCrossRefGoogle Scholar
  43. 43.
    Tam VH, Louie A, Lomaestro BM, et al. Integration of population pharmacokinetics, a pharmacodynamic target, and microbiologic surveillance data to generate a rational empiric dosing strategy for cefepime against Pseudomonas aeruginosa. Pharmacotherapy 2003; 23: 291–5PubMedCrossRefGoogle Scholar
  44. 44.
    Jumbe N, Louie A, Leary R, et al. Application of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy. J Clin Invest 2003; 112: 275–85PubMedGoogle Scholar
  45. 45.
    Tam VH, Louie A, Deziel MR, et al. Bacterial-population responses to drug-selective pressure: examination of garenoxacin’s effect on Pseudomonas aeruginosa. J Infect Dis 2005; 192: 420–8PubMedCrossRefGoogle Scholar
  46. 46.
    Florea NR, Tessier PR, Zhang C, et al. Pharmacodynamics of moxifloxacin and levofloxacin at simulated epithelial lining fluid drug concentrations against Streptococcus pneumoniae. Antimicrob Agents Chemother 2004; 48: 1215–21PubMedCrossRefGoogle Scholar
  47. 47.
    DeRyke CA, Du, Nicolau DP. Evaluation of bacterial kill when modeling the bronchopulomonary pharmacokinetic profile of moxifloxacin (MOX) and levofloxacin (LVX) against parC containing isolates of Streptococcus pneumoniae (SPN) [abstract no. A-453]. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2005 Dec 16–19; Washington, DCGoogle Scholar
  48. 48.
    Fux CA, Costerton JW, Stewart PS, et al. Survival strategies of infectious biofilms. Trends Microbiol 2005; 13: 34–40PubMedCrossRefGoogle Scholar
  49. 49.
    Thomas JK, Forrest A, Bhavnani SM, et al. Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy. Antimicrob Agents Chemother 1998; 42: 521–7PubMedGoogle Scholar
  50. 50.
    Smith HJ, Nichol KA, Hoban DJ, et al. Stretching the mutant prevention concentration (MPC) beyond its limits. J Antimicrob Chemother 2003; 51: 1323–5PubMedCrossRefGoogle Scholar
  51. 51.
    Blondeau JM, Zhao X, Hansen G, et al. Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 2001; 45: 433–8PubMedCrossRefGoogle Scholar
  52. 52.
    Drlica K. The mutant selection window and antimicrobial resistance. J Antimicrob Chemother 2003; 52: 11–7PubMedCrossRefGoogle Scholar
  53. 53.
    Blondeau JM, Hansen G, Metzler K, et al. The role of PK/PD parameters to avoid selection and increase of resistance: mutant prevention concentration. J Chemother 2004; 16 Suppl. 3: 1–19Google Scholar
  54. 54.
    Guillemot D, Carbon C, Balkau B, et al. Low dosage and long treatment duration of beta-lactam: risk factors for carriage of penicillin-resistant Streptococcus pneumoniae. JAMA 1998; 279: 365–70PubMedCrossRefGoogle Scholar
  55. 55.
    Odenholt I, Gustafsson I, Lowdin E, et al. Suboptimal antibiotic dosage as a risk factor for selection of penicillin-resistant Streptococcus pneumoniae: in vitro kinetic model. Antimicrob Agents Chemother 2003; 47: 518–23PubMedCrossRefGoogle Scholar
  56. 56.
    Knudsen JD, Odenholt I, Erlendsdottir H, et al. Selection of resistant Streptococcus pneumoniae during penicillin treatment in vitro and in three animal models. Antimicrob Agents Chemother 2003; 47: 2499–506PubMedCrossRefGoogle Scholar
  57. 57.
    Ong CT, Tessier PR, Li C, et al. In vivo pharmacodynamic characterization of meropenem and its impact on the selection of resistance among Pseudomonas aeruginosa [abstract]. American College of Clinical Pharmacy Annual Meeting; 2003 Nov 2–5; Atlanta (GA)Google Scholar
  58. 58.
    Ong CT, Tessier PR, Li C, et al. Efflux pumps do not translate to in vivo failure in efficacy or emergence of resistance to meropenem, imipenem, or cefepime [abstract no. A-1867]. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2004 Oct 30–Nov 2; Washington, DCGoogle Scholar
  59. 59.
    Tam VH, Schilling AN, Melnick DA, et al. Comparison of beta-lactams in counter-selecting resistance of Pseudomonas aeruginosa. Diagn Microbiol Infect Dis 2005; 52: 145–51PubMedCrossRefGoogle Scholar
  60. 60.
    DeRyke CA, Kuti JK, Nicolau DP. Questioning the paradigm: monotherapy vs combination antimicrobial thearpy for treatment of Pseudomonas aeruginosa. Conn Med 2005; 69: 271–5PubMedGoogle Scholar
  61. 61.
    Bliziotis IA, Samonis G, Vardakas KZ, et al. Effect of aminoglycoside and beta-lactam combination therapy versus beta-lactam monotherapy on the emergence of antimicrobial resistance: a meta-analysis of randomized, controlled trials. Clin Infect Dis 2005; 41: 149–58PubMedCrossRefGoogle Scholar
  62. 62.
    Carmeli Y, Troillet N, Eliopoulos GM, et al. Emergence of antibiotic-resistant Pseudomonas aeruginosa: comparison of risks associated with different antipseudomonal agents. Antimicrob Agents Chemother 1999; 43: 1379–82PubMedGoogle Scholar
  63. 63.
    El Amari EB, Chamot E, Auckenthaler R, et al. Influence of previous exposure to antibiotic therapy on the susceptibility pattern of Pseudomonas aeruginosa bacteremic isolates. Clin Infect Dis 2001; 33: 1859–64PubMedCrossRefGoogle Scholar
  64. 64.
    Paul M, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. BMJ 2003; 326: 1111PubMedCrossRefGoogle Scholar
  65. 65.
    Drusano G, Louie A, Miller MH, et al. Prevention of the emergence of resistance in Pseudomonas aeruginosa infections through pharmacodynamic dosing and combination chemotherapy [abstract]. 98th International Conference of the American Thoracic Society; 2002 May 17–22; Atlanta (GA)Google Scholar
  66. 66.
    Drago L, De Vecchi E, Nicola L, et al. In vitro synergy and selection of resistance by fluoroquinolones plus amikacin or beta-lactams against extended-spectrum beta-lactamase-producing Escherichia coli. J Chemother 2005; 17: 46–53PubMedGoogle Scholar
  67. 67.
    Gerber AU, Vastola AP, Brandel J, et al. Selection of aminoglycoside-resistant variants of Pseudomonas aeruginosa in an in vivo model. J Infect Dis 1982; 146: 691–7PubMedCrossRefGoogle Scholar
  68. 68.
    Tam VH, Schilling AN, Neshat S, et al. Optimization of meropenem minimum concentration/MIC ratio to suppress in vitro resistance of Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005; 49: 4920–7PubMedCrossRefGoogle Scholar
  69. 69.
    Allen GP. The mutant prevention concentration (MPC): a review. J Infect Dis Pharmacother 2003; 6: 27–47CrossRefGoogle Scholar
  70. 70.
    Bodey GP, Jadeja L, Elting L. Pseudomonas bacteremia: retrospective analysis of 410 episodes. Arch Intern Med 1985; 145: 1621-9PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • C. Andrew DeRyke
    • 1
  • Su Young Lee
    • 1
  • Joseph L. Kuti
    • 1
  • David P. Nicolau
    • 1
    Email author
  1. 1.Center for Anti-Infective Research and DevelopmentHartford HospitalHartfordUSA

Personalised recommendations