Microbial pharmacodynamics of piperacillin in neutropenic mice of systematic infection due toPseudomonas aeruginosa

  • Jianguo Zhi
  • Charles H. Nightingale
  • Richard Quintiliani


Mathematical solutions for two possible pharmacodynamic interactions (linear nonsaturable and nonlinear saturable) between antibiotics and microorganisms derived from the incorporation of clinically relevant antibiotic dosage regimens such as single bolus dosing, multiple doses, and constant infusion at steady state have been obtained. It is concluded that the saturable nonlinear interaction model between the tested antibiotic and microorganism appears appropriate. The model and its derived equations are capable of describing in vivobacterial growth of P. aeruginosaafter single bolus dosing and multiple doses of piperacillin as described by a linear one-compartment pharmacokinetic model. The activity of piperacillin against P. aeruginosain the neutropenic mouse systemic infection model can be described by an equation with three dynamic parameters: the bacterial growth rate constant k app ,0.02345min−1, the bacterial killing rate constant k′ kill ,0.02623 min−1, and the Michaelis-Menten type saturation constant Km, 0.05467 μg/ml. The concept and derived equations for the optimal dosing interval and minimum critical concentration are of clinical importance for the proper selection of antibiotic dosage regimens.

Key words

microbial pharmacodynamics linear nonsaturable model nonlinear saturable model antibiotic dosage regimen piperacillin Pseudomonas aeruginosa systemic infection neutropenic mouse 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    G. Levy. Relationship between elimination rate of drugs and rate of decline of their pharmacologic effects.J. Pharm. Sci. 53:342–343 (1964).PubMedCrossRefGoogle Scholar
  2. 2.
    J. G. Wagner. Kinetics of pharmacologic response. I. Proposed relationships between response and drug concentration in the intact animal and man.J. Theor. Biol. 20:173–201 (1968).PubMedCrossRefGoogle Scholar
  3. 3.
    M. Gibaldi. Measurement and interpretation of certain biopharmaceutic and pharmacodynamic parameters.Chemotherapy 13:1–15 (1968).PubMedCrossRefGoogle Scholar
  4. 4.
    L. B. Sheiner, D. R. Stanski, S. Vozeh, R. Miller and J. Ham. Simultaneous modeling of pharamacokinetics and pharmacodynamics: application of d-tubocurarine.Clin. Pharmacol. Ther. 25:358–371 (1979).PubMedGoogle Scholar
  5. 5.
    M. Gibaldi and D. Perrier.Pharmacokinetics, 2nd ed., Marcel Dekker. New York, 1982, pp. 221–269.Google Scholar
  6. 6.
    W. J. Jusko. Pharmacodynamics of chemotherapeutic effects: dose-time-response relationships for phase-nonspecific agents.J. Pharm. Sci. 60:892–895 (1971).PubMedCrossRefGoogle Scholar
  7. 7.
    E. R. Garrett. Kinetics of antimicrobial action.Scand. J. Infect. Dis. 14(suppl.):54–85 (1978).Google Scholar
  8. 8.
    A. Tsuji, S. Hamano, T. Asano, E. Nakashima, T. Yamana, and S. Mitsuhashi. Microbial kinetics of beta-lactam antibiotics againstEscherichia coli.J. Pharm. Sci. 73:1418–1422 (1984).PubMedCrossRefGoogle Scholar
  9. 9.
    A. U. Gerber and W. A. Craig. Aminoglycoside-selected subpopulations ofPseudomonas aeruginosa: characterization and virulence in normal and leukopenic mice.J. Lab. Clin. Med. 100:671–681 (1982).PubMedGoogle Scholar
  10. 10.
    J. B. Schiff and J. E. Pennington. Comparative efficacies of piperacillin, azelocillin, ticarcillin, aztreonam, and tobramycin against experimentalPseudomonas aeruginosa pneumonia.Antimicrob. Agents Chemother. 25:49–52 (1984).PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    H. Mattie. Kinetics of antimicrobial action.Rev. Infection Dis. 3:19–27 (1981).CrossRefGoogle Scholar
  12. 12.
    D. Lewis, D. Reeves, B. Wiedemann, and S. Zinner (eds).Methodology and evaluation of in vitro models of antimicrobial chemotherapy. Proceedings of a joint meeting held in Bad Honnef (Bonn). March 1984.J. Antimicrob. Chemother. (Suppl. A) (1985).Google Scholar
  13. 13.
    T. Bergan, I. B. Carlsen and J. E. Fuglesang. Anin vitro model for monitoring bacterial responses to antibiotic agents under simulatedin vivo conditions.Infection 8(Suppl. 1):S96-S102 (1980).CrossRefGoogle Scholar
  14. 14.
    S. Grasso, G. Meinardi, G. de Carneri, and V. Tamassia. Newin vitro model to study the effect of antibiotic concentration and rate of elimination on antibacterial activity.Antimicrob. Agents Chemother. 13:570–576 (1978).PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    R. D. Toothaker, P. G. Welling, and W. A. Craig. Anin vitro model for the study of antibacterial dosage regimen design.J. Pharm. Sci. 71:861–864 (1982).PubMedCrossRefGoogle Scholar
  16. 16.
    I. M. Gould, J. Dent, and R. Wise.In vitro bacterial killing kinetics of ticarcillin/clavulanic acid.J. Antimicrob. Chemother. 19:307–312 (1987).PubMedCrossRefGoogle Scholar
  17. 17.
    P. König, J. P. Guggenbichler, E. Semenitz, and W. Foisner. Kill kinetics of bacteria under fluctuating concentrations of various antibiotics I. Description of the model; II. Description of experiments.Chemotherapy 32:37–58 (1986).PubMedCrossRefGoogle Scholar
  18. 18.
    W. J. Jusko. A pharmacodynamic model for cell-cycle-specific chemotherapeutic agents.J. Pharmacokin. Biopharm. 1:175–200 (1973).CrossRefGoogle Scholar
  19. 19.
    W. J. Jusko. Interpreting of cell proliferation curves using a two-compartment cell model.Math. Biosci. 21:31–37 (1974).CrossRefGoogle Scholar
  20. 20.
    E. R. Garrett. The pharmacokinetic bases of biological response quantification in toxicology, pharmacology and pharmacodynamics.Prog. Drug. Res. 21:105–230 (1977).PubMedGoogle Scholar
  21. 21.
    J. Zhi, C. H. Nightingale, and R. Quintiliani. A pharmacodynamic model for the activity of antibiotics against microorganisms under nonsaturable conditions.J. Pharm. Sci. 75:1063–67 (1986).PubMedCrossRefGoogle Scholar
  22. 22.
    H. Lineweaver and D. Burk. The determination of enzyme dissociation constants.J. Am. Chem. Soc. 56:658–666 (1934).CrossRefGoogle Scholar
  23. 23.
    J. Zhi. Pharmacodynamic modeling of antimicrobial activity: piperacillin versusPseudomonas aeruginosa Ph. D. dissertation, University of Connecticut, 1987.Google Scholar
  24. 24.
    R. Cleeland and E. Grunberg. Laboratory evaluation of new antibioticsin vitro and in experimental animal infections. In V. Lorian (ed.)Antibiotics in Laboratory Medicine. 2nd ed., Williams & Wilkins, Baltimore, 1986, pp. 825–876.Google Scholar
  25. 25.
    C. M. Metzler, G. L. Elfring, and A. J. McEwen. A package of computer program for pharmacokinetic modeling.Biometrics. September 1974, p. 562.Google Scholar
  26. 26.
    S. Bolton.Pharmaceutical Statistics, Marcel Dekker, New York, 1986, p. 156.Google Scholar
  27. 27.
    P. D. Ellner and H. C. Neu. The inhibitory quotient: A method for interpreting minimum inhibitory concentration data.J. Am. Med. Assoc. 246:1575–1578 (1981).CrossRefGoogle Scholar
  28. 28.
    G. E. Schumacher. Comparison of antibiotic dosage regimens using pharmacokinetic and microbiological factors.Clin. Pharm. 6:59–68 (1987).PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1988

Authors and Affiliations

  • Jianguo Zhi
    • 1
    • 2
  • Charles H. Nightingale
    • 1
    • 3
  • Richard Quintiliani
    • 4
    • 5
  1. 1.School of PharmacyUniversity of ConnecticutStorrs
  2. 2.Pharmacy Research LaboratoryHartford HospitalHartford
  3. 3.Department of PharmacyHartford HospitalHartford
  4. 4.Division Infectious DiseasesHartford HospitalHartford
  5. 5.School of MedicineUniversity of ConnecticutFarmington

Personalised recommendations