Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1997 Jun;41(6):1281–1287. doi: 10.1128/aac.41.6.1281

Parameters of bacterial killing and regrowth kinetics and antimicrobial effect examined in terms of area under the concentration-time curve relationships: action of ciprofloxacin against Escherichia coli in an in vitro dynamic model.

A A Firsov 1, S N Vostrov 1, A A Shevchenko 1, G Cornaglia 1
PMCID: PMC163900  PMID: 9174184

Abstract

Although many parameters have been described to quantitate the killing and regrowth of bacteria, substantial shortcomings are inherent in most of them, such as low sensitivity to pharmacokinetic determinants of the antimicrobial effect, an inability to predict a total effect, insufficient robustness, and uncertain interrelations between the parameters that prevent an ultimate determination of the effect. To examine different parameters, the kinetics of killing and regrowth of Escherichia coli (MIC, 0.013 microg/ml) were studied in vitro by simulating a series of ciprofloxacin monoexponential pharmacokinetic profiles. Initial ciprofloxacin concentrations varied from 0.02 to 19.2 microg/ml, whereas the half-life of 4 h was the same in all experiments. The following parameters were calculated and estimated: the time to reduce the initial inoculum (N0) 10-, 100-, and 1,000-fold (T90%, T99%, and T99.9%, respectively), the rate constant of bacterial elimination (k(elb)), the nadir level (Nmin) in the viable count (N)-versus-time (t) curve, the time to reach Nmin (t(min)), the numbers of bacteria that survived (Ntau) by the end of the observation period (tau), the area under the bacterial killing and regrowth curve (log N(A)-t curve) from the zero point (time zero) to tau (AUBC), the area above this curve (AAC), the area between the control growth curve (log N(C)-t curve) and the bacterial killing and regrowth curve (log N(A)-t curve) from the zero point to tau (ABBC) or to the time point when log N(A) reaches the maximal values observed in the log N(C)-t curve (I(E); intensity of the effect), and the time shift between the control growth and regrowth curves (T(E); duration of the effect). Being highly sensitive to the AUC, I(E), and T(E) showed the most regular AUC relationships: the effect expressed by I(E) or T(E) increased systematically when the AUC or initial concentration of ciprofloxacin rose. Other parameters, especially T90%, T99%, T99.9%, t(min), and log N0 - log Nmin = delta log Nmin, related to the AUC less regularly and were poorly sensitive to the AUC. T(E) proved to be the best predictor and t(min) proved to be the worst predictor of the total antimicrobial effect reflected by I(E). Distinct feedback relationships between the effect determination and the experimental design were demonstrated. It was shown that unjustified shortening of the observation period, i.e., cutting off the log N(A)-t curves, may lead to the degeneration of the AUC-response relationships, as expressed by log N0 - log Ntau = delta log Ntau, AUBC, AAC, or ABBC, to a point where it gives rise to the false idea of an AUC- or concentration-independent effect. Thus, use of I(E) and T(E) provides the most unbiased, robust, and comprehensive means of determining the antimicrobial effect.

Full Text

The Full Text of this article is available as a PDF (237.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bauernfeind A. Questioning dosing regimens of ciprofloxacin. J Antimicrob Chemother. 1993 May;31(5):789–798. doi: 10.1093/jac/31.5.789. [DOI] [PubMed] [Google Scholar]
  2. Blaser J., Zinner S. H. In vitro models for the study of antibiotic activities. Prog Drug Res. 1987;31:349–381. doi: 10.1007/978-3-0348-9289-6_11. [DOI] [PubMed] [Google Scholar]
  3. Carret G., Flandrois J. P., Lobry J. R. Biphasic kinetics of bacterial killing by quinolones. J Antimicrob Chemother. 1991 Mar;27(3):319–327. doi: 10.1093/jac/27.3.319. [DOI] [PubMed] [Google Scholar]
  4. Chambers S. T., Peddie B. A., Robson R. A., Begg E. J., Boswell D. R. Antimicrobial effects of lomefloxacin in vitro. J Antimicrob Chemother. 1991 Apr;27(4):481–489. doi: 10.1093/jac/27.4.481. [DOI] [PubMed] [Google Scholar]
  5. Duffull S. B., Begg E. J., Chambers S. T., Barclay M. L. Efficacies of different vancomycin dosing regimens against Staphylococcus aureus determined with a dynamic in vitro model. Antimicrob Agents Chemother. 1994 Oct;38(10):2480–2482. doi: 10.1128/aac.38.10.2480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Firsov A. A., Chernykh V. M., Fomina I. P. Printsipy analiza krivykh kinetiki antimikrobnogo éffekta v dinamicheskikh sistemakh, modeliruiushchikh farmakokineticheskie profily antibiotikov. Antibiot Med Biotekhnol. 1987 Feb;32(2):122–129. [PubMed] [Google Scholar]
  7. Firsov A. A., Chernykh V. M., Navashin S. M. Quantitative analysis of antimicrobial effect kinetics in an in vitro dynamic model. Antimicrob Agents Chemother. 1990 Jul;34(7):1312–1317. doi: 10.1128/aac.34.7.1312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Firsov A. A. In vitro simulated pharmacokinetics profiles: forecasting antibiotic optimal dosage. Eur J Drug Metab Pharmacokinet. 1991;Spec No 3:406–409. [PubMed] [Google Scholar]
  9. Firsov A. A., Saverino D., Savarino D., Ruble M., Gilbert D., Manzano B., Medeiros A. A., Zinner S. H. Predictors of effect of ampicillin-sulbactam against TEM-1 beta-lactamase-producing Escherichia coli in an in vitro dynamic model: enzyme activity versus MIC. Antimicrob Agents Chemother. 1996 Mar;40(3):734–738. doi: 10.1128/aac.40.3.734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Goi H., Inouye S., Kitasato I. Bacteriolytic combination effect of cefminox and piperacillin evaluated by turbidimetry. Drugs Exp Clin Res. 1989;15(9):397–407. [PubMed] [Google Scholar]
  11. Grasso S. Historical review of in-vitro models. J Antimicrob Chemother. 1985 Jan;15 (Suppl A):99–102. doi: 10.1093/jac/15.suppl_a.99. [DOI] [PubMed] [Google Scholar]
  12. Greenwood D. In vitro veritas? Antimicrobial susceptibility tests and their clinical relevance. J Infect Dis. 1981 Oct;144(4):380–385. doi: 10.1093/infdis/144.4.380. [DOI] [PubMed] [Google Scholar]
  13. Hyatt J. M., Nix D. E., Schentag J. J. Pharmacokinetic and pharmacodynamic activities of ciprofloxacin against strains of Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa for which MICs are similar. Antimicrob Agents Chemother. 1994 Dec;38(12):2730–2737. doi: 10.1128/aac.38.12.2730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hyatt J. M., Nix D. E., Stratton C. W., Schentag J. J. In vitro pharmacodynamics of piperacillin, piperacillin-tazobactam, and ciprofloxacin alone and in combination against Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1995 Aug;39(8):1711–1716. doi: 10.1128/aac.39.8.1711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Höffken G., Lode H., Prinzing C., Borner K., Koeppe P. Pharmacokinetics of ciprofloxacin after oral and parenteral administration. Antimicrob Agents Chemother. 1985 Mar;27(3):375–379. doi: 10.1128/aac.27.3.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jusko W. J. Pharmacodynamics of chemotherapeutic effects: dose-time-response relationships for phase-nonspecific agents. J Pharm Sci. 1971 Jun;60(6):892–895. doi: 10.1002/jps.2600600618. [DOI] [PubMed] [Google Scholar]
  17. Kang S. L., Rybak M. J., McGrath B. J., Kaatz G. W., Seo S. M. Pharmacodynamics of levofloxacin, ofloxacin, and ciprofloxacin, alone and in combination with rifampin, against methicillin-susceptible and -resistant Staphylococcus aureus in an in vitro infection model. Antimicrob Agents Chemother. 1994 Dec;38(12):2702–2709. doi: 10.1128/aac.38.12.2702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Navashin S. M., Fomina I. P., Firsov A. A., Chernykh V. M., Kuznetsova S. M. A dynamic model for in-vitro evaluation of antimicrobial action by simulation of the pharmacokinetic profiles of antibiotics. J Antimicrob Chemother. 1989 Mar;23(3):389–399. doi: 10.1093/jac/23.3.389. [DOI] [PubMed] [Google Scholar]
  19. Rustige C., Wiedemann B. Antibacterial activity of lomefloxacin in a pharmacokinetic in vitro model. Antimicrob Agents Chemother. 1990 Jun;34(6):1107–1111. doi: 10.1128/aac.34.6.1107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Satta G., Cornaglia G., Foddis G., Pompei R. Evaluation of ceftriaxone and other antibiotics against Escherichia coli, Pseudomonas aeruginosa, and Streptococcus pneumoniae under in vitro conditions simulating those of serious infections. Antimicrob Agents Chemother. 1988 Apr;32(4):552–560. doi: 10.1128/aac.32.4.552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. White C. A., Toothaker R. D. Influence of ampicillin elimination half-life on in-vitro bactericidal effect. J Antimicrob Chemother. 1985 Jan;15 (Suppl A):257–260. doi: 10.1093/jac/15.suppl_a.257. [DOI] [PubMed] [Google Scholar]
  22. Wiedemann B., Jansen A. Antibacterial activity of cefpodoxime proxetil in a pharmacokinetic in-vitro model. J Antimicrob Chemother. 1990 Jul;26(1):71–79. doi: 10.1093/jac/26.1.71. [DOI] [PubMed] [Google Scholar]
  23. Wiedemann B., Seeberg A. H. The activity of cefotiam on beta-lactamase-producing bacteria in an in-vitro model. J Antimicrob Chemother. 1984 Feb;13(2):111–119. doi: 10.1093/jac/13.2.111. [DOI] [PubMed] [Google Scholar]
  24. Wise R., Lister D., McNulty C. A., Griggs D., Andrews J. M. The comparative pharmacokinetics of five quinolones. J Antimicrob Chemother. 1986 Nov;18 (Suppl 500):71–81. doi: 10.1093/jac/18.supplement_d.71. [DOI] [PubMed] [Google Scholar]
  25. Xerri L., Broggio R. Study on the antibacterial activity of ceftazidime in an in vitro pharmacokinetic model. Drugs Exp Clin Res. 1985;11(1):49–54. [PubMed] [Google Scholar]
  26. Zhi J., Nightingale C. H., Quintiliani R. A pharmacodynamic model for the activity of antibiotics against microorganisms under nonsaturable conditions. J Pharm Sci. 1986 Nov;75(11):1063–1067. doi: 10.1002/jps.2600751108. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES