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. 1995 Aug;39(8):1711–1716. doi: 10.1128/aac.39.8.1711

In vitro pharmacodynamics of piperacillin, piperacillin-tazobactam, and ciprofloxacin alone and in combination against Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa.

J M Hyatt 1, D E Nix 1, C W Stratton 1, J J Schentag 1
PMCID: PMC162813  PMID: 7486906

Abstract

The time-kill curve methodology was used to determine the pharmacodynamics of piperacillin, ciprofloxacin, piperacillin-tazobactam and the combinations piperacillin-ciprofloxacin and ciprofloxacin-piperacillin-tazobactam. Kill curve studies were performed for piperacillin, ciprofloxacin, and piperacillin-tazobactam at concentrations of 0.25 to 50 times the MICs for 13 strains of bacteria: four Pseudomonas aeruginosa, three Enterobacter cloacae, three Klebsiella pneumoniae, and three Staphylococcus aureus isolates (tazobactam concentrations of 0.5, 4, and 12 micrograms/ml). By using a sigmoid Emax model and nonlinear least squares regression, the 50% lethal concentrations and the maximum lethal rates of each agent were determined for each bacterial strain. For piperacillin-ciprofloxacin and ciprofloxacin-piperacillin-tazobactam, kill curve studies were performed with concentrations obtained by the fractional maximal effect method (R. C. Li, J. J. Schentag, and D. E. Nix, Antimicrob. Agents Chemother. 37:523-531, 1993) and from individual 50% lethal concentrations and maximum lethal rates. Ciprofloxacin-piperacillin-tazobactam was evaluated only against the four P. aeruginosa strains. Interactions between piperacillin and ciprofloxacin were generally additive. At physiologically relevant concentrations of piperacillin and ciprofloxacin, ciprofloxacin had the highest rates of killing against K. pneumoniae. Piperacillin-tazobactam (12 micrograms/ml) had the highest rate of killing against E. cloacae. Piperacillin-ciprofloxacin with relatively higher ciprofloxacin concentrations had the greatest killing rates against S. aureus. This combination had significantly higher killing rates than piperacillin (P < 0.002). For all the bacterial strains tested, killing rates by ciprofloxacin were significantly higher than those by piperacillin-tazobactam (4 and 12 micrograms/ml had significantly higher killing rates than piperacillin alone (P < 0.02 and P < 0.004, respectively). The effect of the combination of piperacillin-ciprofloxacin, in which piperacillin concentrations were relatively higher, was not statistically different from that of piperacillin alone (p > or = 0.71). The combination of ciprofloxacin-piperacillin-tazobactam achieved greater killing than other combinations or monotherapies against P. aeruginosa. The reduction in the initial inoculum was 1 to 4 logs greater with ciprofloxacin-piperacillin-tazobactam at 4 and 12 micrograms/ml than with any other agent or combination of agents. On the basis of the additive effects prevalently demonstrated in the in vitro study, the combinations of piperacillin-ciprofloxacin and piperacillin-tazobactam are rational therapeutic options. Greater killing of P. aeruginosa was demonstrated with ciprofloxacin-piperacillin--tazobactam. Since treatment failure of P. aeruginosa pneumonia is a significant problem, clinical studies are warranted.

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Selected References

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  1. Baltch A. L., Bassey C., Fanciullo G., Smith R. P. In-vitro antimicrobial activity of enoxacin in combination with eight other antibiotics against Pseudomonas aeruginosa, Enterobacteriaceae and Staphylococcus aureus. J Antimicrob Chemother. 1987 Jan;19(1):45–48. doi: 10.1093/jac/19.1.45. [DOI] [PubMed] [Google Scholar]
  2. Barriere S. L., Ely E., Kapusnik J. E., Gambertoglio J. G. Analysis of a new method for assessing activity of combinations of antimicrobials: area under the bactericidal activity curve. J Antimicrob Chemother. 1985 Jul;16(1):49–59. doi: 10.1093/jac/16.1.49. [DOI] [PubMed] [Google Scholar]
  3. Blaser J., Stone B. B., Groner M. C., Zinner S. H. Comparative study with enoxacin and netilmicin in a pharmacodynamic model to determine importance of ratio of antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance. Antimicrob Agents Chemother. 1987 Jul;31(7):1054–1060. doi: 10.1128/aac.31.7.1054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chalkley L. J., Koornhof H. J. Antimicrobial activity of ciprofloxacin against Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus determined by the killing curve method: antibiotic comparisons and synergistic interactions. Antimicrob Agents Chemother. 1985 Aug;28(2):331–342. doi: 10.1128/aac.28.2.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cheng A. F., Li M. K., Ling T. K., French G. L. Emergence of ofloxacin-resistant Citrobacter freundii and Pseudomonas maltophilia after ofloxacin therapy. J Antimicrob Chemother. 1987 Aug;20(2):283–285. doi: 10.1093/jac/20.2.283-a. [DOI] [PubMed] [Google Scholar]
  6. Chin N. X., Jules K., Neu H. C. Synergy of ciprofloxacin and azlocillin in vitro and in a neutropenic mouse model of infection. Eur J Clin Microbiol. 1986 Feb;5(1):23–28. doi: 10.1007/BF02013456. [DOI] [PubMed] [Google Scholar]
  7. Drusano G. L. Human pharmacodynamics of beta-lactams, aminoglycosides and their combination. Scand J Infect Dis Suppl. 1990;74:235–248. [PubMed] [Google Scholar]
  8. Eliopoulos G. M., Eliopoulos C. T. Ciprofloxacin in combination with other antimicrobials. Am J Med. 1989 Nov 30;87(5A):17S–22S. doi: 10.1016/0002-9343(89)90013-2. [DOI] [PubMed] [Google Scholar]
  9. Esposito S., Galante D., Barba D., Bianchi W., Gagliardi R., Giusti R. Efficacy and safety of ciprofloxacin in the treatment of UTIs and RTIs in patients affected by liver diseases. Infection. 1988;16 (Suppl 1):S57–S61. doi: 10.1007/BF01650510. [DOI] [PubMed] [Google Scholar]
  10. Gerber A. U., Craig W. A., Brugger H. P., Feller C., Vastola A. P., Brandel J. Impact of dosing intervals on activity of gentamicin and ticarcillin against Pseudomonas aeruginosa in granulocytopenic mice. J Infect Dis. 1983 May;147(5):910–917. doi: 10.1093/infdis/147.5.910. [DOI] [PubMed] [Google Scholar]
  11. Goldstein E. J., Kahn R. M., Alpert M. L., Ginsberg B. P., Greenway F. L., Citron D. M. Ciprofloxacin versus cinoxacin in therapy of urinary tract infections. A randomized, double-blind trial. Am J Med. 1987 Apr 27;82(4A):284–287. [PubMed] [Google Scholar]
  12. Haller I. Comprehensive evaluation of ciprofloxacin-aminoglycoside combinations against Enterobacteriaceae and Pseudomonas aeruginosa strains. Antimicrob Agents Chemother. 1985 Nov;28(5):663–666. doi: 10.1128/aac.28.5.663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Li R. C., Schentag J. J., Nix D. E. The fractional maximal effect method: a new way to characterize the effect of antibiotic combinations and other nonlinear pharmacodynamic interactions. Antimicrob Agents Chemother. 1993 Mar;37(3):523–531. doi: 10.1128/aac.37.3.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Moody J. A., Gerding D. N., Peterson L. R. Evaluation of ciprofloxacin's synergism with other agents by multiple in vitro methods. Am J Med. 1987 Apr 27;82(4A):44–54. [PubMed] [Google Scholar]
  15. Pearson R. D., Steigbigel R. T., Davis H. T., Chapman S. W. Method of reliable determination of minimal lethal antibiotic concentrations. Antimicrob Agents Chemother. 1980 Nov;18(5):699–708. doi: 10.1128/aac.18.5.699. [DOI] [PMC free article] [PubMed] [Google Scholar]

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