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. 1995 Aug;39(8):1797–1801. doi: 10.1128/aac.39.8.1797

Pharmacodynamics of ceftazidime administered as continuous infusion or intermittent bolus alone and in combination with single daily-dose amikacin against Pseudomonas aeruginosa in an in vitro infection model.

D M Cappelletty 1, S L Kang 1, S M Palmer 1, M J Rybak 1
PMCID: PMC162828  PMID: 7486921

Abstract

We compared the pharmacodynamics and killing activity of ceftazidime, administered by continuous infusion and intermittent bolus, against Pseudomonas aeruginosa ATCC 27853 and ceftazidime-resistant P. aeruginosa 27853CR with and without a single daily dose of amikacin in an in vitro infection model over a 48-h period. Resistance to ceftazidime was selected for by serial passage of P. aeruginosa onto agar containing increasing concentrations of ceftazidime. Human pharmacokinetics and dosages were simulated as follows: half-life, 2 h; intermittent-bolus ceftazidime, 2 g every 8 h (q8h) and q12h; continuous infusion, 2-g loading dose and maintenance infusions of 5, 10, and 20 micrograms/ml; amikacin, 15 mg/kg q24h. There was no significant difference in time to 99.9% killing between any of the monotherapy regimens or between any combination regimen against ceftazidime-susceptible P. aeruginosa. Continuous infusions of 10 and 20 micrograms/ml killed as effectively as an intermittent bolus of 2 g q12h and q8h, respectively. Continuous infusion of 20 micrograms/ml and an intermittent bolus of 2 g q8h were the only regimens which prevented organism regrowth at 48 h, while a continuous infusion of 5 micrograms/ml resulted in the most regrowth. All of the combination regimens exhibited a synergistic response, with rapid killing of ceftazidime-susceptible P. aeruginosa and no regrowth. Against ceftazidime-resistant P. aeruginosa, none of the ceftazidime monotherapy regimens achieved 99.9% killing. The combination regimens exhibited the same rapid killing of the resistant strain as occurred with the susceptible strain; however, regrowth occurred with all regimens. The combination regimens of continuous infusion of 20 micrograms/ml plus amikacin and intermittent bolus q8h or q12h plus amikacin continued to be synergistic. Overall, continuous infusion monotherapy with ceftazidime at concentrations 4 to 5 and 10 to 15 times the MIC was as effective as an intermittent bolus of 2 g q12h (10 to 15 times the MIC) and q8h (25 to 35 times the MIC), respectively, against ceftazidime-susceptible P. aeruginosa. Combination therapy with amikacin plus ceftazidime, either intermittently q8h or by continuous infusion of 20 micrograms/ml, appeared to be effective and exhibited synergism against ceftazidime-resistant P. aeruginosa.

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Selected References

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  1. Bailey E. M., Rybak M. J., Kaatz G. W. Comparative effect of protein binding on the killing activities of teicoplanin and vancomycin. Antimicrob Agents Chemother. 1991 Jun;35(6):1089–1092. doi: 10.1128/aac.35.6.1089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bodey G. P., Ketchel S. J., Rodriguez V. A randomized study of carbenicillin plus cefamandole or tobramycin in the treatment of febrile episodes in cancer patients. Am J Med. 1979 Oct;67(4):608–616. doi: 10.1016/0002-9343(79)90242-0. [DOI] [PubMed] [Google Scholar]
  3. Craig W. A., Ebert S. C. Continuous infusion of beta-lactam antibiotics. Antimicrob Agents Chemother. 1992 Dec;36(12):2577–2583. doi: 10.1128/aac.36.12.2577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Craig W. A., Ebert S. C. Killing and regrowth of bacteria in vitro: a review. Scand J Infect Dis Suppl. 1990;74:63–70. [PubMed] [Google Scholar]
  5. Daenen S., de Vries-Hospers H. Cure of Pseudomonas aeruginosa infection in neutropenic patients by continuous infusion of ceftazidime. Lancet. 1988 Apr 23;1(8591):937–937. doi: 10.1016/s0140-6736(88)91741-2. [DOI] [PubMed] [Google Scholar]
  6. David T. J., Devlin J. Continuous infusion of ceftazidime in cystic fibrosis. Lancet. 1989 Jun 24;1(8652):1454–1455. doi: 10.1016/s0140-6736(89)90164-5. [DOI] [PubMed] [Google Scholar]
  7. Goss T. F., Forrest A., Nix D. E., Ballow C. H., Birmingham M. C., Cumbo T. J., Schentag J. J. 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 Jul-Aug;28(7-8):863–868. doi: 10.1177/106002809402800707. [DOI] [PubMed] [Google Scholar]
  8. Haag R., Lexa P., Werkhäuser I. Artifacts in dilution pharmacokinetic models caused by adherent bacteria. Antimicrob Agents Chemother. 1986 May;29(5):765–768. doi: 10.1128/aac.29.5.765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kapotas N. M. Acclimatization resistance of a Pseudomonas aeruginosa prototype strain to imipenem. J Antibiot (Tokyo) 1991 Sep;44(9):985–994. doi: 10.7164/antibiotics.44.985. [DOI] [PubMed] [Google Scholar]
  10. Lagast H., Meunier-Carpentier F., Klastersky J. Treatment of gram-negative bacillary septicemia with cefoperazone. Eur J Clin Microbiol. 1983 Dec;2(6):554–558. doi: 10.1007/BF02016564. [DOI] [PubMed] [Google Scholar]
  11. Leggett J. E., Fantin B., Ebert S., Totsuka K., Vogelman B., Calame W., Mattie H., Craig W. A. Comparative antibiotic dose-effect relations at several dosing intervals in murine pneumonitis and thigh-infection models. J Infect Dis. 1989 Feb;159(2):281–292. doi: 10.1093/infdis/159.2.281. [DOI] [PubMed] [Google Scholar]
  12. McGrath B. J., Bailey E. M., Lamp K. C., Rybak M. J. Pharmacodynamics of once-daily amikacin in various combinations with cefepime, aztreonam, and ceftazidime against Pseudomonas aeruginosa in an in vitro infection model. Antimicrob Agents Chemother. 1992 Dec;36(12):2741–2746. doi: 10.1128/aac.36.12.2741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Mordenti J. J., Quintiliani R., Nightingale C. H. Combination antibiotic therapy: comparison of constant infusion and intermittent bolus dosing in an experimental animal model. J Antimicrob Chemother. 1985 Jan;15 (Suppl A):313–321. doi: 10.1093/jac/15.suppl_a.313. [DOI] [PubMed] [Google Scholar]
  14. Mouton J. W., den Hollander J. G. Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model. Antimicrob Agents Chemother. 1994 May;38(5):931–936. doi: 10.1128/aac.38.5.931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Peterson L. R., Gerding D. N., Fasching C. E. Effects of method of antibiotic administration on extravascular penetration: cross-over study of cefazolin given by intermittent injection or constant infusion. J Antimicrob Chemother. 1981 Jan;7(1):71–79. doi: 10.1093/jac/7.1.71. [DOI] [PubMed] [Google Scholar]
  16. Roosendaal R., Bakker-Woudenberg I. A., van den Berg J. C., Michel M. F. Therapeutic efficacy of continuous versus intermittent administration of ceftazidime in an experimental Klebsiella pneumoniae pneumonia in rats. J Infect Dis. 1985 Aug;152(2):373–378. doi: 10.1093/infdis/152.2.373. [DOI] [PubMed] [Google Scholar]
  17. Schentag J. J., Nix D. E., Adelman M. H. 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 Oct;25(10):1050–1057. doi: 10.1177/106002809102501003. [DOI] [PubMed] [Google Scholar]

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