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Impact of the dosage schedule on the efficacy of ceftazidime, gentamicin and ciprofloxacin inKlebsiella pneumoniae pneumonia and septicemia in leukopenic rats

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Abstract

The impact of the dosage schedule on the therapeutic efficacy of antibiotics was investigated in experimentalKlebsiella pneumoniae pneumonia and septicemia in leukopenic rats. The daily doses (mg/kg) that protected 50 % of the animals from death, when calculated for administration at 6 h intervals or by continuous infusion, were as follows: ceftazidime 24.4 and 1.5 (p<0.001), gentamicin 2.8 and 3.8 (p>0.05), and ciprofloxacin 3.3 and 6.5 (p<0.05), respectively. This correlates with the observation that ceftazidime killedKlebsiella pneumoniae slowly but constantly, and relatively independently of concentration, whereas killing by gentamicin or ciprofloxacin was rapid, and markedly dependent on antibiotic concentration. Exposure of bacteria for 1 h to concentrations of fivefold the MBC did not give rise to a postantibiotic effect for any of the drugs. In our model ceftazidime was far more effective when given continuously than when administered at 6 h intervals. On the other hand, the activity of gentamicin was not influenced by the mode of administration, whereas ciprofloxacin was slightly more effective when given intermittently. However, to avoid misleading conclusions regarding the use of antibiotics in humans, the pharmacokinetic differences between rats and man must be considered when interpreting these results.

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References

  1. Kunin, C. M.: Dosage schedules of antimicrobial agents: a historical review. Reviews of Infectious Diseases 1981, 3: 4–11.

    PubMed  Google Scholar 

  2. Neu, H. C.: Current practices in antimicrobial dosing. Reviews of Infectious Diseases 1981, 3: 12–18.

    PubMed  Google Scholar 

  3. Roosendaal, R., Bakker-Woudenberg, I. A. J. M., van den Berghe-van Raffe, M., Michel, M. F.: Continuous versus intermittent administration of ceftazidime in experimentalKlebsiella pneumoniae pneumonia in normal and leukopenic rats. Antimicrobial Agents and Chemotherapy 1986, 30: 403–408.

    PubMed  Google Scholar 

  4. Roosendaal, R., Bakker-Woudenberg, I. A. J. M., van den Berghe-van Raffe, M., Vink van den Berg, J. C., Michel, M. F.: Comparative activities of ciprofloxacin and ceftazidime againstKlebsiella pneumoniae in vitro and in experimental pneumonia in leukopenic rats. Antimicrobial Agents and Chemotherapy 1987, 31: 1809–1815.

    PubMed  Google Scholar 

  5. Kramer, B. S., Pizzo, P. A., Robichaud, K. J., Witesbsky, F., Wesley, R.: Role of serial microbiologic surveillance and clinical evaluation in the management of cancer patients with fever and granulocytopenia. American Journal of Medicine 1982, 72: 561–568.

    Article  PubMed  Google Scholar 

  6. Craig, W. A., Gudmundsson, S.: The postantibiotic effect. In: Lorian, V. (ed.). Antibiotics in laboratory medicine. Williams and Wilkins, Baltimore, 1985, p. 515–536.

    Google Scholar 

  7. Bakker-Woudenberg, I. A. J. M., van den Berg, J. C., Michel, M. F.: Therapeutic activities of cefazolin, cefotaxime, and ceftazidime against experimentally inducedKlebsiella pneumoniae pneumonia in rats. Antimicrobial Agents and Chemotherapy 1982, 22: 1042–1050.

    PubMed  Google Scholar 

  8. Thonus, I. P., de Lange-Macdaniël, A. V., Otte, C. J., Michel, M. F.: Tissue cage infusion: a technique for the achievement of prolonged steady state in experimental animals. Journal of Pharmacological Methods 1979, 2: 63–69.

    Article  Google Scholar 

  9. Sachs, L.: Evaluation of biologically active substances based on dosage-dichotomous effect curves. In: Sachs, L. (ed.): Applied statistics. A handbook of techniques. Springer Verlag, New York, 1982, p. 224–228.

    Google Scholar 

  10. Bennett, J. V., Brodie, J. L., Benner, E. J., Kirby, W. M. M.: Simplified accurate method for antibiotic assay of clinical specimens. Applied Microbiology 1986, 14: 170–177.

    Google Scholar 

  11. Craig, W. A., Vogelman, B.: The postantibiotic effect. Annals of Internal Medicine 1987, 106: 900–902.

    PubMed  Google Scholar 

  12. Vogelman, B., Craig, W. A.: Kinetics of antimicrobial activity. Journal of Pediatrics 1986, 108: 835–840.

    PubMed  Google Scholar 

  13. Brugger, H. P., Gerber, A. U., Feller-Segessenmann, C.: Bolusinjection, kurzinfusion oder dauerinfusion von aminoglykosid-antibiotika? In-vivo-studie mit netilmicin undPseudomonas aeruginosa. Schweizerische Medizinische Wochenschrift 1983, 113: 1858–1860.

    PubMed  Google Scholar 

  14. 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 againstPseudomonas aeruginosa in granulocytopenic mice. Journal of Infectious Diseases 1983, 147: 910–917.

    PubMed  Google Scholar 

  15. Gerber, A. U., Brugger, H. P., Feller, C., Stritzko, T., Stalder, B.: Antibiotic therapy of infections due toPseudomonas aeruginosa in normal and granulocytopenic mice: comparison of murine and human pharmacokinetics. Journal of Infectious Diseases 1986, 153: 90–97.

    PubMed  Google Scholar 

  16. Gudmundsson, S., Turnidge, J., Craig, W. A.: Effect of different dosage regimens on in vivo efficacy of antibiotics againstKlebsiella pneumoniae. Clinical Research 1982, 30: 777A.

  17. Powell, S. H., Thompson, W. L., Luthe, M. A., Stern, R. C., Grossniklaus, D. A., Bloxham, D. D., Groden, D. L., Jacobs, M. R., DiScenna, A. O., Cash, H. A., Klinger, J. D.: Once-daily versus continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical studies of gentamicin, netilmicin, and tobramycin. Journal of Infectious Diseases 1983, 147: 918–932.

    PubMed  Google Scholar 

  18. Leggett, J. E., Fantin, B., Ebert, K., 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. Journal of Infectious Diseases 1989, 159: 281–292.

    PubMed  Google Scholar 

  19. Ingerman, M. J., Pitsakis, P. G., Rosenberg, A. F., Levison, M. E.: The importance of pharmacodynamics in determining the dosing interval in therapy for experimentalPseudomonas endocarditis in the rat. Journal of Infectious Diseases 1986, 153: 707–714.

    PubMed  Google Scholar 

  20. Baquero, F., Culebras, E., Patron, C., Perez-Diaz, J. C., Medrano, J. C., Vicente, M. F.: Postantibiotic effect of imipenem on gram-positive and gram-negative micro-organisms. Journal of Antimicrobial Chemotherapy 1986, 18, Supplement E: 47–59.

    Google Scholar 

  21. Grasso, S., Meinardi, G., de Carneri, I., Tamassia, V.: New in vitro model to study the effect of antibiotic concentration and rate of elimination on antibacterial activity. Antimicrobial Agents and Chemotherapy 1978, 13: 570–576.

    PubMed  Google Scholar 

  22. Nishida, M., Murakawa, T., Kamimura, T., Okada, N.: Bactericidal activity of cephalosporins in an vitro model simulating serum levels. Antimicrobial Agents and Chemotherapy 1978, 14: 6–12.

    PubMed  Google Scholar 

  23. Yourassowsky, E., van der Linden, M. P., Lismont, M. J., Crokaert, F., Glupezynski, Y.: A comparative study of the rate of bactericidal activity between netilmicin and piperacillin onEscherichia coli andPseudomonas aeruginosa. Current Therapeutic Research 1987, 41: 823–827.

    Google Scholar 

  24. 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. Antimicrobial Agents and Chemotherapy 1987, 31: 1054–1060.

    PubMed  Google Scholar 

  25. Moore, R. D., Lietman, P. S., Smith, C. R.: Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. Journal of Infectious Diseases 1987, 155: 93–99.

    PubMed  Google Scholar 

  26. Kapusnik, J. E., Sande, M. A.: Challenging conventional aminoglycoside dosing regimens. The value of experimental models. American Journal of Medicine 1986, 80, Supplement 6B: 179–181.

    Article  PubMed  Google Scholar 

  27. Pechère, M., Letarte, R., Pechère, J. C.: Efficacy of different dosing schedules of tobramycin for treating a murineKlebsiella pneumoniae bronchopneumonia. Journal of Antimicrobial Chemotherapy 1987, 19: 487–491.

    PubMed  Google Scholar 

  28. Chalkley, L. J., Koornhof, H. J.: Antimicrobial activity of ciprofloxacin againstPseudomonas aeruginosa, Escherichia coli, andStaphylococcus aureus determined by the killing curve method: antibiotic comparisons and synergistic interactions. Antimicrobial Agetns and Chemotherapy 1985, 28: 331–342.

    Google Scholar 

  29. Bundtzen, R. W., Gerber, A. U., Cohn, D. L., Craig, W. A.: Postantibiotic suppression of bacterial growth. Reviews of Infectious Discases 1981, 3: 28–37.

    Google Scholar 

  30. Neu, H. C., Kumada, T., Chin, N.-X., Mandell, W.: The post-antimicrobial suppressive effect of quinolone agents. Drug Experimental Clinical Research 1987, 13: 63–67.

    Google Scholar 

  31. Lagast, H., Husson, M., Klastersky, J.: Bactericidal activity of ciprofloxacin in serum and urine againstEscherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, andStreptococcus faecalis. Journal of Antimicrobial Chemotherapy 1985, 16: 341–347.

    PubMed  Google Scholar 

  32. Comber, K. R., Boon, R. J., Sutherland, R.: Comparative effects of amoxycillin and ampicillin on the morphology ofEscherichia coli in vivo and in correlation with activity. Antimicrobial Agents and Chemotherapy 1977, 12: 736–744.

    PubMed  Google Scholar 

  33. Zak, O., Kradolfer, F.: Effect of subminimal inhibitory concentrations of antibiotics in experimental infections. Reviews of Infectious Diseases 1979, 1: 826–879.

    Google Scholar 

  34. Forsgren, A., Berkvist, P. I.: Effect of ciprofloxacin on phagocytosis. European Journal of Clinical Microbiology 1985, 4: 575–578.

    PubMed  Google Scholar 

  35. Milatovic, D.: Antibiotics and phagocytosis. European Journal of Clinical Microbiology 1983, 2: 414–425.

    PubMed  Google Scholar 

  36. Easmon, C. S. F., Crane, J. P.: Uptake of ciprofloxacin by human neutrophils. Journal of Antimicrobial Chemotherapy 1985, 16: 67–73.

    PubMed  Google Scholar 

  37. Atkinson, B. A., Amaral, L.: Sublethal concentrations of antibiotics, effects on bacteria and the immune system. CRC Critical Reviews in Microbiology 1982, 9: 101–138.

    PubMed  Google Scholar 

  38. Gerber, A. U., Kozak, S., Segessenman, C., Flückiger, U., Bangerter, T., Greter, U.: Once-daily versus thrice-daily administration of netilmicin in combination therapy ofPseudomonas aeruginosa infection in a manadapted neutropenic animal model. European Journal of Clinical Microbiology and Infectious Diseases 1989, 8: 233–237.

    Google Scholar 

  39. Bennet, W. M., Plamp, C. E., Gilbert, D. N., Parker, R. A., Porter, G. A.: The influence of dosage regimen on experimental gentamicin nephrotoxicity: dissociation of peak serum levels from renal failure. Journal of Infectious Diseases 1979, 140: 576–580.

    PubMed  Google Scholar 

  40. Frame, P. T., Phair, J. P., Watanakunakorn, C., Bannister, T. W. P.: Pharmacologic factors associated with gentamicin nephrotoxicity in rabbits. Journal of Infectious Diseases 1977, 135: 952–956.

    PubMed  Google Scholar 

  41. Reiner, N. E., Bloxham, D. D., Thompson, W. L.: Nephrotoxicity of gentamicin and tobramycin given once daily or continuously in dogs. Journal of Antimicrobial Chemotherapy 1978, 4, Supplement A: 85–101.

    Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Microbiology and Antimicrobial Therapy, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands

    R. Roosendaal, I. A. J. Bakker-Woudenberg, M. van den Berghe-van Raffe, J. C. Vink-van den Berg & M. F. Michel

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  1. R. Roosendaal
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  2. I. A. J. Bakker-Woudenberg
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  3. M. van den Berghe-van Raffe
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  4. J. C. Vink-van den Berg
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  5. M. F. Michel
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Roosendaal, R., Bakker-Woudenberg, I.A.J., van den Berghe-van Raffe, M. et al. Impact of the dosage schedule on the efficacy of ceftazidime, gentamicin and ciprofloxacin inKlebsiella pneumoniae pneumonia and septicemia in leukopenic rats. Eur. J. Clin. Microbiol. Infect. Dis. 8, 878–887 (1989). https://doi.org/10.1007/BF01963774

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