Abstract
Bactericidal activity, historically assessed by in vitro tests which employ fixed drug concentrations, may also be evaluated in in vitro pharmacodynamic models in which in vivo pharmacokinetics and bacterial growth conditions can be simulated. However, systematic comparisons between the two methods are lacking. We evaluated the bactericidal activities of ceftazidime, at two different concentration/MIC ratios (C/MICs), against 10 clinical isolates of Pseudomonas aeruginosa in a two-compartment model with continuous-infusion conditions and a 2-h half-life. These values were compared to those determined by traditional 24-h time-kill (TTK) methods at the same C/MICs. Bactericidal activities were compared by using area under the colony count-time curves. Antibiotic exposure (area under the drug concentration-time curve) was also evaluated. Although bactericidal activity appeared greater by the TTK method (P = 0.05), when it was normalized for drug exposure, these differences disappeared (P = 0.2). This disparity was likely due to differences in drug exposure in the TTK method and in the peripheral compartment of the model (site of bacteria) over the first 8 h of the experiment, during which the antibiotic accumulated to target concentrations. This suggests that the bactericidal effects with constant antibiotic concentrations are similar in the two methods; however, this may not hold true with fluctuating drug concentrations. Further, results from the pharmacodynamic model may theoretically be more relevant, as in vivo pharmacokinetics and bacterial growth conditions call be more faithfully simulated.
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- Blaser J., Rieder H. L., Lüthy R. Interface-area-to-volume ratio of interstitial fluid in humans determined by pharmacokinetic analysis of netilmicin in small and large skin blisters. Antimicrob Agents Chemother. 1991 May;35(5):837–839. doi: 10.1128/aac.35.5.837. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Bosso J. A., Prince R. A., Fox J. L. Compatibility of ondansetron hydrochloride with fluconazole, ceftazidime, aztreonam, and cefazolin sodium under simulated Y-site conditions. Am J Hosp Pharm. 1994 Feb 1;51(3):389–391. [PubMed] [Google Scholar]
- Garrison M. W., Vance-Bryan K., Larson T. A., Toscano J. P., Rotschafer J. C. Assessment of effects of protein binding on daptomycin and vancomycin killing of Staphylococcus aureus by using an in vitro pharmacodynamic model. Antimicrob Agents Chemother. 1990 Oct;34(10):1925–1931. doi: 10.1128/aac.34.10.1925. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Holford N. H., Sheiner L. B. Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet. 1981 Nov-Dec;6(6):429–453. doi: 10.2165/00003088-198106060-00002. [DOI] [PubMed] [Google Scholar]
- Manduru M., Mihm L. B., White R. L., Friedrich L. V., Flume P. A., Bosso J. A. In vitro pharmacodynamics of ceftazidime against Pseudomonas aeruginosa isolates from cystic fibrosis patients. Antimicrob Agents Chemother. 1997 Sep;41(9):2053–2056. doi: 10.1128/aac.41.9.2053. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Quagliarello V., Scheld W. M. Bacterial meningitis: pathogenesis, pathophysiology, and progress. N Engl J Med. 1992 Sep 17;327(12):864–872. doi: 10.1056/NEJM199209173271208. [DOI] [PubMed] [Google Scholar]
- Schentag J. J., Smith I. L., Swanson D. J., DeAngelis C., Fracasso J. E., Vari A., Vance J. W. Role for dual individualization with cefmenoxime. Am J Med. 1984 Dec 21;77(6A):43–50. doi: 10.1016/s0002-9343(84)80074-1. [DOI] [PubMed] [Google Scholar]
- Shah P. M., Junghanns, Stille W. Dosis-Wirkungs-Beziehung der Bakterizidie bei E. coli, K. pneumoniae und Staphylococcus aureus. Dtsch Med Wochenschr. 1976 Feb 27;101(9):325–328. doi: 10.1055/s-0028-1104083. [DOI] [PubMed] [Google Scholar]
- Van Etta L. L., Peterson L. R., Fasching C. E., Gerding D. N. Effect of the ratio of surface area to volume on the penetration of antibiotics in to extravascular spaces in an in vitro model. J Infect Dis. 1982 Sep;146(3):423–428. doi: 10.1093/infdis/146.3.423. [DOI] [PubMed] [Google Scholar]