Assessment of Differences in Antimicrobial Effect Determined with Two In Vitro Pharmacodynamic Models: Impact of Surface Area to Volume Ratio

Roger L. White, Pharm.D., Charles R. Bonapace, Pharm.D., Lawrence V. Friedrich, Pharm.D., Michael J. Rybak, Pharm.D., Diane M. Cappelletty, Pharm.D., Renee-Claude Mercier, Pharm.D., Heather H. Houlihan, Pharm.D., Jeffrey R. Aeschlimann, Pharm.D., John A. Bosso, Pharm.D.

Pharmacotherapy. 2003;23(5) 

In This Article

Abstract and Introduction

Study Objective: To measure the influence of different surface area:volume ratios (SA:Vs) on antibiotic penetration and subsequent antibacterial effect.
Design: In vitro laboratory experiment.
Setting: Two academic research laboratories.
Intervention: The two models with effective SA:Vs of 5.34 and 4.80 cm-1 were evaluated by conducting a time-kill experiment with Pseudomonas aeruginosa ATCC 27853 and ceftazidime.
Measurements and Main Results: Ceftazidime was administered by constant infusion into the central compartment. Its penetration into the peripheral compartment and bacterial counts were determined over 24 hours, and antibacterial effect was quantified. Antibiotic penetration, calculated using central compartment and peripheral compartment area under the concentration-time curves, and effect, quantified as the relationship between the areas under growth and kill curves, differed between the models. Antibiotic penetration into the peripheral compartment was 53% greater over the first 4 hours of the experiment in the model with the larger SA:V. This was associated with antibacterial effects that were 64% and 38% greater in the 0-4-hour and 0-24-hour time periods, respectively.
Conclusion: Differences in antibiotic penetration and effect observed between these models are likely explained by differences in SA:V.

In vitro models have been used to mimic the in vivo effects of antimicrobials on bacterial killing. Although early models initially were composed of one compartment, many contemporary models contain two compartments that simulate the central compartment and extravascular peripheral compartment.[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17] Earlier studies used the peripheral compartment to simulate drug concentrations at the site of infection; however, with lack of a standard in vitro model, the design of these models varies appreciably. Differences include volumes of the central and peripheral compartments, the nature of the membrane used to enclose the peripheral compartment (e.g., material, pore size, surface area), and potential inclusion of physiologic elements (e.g., albumin, white blood cells). Because of these differences, it is reasonable to speculate that performance characteristics, and thus results of antibiotic effect experiments, may vary from model to model. The objective of this collaborative pilot study was to compare antibiotic penetration into the peripheral compartment of two different in vitro models, as well as compare the resultant antibacterial effect of a continuous infusion of ceftazidime against the same organism.

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