title: Comparative bactericidal activity of ceftazidime against isolates of Pseudomonas aeruginosa as assessed in an in vitro pharmacodynamic model versus the traditional time-kill method.
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.
authors.affiliation: Anti-Infective Research Laboratory, College of Pharmacy, Medical University of South Carolina, Charleston 29425-2303, USA.
authors.forename: M
authors.initials: M
authors.lastname: Manduru
authors.forename: L B
authors.initials: LB
authors.lastname: Mihm
authors.forename: R L
authors.initials: RL
authors.lastname: White
authors.forename: L V
authors.initials: LV
authors.lastname: Friedrich
authors.forename: P A
authors.initials: PA
authors.lastname: Flume
authors.forename: J A
authors.initials: JA
authors.lastname: Bosso
mesh_terms: D019540:Area Under Curve; D002442:Ceftazidime / Q000493:pharmacokinetics / Q000494:pharmacology*; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013997:Time Factors
chemical_list: D002511:Cephalosporins; D002442:Ceftazidime