title: The integration of four major determinants of antibiotic action: bactericidal activity, postantibiotic effect, susceptibility, and pharmacokinetics.
abstract: A functional pharmacokinetic/pharmacodynamic (PK/PD) index that could simultaneously describe three controlling PD variables, i.e., bactericidal activity, postantibiotic effect (PAE), and susceptibility, in relation to pharmacokinetics, was designed using an in vitro kinetic model. Tobramycin was tested against one standard and five clinical strains of Pseudomonas aeruginosa. The organisms showed minimum inhibitory concentrations (MICs) ranging between 1 and >1000 microg/ml. The model allowed antibiotic concentrations to be reduced exponentially from initial concentrations at fixed multiples of MIC. Antibiotic removal was performed when the decreasing concentrations hit the MIC of individual strain to provide a wide range of AUC(>MIC) within an identical frame of AUC(>MIC)/MIC (AUIC) values. Viable counts were measured at antibiotic addition and before/after its removal for bactericidal activity and PAE assessments. A linear relationship was observed between PAE and bactericidal rate constants, though the pattern varied among different strains. Characterization of the exposure (AUC(>MIC))-effect relationships using the Emax model revealed that the less susceptible strains displayed lower Emax and higher EC50 for both antimicrobial effects. By employing the AUIC as a common frame of reference, regression analysis showed a significant linear correlation (p < 0.05) between the mean PAE and bactericidal rate data and, thereby simultaneously defining the four contributing factors of the PK/PD system. It appears that the AUIC, by conveying the pharmacokinetic and susceptibility information, could serve as a PK/PD index in bridging the interdependency of PAE and bactericidal activity. More importantly, the collective assessment of these four factors would allow more optimal evaluation of dosage regimens.
authors.affiliation: Department of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong. rli1@prdus.jnj.com
authors.forename: R C
authors.initials: RC
authors.lastname: Li
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Zhu
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000592:standards; D015169:Colony Count, Microbial; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D014031:Tobramycin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000592:standards
chemical_list: D000900:Anti-Bacterial Agents; D014031:Tobramycin