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.

Comparison of Pharmacodynamic and Pharmacokinetic Indices of Efficacy for 5 Fluoroquinolones toward Pathogens of Dogs and Cats

“…26 However, as a pharmacodynamic parameter, potency does not account for patient pharmacokinetics such as C max and AUC. [7][8][9][10][11][12][13][14][15] Potency rankings did not accurately reflect predicted efficacy rankings.…”

“…Within the last 10 years, emphasis has been placed on the importance of combining pharmacodynamic and pharmacokinetic data as a basis for predicting potential antimicrobial efficacy in a patient. [7][8][9][10][11][12][13][14][15] Among predictors most commonly associated with fluoroquinolone efficacy are the ratio of C max to MIC (C max /MIC, sometimes referred to as an inhibitory quotient or IQ), and the ratio of area under the plasma drug concentration versus time curve to the MIC (AUC/MIC; sometimes referred to as area under the inhibitory curve or AUIC). [7][8][9][10][11][12][13][14][15] In vitro studies for concentration-dependent antimicrobials (including fluoroquinolones) suggest that antibacterial efficacy is more likely if the C max /MIC is $ 10, 8,9 or the AUC/MIC is $125, particularly for Gram-negative organisms.…”

Antimicrobial Use in the Critical Care Patient

“…These drugs are best represented by the fluoroquinolones and aminoglycosides (both of which result in irreversible inhibition of their targets). 31,32 More recently, the effectiveness of concentration-dependent drugs has been best predicted by the area under the inhibitory curve (AUIC), the ratio of the AUC (area under the curve for 24 hours, which is influenced by both dose and interval) to the MIC. Their effectiveness is predicted by comparing the C max with the MIC of the infecting organism.…”

How to Optimize the Evaluation and Use of Antibiotics in Neonates

“…Based on these parameters, the bacterial killing activity is primarily defined as time dependent or concentration dependent. 24 …”