Using Chemical Reaction Kinetics to Predict Optimal Antibiotic Treatment Strategies
Fig 5
Biochemical properties shape antibiotic pharmacodynamics.
These graphs show the expected dynamics of antibiotic-target reaction according to model 2 with all parameters adapted to ampicillin except stated. The x-axes show the time after initiation of antibiotic therapy in hours, the y-axes the current antibiotic concentration in fold MIC (black, left side) and the % bound target (violet, right side). Note that the y-axis is on a logarithmic scale. The green line shows the antibiotic concentration outside and the red inside the cell (both refer to the y-axis on the left), the violet line shows the amount of bound target (refers to y-axis on the right). The grey area indicates that either the antibiotic concentration is below MIC or the fraction of bound target is below the inhibitory threshold fc. The dotted vertical lines indicate beginning and end of antibiotic action. Graphs in the first column depict bolus injections with an initial antibiotic concentration of 50MIC and a half-life of 1h. The second column shows a hypothetical dosing regimen with a constant concentration just above the MIC (1.01 MIC) that has the same TC>MIC as in the first column. The third column shows a hypothetical dosing regimen with a constant concentration just above the MIC (1.01 MIC) that has the equivalent area under the curve (AUC) as in the first column. Note the different timescale in the third column. (A) Biochemical properties are sufficient to explain time-dependent action of beta-lactams. The graphs show drug-target binding expected based on physicochemical characteristics of ampicillin drug-target binding from the literature (Table 1). (B) Area under the curve is best predictor of antibiotic action for equilibration times in the range of hours. We introduced a diffusion barrier of p = 10-4s-1 while all other parameters remain as in (A). (C) Peak concentration is best predictor of drug action when equilibration is slow. We introduced a stronger diffusion barrier of p = 10-5s-1 while all other parameters remain as in (A).