Figure 1.
Dose fractionation designs of an identical daily dose.
Table 1.
Dose fractionation designs of an identical daily dose.
Figure 2.
Concentration dependent killing; AUC/MIC most important.
Kk = 60.0 h−1. C50 = 600.0 mg/l. H = 1.0. Black solid line depicts the relationship between drug concentration and killing rate; black dotted line represents the microbial growth rate. Arrows below represent concentration ranges achieved with various dosing regimens (red – once daily; green – twice daily; blue – four times daily). Two intersecting planes are shown: a translucent surface and an opaque mesh surface (where the average kill rate = 1.0 h−1). The 3-dimensional mesh surface is made up of a collection of data points; each datum point is characterized by a value on the x, y and z axes, corresponding to the daily dose (x), dosing interval (y) and average kill rate (z). For a dosing regimen to suppress resistance development, it is imperative that the average kill rate (D) is more than the growth rate (Kg) of the target pathogen. To identify promising dosing regimens (combinations of dose and dosing interval) to suppress resistance development, D must be greater than Kg (the region where the translucent surface is above the opaque mesh plane). White area depicts dosing regimens (combinations of daily dose and dosing interval which the average kill rate is >1.0 h−1. Using a daily dose of 6000 mg, the average kill rates for different regimens are: 1.463 h−1 (q24h), 1.610 h−1 (q12h), and 1.690 h−1(q6h).
Figure 3.
Concentration dependent killing; Cmax/MIC most important.
Kk = 40.0 h−1. C50 = 100.0 mg/l. H = 4.0. Black solid line depicts the relationship between drug concentration and killing rate; black dotted line represents the microbial growth rate. Arrows below represent concentration ranges achieved with various dosing regimens (red – once daily; green – twice daily; blue – four times daily). White area depicts dosing regimens (combinations of daily dose and dosing interval which the average kill rate is >1.0 h−1. Using a daily dose of 6000 mg, the average kill rates for different regimens are: 2.650 h−1 (q24h), 2.168 h−1 (q12h), and 0.689 h−1(q6h). Using a conventional dose fractionation design with 16000 mg daily (e.g., 16000 mg q24h, 8000 mg q12h, 4000 mg q6h, etc.), all regimens are expected to suppress the bacterial population, thus AUC/MIC is likely to be concluded as the pharmacodynamic index associated with resistance suppression. In addition, if a daily dose of 2000 mg is selected (e.g., 2000 mg q24h, 1000 mg q12h, 500 mg q6h, etc.), all regimens are expected to be associated with regrowth, and therefore AUC/MIC is also likely to be deemed as the pharmacodynamic index associated with resistance development. However, if a daily dose of 6000 mg is chosen (e.g., 6000 mg q24h, 3000 mg q12h, 1500 mg q6h, etc.), a less frequent dosing regimen (e.g., q24h) is anticipated to have a higher likelihood of suppressing resistance, and as such Cmax/MIC is likely to be concluded as the pharmacodynamic index associated with resistance suppression. Therefore, the strict use of surrogate indices in pharmacodynamic modeling is not always optimal as they may be subjected to selection basis of the concentration range examined.
Figure 4.
Time dependent killing; %T>MIC most important.
Kk = 4.0 h−1. C50 = 10.0 mg/l. H = 4.0. Black solid line depicts the relationship between drug concentration and killing rate; black dotted line represents the microbial growth rate. Arrows below represent concentration ranges achieved with various dosing regimens (red – once daily; green – twice daily; blue – four times daily). White area depicts dosing regimens (combinations of daily dose and dosing interval which the average kill rate is >1.0 h−1. Using a daily dose of 6000 mg, the average kill rates for different regimens are: 0.818 h−1 (q24h), 1.303 h−1 (q12h), and 1.950 h−1(q6h).
Table 2.
Summary of selected dose fractionation studies to suppress bacterial resistance development.