Mathematical Examination of Dual Individualization Principles (I): Relationships between AUC above MIC and Area under the Inhibitory Curve for Cefmenoxime, Ciprofloxacin, and Tobramycin

Abstract

Traditional antibiotic dosage adjustments target predetermined serum concentrations, whereas a host of in vitro studies and recent clinical trials establish that bacteria vary in their susceptibility. Dual individualization, which considers the variance in both antibiotic pharmacokinetics and bacterial susceptibility, has been employed to describe different rates of bacterial eradication in relation to varying serum concentrations. In patients with nosocomial pneumonia, one of the model compounds studied was cefmenoxime, where a target six-hour area under the serum concentration-time curve (AUC) of 140 μg·h/mL above minimum inhibitory concentration (MIC) was previously associated with bacterial eradication in an average of four days. The target AUC value of 140 μg·h/mL above MIC is unique to cefmenoxime. Ideally, there should be a dual individualized target useful to adjust the dose of any antibiotic. Computer simulations performed to evaluate this hypothesis suggested that each antibiotic had a unique value for target AUC above MIC. These simulations indicated that an optimal AUC above MIC was about 80 percent of the total AUC above the MIC. Predictable rates of bacterial eradication would presumably result from maintaining these relationships across the range of bacterial susceptibility and the range of serum concentration profiles. Each antibiotic has a unique and different 24-hour AUC over MIC value associated with bacterial eradication in 4 days. For cefmenoxime, the target was 540 area units over MIC per 24 hours, tobramycin with 34 area units, and ciprofloxacin with 23 area units per 24 hours. Because it would clearly be desirable to have a target for dosing adjustment that is independent of the particular antibiotic, we then used computer simulations to determine whether the AUIC (area under the inhibitory curve, or integrated AUC above MIC vs. time) could be descriptive of bacterial eradication with the cephalosporin, cefmenoxime; the aminoglycoside, tobramycin; and the fluoroquinolone, ciprofloxacin. Computer simulation revealed that appropriate doses of all three of these antibiotics yield 24-hour AUIC values in the range of 125. On the basis of these simulations, we propose that target AUIC values are likely to be applicable across antibiotic classes, whereas AUC above MIC targets must be unique values to the particular antibiotic. Furthermore, these relationships can be used to make comparisons of antibiotic activity either across different antibiotic classes or within the same class.