Prediction of antibiotic dosing intervals from in vitro susceptibility, pharmacokinetics and post-antibiotic effect: theoretical considerations.

Because of the complexity of determining minimum inhibitory concentration (MIC) values on multiple drugs in routine laboratories, susceptibility testing has been designed to generate 2 or 3 broadly-predictive susceptibility categories: susceptible, (intermediate), and resistant. In contrast, recent dosing studies in vivo have shown that for some antibiotics optimum efficacy is best predicted by time above the known MIC and any postantibiotic effect (PAE). It is possible that the optimum dosing interval can be approximated by the sum of the time greater than MIC and the duration of PAE. PAE is known to be related to AUC of drug concentration and time of exposure. Formulae are presented that should make it possible to calculate the optimum dosing interval mathematically by knowing (i) the drug's pharmacological parameters and dose, (ii) the organism's MIC and (iii) the relationship between AUC and PAE for the drug-organism combination. Both (i) and (iii) are predetermined values obtained from studies. For some bacterial species, isolates in the susceptible range have very similar MICs (narrow range) and the MIC is therefore reasonably predictable. However, for other species, the precise MIC needs to be measured to perform the calculations. Examples of the application of these formulae are given.