The answer to this depends on a number of factors and was first investigated using a neutropenic rat model and lomefloxacin (5). After the rats become neutropenic following cyclophosphamide administration, they were challenged intraperitoneally with a 9-log dose of virulent Pseudomonas aeruginosa. The study then evaluated the factor most closely associated with the drug that prevented death in this model system. Initially, a single-dose-rising experiment was performed, which identified 80 mg/kg o.d. as being the regimen associated with a survivorship of 70-80%. A dose-fractionation experiment was then carried out, looking at peak concentration, AUC and time > MIC.

Results demonstrated that the 80 mg/kg q24hr regimen produced 74% survivorship, while regimens with 40 mg/kg q12hr and 20 mg/kg q6hr produced survivorships of 32% and 36%, respectively (5). These results support the peak/MIC ratio as the main factor that drives outcome following fluoroquinolone therapy.

However, this does not explain why the regimens with 40 mg/kg q12hr and 20 mg/kg q6hr produced virtually identical survivorship curves. Further investigation (with a lower lomefloxacin q24hr dose) revealed that regimens with 40 mg/kg q24hr and 20 mg/kg q12hr had true equivalence, supporting the conclusion that the AUC/MIC ratio is the main factor linked to outcome (5). Thus, for the fluoroquinolones, sometimes peak/MIC and sometimes AUC/MIC are the main outcome variables. This difference may be due to a mixture of two pathogenic populations, a very large susceptible population and a much smaller but more resistant population that coexist.

In regard to levofloxacin, a 10,000-subject Monte Carlo simulation was performed from pharmacokinetic data derived from a study of community-acquired infection (6) to determine the probability with which the target AUC/MIC ratio necessary to achieve a 1-log drop in Streptococcus pneumoniae (34.5), and to achieve stasis (27) was achieved by a 500 mg dose once daily of levofloxacin for a range of MIC values.

A total of 94.7% of 10,000 subjects treated with levofloxacin 500 mg o.d were able to achieve the AUC/MIC ratio of 34.5, while 97.8% achieved the AUC/MIC ratio of 27 (6).