George L. Drusano, MD

20 June, 2018

Dr Drusano began by discussing variables linked to therapeutic outcome following treatment with fluoroquinolones. He demonstrated that when a drug is concentration-dependent in its kill rate, as illustrated by the fluoroquinolones, the kill rate engendered by concentrations near the peak is greater than the kill rate engendered in the middle of the curve. Thus, the AUC time curve relative to the MIC determines the amount and rate of cell kill at the primary infection site for fluoroquinolones.

Peak concentration is probably not linked to cell kill but to the prevention of emergence of resistance. In every dense population of microorganisms some have developed resistance either through a mutation in the gyr A or the par C subunit. A high peak concentration can suppress not only parent strains, but also mutant organisms.

The pharmacokinetic and pharmacodynamic parameters were investigated with the mean peak concentration, time above the MIC, and AUC per 24 hours identified for each dose. If peak to MIC ratio is most important, a once-daily dose should be optimal. If time above MIC is important, the most fractionated regimen should be best. If AUC to MIC ratio is most important, all three regimes should achieve identical outcome.

A 74% survivorship for the once-daily 80mg dose was statistically significantly better than the twice- and four-times daily schedules, implying that peak to MIC ratio is linked to outcome. To explain why there was no difference between the q12 and q6 schedules, it was hypothesized that the once-daily group achieved a peak to MIC ratio greater than 10 to 1, and suppressed gyr A mutants already present. If this ratio is not achieved then AUC to MIC is linked to outcome.

A prospective trial was performed to develop quantitative relationships between levofloxacin exposure and measure of patient outcome. Results confirmed patients had a statistically better clinical outcome if their peak to MIC ratio was greater than 12.

Levofloxacin was compared with ciprofloxacin and shown to achieve complete bacterial eradication of all four isolates tested. Ciprofloxacin achieved an early fall in pathogen numbers, but by hour 48 regrowth was seen, and later emergence of resistance.

Detailed data illustrates that by hour 24, levofloxacin killed 3 to 4.7 logs of organisms. Ciprofloxacin had no affect on one strain, and two other strains had less than 2 logs of kill.

By hour 48, levofloxacin eradicated three of the four isolates. Three of four regrew following ciprofloxacin administration. In none of the levofloxacin strains was resistance noted. These results confirm the excellent activity and favorable pharmacological features of levofloxacin.