抗生素英文课件精品——Antibiotic dosage regimen based on PK-PD concepts and the possible minimization of resistance教学教程.ppt

In the early 1990s New York City experienced an outbreak of MDR tuberculosis. At the time we were studying DNA topoisomerases to better understand chromosome structure. We had used quinolones as tools, and so we were familiar with them. During the outbreak it became clear that the use of ciprofloxacin quickly led, sometimes within a month, to ciprofloxacin-resistant tuberculosis (13, 17). At the time it seemed that the problem was to find a way to halt the development of resistance. From a na?ve microbiological point of view we thought that we should look for new quinolones that would readily attack resistant mutants. We had gyrase mutants available for several bacterial species, and we obtained some investigational compounds from John Domagala at Parke-Davis. The general idea, as shown in the slide, was to find a compound that would be exceptionally active against a resistant mutant. Such a compound, if used against wild-type cells, would require a double mutation for growth. Since the mutation frequency for fluoroquinolones is on the order of 10-7, a pair of independent mutations would arise at frequency of 10-14. Infections rarely have more than 1010 cells, so a mutant-active compound would prevent the selective enrichment of mutants. The story that emerged can be divided into several subtopics, as shown on the next slide. This lecture was prepared on April 5, 2003. Literature cited is listed as a note to the last slide. Placing MIC near the lower boundary of the selection window contradicts traditional medical teaching in which resistant mutants are thought to be selected primarily when drug concentrations are below MIC (shown in a figure taken from a book published in 2002 (2)). This distinction is important because traditional dosing recommendations to exceed MIC are likely to place drug concentrations inside the selection window where they will enrich resistant mutant subpopulations. While low drug concentrations do not enrich resistant mutant