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186 Ambrose et al.Human PK-PD DataClinical PK-PD studies evaluating the relationship between drug exposure andresistance are very few. Thomas et al. evaluated data from four clinical trials ofacutely ill patients with hospital-acquired respiratory tract infections (30). PK-PDmeasures for five antimicrobial regimens and microbiological results for serialtracheal aspirates were examined across and by organism. Total-drug AUC 24 :MICratios below 100 were associated with an 82.4% likelihood of emergence ofresistance while ratios above 100 were only associated with a 9.3% emergence ofresistance. Given that the greatest frequency of selected resistance was observedfor Pseudomonas spp. treated with ciprofloxacin and that ratios exceeding 100 didnot reduce the risk of emergence of resistance among patients with b-lactamaseproducinggram-negative bacilli treated with b-lactam monotherapy, the reportedPK-PD breakpoint was likely more reflective of that for ciprofloxacin for Pseudomonasspp. More data from clinical trials looking at such relationships by organismand drug are needed to further elucidate this question and confirm in vitrofindings. While this analysis represented a step forward in the paradigm of usingmicrobiological endpoints for evaluating the time-course of antimicrobial effect(i.e., by evaluating a serial microbiological endpoint which is more sensitive thandichotomous endpoints, like “success” and “failure” at test-of-cure), there werecertain important limitations including the retrospective nature of the review andthe controversy surrounding the relative value of tracheal aspirate specimens.SUMMARYAn understanding of PK-PD concepts forms the basis for the rational use ofantimicrobial agents. For quinolones against various bacterial genera, there hasbeen good concordance among findings from in vitro infection models and animalinfection models and data from well-controlled clinical trials. However, thereremains much work to do, especially with regard to resistance prevention, wherethe mutation prevention concentration data and that from dynamic infectionmodels are playing a critical role.REFERENCES1. Ambrose PG, Bhavnani SM, Rubino CM, et al. Pharmacokinetics-pharmacodynamicsof antimicrobial therapy: it‘s not just for mice anymore. Clin Infect Dis 2007; 44:79–86.2. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterialdosing in mice and men. Clin Infect Dis 1997; 26:1–12.3. Craig WA. Pharmacodynamics of antimicrobials: general concepts and application. In:Nightingale CH, Murakawa T, Ambrose PG, eds. Antimicrobial Pharmacodynamics inTheory and Clinical Practice. New York: Marcel-Dekker, 2002:1–21.4. Andes DR, Craig WA. Pharmacodynamics of fluoroquinolones in experimental modelsof endocarditis. Clin Infect Dis 1998; 27:47–50.5. Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ. Pharmacodynamicsof intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother1993; 37:1073–1081.6. Forrest A, Chodash S, Amantea MA, Collins DA, Schentag JJ. Pharmacokinetics andpharmacodynamics of oral grepafloxacin in patients with acute bacterial exacerbationsof chronic bronchitis. J Antimicrob Chermother 1997; 40(suppl A):45–57.7. Preston SL, Drusano GL, Berman AL, et al. Pharmacodynamics of levofloxacin: a newparadigm for early clinical trials. JAMA 1997; 279:125–129.