title: Declining susceptibilities of gram-negative bacteria to the fluoroquinolones: effects on pharmacokinetics, pharmacodynamics, and clinical outcomes.
abstract: OBJECTIVE
  Published evidence of rising gram-negative bacterial resistance to fluoroquinolone therapy is reviewed, with a focus on the potential need for revising pharmacokinetic-pharmacodynamic (PK-PD) targets in order to maintain acceptable clinical outcomes.
  
  
  CONCLUSIONS
  With a more than threefold increase in fluoroquinolone use among U.S. adults since the introduction of second- and third-generation (i.e., "respiratory") fluoroquinolones 15 years ago, surveillance data indicate a decline in some gram-negative organisms' susceptibility to this antimicrobial class. These trends have raised concerns that the need to attain higher organism-specific minimum inhibitory concentrations (MICs) may lead to worse patient outcomes, even when MIC values are below current established "clinical breakpoints" for fluoroquinolone susceptibility. A growing body of evidence from PK-PD studies suggests that current fluoroquinolone dosing regimens are no longer adequate to achieve validated PK-PD targets. For example, a Monte Carlo simulation using PK data from U.S. hospitals showed decreasing rates of response to standard ciprofloxacin and levofloxacin i.v. dosing regimens among patients treated for infections with Escherichia coli and Klebsiella species. These findings suggest that currently accepted PK-PD targets may need to be revised for certain patient populations, including patients with bloodstream infections (BSIs). More research is needed to confirm the appropriateness of adjusting clinical breakpoints and other strategies to combat rising fluoroquinolone resistance.
  
  
  CONCLUSIONS
  The use of the fluoroquinolones has markedly increased since the introduction of the respiratory fluoroquinolones. Surveillance data and PK-PD studies have raised concerns about suboptimal patient outcomes with the use of fluoroquinolones for some gram-negative infections, particularly BSIs. PK-PD goals and clinical breakpoints may need to be revised for these infections.
authors.affiliation: The Johns Hopkins Hospital, Baltimore, MD, USA. mlabrec3@jhmi.edu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Labreche
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Frei
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D024841:Fluoroquinolones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D017063:Outcome Assessment, Health Care
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones