Application of fluoroquinolone pharmacodynamics

Abstract

Pharmacodynamics provides a rational basis for optimizing dosing regimens by describing the relationship between drug, host and antimicrobial effect. The successful identification of meaningful pharmacodynamic outcome parameters can, therefore, greatly assist clinicians in making objective prescribing decisions rather than relying on static in vitro MIC data. While pharmacodynamic outcome parameters have been proposed for select antimicrobial agents, their clinical application remains to be defined fully. Quinolone antibiotics are generally considered to have concentration-dependent bactericidal activity and peak/MIC and AUC/MIC ratios have been identified as possible pharmacodynamic predictors of clinical and microbiological outcome as well as the development of bacterial resistance. Investigators have suggested that AUC/MIC ratios of 100-125 or peak/MIC ratios of >10 are required to predict clinical and microbiological success and to limit the development of bacterial resistance. These conclusions are derived primarily from studies of Gram-negative bacteria, and recent data suggest that these ratios may not be applicable for Streptococcus pneumoniae, where an AUC/MIC ratio of <40 appears to be a more accurate predictor. There is considerable variation in pharmacodynamic calculations and outcome parameters appear to be quinolone- and pathogen-specific. Additional prospective clinical research is needed to characterize quinolone pharmacodynamic parameters and answer unresolved questions regarding optimal pharmacodynamic outcome predictors for Gram-positive bacteria, anaerobes and atypical respiratory pathogens.

Pharmacokinetic – Pharmacodynamic Considerations for Bovine Mastitis Treatment

“…Similarly, the AUC/MIC ratio of 100-125 frequently quoted as a target for FQ ATM activity may be an appropriate predictor of success for many Gram-negative infections, but lower AUC/MIC ratios (e.g. 35 to 40) may be appropriate for infections due to Gram positive organisms (Wright et al, 2000). With regard to the β-lactams, while there tends to be a substantial in vivo PAE for S. aureus, a substantially shorter PAE is associated with Gram negative organisms (Craig, 1993).…”

“…For Gram-negative organisms, the estimated AUC/MIC ratios needed to ensure effective treatment and prevent the selection of resistant strains is estimated to be approximately 100 to 125 (Forrest et al, 1993). In contrast, the AUC/MIC ratio for Grampositive bacteria is considerably lower, approximately 30 to 50 for a number of drugpathogen combinations (Wright et al, 2000). Studies involving the third and fourth generation FQ suggest that for Gram-positive organisms AUC/MIC values are substantially lower when C max /MIC values are ≥10 (Nightingale et al, 2000).…”

Serum pharmacokinetics and tissue concentrations of a newrecrystallized enrofloxacin hydrochloride-dihydrate in hamsters

“…Optimal clinical efficacy of enrofloxacin has been linked to specific PK/PD ratios, i.e. maximum serum concentration (C MAX ) should reach at least 10-12 times the value of the minimal inhibitory concentration (MIC) (C MAX > 10-12 MIC), and the area under the serum concentration vs. time curve (AUC 0-24 )/MIC should be equal to or higher than 125 (AUC/MIC ≥ 125) (10). These ratios are not always accomplished for enrofloxacin due to many factors, such as defective maneuvers to deliver the correct dose (11,12), the lack of bioequivalence of many pharmaceutical preparations (4)(5)(6)(7), and the presence of resistant bacteria to this antimicrobial agent.…”

Delafloxacin: A Novel Fluoroquinolone Introduced in Clinical Trials

“…These structure modifications resulted in development of ofloxacin, ciprofloxacin, norfloxacin, levofloxacin, moxifloxacin and several other agents [1][2][3][4]. All above mentioned structure modifications yielded fluoroquinolones and resulted in improved antibacterial efficacy, broaden spectrum and enhanced tissue penetration [5].…”

“…These structure modifications resulted in development of ofloxacin, ciprofloxacin, norfloxacin, levofloxacin, moxifloxacin and several other agents [1][2][3][4]. All above mentioned structure modifications yielded fluoroquinolones and resulted in improved antibacterial efficacy, broaden spectrum and enhanced tissue penetration [5].Delafloxacin (WQ-3034) is a novel fluoroquinolone agent, discovered by Wakunaga Pharmaceutical Co., Ltd., Osaka & Hiroshima, Japan. Its chemical structure is 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.…”