Delafloxacin: A Novel Fluoroquinolone Introduced in Clinical Trials

Abstract

CommentaryOpen AccessQuinolones were developed and introduced into clinical practice in the 1960s. During the past decades numerous agents have been synthetised by addition of certain substituents on the basic quinolone ring namely, in position C1 cyclopropyl or difluorophenyl, in position C6 a fluorine and in position C8 a halogen, metoxy or fused third ring. 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. This structure has three unique features: lack of a strongly basic group in position C7 that confers weak acidity; a chlorine in position C8 that exhibits a strong electron withdraw on aromatic ring; heteroaromatic substitution in position N1 that leads to a larger molecular surface compared to currently used fluoroquinolones [6]. The anionic structure of delafloxacin increases its potency in acidic environment, therefore its antibacterial activity is enhanced in site of infection with reduced pH (e.g.: skin and soft tissue infections). This feature makes delafloxacin special among fluoroquinolones as ciprofloxacin and moxifloxacin lose potency in acidic environment [7,8]. Delafloxacin is a broad-spectrum agent, as it targets both DNA gyrase and topoisomerase IV enzymes [9]. Based on in vitro testing delafloxacin proved to be effective with MICs between 0.004-0.015 mg/L against various pathogens namely, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis. Delafloxacin MIC values ranged between 0.12 and 0.5 mg/L against levofloxacin resistant (MIC >4 mg/L) S. pneumoniae strains [10]. Delafloxacin MICs were between 0.008 and 1 mg/L in ciprofloxacin resistant (MIC 0.5-256 mg/L) S. aureus strains [6]. In the case of Neisseria gonorrhoeae delafloxacin exhibited bactericid effect with MICs between 0.001 and 0.25 mg/L that is comparable to those of ceftriaxone (0.001 to 0.25 mg/L) and cefixime (0.001 to 0.5mg/L) [11]. Appart from bactericid effect delafloxacin inhibits biofilm formation of S. aureus [12]. Several murine lung infectious models showed in vivo efficacy of delafoxacin in infections caused by S. aureus, S. pneumoniae and Klebsiella pneumoniae [13,14]. Delafloxacin has been introduced into clinical trials to evaluate its pharmacokinetic properties and to compare its antibacterial efficacy with other antimicrobials. A Phase 1 clinical trial investigated a single per os dose of 900 mg delafloxacin in 30 healthy individuals under different feeding conditions namely, individuals under fasting conditions fo...