Clinical review of delafloxacin: a novel anionic fluoroquinolone

J Antimicrob Chemother 2018; 73: 1439–1451 doi:10.1093/jac/dkx543 Advance Access publication 7 February 2018 Clinical review of delafloxacin: a novel anionic fluoroquinolone Bryan T. Mogle1, Jeffrey M. Steele1,2, Stephen J. Thomas3,4, KarenBeth H. Bohan5 and Wesley D. Kufel1,5,6* 1 *Corresponding author. Binghamton University School of Pharmacy and Pharmaceutical Sciences, PO Box 6000, Binghamton, NY 13902-6000, USA. Tel: !1-607-777-5849; Fax: 1-607-777-3020; E-mail: Delafloxacin is a novel anionic fluoroquinolone (FQ) approved for treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by a number of Gram-positive and Gram-negative organisms including MRSA and Pseudomonas aeruginosa. The unique chemical structure of delafloxacin renders it a weak acid and results in increased potency in acidic environments. In Phase III studies, delafloxacin had similar outcomes to comparator regimens for treatment of ABSSSIs, and was well tolerated overall. Similar to other FQs, delafloxacin is available in both intravenous and oral formulations, but differs in that delafloxacin exerts a minimal effect on cytochrome P450 enzymes and on the corrected QT interval. This novel FQ has the potential to be utilized across a wide variety of clinical settings; however, post-marketing surveillance and long-term safety and resistance data will be essential to identify optimal use scenarios. Introduction Fluoroquinolones (FQs) are one of the most commonly prescribed antibiotic classes in the USA.1 Clinical efficacy has been demonstrated for multiple infectious diseases such as respiratory tract infections, acute bacterial skin and skin structure infections (ABSSSIs), urinary tract infections (UTIs), bone and joint infections and sexually transmitted infections.2 The FQs are pharmacologically advantageous due to their excellent oral (po) bioavailability, distribution and penetration to various sites of infection, intravenous (iv) and po formulations, convenient dosing regimens and broad spectrum of activity.3 As such, FQs are an appealing antibiotic class for clinicians to utilize in clinical practice. Nevertheless, the increased and potentially inappropriate use of FQs has largely driven the emergence of FQ-resistant Gramnegative (GN) bacteria and contributed to the overall epidemic of antibiotic-resistant infections.4,5 FQs have also been associated with several notable adverse effects, including Clostridium difficileassociated diarrhoea (CDAD), tendonitis and tendon rupture, corrected QT interval (QTc) prolongation and torsade de pointes, peripheral neuropathy, myasthenia gravis exacerbations, dysglycaemia and CNS effects.6–11 In 2016, the US FDA issued a warning stating that the adverse effects associated with FQ use may outweigh the benefits of use in certain infections.12 Therefore, antimicrobial stewardship programmes frequently target FQs to ensure appropriate prescribing and to reduce associated adverse consequences. Although there is uncertainty regarding optimal FQ use for various infectious processes, FQs remain an essential class of antibiotics. Most recently, delafloxacin (BaxdelaTM), was approved by the US FDA on 19 June 2017 for ABSSSIs. This novel anionic FQ antibiotic is available in both iv and po formulations and has a broad spectrum of in vitro activity against Gram-positive (GP), GN, atypical (i.e. Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila) and anaerobic bacteria. Herein, the pharmacology, pharmacokinetics (PK), pharmacodynamics (PD), clinical data and practical considerations for delafloxacin are reviewed. Literature searches of PubMed, EMBASE and Google Scholar were performed to identify peer-reviewed publications as of 15 October 2017 using the search terms delafloxacin, ABT-492, RX-3341 and WQ-3034. When data were not yet available as a published article, abstracts and posters were obtained and utilized to review pertinent data. Pharmacology Chemistry Delafloxacin is an anionic FQ with the chemical structure 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.13,14 Delafloxacin differs from other members of the FQ class by three distinct chemical features as illustrated in Figure 1: a heteroaromatic substitution at the N-1 position, which contributes to a larger molecular surface area; addition C The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. V For Permissions, please email: . 1439 Department of Pharmacy, Upstate Medical University Hospital, Syracuse, NY, USA; 2Department of Pharmacology, Upstate Medical University, Syracuse, NY, USA; 3Division of Infectious Diseases, Upstate Medical University, Syracuse, NY, USA; 4Department of Microbiology and Immunology, Upstate Medical University, Syracuse, NY, USA; 5Department of Pharmacy Practice, Binghamton University School of Pharmacy and Pharmaceutical Sciences, Binghamton, NY, USA; 6Department of Medicine, Upstate Medical University, Syracuse, NY, USA Review O F Lack of a strongly basic group at C-7 7 H O H N H Addition of chlorine at C-8 F N H O H F N H O N N O O O H N N O H Ciprofloxacin O F O H N N F O F N N Delafloxacin (neutral pH) O O H H Aromatic substitution at N-1 F N Levofloxacin NH Moxifloxacin Figure 1. Chemical structures of delafloxacin and selected fluoroquinolones. of a chlorine at the C-8 position, which exerts a strong electron-withdrawing effect on the aromatic ring at N-1 and stabilizes the molecule; and lack of a strongly basic group at the C-7 position, which renders it a weakly acidic molecule (pKa 5.4).13,15,16 Thus, delafloxacin primarily exists as an uncharged molecule in acidic pH, which facilitates transmembrane passage and concentration within the bacterium.16 Once the molecule has gained entry within the cell, where pH is neutral, delafloxacin is deprotonated and resides within the bacterium in ionic form. This property is unique compared with other FQs such as moxifloxacin, which remains primarily in zwitterion form within the bacterium, permitting return of the drug to the cell’s exterior. The unique anionic property of delafloxacin results in increased potency in acidic environments (i.e. abscesses), whereby 2- to 32-fold reduction in MICs has been observed.16,17 Mechanism of action FQs target the essential bacterial enzymes DNA gyrase and topoisomerase IV to varying degrees in different bacteria.15,18,19 It is thought that DNA gyrase is more susceptible to inhibition by FQs in GN bacteria, whereas topoisomerase IV is more susceptible to inhibition in GP bacteria.15,18 The selectivity and affinity for these drug targets is largely determined by substitutions at the C-7 and C-8 positions of the FQ nucleus,20 and considerably influences the spectrum of activity of each FQ. Unlike other FQs, delafloxacin is considered a dual-t (...truncated)