Delafloxacin
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Delafloxacin sold under the brand name Baxdela among others, is a fluoroquinolone
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
used to treat acute bacterial
skin and skin structure infection Skin and skin structure infections (SSSIs), also referred to as skin and soft tissue infections (SSTIs), or acute bacterial skin and skin structure infections (ABSSSIs), are infections of skin and associated soft tissues (such as loose connective ti ...
s.


Medical use

Delafloxacin is indicated to treat adults with acute bacterial skin and skin structure infections (ABSSSI) caused by designated susceptible bacteria or adults with community-acquired bacterial pneumonia (CABP) caused by designated susceptible bacteria. Susceptible bacteria for ABSSSI are: * Gram-positive organisms: ''Staphylococcus aureus'' (including methicillin-resistant RSAand methicillin-susceptible SSAisolates), ''Staphylococcus haemolyticus'', ''Staphylococcus lugdunensis'', ''Streptococcus agalactiae'', ''Streptococcus anginosus'' group (including ''Streptococcus anginosus'', ''Streptococcus intermedius'', and ''Streptococcus constellatus''), ''Streptococcus pyogenes'', and ''Enterococcus faecalis'' * Gram-negative organisms: ''Escherichia coli'', ''Enterobacter cloacae'', ''Klebsiella pneumoniae'', and ''Pseudomonas aeruginosa''. Susceptible bacteria for CABP are: ''Streptococcus pneumoniae'', ''Staphylococcus aureus'' (methicillin-susceptible SSAisolates only), ''Klebsiella pneumoniae'', ''Escherichia coli'', ''Pseudomonas aeruginosa'', ''Haemophilus influenzae'', ''Haemophilus parainfluenzae'', ''Chlamydia pneumoniae'', ''Legionella pneumophila'', and ''Mycoplasma pneumoniae''. It has not been tested in pregnant women. In the European Union it is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the initial treatment of these infections.


Adverse effects

Like other drugs in the fluoroquinolone class, delafloxacin contains a
black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it i ...
about the risk of tendinitis, tendon rupture, peripheral neuropathy, central nervous system effects, and exacerbation of myasthenia gravis. The label also warns against the risk of
hypersensitivity reaction Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune s ...
s and ''
Clostridium difficile ''Clostridioides difficile'' (syn. ''Clostridium difficile'') is a bacterium that is well known for causing serious diarrheal infections, and may also cause colon cancer. Also known as ''C. difficile'', or ''C. diff'' (), is Gram-positive spec ...
''-associated diarrhea. Adverse effects occurring in more than 2% of clinical trial subjects included nausea, diarrhea, headache,
elevated transaminases In medicine, the presence of elevated transaminases, commonly the transaminases alanine transaminase (ALT) and aspartate transaminase (AST), may be an indicator of liver dysfunction. Other terms include transaminasemia, transaminitis, and elevated ...
, and vomiting.


Interactions

Like other fluoroquinolones, delafloxacin
chelates Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These ligands are ...
metals including aluminum, magnesium, sucralfate, iron, zinc, and divalent and trivalent cations like didanosine; using this drugs with antacids, some dietary supplements, or drugs buffered with any of these ions will interfere with available amounts of delafloxacin.


Pharmacology

The half-life varies in around 8 hours at normal doses. Excretion is 65% through urine, mostly in unmetabolized form, and 28% via feces. Clearance is reduced in people with severe kidney disease. Delafloxacin is more active (lower MIC90) than other quinolones against
Gram-positive bacteria In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...
such as methicillin-resistant ''Staphylococcus aureus'' (MRSA). In contrast to most approved fluoroquinolones, which are zwitterionic, delafloxacin has an
anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
ic character, which results in a 10-fold increase in delafloxacin accumulation in both bacteria and cells at acidic pH. This property is believed to confer to delafloxacin an advantage for the eradication of ''
Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive ...
'' in acidic environments, including intracellular infections and biofilms.


Chemistry

The chemical name is 1-deoxy-1 (methylamino)-D-glucitol, 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (salt). The injectable form of delafloxacin is sold as the
meglumine Meglumine is a sugar alcohol derived from glucose that contains an amino group modification. It is often used as an excipient in pharmaceuticals and in conjunction with iodinated compounds in contrast media such as diatrizoate meglumine, ioth ...
salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...
of the active ingredient and its
United States Adopted Name A United States Adopted Name (USAN) is a unique nonproprietary name assigned to a medication marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association (AMA), the United Stat ...
, delafloxacin meglumine, reflects that; the injection formulation also includes EDTA and sulfobutylether-β-cyclodextrin. The tablet is made of delafloxacin, citric acid anhydrous, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, sodium bicarbonate, and sodium phosphate monobasic monohydrate.


History

Delafloxacin was known as ABT-492, RX-3341, and WQ-3034 while it was under development. Rib-X Pharmaceuticals acquired delafloxacin from Wakunaga Pharmaceutical in 2006. Rib-X was renamed to Melinta Therapeutics in 2013. It was developed and marketed by
Melinta Therapeutics Melinta Therapeutics, founded in 2000 as Rib-X Pharmaceuticals, is an American publicly traded biopharmaceutical firm that focuses on the design and development of novel broad-spectrum antibiotics for the treatment of antibiotic-resistant infectio ...
(formerly Rib-X Pharmaceuticals), which subsequently merged with Cempra. Key clinical trials for delafloxacin have been performed by Melinta regarding indications for skin and skin structure infections as well as complicated bacterial infections and uncomplicated gonorrhea. The trial on gonorrhea was terminated before data was released. Delafloxacin was approved by the FDA in June 2017, after it was noninferior to vancomycin plus aztreonam in two trials on 1042 patients with acute bacterial skin and skin structure infection. New Drug Applications (NDA) for delafloxacin (Baxdela) 450 mg tablets and 300 mg injections were approved by the FDA in June 2017. The FDA obligated Melinta to conduct further studies as follows: * a 5-year surveillance study to determine if resistance emerges, with the final report due in December 2022 * a study of the IV form in pregnant rats to determine distribution to the reproductive tract, due June 2018, with further studies required if there is significant distribution. Melinta merged with Cempra in August, 2017. Melinta has entered into commercialization and distribution agreements with both Menarini Therapeutics (March 2017) and Eurofarma Laboratórios (January 2015) for international commercialization of delafloxacin. The agreement with Menarini allows them to commercialize and distribute in 68 countries, including Europe, China, and South Korea among others. A similar agreement with Eurofarma allows for commercialization in Brazil.


References


External links

* * {{Portal bar , Medicine Azetidines Chloroarenes Fluoroquinolone antibiotics Pyridines Carboxylic acids