Nemonoxacin (TG-873870) for treatment of community-acquired pneumonia

Abstract

With a broad-spectrum of activity, fluoroquinolones have been widely and successfully used for decades for the treatment of and prophylaxis against various bacterial infections, including community-acquired pneumonia (CAP). However, the use of fluoroquinolones has been compromised by the emergence and spreading of bacterial resistance and the potential for adverse effects. Therefore, there is an unmet need for newer compounds that have a broader spectrum of activity to overcome existing bacterial resistance as well as the potential to minimize the risk of adverse effects. Nemonoxacin (TG-873870), a newly developed quinolone, has demonstrated broad-spectrum activity against Gram-positive, Gram-negative and atypical pathogens, including drug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus. Results from Phases I and II studies of treatment of CAP are encouraging. This article reviews the updated data on nemonoxacin, including the bacterial susceptibility, the pharmacologic characteristics, and toxicities, and clinical trials using nemonoxacin for treatment of CAP.

Keywords::

• antimicrobial resistance
• atypical pathogens
• in vitro activity
• methicillin-resistant Staphylococcus aureus
• pharmacokinetics
• quinolones
• Streptococcus pneumoniae

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Community-acquired pneumonia (CAP), with substantial mortality, morbidity and cost, is a major public health challenge worldwide. Many issues for management of CAP, however, are still debated.

• Respiratory fluoroquinolones are recommended by current treatment guidelines as the empirical therapy for CAP. The drawbacks of fluoroquinolones include diminishing susceptibility against several major respiratory pathogens, tendency for resistance development, potential adverse drug reactions and potential for delaying the diagnosis of tuberculosis.

• Nemonoxacin is a novel C-8-methoxy nonfluorinated quinolone. The removal of the fluorine residue might reduce the toxicities, while the addition of a methoxy group at the C-8 position extends its antibacterial spectrum. Nemonoxacin is also less likely to select resistant strains compared with other fluoroquinolones.

• For Gram-positive bacteria, nemonoxacin has comparable or better activity than current fluoroquinolones including MRSA and levofloxacin-resistant Streptococcus pneumoniae. However, its activity against ciprofloxacin-resistant and hospital-acquired MRSA isolates is remarkably compromised.

• Nemonoxacin is less active against common species of Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa than levofloxacin. The PK and pharmacodynamics profiles further support its use to treat these pathogens. Nemonoxacin also has a great activity against Nocardia species, Helicobacter pylori and Clostridium difficile.

• The poor activity against Mycobacterium tuberculosis compared with classic fluoroquinolones may be particularly valuable in areas with a high endemicity of tuberculosis.

• Animal studies are generally in parallel to its in vitro activity, with favorable efficacy for infections caused by Gram-positive isolates and similar or less potent efficacy for Gram-negative bacteria.

• A pilot Phase II study has demonstrated noninferiority of nemonoxacin to levofloxacin, both in oral formulations, for treatment of CAP. However, slightly inferior bacteriological responses have been observed, especially for nemonoxacin at 500 mg. A Phase III trial was just completed. Further clinical data are warranted to confirm its efficacy.

• Nemonoxacin is generally well tolerated within the dose range of 125–1000 mg.

• Intravenous formulation of nemonoxacin is currently under investigation.

Notes