The role of solithromycin in the management of bacterial community-acquired pneumonia

ABSTRACT

The fluoroketolide solithromycin is 2-fold more potent in vitro than telithromycin against pneumococci (including macrolide-resistant strains) and Haemophilus influenzae and very active on pathogens causing atypical pneumonia. In contrast, it is a 30-fold less potent inhibitor of nicotinic receptors incriminated in telithromycin toxicity. In Phase II/III trials, oral solithromycin once-daily (800 mg on day 1; 400 mg on days 2-5) proved effective and safe when compared to respiratory fluoroquinolones for the treatment of community-acquired bacterial pneumonia (CABP). A Phase III intravenous trial vs. moxifloxacin has been recently completed for the same indication. Solithromycin may restore interest in ketolides as a first-line therapy for CAPB. Solithromycin safety should nevertheless be confirmed in larger populations allowing for detection of rare adverse events.

KEYWORDS:

• solithromycin
• ketolide
• community-acquired bacterial pneumonia
• Streptococcus pneumoniae
• Chlamydophila pneumoniae
• Legionella pneumophila
• Mycoplasma pneumoniae
• Haemophilus influenzae
• moxifloxacin
• levofloxacin

Financial & competing interests disclosure

F Van Bambeke is maître de recherches of the Belgian Fonds de la Recherche Scientifique. PM Tulkens and F Van Bambeke have received research grants from Cempra for in vitro studies with solithromycin. The authors have no other 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 apart from those disclosed.

Key issues

• Solithromycin is the first fluoroketolide with extensive preclinical and almost complete clinical development. As other ketolides, it binds to domains II and V of 50S ribosomal subunit; its fluor substituent further increases its affinity for its target and stabilizes the molecule.

• Solithromycin shows low MICs against pneumococci (including macrolide-resistant strains), intracellular pathogens causing atypical pneumonia (C. pneumoniae, M. pneumoniae, L. pneumophila), and S. aureus, but, as other macrolides, it is poorly active against H. influenzae and M. catharralis.

• As for other ketolides, solithromycin efficacy is best predicted by free AUC/MIC ratio in serum, a value of 1.6 for this ratio allowing to reach a bacteriostatic effect in a murine model of pneumonia.

• In vitro data show that solithromycin has a 30-fold lower affinity for nicotinic receptors than telithromycin. This interaction is thought to be critical for telithromycin toxicity (acute hepatic failure and severe liver injury, visual disturbance, transient loss of consciousness, and life-threatening respiratory failure in patients with myasthenia gravis).

• In clinical trials, solithromycin has been successfully used by both oral and intravenous routes, at a daily dose of 400 mg (with a 800 mg loading dose at day one when used orally) for a treatment duration of 5 days, with no need for dose adjustment in case of hepatic insufficiency.

• Solithromycin has completed one Phase II and two (SOLITAIRE-ORAL and SOLITAIRE-IV) Phase III clinical trials for the treatment of community-acquired bacterial pneumonia with levofloxacin (Phase II) or moxifloxacin (Phase III) as comparators.

• In these trials, solithromycin was noninferior to the comparator and safe, with a nonsignificant trend to higher success in elderly patients or patients suffering from COPD or asthma in the oral Phase III trial. Results from the intravenous Phase III trial have not yet been released.

• FDA granted Qualified Infectious Disease Product and Fast Track Designations to Cempra for solithromycin in the treatment of CABP in August 2015.