<p>Levonadifloxacin, a Novel Broad-Spectrum Anti-MRSA Benzoquinolizine Quinolone Agent: Review of Current Evidence</p>

Abstract

Levonadifloxacin and its prodrug alalevonadifloxacin are novel broad-spectrum anti-MRSA agents belonging to the benzoquinolizine subclass of quinolone, formulated for intravenous and oral administration, respectively. Various in vitro and in vivo studies have established their antimicrobial spectrum against clinically significant Gram-positive, Gram-negative, atypical, and anaerobic pathogens. The potent activity of levonadifloxacin against MRSA, quinolone-resistant Staphylococcus aureus, and hetero-vancomycin-intermediate strains is an outcome of its welldifferentiated mechanism of action involving preferential targeting to DNA gyrase. Potent antistaphylococcal activity of levonadifloxacin was also observed in clinically relevant experimental conditions such as acidic pH, the intracellular environment, and biofilms, suggesting that the drug is bestowed with enabling features for the treatment of difficult-to-treat MRSA infections. Levonadifloxacin also retains clinically relevant activity against resistant respiratory pathogens such as macrolide-and penicillin-resistant Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis and, in conjunction with clinically established best-in-class human epithelial lung fluid concentration, has promising potential in the management of recalcitrant respiratory infections. Attractive features, such as resistance to NorA efflux, divergent mechanism of action in S. aureus, cidality against high-inoculum cultures, and low mutant prevention concentration, are likely to confer favorable resistance-suppression features to both agents. In vivo studies have shown promising efficacy in models of acute bacterial skin and skin structure infection, respiratory infections, pyelonephritis, and peritonitis at human-equivalent mouse doses. Both formulations were well tolerated in multiple phase I studies and overall showed a dose-dependent exposure. In particular, oral alalevonadifloxacin showed excellent bioavailability (~90%), almost mirroring the pharmacokinetic profile of intravenous levonadifloxacin, indicating the prodrug's seamless absorption and efficient cleavage to release the active parent drug. Hepatic impairment studies showed that clinical doses of levonadifloxacin/alalevonadifloxacin are not required to be adjusted for various degrees of hepatic impairment. With the successful completion of phase II and phase III studies for both levonadifloxacin and alalevonadifloxacin, they represent clinically attractive therapeutic options for the treatment of infections caused by multi-drugresistant Gram-positive organisms. Herein, we review the current evidence on therapeutically appealing attributes of levonadifloxacin and alalevonadifloxacin, which are based on a range of nonclinical in vitro and in vivo investigations and clinical studies.

Prediction of vancomycin dose on high-dimensional data using machine learning techniques

“…Quinolones and fluconazole are widely used antibacterial agents in treatment against infection clinically [37,38]. Credito et al has reported there was vitro synergy in combination of a new des-F(6)-quinolone DX-619 and vancomycin.…”

Structural Characterization of the Millennial Antibacterial (Fluoro)Quinolones—Shaping the Fifth Generation

“…Also, the levorotatory ( S )-isomer is approximately twice as active as the racemate against Gram-positive and Gram-negative pathogens [ 180 ]. This stereoisomer is under study as an arginine salt for intravenous administration (WCK 771) and is known as levonadifloxacin [ 193 ]. In general, the introduction of hydroxyl groups into the structure of a compound will produce analogues with increased hydrophilicity and low solubility in lipids.…”

“…Levonadifloxacin (WCK 771) ( S -(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L -arginine salt tetrahydrate) is administered parenterally (intravenous) in the form of an L -arginine salt while its prodrug alalevonadifloxacin (WCK 2349) (( S )-(−)-9-fluoro-8-(4- L -alaninyl oxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid, methane sulfonic acid salt) in the form developed of an L -alanine ester mesylate salt can be administered orally. Both substances are being developed by Wockhardt Limited (India) [ 193 , 196 ].…”

Management of acute bacterial skin and skin structure infections in India: are we equipped to meet the challenges of the growing menace of methicillin-resistant Staphylococcus aureus?

“…The well differentiated mechanism of action primarily towards the DNA gyrase has led to a distinctive potent activity of levonadifloxacin against MRSA, QRSA and hVISA strains. 38 Levonadifloxacin also retains a potent antibacterial activity against respiratory pathogens such as macrolideand penicillin -resistant S. pneumonia, S.pyogenes, H. influenza and M. catarhalis. It provides best in class epithelial lung fluid concentration, thereby promising potential in the treatment of lower respiratory tract infections.…”