Levonadifloxacin (intravenous) and alalevonadifloxacin (oral prodrug) are novel antibiotics based on benzoquinolizine subclass of fluoroquinolone, licensed for clinical use in India in 2019. The active moiety, levonadifloxacin, is a broad-spectrum antibiotic with a high potency against methicillin-resistant Staphylococcus. aureus, multi-drug resistant pneumococci and anaerobes.
This review, for the first time, critically analyses the antimicrobial susceptibility testing methods, Clinical Laboratory & Standards Institute (CLSI)-quality control of susceptibility testing and breakpoints of levonadifloxacin. Further, the genesis, discovery and developmental aspects as well as therapeutic profile of levonadifloxacin and alalevonadifloxacin are briefly described.
In order to aid the scientific and clinician communities with a single comprehensive overview on all the key aspects of levonadifloxacin and alalevonadifloxacin, the present article covers the reference MIC and disk diffusion methods for levonadifloxacin susceptibility testing that were approved by CLSI and the reference ranges for quality control strains published in the CLSI M100 document. The breakpoints of levonadifloxacin were derived in concordance to US FDA, European Committee on Antibiotic Susceptibility Testing (EUCAST) and CLSI approaches. Further, the article provides a brief account of challenges encountered during the discovery stages of levonadifloxacin and alalevonadifloxacin, activity spectrum and safety benefits accruing from structural novelty-linked mechanism of action. Further, the review also covers in vitro and in vivo activities, registrational clinical studies and patient-friendly features of levonadifloxacin/alalevonadifloxacin. Cumulatively, levonadifloxacin has a potential to offer a long awaited new standard-of-care treatment for the resistant Gram-positive bacterial infections.

UNASSIGNED: This study compared the clinical efficacy and safety of anti-methicillin-resistant Staphylococcus aureus (MRSA) quinolones for treating acute bacterial skin and skin structure infections (ABSSSIs).
UNASSIGNED: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant articles from inception to 21 July 2021. RCTs comparing the clinical efficacy and safety of anti-MRSA quinolones with other antibiotics for treating adult patients with ABSSSIs were included.
UNASSIGNED: Six RCTs were included. A total of 1,264 and 1,307 participants received the anti-MRSA quinolone-based study group and the control group. In the study group receiving anti-MRSA quinolone-based treatment, 935, 246, and 83 patients received delafloxacin, levonadifloxacin, and acorafloxacin, respectively. No significant difference was observed in the clinical cure rate at test of cure between the study and control groups (OR, 1.08; 95% CI, 0.91-1.29; I2 = 0%). In patients with MRSA-associated ABSSSIs, the clinical cure rate (OR, 1.09; 95% CI, 0.71-1.65; I2 = 0%) and microbiological response rate (OR, 1.24; 95% CI, 0.48-3.21; I2 = 0%) of anti-MRSA quinolones were similar to those of other antibiotics.
UNASSIGNED: The efficacy of anti-MRSA quinolone-based treatment is comparable to that of other anti-MRSA antibiotics for treating ABSSSIs.

Increased use of antibiotics globally has led to the threat of antibiotic resistance; this drove the urge of researchers toward discovering more potent and broad-spectrum antibiotics. Levonadifloxacin (LND) is the very first antibiotic developed by an Indian company Wockhardt. It is S (-) isomer of another broad-spectrum antibiotic Nadifloxacin which is used topically for skin, soft tissue bacterial infection. LND belongs to the benzo quinolizine category which is a subclass of fluoroquinolone, indicated for ABSSIS, CABP, and other infections including diabetic foot infection; formulated as l-arginine salt of levonadifloxacin (WCK177) for IV and l-alanine ester mesylate salt as alalevonadifloxacin (WCK2349) for oral administration. It generally shows dominant antibacterial activity against Gram-negative, and positive bacterial infections, particularly toward methicillin-resistant Staphylococcus aureus (MRSA) by dual inhibition of DNA gyrase and topoisomerase IV. Producing quality product that complies to regulatory requirements is a big concern for pharma industries. To this context, validated analytical methods for routine quality control are essential for quantification of LND as an API alone and together with pharmaceutical formulations. This review suggests therapeutic, pharmacological, and analytical aspects regarding the novel drug LND and particularly focuses on discussing various reported analytical methods present for analytical or bioanalytical estimation of the drug and suggest to develop a simple and validated method which also complies to green chemistry.

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 well-differentiated mechanism of action involving preferential targeting to DNA gyrase. Potent anti-staphylococcal 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-drug-resistant Gram-positive organisms. Herein, we review the current evidence on therapeutically appealing attributes of levonadifloxacin and alalevonadifloxacin, which are based on a range of non-clinical in vitro and in vivo investigations and clinical studies.