India-discovered levonadifloxacin & alalevonadifloxacin: A review on susceptibility testing methods, CLSI quality control and breakpoints along with a brief account of their emerging therapeutic profile as a novel standard-of-care.

BACKGROUND: 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. OBJECTIVE: 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. CONTENTS: 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.

Assessment of antibacterial activity of levonadifloxacin against contemporary gram-positive clinical isolates collected from various Indian hospitals using disk-diffusion assay.

Objectives: Levonadifloxacin is a novel benzoquinolizine subclass of quinolone with broad-spectrum activities against problematic pathogens such as methicillin-resistant Staphylococcus aureus, quinolone-resistant S. aureus, vancomycin intermediate S. aureus, and vancomycin-resistant S. aureus. Levonadifloxacin and its oral prodrug, alalevonadifloxacin, have been recently approved in India for the treatment of acute bacterial skin and skin structure infections, including concurrent bacteraemia and diabetic foot infections. The aim of the study is to assess the activity of levonadifloxacin against Gram-positive clinical isolates collected from various Indian hospitals using the disc-diffusion method. Materials and Methods: Nonduplicate isolates of S. aureus and other Gram-positive isolates collected from June 2019 to March 2020 were subjected to levonadifloxacin susceptibility testing (disk diffusion method) as per the Clinical and Laboratory Standards Institute guidelines (Year 2019). Levonadifloxacin 10 µg impregnated disks were used during the testing. Results: A total of 664 diverse Gram-positive clinical isolates collected from six different hospitals in India were analyzed. Majority (65.5%) of the isolates were S. aureus. All the S. aureus and other Gram-positive isolates were found to be susceptible to levonadifloxacin as per the prespecified interpretive criteria identified based on population pharmacokinetic model and Monte Carlo simulation enabled probability of pharmacodynamic target attainment analysis. Conclusions: The present study showed that levonadifloxacin was highly active against contemporary Gram-positive pathogens and furthermore demonstrated that levonadifloxacin susceptibilities can be reliably determined using the disc-diffusion method.

In vitro activity of a novel antibacterial agent, levonadifloxacin, against clinical isolates collected in a prospective, multicentre surveillance study in India during 2016-18.

BACKGROUND: Levonadifloxacin is a novel antibiotic belonging to the benzoquinolizine subclass of fluoroquinolones with potent activity against MRSA and quinolone-resistant Staphylococcus aureus. IV levonadifloxacin and its oral prodrug alalevonadifloxacin have recently been approved in India for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) including diabetic foot infections. OBJECTIVES: To investigate the in vitro activity of levonadifloxacin against contemporary clinical isolates collected from multiple tertiary care hospitals across India in the Antimicrobial Susceptibility Profiling of Indian Resistotypes (ASPIRE) surveillance study. METHODS: A total of 1376 clinical isolates, consisting of staphylococci (n = 677), streptococci (n = 178), Enterobacterales (n = 320), Pseudomonas aeruginosa (n = 140) and Acinetobacter baumannii (n = 61), collected (2016-18) from 16 tertiary hospitals located across 12 states in India, were included in the study. The MICs of levonadifloxacin and comparator antibiotics were determined using the reference agar dilution method and broth microdilution method. RESULTS: Levonadifloxacin exhibited potent activity against MSSA (MIC50/90: 0.5/1 mg/L), MRSA (MIC50/90: 0.5/1 mg/L) and levofloxacin-resistant S. aureus (MIC50/90: 1/1 mg/L) isolates. Similarly, potent activity of levonadifloxacin was also observed against CoNS including MDR isolates (MIC50/90: 1/2 mg/L). Against Streptococcus pneumoniae, levonadifloxacin (MIC50/90: 0.5/0.5 mg/L) showed superior activity compared with levofloxacin (MIC50/90: 1/2 mg/L). Among levofloxacin-susceptible Enterobacterales, 80.6% of isolates were inhibited at ≤2 mg/L levonadifloxacin. CONCLUSIONS: Levonadifloxacin displayed potent activity against contemporary MRSA and fluoroquinolone-resistant staphylococcal isolates, thus offering a valuable IV as well as an oral therapeutic option for the treatment of ABSSSIs. Furthermore, levonadifloxacin exhibited a broad-spectrum activity profile as evident from its activity against streptococci and levofloxacin-susceptible Gram-negative isolates.