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.

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.

Bacteriological Study Among Influenza-like Illness Cases in a Community Setting in Pune, India.

Influenza-like illness (ILI) and acute respiratory infection (ARI) are common presentations during winter, and indiscriminate antibiotic use contributes significantly to the emerging post-antibiotic era. Although viral agents causing ILI are predominant, they are indistinguishable from the bacterial agents based on the clinical features alone. The present study was aimed at determining the bacterial agents associated with ILI and their susceptibility pattern during a study done in a community setting in Pune during a surveillance of ILI between March 2013 to November 2016. Throat swabs from 512 suspected ILI cases were processed, and organisms were identified by the standard conventional method. An antimicrobial susceptibility testing was done as per the Clinical Laboratory Standard Institute (CLSI) guidelines. The patients comprised 238 males and 274 females with the majority (38.7%) in the age group of ≤10 years. Bacteria could be isolated from 9.8 % of the patients. The predominant bacteria included beta-hemolytic Streptococcus (42%) followed by group G Streptococcus (30%) and group A Streptococcus (20%). All organisms were sensitive to Penicillin except two isolates of Staphylococcus aureus (50%). Tetracycline (98.8%) and ciprofloxacin (87%) were the next most effective drugs. Overall resistance was observed for erythromycin (37%) and co-trimoxazole (32%).

A Study of Parasitic and Bacterial Pathogens Associated with Diarrhea in HIV-Positive Patients.

INTRODUCTION: Diarrhea is a common complication of acquired immune deficiency syndrome (AIDS), occurring in almost 90% of AIDS patients in developing countries like India. The present study was aimed to determine the prevalence and microbiological profile of pathogens associated with diarrhea in human immunodeficiency virus (HIV) positive patients and their relation to CD4 counts. MATERIALS AND METHODS: Forty-five successive HIV-positive patients, 27 with diarrhea (study group) and 18 without diarrhea (control group), were included in the three-month study. The HIV infection was confirmed by three different antibody detection tests. The stool samples were collected on two consecutive days and were examined for parasites by microscopy using wet mount and modified Ziehl-Neelsen stain. They were examined for bacteria by Gram stain and conventional Ziehl-Neelsen stain and were inoculated on appropriate culture media. The isolates were identified by standard biochemical tests, followed by antibiotic susceptibility testing using the Kirby-Bauer disc diffusion method. RESULTS: Twenty-four pathogens were detected in diarrheal HIV-positive patients, including 14 parasites (58.33%), seven bacteria (29.17%), and three fungi (12.50%). Isospora sp. was the most common parasite (25.9%) followed by Cryptosporidium sp. (14.8%). Other parasites included Cyclospora sp., Strongyloides stercoralis, and Entamoeba histolytica (3.7% each).​ Escherichia coli (18.5%) was the most common bacterial isolate, of which, 80% were Enterotoxigenic E. coli (ETEC) while 20% were Enteropathogenic E. coli (EPEC). Other isolates included Shigella flexneri and Mycobacterium tuberculosis (3.7% each). The isolates were sensitive to furazolidone (94.11%), chloramphenicol (76.47%), and gentamicin (52.94%). The isolates from diarrheal patients showed resistance to norfloxacin (5.88% vs. 50%, p<0.05) as compared to those from non-diarrheal patients. The diarrheal HIV-positive patients had lower mean CD4 counts (202.6 cells/µL), as compared to those without diarrhea (239.28 cells/µL). CONCLUSION: Isospora sp. is the most common parasite and Escherichia​ coli is the most common bacterium associated with diarrhea in HIV patients. The antibiotic sensitivity patterns should be monitored regularly to detect resistance to commonly used drugs. The prevalence of organisms in a region, various clinical manifestations, sensitivity patterns of isolates, and relation with CD4 count should be considered while instituting therapy in HIV patients with diarrhea.