Potential of the fluoroketolide RBx 14255 against Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae in an experimental murine meningitis model

Article

Author: Gangadharan, Ramkumar ; Chaira, Tridib ; Raj, V Samuel ; Bhateja, Pragya ; Mathur, Tarun ; Das, Biswajit ; Chakrabarti, Anjan ; Kumar, Manoj ; Barman, Tarani Kanta ; Ramadass, Venkataramanan ; Upadhyay, Dilip J ; Pandya, Manisha ; Rao, Madhvi ; Singhal, Smita

BACKGROUNDRBx 14255 is a fluoroketolide in pre-clinical evaluation with potent activity against MDR Gram-positive pathogens.OBJECTIVESTo investigate the efficacy of RBx 14255 against bacterial meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis or Haemophilus influenzae in an experimental murine meningitis model.METHODSIn vitro activity of RBx 14255 was evaluated against clinical isolates of S. pneumoniae, N. meningitidis and H. influenzae. The in vivo efficacy of RBx 14255 was evaluated against bacterial meningitis, induced with S. pneumoniae 3579 erm(B), S. pneumoniae MA 80 erm(B), N. meningitidis 1852 and H. influenzae B1414 in a murine meningitis model.RESULTSRBx 14255 showed strong in vitro bactericidal potential against S. pneumoniae, N. meningitidis and H. influenzae with MIC ranges of 0.004-0.1, 0.03-0.5 and 1-4 mg/L, respectively. In a murine meningitis model, a 50 mg/kg dose of RBx 14255, q12h, resulted in significant reduction of bacterial counts in the brain compared with the pretreatment control. The concentration of RBx 14255 in brain tissue correlated well with the efficacy in this mouse model.CONCLUSIONSRBx 14255 showed superior bactericidal activity in time-kill assays in vitro and in vivo in an experimental murine meningitis model. RBx 14255 could be a promising candidate for future drug development against bacterial meningitis.

01 Aug 2014·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

A Novel Ketolide, RBx 14255, with Activity against Multidrug-Resistant Streptococcus pneumoniae

Q2 · MEDICINE

Article

Author: Barman, Tarani Kanta ; G., Ramkumar ; Kalia, Vandana ; Chaira, Tridib ; Surase, Yogesh B. ; Upadhyay, Dilip J. ; Venkataramanan, R. ; Bhatnagar, Pradip K. ; Dube, Smita ; Chakrabarti, Anjan ; Das, Biswajit ; Raj, V. Samuel ; Mathur, Tarun ; Bhateja, Pragya ; Purnapatre, Kedar

ABSTRACTWe present here the novel ketolide RBx 14255, a semisynthetic macrolide derivative obtained by the derivatization of clarithromycin, for itsin vitroandin vivoactivities against sensitive and macrolide-resistantStreptococcus pneumoniae. RBx 14255 showed excellentin vitroactivity against macrolide-resistantS. pneumoniae, including an in-house-generated telithromycin-resistant strain (S. pneumoniae3390 NDDR). RBx 14255 also showed potent protein synthesis inhibition against telithromycin-resistantS. pneumoniae3390 NDDR. The binding affinity of RBx 14255 toward ribosomes was found to be more than that for other tested drugs. Thein vivoefficacy of RBx 14255 was determined in murine pulmonary infection induced by intranasal inoculation ofS. pneumoniaeATCC 6303 and systemic infection withS. pneumoniae3390 NDDR strains. The 50% effective dose (ED50) of RBx 14255 againstS. pneumoniaeATCC 6303 in a murine pulmonary infection model was 3.12 mg/kg of body weight. In addition, RBx 14255 resulted in 100% survival of mice with systemic infection caused by macrolide-resistantS. pneumoniae3390 NDDR at 100 mg/kg four times daily (QID) and at 50 mg/kg QID. RBx 14255 showed favorable pharmacokinetic properties that were comparable to those of telithromycin.

01 Nov 2012·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

In Vitro and In Vivo Activities of the Novel Ketolide RBx 14255 against Clostridium difficile

Q2 · MEDICINE

Article

Author: Ramkumar, G. ; Pandya, Manisha ; Upadhyay, Dilip J. ; Raj, V. Samuel ; Kalia, Vandana ; Barman, Tarani K. ; Shukla, Gunjan ; Chakrabarti, Anjan ; Vaishnavi, Chetana ; Das, Biswajit ; Kumar, Manoj ; Bhatnagar, Pradip K. ; Mathur, Tarun ; Bhati, Ashish

ABSTRACT The MIC 90 of RBx 14255, a novel ketolide, against Clostridium difficile was 4 μg/ml (MIC range, 0.125 to 8 μg/ml), and this drug was found to be more potent than comparator drugs. An in vitro time-kill kinetics study of RBx 14255 showed time-dependent bacterial killing for C. difficile . Furthermore, in the hamster model of C. difficile infection, RBx 14255 demonstrated greater efficacy than metronidazole and vancomycin, making it a promising candidate for C. difficile treatment.

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Indication	Highest Phase	Country/Location	Organization	Date
Haemophilus Infections	Preclinical	India	Ranbaxy Laboratories Ltd.	22 Jun 2020
invasive Streptococcus pneumoniae infection	Preclinical	India	Ranbaxy Laboratories Ltd.	22 Jun 2020
Gram-Positive Bacterial Infections	Preclinical	India	Daiichi Sankyo India Pharma Pvt Ltd.	02 May 2019
Meningitis, Bacterial	Preclinical	India	Ranbaxy Laboratories Ltd.	02 May 2019
Meningitis, Bacterial	Preclinical	India	Daiichi Sankyo India Pharma Pvt Ltd.	02 May 2019
Community-acquired bacterial pneumonia	Preclinical	India	Ranbaxy Laboratories Ltd.	02 Aug 2014

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