Nafithromycin (MIQNAF®): ultramodern lactone ketolide designed to treat community acquired bacterial pneumonia (CABP)

Abstract

Community acquired bacterial pneumoniae (CABP) infections is the major cause of mortality and morbidity, especially in elderly patients. India accounts for 23% of global pneumonia burden with case fatality rates between 14 and 30%. There is an urgent unmet medical need for safe and effective antibiotic for CABP, due to lack of effective empirical therapy because of widespread resistance to β-lactams antibiotics. On other hand, fluoroquinolone antibiotics have poor tolerability, like hypersensitive reactions and associated disabilities. Hence, our objective was to find an antibiotic having broad coverage of multidrug resistance (MDR) pathogens including typical and atypical respiratory pathogens, with good lung penetration and safety features. Nafithromycin (MIQNAF^®) is a novel “lactone-ketolide” antibiotic developed by Wockhardt Ltd. for the treatment of CABP infections. Recently it has completed phase III clinical trials in India and NDA submitted to drug controller general of India (DCGI). Distinctive features of nafithromycin are ultra-short duration of therapy, oral dosing, high concentration build up in lung i.e. target organ and safety profile. Structurally, it features novel amidoxime core with 2-pyridine-1,3,4-thiadiazole biaryl tether separated with non-flexible four atom spacer having cis double bond and chiral methyl with (S)- configuration resulted in dual target interaction. The novel conformational arrangement interacts favorably with 23S rRNA and domain V of 50S ribosome subunit to elicit outstanding potency against gram-positive bacteria. The preclinical data provided strong scientific evidences for its effectiveness against difficult-to-treat respiratory tract infections (RTIs) caused by multidrug-resistant pathogens such as macrolide-resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes as well as other important pathogens including Haemophilus influenzae. Upon successful phase I clinical findings, nafithromycin was granted Qualified Infectious Disease Product (QIDP) status by the US Food and Drug Administration (USFDA). Presently besides India specific phase III clinical study completion with partial funding support from Biotechnology Industry Research Assistance Council (BIRAC), it has successfully completed global phase II clinical development, including pharmacokinetic study (NCT02770404) and study for the treatment of community-acquired bacterial pneumonia (NCT02903836). In Europe it has completed single ascending dose (SAD) and multiple ascending dose (MAD) phase I pharmacokinetic studies. This mini review covers relevant published data on nafithromycin and its potential role in management of infections caused by gram-positive pathogens along with summary of different clinical trials conducted in United States, Europe and India.