Activity of novel lactone ketolide nafithromycin against multicentric invasive and non-invasive pneumococcal isolates collected in India

Abstract

Background India is among the nations reporting substantial healthcare burden linked to pneumococcal infections. Nafithromycin is a novel lactone ketolide antibiotic, which recently entered Phase 3 development in India for the indication of community-acquired bacterial pneumonia (CABP). Objectives To assess the in vitro activity of nafithromycin against serotyped invasive and non-invasive Streptococcus pneumoniae isolates, collected from nine medical centres across India. Methods A total of 534 isolates of S. pneumoniae were collected during 2015–20 and serotyped as per CDC protocol. A subset of erythromycin-non-susceptible S. pneumoniae (n = 200) was screened for the presence of erm(B) and mef(A/E) genes. A subset of MDR isolates (n = 54) were also subjected to MLST. The MICs of antibiotics were determined by the reference agar-dilution method (CLSI). Susceptibilities of the comparators were interpreted as per CLSI criteria. Results Fifty-nine distinct serotypes were identified among the 534 isolates. Among erythromycin-non-susceptible isolates, erm(B) and mef(A/E) genes were found in 49% and 59% strains respectively, while MLST showed clonal diversity. Azithromycin (67.6% non-susceptible) and clindamycin (31.8% non-susceptible) showed limited activity. Penicillin (for non-meningitis) or quinolone non-susceptibility was low (<11% and <6%, respectively). Nafithromycin showed potent activity with MIC50 and MIC90 of 0.015–0.03 and 0.06 mg/L, respectively, regardless of the macrolide resistance mechanisms. Conclusions Indian pneumococcal isolates show poor susceptibilities to macrolides, in concordance with the global trend. Nafithromycin overcomes erm as well as mef-mediated macrolide resistance mechanisms expressed individually or concurrently in S. pneumoniae. This study supports continued clinical development of nafithromycin for pneumococcal infections including CABP.

In vitro activity of lactone ketolide nafithromycin (WCK 4873) against Streptococcus pneumoniae isolates enriched with macrolide-resistance phenotype collected from mainland China

“… 17 Furthermore, in a recent study conducted using S. pneumoniae isolated from nine medical centres located in India, nafithromycin showed potent activity with MIC 50/90 of 0.03/0.06 mg/L, regardless of the resistance mechanisms. 13 Thus, the activity profile of nafithromycin against S. pneumoniae isolates observed in this study is in agreement with previous studies. The consistent high potency demonstrated by nafithromycin against worldwide S. pneumoniae isolates, including those from China, suggests its ability to overcome diverse resistance mechanisms in pneumococci.…”

“…Nafithromycin is a novel lactone ketolide in clinical development (global Phase 2 completed, Phase 3 ongoing in India, scheduled to enter Phase 1 in China), designed to overcome all macrolide-resistance mechanisms in S. pneumoniae as well as offering a shorter regimen (QD × 3 days) therapy, owing to high and sustained lung concentrations. 13 For instance, a clinical pulmonary PK study has shown that nafithromycin exposures in epithelial lining fluid (ELF) are 69 × higher and in alveolar macrophages are 2635 × higher compared with unbound concentrations in plasma. 14 Nafithromycin’s therapeutically relevant ELF concentrations are sustained even 2 days after the last dose, which helped evolve a once-daily, 3 day regimen that was non-inferior to a 7 days regimen of moxifloxacin in a Phase 2 multinational randomized and controlled trial in CABP indication (ClinicalTrials.gov Identifier: NCT02903836).…”

“…In vitro activity of nafithromycin against respiratory pathogens, including S. pneumoniae , was earlier assessed in a global surveillance programme (barring isolates from mainland China) 17 and also in a recent study against the S. pneumoniae isolates collected from India. 13 This work describes the activity of nafithromycin against a large collection of S. pneumoniae isolates from mainland China, which are known to display higher macrolide/clindamycin and penicillin resistance.…”

Antimicrobial Activity of Lactones

“…That unique structural feature plays a key role in inhibiting RNA-dependent protein biosynthesis and enables nafithromycin to demonstrate potent activity against macrolide-resistant S. pneumoniae [ 92 ]. Nafithromycin also showed excellent activity against methicillin-susceptible S. aureus ATCC 29213, E. faecalis ATCC 29212, S. pyogenes and moderate activity against H. influenzae , and potent activity against M. catarrhalis [ 93 , 94 , 95 ]. Safety, tolerability, and pharmacokinetics during oral administration of nafithromycin was also tested in randomized, double-blind, placebo-controlled studies (registered at at the no.…”