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

Background Widespread MDR Streptococcus pneumoniae in China translates clinically into a substantial pneumococcal disease burden and related morbidity and mortality, particularly in the elderly and children. Nafithromycin (WCK 4873), a novel lactone ketolide class of antibiotic designed with a 3 day, once-daily regimen is highly active against resistant pneumococci and other community respiratory pathogens. It is currently in clinical development for the treatment of community-acquired bacterial pneumonia (CABP). Objectives To determine the in vitro activity of nafithromycin against clinical S. pneumoniae isolates collected during 2015-21 from three hospitals in mainland China. Methods A total of 920 clinical isolates (one isolate per patient), which predominantly with the macrolide- and clindamycin-resistant phenotype were included in this study. The MICs of nafithromycin and other antibiotics tested were determined using the reference broth microdilution method. Results Clinical S. pneumoniae isolates used in this study showed high macrolide and clindamycin resistance (>95% against erythromycin and azithromycin and 80% against clindamycin) for which nafithromycin showed potent activity (MIC50/90; 0.03/0.06 mg/L) with 100% susceptibility at a proposed pharmacokinetics/pharmacodynamics (PK/PD) breakpoint of 0.25 mg/L. Among other classes of antibiotics tested, moxifloxacin also showed good activity while amoxicillin/clavulanate and ceftriaxone showed lower susceptibility. Conclusions Nafithromycin exhibited therapeutically relevant in vitro antibacterial activity against contemporary highly resistant pneumococci collected from mainland China. This study supports the clinical development of nafithromycin for the management of CABP caused by pneumococci in China.