In Vitro Activity of the Novel Lactone Ketolide Nafithromycin (WCK 4873) against Contemporary Clinical Bacteria from a Global Surveillance Program

Abstract

Nafithromycin (WCK 4873), a novel antimicrobial agent of the lactone ketolide class, is currently in phase 2 development for treatment of community-acquired bacterial pneumonia (CABP). A total of 4,739 nonduplicate isolates were selected from a 2014 global surveillance program at medical institutions located in 43 countries within the United States, Europe, Latin America, and the Asia-Pacific region. Nafithromycin and comparator agents were used for susceptibility testing by reference broth microdilution methods. Nafithromycin was active against Staphylococcus aureus (MIC_50/90, 0.06/>2 μg/ml), including erythromycin-resistant strains exhibiting an inducible clindamycin resistance phenotype (MIC_50/90, 0.06/0.06 μg/ml) and telithromycin-susceptible strains (MIC_50/90, 0.06/0.06 μg/ml), but it exhibited limited activity against most telithromycin-resistant and clindamycin-resistant isolates that were constitutively resistant to macrolides (MIC_50/90, >2/>2 μg/ml). Nafithromycin was very active (MIC_50/90, 0.015/0.06 μg/ml) against 1,911 Streptococcus pneumoniae strains, inhibiting all strains, with MIC values of ≤0.25 μg/ml. Telithromycin susceptibility was 99.9% for Streptococcus pneumoniae strains, and nafithromycin was up to 8-fold more potent than telithromycin. Overall, 37.9% of S. pneumoniae strains were resistant to erythromycin, and 19.7% were resistant to clindamycin. Nafithromycin was highly active against 606 Streptococcus pyogenes strains (MIC_50/90, 0.015/0.015 μg/ml), inhibiting 100.0% of isolates at ≤0.5 μg/ml, and MIC_50/90 values (0.015/0.015 to 0.03 μg/ml) were similar for the 4 geographic regions. Nafithromycin and telithromycin demonstrated comparable in vitro activities against 1,002 Haemophilus influenzae isolates and 504 Moraxella catarrhalis isolates. Overall, nafithromycin showed potent in vitro activity against a broad range of contemporary (2014) global pathogens. These results support the continued clinical development of nafithromycin for treatment of CABP.

Keywords: Streptococcus pneumoniae; Streptococcus pyogenes; ketolides.