Dataset Information

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.

SUBMITTER: Veeraraghavan B

PROVIDER: S-EPMC8210042 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 (MIC50/90, 0.06/>2 ?g/ml), including erythromycin-resistant strains exhibiting an inducible clindamycin resistance phenotype (MIC50/90, 0.06/0.06 ?g/ml) and telithromycin-susceptible strains (MIC50/90, 0.06/0.06 ?g/ml), but it exhibited limited activity against most telithromycin-resistant and clindamycin-resistant isolates that were constitutively resistant to macrolides (MIC50/90, >2/>2 ?g/ml). Nafithromycin was very active (MIC50/90, 0.015/0.06 ?g/ml) against 1,911 Streptococcus pneumoniae strains, inhibiting all strains, with MIC values of ?0.25 ?g/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 (MIC50/90, 0.015/0.015 ?g/ml), inhibiting 100.0% of isolates at ?0.5 ?g/ml, and MIC50/90 values (0.015/0.015 to 0.03 ?g/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.