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

Balaji Veeraraghavan; Rosemol Varghese; Karnika Saigal; S Balasubramanian; P Sulochana Putli Bai; Binesh Lal Y; Ayyanraj Neeravi; Pavithra Baskar; Kavipriya Anandhan; C P Girish Kumar; Yuvraj Jayaraman; Vijaya Lakshmi Nag; Sujata Baveja; Bhavana J; Shrikrishna A Joshi; Ranganathan Iyer

doi:10.1093/jacamr/dlab066

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

JAC Antimicrob Resist. 2021 Jun 1;3(2):dlab066. doi: 10.1093/jacamr/dlab066. eCollection 2021 Jun.

Authors

Balaji Veeraraghavan¹, Rosemol Varghese¹, Karnika Saigal², S Balasubramanian³, P Sulochana Putli Bai⁴, Binesh Lal Y¹, Ayyanraj Neeravi¹, Pavithra Baskar¹, Kavipriya Anandhan¹, C P Girish Kumar⁴, Yuvraj Jayaraman⁴, Vijaya Lakshmi Nag⁵, Sujata Baveja⁶, Bhavana J⁷, Shrikrishna A Joshi⁸, Ranganathan Iyer⁹

Affiliations

¹ Christian Medical College, Vellore, Tamil Nadu, India.
² Chacha Nehru Bal Chikitsalaya, New Delhi, India.
³ Kanchi Kamakoti Children's Trust Hospital, Chennai, Tamil Nadu, India.
⁴ ICMR-National Institute of Epidemiology, Chennai, Tamil Nadu, India.
⁵ All India Institute of Medical Science, Jodhpur, Rajasthan, India.
⁶ Lokmanya Tilak Municipal Medical College and Hospital, Sion, Mumbai, India.
⁷ Indira Gandhi Institute of Child Health, Bengaluru, India.
⁸ Central Clinical Microbiology Laboratory, Navi, Mumbai, India.
⁹ Global Hospitals, Hyderabad, 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.