Analysis of Amino Acid Sequences of Penicillin-Binding Proteins 1a, 2b, and 2x in Invasive Streptococcus pneumoniae Nonsusceptible to Penicillin Isolated from Children in India.

Penicillin-binding proteins are the primary targets for beta lactam drugs, which are main stay of treatment for Streptococcus pneumoniae. The emergence of increased penicillin resistance in meningeal isolates of S. pneumoniae in India is alarming. With this background, we aimed to analyze the pbp gene mutations of penicillin nonsusceptible pneumococcal (PNSP) isolates from within India and their association with international clones. A total of 32 PNSP invasive isolates with a penicillin minimal inhibitory concentrations (MIC) of ≥0.12 µg/mL were subjected to PCR and sequencing for multilocus sequence typing and the pbp genes (pbp2b, pbp2x, and pbp1a). The S. pneumoniae R6 susceptible strain was used as the reference for the comparison analyses. In the majority of the present study isolates, amino acid substitutions were only seen in one of the three active sites of one of the three pbp genes. Thus, pbp genes in the absence of the major substitutions usually associated with penicillin resistance combined with mosaicism in pbp1a resulted in a slight increase in the penicillin MIC to between 0.06 and 2.0 µg/mL, which according to meningeal break point denote resistance. Clonal analyses revealed that the emergence of PNSP in India is due to the gradual expansion of the resistant clones CC320, CC230, and CC63.

Pneumococcal serotypes causing non-invasive pneumonia in adults from a South Indian tertiary care hospital and the impact of the newer conjugate vaccines.

BACKGROUND: Streptococcus pneumoniae is the leading cause of community-acquired pneumonia (CAP) in adults. Ageing, chronic conditions and comorbidities are important risk factors for pneumococcal pneumonia. PURPOSE: There is lack of data on the pneumococcal serotypes causing non-invasive pneumonia in India. This study aims to determine the prevalent pneumococcal serotypes causing non-invasive pneumonia, the associated comorbidities, and the coverage of both the available pneumococcal vaccines in India and conjugate vaccines that are currently undergoing clinical trials. METHODS: A total of 280 subjects (aged >16 years) who had clinical symptoms correlating with radiological findings for non-invasive bacteremic pneumonia and microbiological evidence of S. pneumoniae between 2018 and 2020 were included. The clinical, demographic, radiological and microbiological findings were retrieved from the Hospital Information System (HIS). RESULT: The common serotypes in order of prevalence were 19F, 9V, 23F, 6B, 11A, 13, 34, 10A, 19A and 6A. The predominant non-vaccine serotypes were 13, 34, 35B, 31 and 16F. The associated radiological findings were pneumonic consolidation and multi-lobar involvement. Other coinfected bacterial pathogens included H. influenzae, S. aureus, K. pneumoniae and P. aeruginosa. CONCLUSION: The pneumococcal vaccines: PCV10/GSK, PCV10/SII, PCV13, PCV15, PCV20 and PPSV23 provide an overall serotype coverage of 36, 41, 47, 48, 61 and 69 %, respectively of S. pneumoniae causing non-invasive pneumonia in South India. Increasing catch-up vaccination using PCV10(SII) in pre-school children could have a more significant impact on reducing pneumococcal pneumonia in adults (>50 years) in terms of increased herd immunity at an affordable cost.

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

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.