Point prevalence surveys of antimicrobial use among eight neonatal intensive care units in India: 2016

BACKGROUND: Information about antimicrobial use is scarce and poorly understood among neonatal intensive care units (NICUs) in India. In this study, we describe antimicrobial use in eight NICUs using four point prevalence surveys (PPSs). METHODS: As part of the Global Antimicrobial Resistance, Prescribing, and Efficacy in Neonates and Children (GARPEC) study, one-day, cross-sectional, hospital-based PPSs were conducted four times between 1 February 2016 and 28 February 2017 in eight NICUs. Using a standardized web-based electronic data entry form, detailed data were collected for babies on antimicrobials. RESULTS: A total of 403 babies were admitted to NICUs across all survey days, and 208 (51.6%) were prescribed one or more antimicrobials. Among 208 babies, 155 (74.5%) were prescribed antimicrobials for treatment of an active infection. Among 155 babies with an active infection, treatment was empiric in 109 (70.3%). Sepsis (108, 49.1%) was the most common reason for prescribing antimicrobials. Amikacin (17%) followed by meropenem (12%) were the two most commonly prescribed antimicrobials. For community-acquired sepsis, piperacillin-tazobactam (17.5%) was the most commonly prescribed drug. A combination of ampicillin and gentamicin was prescribed in only two babies (5%). CONCLUSIONS: The recommended first-line antimicrobial agents, ampicillin and gentamicin, were rarely prescribed in Indian NICUs for community acquired neonatal sepsis

Global diversity and antimicrobial resistance of typhoid fever pathogens: insights from a meta-analysis of 13,000 Salmonella Typhi genomes

Background: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). Methods: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. Results: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal ‘sentinel’ surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. Conclusions: The consortium’s aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies

Genomic analysis unveils genome degradation events and gene flux in the emergence and persistence of S. Paratyphi A lineages.

Acknowledgements: We thank Prof. Nicholas Grassly, Imperial College London, for assistance with study design and research proposal development. We gratefully acknowledge Dr. Arif M. Tanmoy, Dr. Senjuti Saha and Dr. Yogesh Hooda (CHRF, Dhaka, Bangladesh) for help with the genotyping analysis. We acknowledge Dr. Duncan Steele, Ms. Megan Carey & Dr. Supriya Kumar, Bill & Melinda Gates Foundation for their technical support throughout the study on behalf of SEFI consortium. We thank all the lab members involved in SEFI reference lab activities, especially Dr. Anushree Amladi, Ms. Baby Abirami S, Ms. Dhanabhagyam K, Ms. Beebi E, Ms. Suganya S, Ms. Udaya and Mr. Ayyanraj N, CMC Vellore implicated in phenotypic testing and stock culture maintenance. We would also like to thank all the members of SEFI consortium, Wellcome Trust Research Laboratory, CMC Vellore and core sequencing teams at the Wellcome Trust Sanger Institute for their contribution to genome sequencing. The authors thank Ms Catherine Trueman (Clinical Pharmacist, CMC Vellore) for helping with language editing.Paratyphoid fever caused by S. Paratyphi A is endemic in parts of South Asia and Southeast Asia. The proportion of enteric fever cases caused by S. Paratyphi A has substantially increased, yet only limited data is available on the population structure and genetic diversity of this serovar. We examined the phylogenetic distribution and evolutionary trajectory of S. Paratyphi A isolates collected as part of the Indian enteric fever surveillance study "Surveillance of Enteric Fever in India (SEFI)." In the study period (2017-2020), S. Paratyphi A comprised 17.6% (441/2503) of total enteric fever cases in India, with the isolates highly susceptible to all the major antibiotics used for treatment except fluoroquinolones. Phylogenetic analysis clustered the global S. Paratyphi A collection into seven lineages (A-G), and the present study isolates were distributed in lineages A, C and F. Our analysis highlights that the genome degradation events and gene acquisitions or losses are key molecular events in the evolution of new S. Paratyphi A lineages/sub-lineages. A total of 10 hypothetically disrupted coding sequences (HDCS) or pseudogenes-forming mutations possibly associated with the emergence of lineages were identified. The pan-genome analysis identified the insertion of P2/PSP3 phage and acquisition of IncX1 plasmid during the selection in 2.3.2/2.3.3 and 1.2.2 genotypes, respectively. We have identified six characteristic missense mutations associated with lipopolysaccharide (LPS) biosynthesis genes of S. Paratyphi A, however, these mutations confer only a low structural impact and possibly have minimal impact on vaccine effectiveness. Since S. Paratyphi A is human-restricted, high levels of genetic drift are not expected unless these bacteria transmit to naive hosts. However, public-health investigation and monitoring by means of genomic surveillance would be constantly needed to avoid S. Paratyphi A serovar becoming a public health threat similar to the S. Typhi of today

Lineage-defining missense mutations in <i>S</i>. Paratyphi A genomes.

Lineage-defining missense mutations in S. Paratyphi A genomes.</p

Antimicrobial susceptibility profile of <i>S</i>. Paratyphi A tested in the present study.

Antimicrobial susceptibility profile of S. Paratyphi A tested in the present study.</p

Rooted maximum likelihood phylogenetic tree of <i>rfb</i> loci of <i>S</i>. Paratyphi A isolates derived from the whole genome alignment by mapping against the reference genome of <i>S</i>. Paratyphi ATCC 9150 (Accession No: CP000026.1) using Snippy.

Lineages and genotypes are labelled as colour strips. Amino acid substitutions in the rfb loci are represented by heat maps. (TIF)</p

Distribution of <i>S</i>. Typhi and <i>S</i>. Paratyphi A isolates collected across the participating sites of the SEFI network.

Distribution of S. Typhi and S. Paratyphi A isolates collected across the participating sites of the SEFI network.</p

List of whole genome sequenced isolates collected from the participating sites of the SEFI network.

List of whole genome sequenced isolates collected from the participating sites of the SEFI network.</p

List of functional gene inactivation mutations identified between phylogenetic lineages.

List of functional gene inactivation mutations identified between phylogenetic lineages.</p

<i>Phylogenetic distribution of contemporary Indian S</i>. <i>Paratyphi A isolates in a global context</i>: Rooted maximum likelihood phylogenetic tree of contemporary Indian <i>S</i>. Paratyphi A (<i>n = 152)</i>, combined with global genome collection (<i>n = 400</i>) representing the current global distribution.

The tree was derived from 4286 SNPs mapped against the reference genome of S. Paratyphi ATCC 9150 (Accession No: CP000026.1) using Snippy and rooted to the outgroup strain (ERR028986: Lineage G). Red-colored dots at the tip of the branches indicates the position of this study isolates. Contemporary Indian S. Paratyphi A isolates of this study were found distributed across the global tree with both lineages A, C and F. Genomes with their respective metadata are labeled as color strips and key for each variable were mentioned. Strip 1 and 2 indicate the location and 3 represent MLST of each isolate. Heatmap represents the QRDR mutations that confer resistance to fluoroquinolone and the presence of plasmids. The scale bar indicates substitutions per site. Color keys for all the variables are given in the inset legend. The tree was visualized and labeled using iTOL (https://itol.embl.de/).</p