Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study

David L. Paterson ,Ravikumar Balakrishnan,Rachel Pike,Tabassum Noorie,M A Thirunarayan ,Sunil Maharjan,Uma Chaudhary,Timothy R. Walsh ,David M. Livermore ,Mark A. Toleman ,Christian G. Giske ,William Welfare,S.k. Upadhyay ,Neil Woodford,Seema Irfan,Jogesh Sarma ,Kaliaperumal Karthikeyan ,Ujjwayini Ray,Michel Doumith,Elizabeth Sheridan,Marina Warner,Jane F. Turton ,Claire Perry,Madhu Sharma,A. Pearson ,Bhargavi Rao,Fafhana Butt,Anil Kumar ,Jay Bagaria,Padma Krishnan,Shazad Mushtaq

doi:10.1016/s1473-3099(10)70143-2

Abstract

SummaryBackgroundGram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1 (NDM-1) are potentially a major global health problem. We investigated the prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK.MethodsEnterobacteriaceae isolates were studied from two major centres in India—Chennai (south India), Haryana (north India)—and those referred to the UK's national reference laboratory. Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene blaNDM-1 was established by PCR. Isolates were typed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Plasmids were analysed by S1 nuclease digestion and PCR typing. Case data for UK patients were reviewed for evidence of travel and recent admission to hospitals in India or Pakistan.FindingsWe identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids: those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year, or had links with these countries.InterpretationThe potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed.FundingEuropean Union, Wellcome Trust, and Wyeth.

Highlights

Bacteria from clinical and non-clinical settings are becoming increasingly resistant to conventional antibiotics. 10 years ago, concern centred on Gram-positive bacteria, meticillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp
The increase in resistance of Gram-negative bacteria is mainly due to mobile genes on plasmids that can readily spread through bacterial populations
We recently reported a new type of carbapenem resistance gene, designated blaNDM-1.22 A patient, repatriated to Sweden after admission to hospital in New Delhi, India, was colonised by K pneumoniae and Escherichia coli with blaNDM-1 on plasmids of varying size, which readily transferred between bacterial strains in vitro

Summary

Introduction

Bacteria from clinical and non-clinical settings are becoming increasingly resistant to conventional antibiotics. 10 years ago, concern centred on Gram-positive bacteria, meticillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. Is the increase in resistance of Gram-negative bacteria faster than in Gram-positive bacteria,[1,2] and there are fewer new and developmental antibiotics active against Gram-negative bacteria[3,4,5,6] and drug development programmes seem insufficient to provide therapeutic cover in 10–20 years.[7,8,9]. The increase in resistance of Gram-negative bacteria is mainly due to mobile genes on plasmids that can readily spread through bacterial populations. The gene jumped from the chromosome of its natural hosts, Kluyvera spp, to plasmids that have subsequently spread widely,[10,16] establishing CTX-M-15 as the globally-dominant ESBL and the primary cause of acquired resistance to thirdgeneration cephalosporins in Enterobacteriaceae.[17,18] The CTX-M-15 extended-spectrum β-lactamase (ESBL) encoded by blaCTX-M-15 was first reported in India in the mid-1990s.14,15 The gene jumped from the chromosome of its natural hosts, Kluyvera spp, to plasmids that have subsequently spread widely,[10,16] establishing CTX-M-15 as the globally-dominant ESBL and the primary cause of acquired resistance to thirdgeneration cephalosporins in Enterobacteriaceae.[17,18]

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