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      Rapid Emergence of Multidrug Resistant, H58-Lineage Salmonella Typhi in Blantyre, Malawi

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          Abstract

          Introduction

          Between 1998 and 2010, S. Typhi was an uncommon cause of bloodstream infection (BSI) in Blantyre, Malawi and it was usually susceptible to first-line antimicrobial therapy. In 2011 an increase in a multidrug resistant (MDR) strain was detected through routine bacteriological surveillance conducted at Queen Elizabeth Central Hospital (QECH).

          Methods

          Longitudinal trends in culture-confirmed Typhoid admissions at QECH were described between 1998–2014. A retrospective review of patient cases notes was conducted, focusing on clinical presentation, prevalence of HIV and case-fatality. Isolates of S. Typhi were sequenced and the phylogeny of Typhoid in Blantyre was reconstructed and placed in a global context.

          Results

          Between 1998–2010, there were a mean of 14 microbiological diagnoses of Typhoid/year at QECH, of which 6.8% were MDR. This increased to 67 in 2011 and 782 in 2014 at which time 97% were MDR. The disease predominantly affected children and young adults (median age 11 [IQR 6-21] in 2014). The prevalence of HIV in adult patients was 16.7% [8/48], similar to that of the general population (17.8%). Overall, the case fatality rate was 2.5% (3/94). Complications included anaemia, myocarditis, pneumonia and intestinal perforation. 112 isolates were sequenced and the phylogeny demonstrated the introduction and clonal expansion of the H58 lineage of S. Typhi.

          Conclusions

          Since 2011, there has been a rapid increase in the incidence of multidrug resistant, H58-lineage Typhoid in Blantyre. This is one of a number of reports of the re-emergence of Typhoid in Southern and Eastern Africa. There is an urgent need to understand the reservoirs and transmission of disease and how to arrest this regional increase.

          Author Summary

          Typhoid fever is a major cause of disease and death around the world, particularly in resource limited settings, although reports suggest that until recently it has been much less prominent in sub-Saharan Africa (SSA) than Asia. Estimates of the precise burden of this disease are, however, difficult, as diagnosis requires advanced laboratory diagnostics. This is a particular problem in much of SSA where long-term laboratory surveillance has been available in just a few settings. Queen Elizabeth Central Hospital (QECH), Blantyre, Malawi is one such setting; between 1998 and 2010, cases of Typhoid fever at QECH were both uncommon and responsive to all antibiotics. In 2011 a marked increase in highly antibiotic resistant Typhoid fever began, with 843 confirmed cases in 2013. A review of cases revealed that one in 40 patients died and one in five had complicated disease. A further study of the DNA of bacteria associated with the outbreak revealed a novel strain, common to Asia, has arrived in Malawi. This is one of a number of reports of the re-emergence of Typhoid fever in Southern and Eastern Africa. There is an urgent need to understand the reservoirs and transmission of disease and how to arrest this regional increase.

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          Most cited references18

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          Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18.

          Salmonella enterica serovar Typhi (S. typhi) is the aetiological agent of typhoid fever, a serious invasive bacterial disease of humans with an annual global burden of approximately 16 million cases, leading to 600,000 fatalities. Many S. enterica serovars actively invade the mucosal surface of the intestine but are normally contained in healthy individuals by the local immune defence mechanisms. However, S. typhi has evolved the ability to spread to the deeper tissues of humans, including liver, spleen and bone marrow. Here we have sequenced the 4,809,037-base pair (bp) genome of a S. typhi (CT18) that is resistant to multiple drugs, revealing the presence of hundreds of insertions and deletions compared with the Escherichia coli genome, ranging in size from single genes to large islands. Notably, the genome sequence identifies over two hundred pseudogenes, several corresponding to genes that are known to contribute to virulence in Salmonella typhimurium. This genetic degradation may contribute to the human-restricted host range for S. typhi. CT18 harbours a 218,150-bp multiple-drug-resistance incH1 plasmid (pHCM1), and a 106,516-bp cryptic plasmid (pHCM2), which shows recent common ancestry with a virulence plasmid of Yersinia pestis.
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            Whole-genome sequencing for analysis of an outbreak of meticillin-resistant Staphylococcus aureus: a descriptive study

            Summary Background The emergence of meticillin-resistant Staphylococcus aureus (MRSA) that can persist in the community and replace existing hospital-adapted lineages of MRSA means that it is necessary to understand transmission dynamics in terms of hospitals and the community as one entity. We assessed the use of whole-genome sequencing to enhance detection of MRSA transmission between these settings. Methods We studied a putative MRSA outbreak on a special care baby unit (SCBU) at a National Health Service Foundation Trust in Cambridge, UK. We used whole-genome sequencing to validate and expand findings from an infection-control team who assessed the outbreak through conventional analysis of epidemiological data and antibiogram profiles. We sequenced isolates from all colonised patients in the SCBU, and sequenced MRSA isolates from patients in the hospital or community with the same antibiotic susceptibility profile as the outbreak strain. Findings The hospital infection-control team identified 12 infants colonised with MRSA in a 6 month period in 2011, who were suspected of being linked, but a persistent outbreak could not be confirmed with conventional methods. With whole-genome sequencing, we identified 26 related cases of MRSA carriage, and showed transmission occurred within the SCBU, between mothers on a postnatal ward, and in the community. The outbreak MRSA type was a new sequence type (ST) 2371, which is closely related to ST22, but contains genes encoding Panton-Valentine leucocidin. Whole-genome sequencing data were used to propose and confirm that MRSA carriage by a staff member had allowed the outbreak to persist during periods without known infection on the SCBU and after a deep clean. Interpretation Whole-genome sequencing holds great promise for rapid, accurate, and comprehensive identification of bacterial transmission pathways in hospital and community settings, with concomitant reductions in infections, morbidity, and costs. Funding UK Clinical Research Collaboration Translational Infection Research Initiative, Wellcome Trust, Health Protection Agency, and the National Institute for Health Research Cambridge Biomedical Research Centre.
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              Typhoid fever and paratyphoid fever: Systematic review to estimate global morbidity and mortality for 2010

              Background Typhoid and paratyphoid fever remain important causes of morbidity worldwide. Accurate disease burden estimates are needed to guide policy decisions and prevention and control strategies. Methods We conducted a systematic literature review of the PubMed and Scopus databases using pre-defined criteria to identify population-based studies with typhoid fever incidence data published between 1980 and 2009. We also abstracted data from annual reports of notifiable diseases in countries with advanced surveillance systems. Typhoid and paratyphoid fever input data were grouped into regions and regional incidence and mortality rates were estimated. Incidence data were extrapolated across regions for those lacking data. Age-specific incidence rates were derived for regions where age-specific data were available. Crude and adjusted estimates of the global typhoid fever burden were calculated. Results Twenty-five studies were identified, all of which contained incidence data on typhoid fever and 12 on paratyphoid fever. Five advanced surveillance systems contributed data on typhoid fever; 2 on paratyphoid fever. Regional typhoid fever incidence rates ranged from <0.1/100 000 cases/y in Central and Eastern Europe and Central Asia to 724.6/100 000 cases/y in Sub-Saharan Africa. Regional paratyphoid incidence rates ranged from 0.8/100 000 cases/y in North Africa/Middle East to 77.4/100 000 cases/y in Sub-Saharan Africa and South Asia. The estimated total number of typhoid fever episodes in 2010 was 13.5 million (interquartile range 9.1–17.8 million). The adjusted estimate accounting for the low sensitivity of blood cultures for isolation of the bacteria was 26.9 million (interquartile range 18.3–35.7 million) episodes. These findings are comparable to the most recent analysis of global typhoid fever morbidity, which reported crude and adjusted estimates of 10.8 million and 21.7 million typhoid fever episodes globally in 2000. Conclusion Typhoid fever remains a significant health burden, especially in low- and middle-income countries. Despite the availability of more recent data on both enteric fevers, additional research is needed in many regions, particularly Africa, Latin America and other developing countries.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                24 April 2015
                April 2015
                : 9
                : 4
                : e0003748
                Affiliations
                [1 ]Malawi Liverpool Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi
                [2 ]Liverpool School of Tropical Medicine, Liverpool, United Kingdom
                [3 ]Wellcome Trust Sanger Institute, Hinxton, United Kingdom
                [4 ]University of Malawi College of Medicine, Blantyre, Malawi
                [5 ]University of Malawi, The Polytechnic, Blantyre, Malawi
                [6 ]Institute for Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
                University of Otago, NEW ZEALAND
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: NAF MAG RSH GD JP NK. Performed the experiments: NAF KG VW AB JON MDZ PAN CM GS. Analyzed the data: NAF KG VW AB JON MDZ PAN. Contributed reagents/materials/analysis tools: TJA JM GD JP RSH. Wrote the paper: NAF KG VW CM GS SK TJA JM NK AB JON PAN MDZ JP GD MAG RSH.

                Article
                PNTD-D-15-00131
                10.1371/journal.pntd.0003748
                4409211
                25909750
                d23d645b-5e6f-43a3-8371-bc92cb04fb30
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 27 January 2015
                : 8 April 2015
                Page count
                Figures: 4, Tables: 3, Pages: 13
                Funding
                This work was supported by the Wellcome Trust: NAF was supported by Wellcome Trust Research Fellowship WT092152MA and MLW is supported by Wellcome Trust Core Award 101113/Z/13/Z084. The Wellcome Trust Sanger Institute is funded by Wellcome Trust Award 098051. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Wellcome Trust URL: www.wellcome.ac.uk
                Categories
                Research Article
                Custom metadata
                All clinical data are contained within the paper. We have attached a supplementary file containing accession numbers of all the Salmonella Typhi genomes used in this study ( S1 Table).

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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