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Persistent transmission of shigellosis in England is associated with a recently emerged multi-drug resistant strain of Shigella sonnei

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Abstract

Background Whole genome sequencing has enhanced surveillance and facilitated detailed monitoring of transmission of Shigella species in England. Methods We undertook an epidemiological and phylogenetic analysis of isolates from all cases of shigellosis referred to Public Health England between 2015 to 2018 to explore recent strain characteristics and transmission dynamics of Shigella species. Results Of the 4950 confirmed cases of shigellosis identified during this period, the highest proportion of isolates were S. sonnei (54.4%), followed by S. flexneri (39.2%), S. boydii (4.1%) and S. dysenteriae (2.2%). Most cases were adults (82.9%) and male (59.5%), and 34.9% cases reported recent travel outside the UK. Throughout the study period diagnoses of S. flexneri and S. sonnei were most common in men with no history of recent travel abroad. Species prevalence was not static with cases of S. flexneri in men decreasing from 2015-2016, and the number of cases of S. sonnei increasing from 2017. Phylogenetic analysis showed this recent increase in S. sonnei was attributed to a novel clade exhibiting resistance to ciprofloxacin and azithromycin, which had emerged from a Central Asia sub-lineage. Conclusions Despite changes in species prevalence, Shigella diagnoses in England are persistently the most common in adult males without reported travel history, consistent with sexual transmission amongst men who have sex with men. The trend in increasing ciprofloxacin resistance, in addition to plasmid-mediated azithromycin resistance, in S. sonnei is of significant public health concern with respect to transmission of multi-drug resistant gastrointestinal pathogens and the risk of treatment failures. Summary Shigella diagnoses in England are most prevalent amongst men who have sex with men. S. sonnei exhibiting resistance to both azithromycin and ciprofloxacin has replaced azithromycin-resistant S. flexneri as the most commonly isolated species in this setting.

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This guideline is intended for use in UK Genitourinary medicine clinics and sexual health services but is likely to be of relevance in all sexual health settings, including general practice and Contraception and Sexual Health (CASH) services, where men who have sex with men (MSM) seek sexual health care or where addressing the sexual health needs of MSM may have public health benefits. For the purposes of this document, MSM includes all gay, bisexual and all other males who have sex with other males and both cis and trans men. This document does not provide guidance on the treatment of particular conditions where this is covered in other British Association for Sexual Health and HIV (BASHH) Guidelines but outlines best practice in multiple aspects of the sexual health care of MSM. Where prevention of sexually transmitted infections including HIV can be addressed as an integral part of clinical care, this is consistent with the concept of combination prevention and is included. The document is designed primarily to provide guidance on the direct clinical care of MSM but also makes reference to the design and delivery of services with the aim of supporting clinicians and commissioners in providing effective services. Methodology This document was produced in accordance with the guidance set out in the BASHH CEG’s document ‘Framework for guideline development and assessment’ published in 2010 at http://www.bashh.org/guidelines and with reference to the Agree II instrument. Following the production of the updated framework in April 2015, the GRADE system for assessing evidence was adopted and the draft recommendations were regraded. Search strategy (see also Appendix 1) Ovid Medline 1946 to December 2014, Medline daily update, Embase 1974 to December 2014, Pubmed NeLH Guidelines Database, Cochrane library from 2000 to December 2014. Search language English only. The search for Section 3 was conducted on PubMed to December 2014. Priority was given to peer-reviewed papers published in scientific journals, although for many issues evidence includes conference abstracts listed on the Embase database. In addition, for ‘Identification of problematic recreational drug and alcohol use’ section and ‘Sexual problems and dysfunctions in MSM’ section, searches included PsycINFO. Methods Article titles and abstracts were reviewed and if relevant the full text article was obtained. Priority was given to randomised controlled trial and systematic review evidence, and recommendations made and graded on the basis of best available evidence. Piloting and feedback The first draft of the guideline was circulated to the writing group and to a small group of relevant experts, third sector partners and patient representatives who were invited to comment on the whole document and specifically on particular sections. The revised draft was reviewed by the CEG and then reviewed by the BASHH patient/public panel and posted on the BASHH website for public consultation. The final draft was piloted before publication. Guideline update The guidelines will be reviewed and revised in five years’ time, 2022.
Article
Background: Shigellosis is an acute, severe bacterial colitis that, in high-income countries, is typically associated with travel to high-risk regions (Africa, Asia, and Latin America). Since the 1970s, shigellosis has also been reported as a sexually transmitted infection in men who have sex with men (MSM), in whom transmission is an important component of shigellosis epidemiology in high-income nations. We aimed to use sophisticated subtyping and international sampling to determine factors driving shigellosis emergence in MSM linked to an outbreak in the UK. Methods: We did a large-scale, cross-sectional genomic epidemiological study of shigellosis cases collected from 29 countries between December, 1995, and June 8, 2014. Focusing on an ongoing epidemic in the UK, we collected and whole-genome sequenced clinical isolates of Shigella flexneri serotype 3a from high-risk and low-risk regions, including cases associated with travel and sex between men. We examined relationships between geographical, demographic, and clinical patient data with the isolate antimicrobial susceptibility, genetic data, and inferred evolutionary relationships. Findings: We obtained 331 clinical isolates of S flexneri serotype 3a, including 275 from low-risk regions (44 from individuals who travelled to high-risk regions), 52 from high-risk regions, and four outgroup samples (ie, closely related, but genetically distinct isolates used to determine the root of the phylogenetic tree). We identified a recently emerged lineage of S flexneri 3a that has spread intercontinentally in less than 20 years throughout regions traditionally at low risk for shigellosis via sexual transmission in MSM. The lineage had acquired multiple antimicrobial resistance determinants, and prevailing sublineages were strongly associated with resistance to the macrolide azithromycin. Eight (4%) of 206 isolates from the MSM-associated lineage were obtained from patients who had previously provided an isolate; these serial isolations indicated atypical infection patterns (eg, reinfection). Interpretation: We identified transmission-facilitating behaviours and atypical course(s) of infection as precipitating factors in shigellosis-affected MSM. The intercontinental spread of antimicrobial-resistant shigella through established transmission routes emphasises the need for new approaches to tackle the public health challenge of sexually transmitted infections in MSM. Funding: Wellcome Trust (grant number 098051).
Article
There is increasing evidence that shigellosis is a predominantly sexually transmitted disease among men who have sex with men (MSM) and that infection with the human immunodeficiency virus (HIV) is a risk factor for shigellosis. Retrospective analysis of antibiotic resistance profiles of Shigella species isolated from stool specimens of patients presenting with diarrhea from January 2010 to July 2012 in three German outpatient clinics specialized in HIV care. Among 79 cases of Shigella sonnei, 56 occurred in HIV-infected MSM, while 23 were observed in HIV-negative MSM. High resistance rates (>90 %) were found for doxycycline, tetracycline, aminoglycosides, all cephalosporins of first and second generations tested, and trimethoprim/sulfamethoxazole. In total, 54 % of cases were resistant to ciprofloxacin. Compared to negative subjects, HIV-infected MSM had a significantly higher rate of quinolone resistance. For ciprofloxacin, the resistance rates were 66 versus 24 %, respectively (p = 0.0016). Individual resistance patterns did not indicate that this was due to a limited outbreak. Rates of resistance to other antibiotics than quinolones showed no differences between HIV-infected and HIV-negative cases. No resistance was found for carbapenems or newer cephalosporins such as ceftriaxone. The high rates of S. sonnei isolates resistant to quinolones and other traditional antibiotics are of concern. Innovative prevention efforts are urgently needed. The empirical use of quinolones in HIV-infected patients presenting with S. sonnei infection is no longer recommended.
Article
Next-generation DNA sequencing (NGS) projects, such as the 1000 Genomes Project, are already revolutionizing our understanding of genetic variation among individuals. However, the massive data sets generated by NGS--the 1000 Genome pilot alone includes nearly five terabases--make writing feature-rich, efficient, and robust analysis tools difficult for even computationally sophisticated individuals. Indeed, many professionals are limited in the scope and the ease with which they can answer scientific questions by the complexity of accessing and manipulating the data produced by these machines. Here, we discuss our Genome Analysis Toolkit (GATK), a structured programming framework designed to ease the development of efficient and robust analysis tools for next-generation DNA sequencers using the functional programming philosophy of MapReduce. The GATK provides a small but rich set of data access patterns that encompass the majority of analysis tool needs. Separating specific analysis calculations from common data management infrastructure enables us to optimize the GATK framework for correctness, stability, and CPU and memory efficiency and to enable distributed and shared memory parallelization. We highlight the capabilities of the GATK by describing the implementation and application of robust, scale-tolerant tools like coverage calculators and single nucleotide polymorphism (SNP) calling. We conclude that the GATK programming framework enables developers and analysts to quickly and easily write efficient and robust NGS tools, many of which have already been incorporated into large-scale sequencing projects like the 1000 Genomes Project and The Cancer Genome Atlas.
Article
Following the clinical observation that there appeared to be an association between shigellosis and male homosexuality, the medical records of 113 patients at The New York Hospital were reviewed retrospectively. Of the 38 males studied who were between the ages 19 and 61, seventeen were homosexual (44-7 per cent.). Only one of the matched controls was homosexual. Of the men with shigellosis who had a history of foreign travel, 10 per cent. were homosexual; however, among the patients without a travel history, 57-1 per cent. were homosexual (P less than 0-05). For male patients with shigellosis who do not have an appropriate travel history, the physician should expand his epidemiological investigation to include sexual contacts. Men and women who perform rectal intercourse should be cautioned to abstain from this activity until their stool cultures are negative for shigella. If a male patient with shigellosis is homosexual, he should be screened for other sexually transmitted diseases such as syphilis, gonorrhoea, hepatitis B, and amoebiasis.
Estimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study
GBD Diarrhoeal Diseases Collaborators. Estimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Infect Dis, 2017;17:909-948. doi: 10.1016/S1473-3099(17)30276-1
No reuse allowed without permission. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint
All rights reserved. No reuse allowed without permission. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint . http://dx.doi.org/10.1101/798835 doi: bioRxiv preprint first posted online Oct. 9, 2019;
  • Sci Rep
Sci Rep. 2018 May 9;8(1):7389. doi: 10.1038/s41598-018-25764-3.
Comparison of phenotypic and WGS-derived antimicrobial All rights reserved. No reuse allowed without permission. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint
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Sadouki Z, Day MR, Doumith M, Chattaway MA, Dallman TJ, Hopkins KL, Elson R, Woodford N, Godbole G, Jenkins C. Comparison of phenotypic and WGS-derived antimicrobial All rights reserved. No reuse allowed without permission. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint . http://dx.doi.org/10.1101/798835 doi: bioRxiv preprint first posted online Oct. 9, 2019;
All rights reserved. No reuse allowed without permission. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint
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Childs, T., et al., Rapid increase in lymphogranuloma venereum in men who have sex with men, United Kingdom, 2003 to September 2015. Eurosurveillance, 2015. 20(48): p. 30076. All rights reserved. No reuse allowed without permission. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint . http://dx.doi.org/10.1101/798835 doi: bioRxiv preprint first posted online Oct. 9, 2019;