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      Typhoid Outbreaks, 1989–2018: Implications for Prevention and Control

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          Abstract.

          Typhoid fever remains an important public health problem in low- and middle-income countries, with large outbreaks reported from Africa and Asia. Although the WHO recommends typhoid vaccination for control of confirmed outbreaks, there are limited data on the epidemiologic characteristics of outbreaks to inform vaccine use in outbreak settings. We conducted a literature review for typhoid outbreaks published since 1990. We found 47 publications describing 45,215 cases in outbreaks occurring in 25 countries from 1989 through 2018. Outbreak characteristics varied considerably by WHO region, with median outbreak size ranging from 12 to 1,101 cases, median duration from 23 to 140 days, and median case fatality ratio from 0% to 1%. The largest number of outbreaks occurred in WHO Southeast Asia, 13 (28%), and African regions, 12 (26%). Among 43 outbreaks reporting a mode of disease transmission, 24 (56%) were waterborne, 17 (40%) were foodborne, and two (5%) were by direct contact transmission. Among the 34 outbreaks with antimicrobial resistance data, 11 (32%) reported Typhi non-susceptible to ciprofloxacin, 16 (47%) reported multidrug-resistant (MDR) strains, and one reported extensively drug-resistant strains. Our review showed a longer median duration of outbreaks caused by MDR strains (148 days versus 34 days for susceptible strains), although this difference was not statistically significant. Control strategies focused on water, sanitation, and food safety, with vaccine use described in only six (13%) outbreaks. As typhoid conjugate vaccines become more widely used, their potential role and impact in outbreak control warrant further evaluation.

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          Emergence of an Extensively Drug-Resistant Salmonella enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins

          ABSTRACT Antibiotic resistance is a major problem in Salmonella enterica serovar Typhi, the causative agent of typhoid. Multidrug-resistant (MDR) isolates are prevalent in parts of Asia and Africa and are often associated with the dominant H58 haplotype. Reduced susceptibility to fluoroquinolones is also widespread, and sporadic cases of resistance to third-generation cephalosporins or azithromycin have also been reported. Here, we report the first large-scale emergence and spread of a novel S. Typhi clone harboring resistance to three first-line drugs (chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole) as well as fluoroquinolones and third-generation cephalosporins in Sindh, Pakistan, which we classify as extensively drug resistant (XDR). Over 300 XDR typhoid cases have emerged in Sindh, Pakistan, since November 2016. Additionally, a single case of travel-associated XDR typhoid has recently been identified in the United Kingdom. Whole-genome sequencing of over 80 of the XDR isolates revealed remarkable genetic clonality and sequence conservation, identified a large number of resistance determinants, and showed that these isolates were of haplotype H58. The XDR S. Typhi clone encodes a chromosomally located resistance region and harbors a plasmid encoding additional resistance elements, including the bla CTX-M-15 extended-spectrum β-lactamase, and carrying the qnrS fluoroquinolone resistance gene. This antibiotic resistance-associated IncY plasmid exhibited high sequence identity to plasmids found in other enteric bacteria isolated from widely distributed geographic locations. This study highlights three concerning problems: the receding antibiotic arsenal for typhoid treatment, the ability of S. Typhi to transform from MDR to XDR in a single step by acquisition of a plasmid, and the ability of XDR clones to spread globally.
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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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              A systematic review of antimicrobial resistance in Salmonella enterica serovar Typhi, the etiological agent of typhoid

              Background The temporal and spatial change in trends of antimicrobial resistance (AMR) in typhoid have not been systematically studied, and such information will be critical for defining intervention, as well as planning sustainable prevention strategies. Methodology and findings To identify the phenotypic trends in AMR, 13,833 individual S. Typhi isolates, reported from 1973 to 2018 in 62 publications, were analysed to determine the AMR preponderance over time. Separate analyses of molecular resistance determinants present in over 4,000 isolates reported in 61 publications were also conducted. Multi-drug resistant (MDR) typhoid is in decline in Asia in a setting of high fluoroquinolone resistance while it is on the increase in Africa. Mutations in QRDRs in gyrA (S83F, D87N) and parC (S80I) are the most common mechanisms responsible for fluoroquinolone resistance. Cephalosporin resistant S. Typhi, dubbed extensively drug-resistant (XDR) is a real threat and underscores the urgency in deploying the Vi-conjugate vaccines. Conclusion From these observations, it appears that AMR in S. Typhi will continue to emerge leading to treatment failure, changes in antimicrobial policy and further resistance developing in S. Typhi isolates and other Gram-negative bacteria in endemic regions. The deployment of typhoid conjugate vaccines to control the disease in endemic regions may be the best defence.
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                Author and article information

                Journal
                Am J Trop Med Hyg
                Am. J. Trop. Med. Hyg
                tpmd
                tropmed
                The American Journal of Tropical Medicine and Hygiene
                The American Society of Tropical Medicine and Hygiene
                0002-9637
                1476-1645
                June 2020
                30 March 2020
                30 March 2020
                : 102
                : 6
                : 1296-1305
                Affiliations
                [1 ]Division of Foodborne, Waterborne and Environmental Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia;
                [2 ]Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom;
                [3 ]Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland;
                [4 ]Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, North Carolina;
                [5 ]Centre for International Health, University of Otago, Dunedin, New Zealand;
                [6 ]Policy and Economic Research Department, Development and Delivery Unit, International Vaccine Institute, Seoul, South Korea;
                [7 ]Johns Hopkins University School of Medicine, Baltimore, Maryland;
                [8 ]Division of Healthcare Quality and Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia
                Author notes
                [* ]Address correspondence to Grace D. Appiah, Division of Foodborne, Waterborne and Environmental Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, H24-9, Atlanta, GA 30329. E-mail: gappiah@ 123456cdc.gov

                Disclosure: A. D. B.-E. is a staff member of the World Health Organization.

                Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the views of the World Health Organization.

                Financial support: The work reported in this article was supported by a grant from the Bill & Melinda Gates Foundation to the World Health Organization. The study received grants from the Bill & Melinda Gates Foundation to the WHO covering the conduct of this study, and. J. A. C. also reports grants from the Bill & Melinda Gates Foundation during the conduct of the study.

                Authors’ addresses: Grace D. Appiah, Sunkyung Kim, and Eric D. Mintz, Division of Foodborne, Waterborne and Environmental Diseases, Centers for Disease Control and Prevention, Atlanta, GA, E-mails: ydg3@ 123456cdc.gov , wox0@ 123456cdc.gov , and edm1@ 123456cdc.gov . Alexandria Chung, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom, E-mail: s1508032@ 123456sms.ed.ac.uk . Adwoa D. Bentsi-Enchill, Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland, E-mail: bentsienchilla@ 123456who.int . John A. Crump, Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, NC, and Centre for International Health, University of Otago, Dunedin, New Zealand, E-mail: zcn0@ 123456cdc.gov . Vittal Mogasale, Policy and Economic Research Department, Development and Delivery Unit, International Vaccine Institute, Seoul, South Korea, E-mail: vmogasale@ 123456ivi.int . Rachael Pellegrino, Johns Hopkins University School of Medicine, Baltimore, MD, E-mail: vmogasale@ 123456ivi.int . Rachel B. Slayton, Division of Healthcare Quality and Promotion, Centers for Disease Control and Prevention, Atlanta, GA, E-mail: via3@ 123456cdc.gov .

                Article
                tpmd190624
                10.4269/ajtmh.19-0624
                7253085
                32228795
                95e6c48e-91cb-464a-9c09-3bb597828485
                © The American Society of Tropical Medicine and Hygiene

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

                History
                : 22 August 2019
                : 16 February 2020
                Page count
                Pages: 10
                Categories
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                Infectious disease & Microbiology
                Infectious disease & Microbiology

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