{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:24:42Z","timestamp":1791390282195,"version":"4.3.3"},"posted":{"date-parts":[[2026,5,21]]},"group-title":"Epidemiology","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,21]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n Shigella<\/jats:italic>\n is a leading cause of childhood diarrhea in low- and middle-income countries and is increasingly resistant to first-line antibiotics. We conducted a surveillance study to determine the incidence, genomic characteristics, and AMR profiles of\n Shigella<\/jats:italic>\n infections in children under five with moderate to severe diarrhea (MSD) in Lusaka, Zambia.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Between 15 September 2020 and 30 November 2021, a prospective cohort study of 1,400 children under five was enrolled during a community census in a peri-urban setting and passively followed for 9.5 months for MSD. During enrollment, socio-demographic data were collected using electronic questionnaires, while clinical data were collected through the DHIS platform. The main outcome,\n Shigella<\/jats:italic>\n in diarrheal stool in under 5 children, was detected using culture and Loop-mediated Isothermal Amplification (LAMP) targeting the ipaH gene. Cox proportional hazards models were used to assess the incidence and risk factors of\n Shigella<\/jats:italic>\n (ipaH) infections. Whole-genome sequencing (WGS) was used to characterize the genomic diversity and antimicrobial resistance genes, complemented by phenotypic antibiotic susceptibility testing.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n There were 230 first episodes of\n Shigella<\/jats:italic>\n over a follow-up time of 9,581.7 child-months, yielding an incidence of 24.0 (95% CI 21.1-27.3) cases per 1,000 child-months, with the highest incidence among 2 to 3-year-olds. The key risk factors identified were the water source (p=0.025) and age group (p=0.014). Genotypic characterization revealed 10\n S. flexneri<\/jats:italic>\n , 9\n S. sonnei<\/jats:italic>\n , and 3\n S. boydii<\/jats:italic>\n . The\n S. sonnei<\/jats:italic>\n isolates formed two clusters, differing in virulence factors and plasmid profiles, indicating two possible circulating strains.\n Shigella<\/jats:italic>\n isolates exhibited phenotypic and genotypic multidrug resistance, including against trimethoprim, aminoglycosides, and beta-lactams. Plasmid-mediated quinolone resistance (qnrS1) was identified in four\n S. flexneri<\/jats:italic>\n isolates, with these genes located on the IncFIB(K) plasmid, highlighting the potential for horizontal transmission and spread of quinolone resistance in this region. No phenotypic and genotypic resistance to macrolides, the first-line treatment for Shigella in Zambia, was observed.\n <\/jats:p>\n <\/jats:sec>\n \n Interpretation<\/jats:title>\n \n We report a high burden of\n Shigella<\/jats:italic>\n with multidrug resistance, including resistance to fluoroquinolones. These findings highlight the increasing resistance of\n Shigella<\/jats:italic>\n to first-line antibiotics and underscore the importance of developing safe and effective vaccines, improving WASH conditions, and ongoing AMR surveillance.\n <\/jats:p>\n <\/jats:sec>\n \n Funding<\/jats:title>\n The EDCTP2 program, supported by the European Union, the Faculty for the Future Foundation (FFTF), the Netherlands Organization for Health Research and Development (ZonMw), and Health-Holland AMR-Global, Gloria, and Track-AMR.<\/jats:p>\n <\/jats:sec>\n \n Research in context<\/jats:title>\n \n Evidence before this study<\/jats:title>\n \n Despite\n Shigella<\/jats:italic>\n being a leading cause of bacterial diarrheal mortality globally, there is a critical lack of up-to-date data on its burden and associated antimicrobial resistance (AMR) in high-risk settings, such as sub-Saharan Africa (SSA). We searched PubMed for studies published between 2000 and May 2025, using the terms \u201c\n Shigella<\/jats:italic>\n ,\u201d \u201cantimicrobial resistance,\u201d and \u201csub-Saharan Africa.\u201d Only three studies (GEMS, MAL-ED, VIDA) involving extensive surveillance in SSA countries were identified, all conducted before 2018. None integrated disease burden, genomic characterization of circulating strains, and both phenotypic and genotypic AMR profiling. In Zambia, we found no published surveillance data on\n Shigella<\/jats:italic>\n or resistance patterns in children.\n <\/jats:p>\n <\/jats:sec>\n \n The added value of the study<\/jats:title>\n \n We present an up-to-date, integrated assessment of the burden, genomic diversity, and AMR profiles among\n Shigella<\/jats:italic>\n isolates in children under five in SSA, specifically in a high-risk peri-urban setting in Lusaka, Zambia. By prospectively following a large cohort of 1,400 children and combining culture with WGS, we provide detailed insights into the disease burden and epidemiology of circulating\n Shigella<\/jats:italic>\n strains and the relevance of candidate vaccine antigens. We reveal a high prevalence of multidrug resistance (MDR), including plasmid-mediated and phenotypic resistance to ciprofloxacin, the first-line treatment for\n Shigella<\/jats:italic>\n . We further complement genotypic AMR with phenotypic AMR testing to predict potential resistance genes while measuring antibiotic susceptibility in real clinical settings.\n <\/jats:p>\n <\/jats:sec>\n \n Implications of all the available evidence<\/jats:title>\n \n We demonstrate that\n Shigella<\/jats:italic>\n is genomically diverse and an important etiology of moderate to severe gastroenteritis in Zambian children. Risk factors include increasing age and poor WASH. We observed plasmid-mediated resistance to ciprofloxacin and MDR, which threatens the efficacy of current\n Shigella<\/jats:italic>\n treatment and risks population-level AMR spread. These results highlight the need for improved WASH, antibiotic stewardship, and the development of effective vaccines, supported by ongoing genomic surveillance, to facilitate disease monitoring, inform treatment guidelines, guide vaccine antigen selection, and inform evidence-based antibiotic stewardship.\n <\/jats:p>\n <\/jats:sec>\n <\/jats:sec>","DOI":"10.64898\/2026.05.14.26353268","type":"posted-content","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T23:45:13Z","timestamp":1779407113000},"source":"Crossref","is-referenced-by-count":1,"title":["The Burden and Genomic Characterization of\n Shigella<\/i>\n -Associated Diarrhea in Children Under Five in Lusaka, Zambia: A Prospective Cohort Study"],"prefix":"10.64898","author":[{"given":"Mwelwa","family":"Chibuye","sequence":"first","affiliation":[{"name":"Department of Global Health, Amsterdam Institute for Global Health and Development (AIGHD), Amsterdam University Medical Centers, University of Amsterdam, The 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