Dyson Zoe A, Ashton Philip M, Khanam Farhana, Chunga Chirambo Angeziwa, Shakya Mila, Meiring James E, Tonks Susan, Karkey Abhilasha, Msefula Chisomo, Clemens John D, Dunstan Sarah J, Baker Stephen, Dougan Gordon, Pitzer Virginia E, Basnyat Buddha, Qadri Firdausi, Heyderman Robert S, Gordon Melita A, Pollard Andrew J, Holt Kathryn E
Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK; Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, VIC, Australia; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Malawi-Liverpool-Wellcome Programme, Blantyre, Malawi; Institute of Infection, Veterinary & Ecological Sciences, University of Liverpool, Liverpool, UK.
Lancet Microbe. 2024 Aug;5(8):100841. doi: 10.1016/S2666-5247(24)00047-8. Epub 2024 Jul 9.
Enteric fever is a serious public health concern. The causative agents, Salmonella enterica serovars Typhi and Paratyphi A, frequently have antimicrobial resistance (AMR), leading to limited treatment options and poorer clinical outcomes. We investigated the genomic epidemiology, resistance mechanisms, and transmission dynamics of these pathogens at three urban sites in Africa and Asia.
S Typhi and S Paratyphi A bacteria isolated from blood cultures of febrile children and adults at study sites in Dhaka (Bangladesh), Kathmandu (Nepal), and Blantyre (Malawi) during STRATAA surveillance were sequenced. Isolates were charactered in terms of their serotypes, genotypes (according to GenoTyphi and Paratype), molecular determinants of AMR, and population structure. We used phylogenomic analyses incorporating globally representative genomic data from previously published surveillance studies and ancestral state reconstruction to differentiate locally circulating from imported pathogen AMR variants. Clusters of sequences without any single-nucleotide variants in their core genome were identified and used to explore spatiotemporal patterns and transmission dynamics.
We sequenced 731 genomes from isolates obtained during surveillance across the three sites between Oct 1, 2016, and Aug 31, 2019 (24 months in Dhaka and Kathmandu and 34 months in Blantyre). S Paratyphi A was present in Dhaka and Kathmandu but not Blantyre. S Typhi genotype 4.3.1 (H58) was common in all sites, but with different dominant variants (4.3.1.1.EA1 in Blantyre, 4.3.1.1 in Dhaka, and 4.3.1.2 in Kathmandu). Multidrug resistance (ie, resistance to chloramphenicol, co-trimoxazole, and ampicillin) was common in Blantyre (138 [98%] of 141 cases) and Dhaka (143 [32%] of 452), but absent from Kathmandu. Quinolone-resistance mutations were common in Dhaka (451 [>99%] of 452) and Kathmandu (123 [89%] of 138), but not in Blantyre (three [2%] of 141). Azithromycin-resistance mutations in acrB were rare, appearing only in Dhaka (five [1%] of 452). Phylogenetic analyses showed that most cases derived from pre-existing, locally established pathogen variants; 702 (98%) of 713 drug-resistant infections resulted from local circulation of AMR variants, not imported variants or recent de novo emergence; and pathogen variants circulated across age groups. 479 (66%) of 731 cases clustered with others that were indistinguishable by point mutations; individual clusters included multiple age groups and persisted for up to 2·3 years, and AMR determinants were invariant within clusters.
Enteric fever was associated with locally established pathogen variants that circulate across age groups. AMR infections resulted from local transmission of resistant strains. These results form a baseline against which to monitor the impacts of control measures.
Wellcome Trust, Bill & Melinda Gates Foundation, EU Horizon 2020, and UK National Institute for Health and Care Research.
伤寒热是一个严重的公共卫生问题。病原体，即伤寒沙门氏菌血清型伤寒杆菌和甲型副伤寒杆菌，经常具有抗菌药物耐药性（AMR），导致治疗选择有限且临床结果较差。我们调查了这些病原体在非洲和亚洲三个城市地点的基因组流行病学、耐药机制和传播动态。
对在STRATAA监测期间从达卡（孟加拉国）、加德满都（尼泊尔）和布兰太尔（马拉维）的研究地点发热儿童和成人的血培养物中分离出的伤寒杆菌和甲型副伤寒杆菌进行测序。根据血清型、基因型（根据GenoTyphi和Paratype）、AMR的分子决定因素和种群结构对分离株进行特征分析。我们使用了系统发育基因组分析，纳入了来自先前发表的监测研究的全球代表性基因组数据以及祖先状态重建，以区分本地传播的病原体AMR变体和输入的变体。识别出核心基因组中没有任何单核苷酸变体的序列簇，并用于探索时空模式和传播动态。
我们对2016年10月1日至2019年8月31日期间在三个地点监测期间获得的分离株的731个基因组进行了测序（达卡和加德满都为24个月，布兰太尔为34个月）。甲型副伤寒杆菌存在于达卡和加德满都，但不存在于布兰太尔。伤寒杆菌基因型4.3.1（H58）在所有地点都很常见，但具有不同的主要变体（布兰太尔为4.3.1.1.EA1，达卡为4.3.1.1，加德满都为4.3.1.2）。多重耐药性（即对氯霉素、复方新诺明和氨苄青霉素耐药）在布兰太尔（14日1例中的1例38例[98%]）和达卡（452例中的143例[32%]）很常见，但在加德满都不存在。喹诺酮耐药突变在达卡（452例中的451例[>99%]）和加德满都（138例中的123例[89%]）很常见，但在布兰太尔（141例中的3例[2%]）不常见。acrB中的阿奇霉素耐药突变很少见，仅出现在达卡（452例中的5例[1%]）。系统发育分析表明，大多数病例源自预先存在的、本地存在的病原体变体；713例耐药感染中的702例（98%）是由AMR变体的本地传播引起的，而不是输入变体或最近的从头出现；病原体变体在不同年龄组中传播。731例病例中的479例（66%）与其他通过点突变无法区分的病例聚集在一起；单个簇包括多个年龄组，并持续长达2·3年，并且AMR决定因素在簇内是不变的。
伤寒热与在不同年龄组中传播的本地存在的病原体变体有关。AMR感染是由耐药菌株的本地传播引起的。这些结果形成了一个基线，据此可以监测控制措施的影响。
惠康信托基金会、比尔及梅琳达·盖茨基金会、欧盟地平线2020计划以及英国国家卫生与保健研究所。
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