27 results on '"Baker, Stephen"'
Search Results
2. Ascertaining the burden of invasive Salmonella disease in hospitalised febrile children aged under four years in Blantyre, Malawi.
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Msefula, Chisomo L., Olgemoeller, Franziska, Jambo, Ndaru, Segula, Dalitso, Van Tan, Trinh, Nyirenda, Tonney S., Nedi, Wilfred, Kennedy, Neil, Graham, Matthew, Henrion, Marc Y. R., Baker, Stephen, Feasey, Nicholas, Gordon, Melita, and Heyderman, Robert S.
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SALMONELLA diseases ,TYPHOID fever ,VACCINE effectiveness ,BLOOD volume ,CHILDREN - Abstract
Typhoid fever is endemic across sub-Saharan Africa. However, estimates of the burden of typhoid are undermined by insufficient blood volumes and lack of sensitivity of blood culture. Here, we aimed to address this limitation by exploiting pre-enrichment culture followed by PCR, alongside routine blood culture to improve typhoid case detection. We carried out a prospective diagnostic cohort study and enrolled children (aged 0–4 years) with non-specific febrile disease admitted to a tertiary hospital in Blantyre, Malawi from August 2014 to July 2016. Blood was collected for culture (BC) and real-time PCR after a pre-enrichment culture in tryptone soy broth and ox-bile. DNA was subjected to PCR for invA (Pan-Salmonella), staG (S. Typhi), and fliC (S. Typhimurium) genes. A positive PCR was defined as invA plus either staG or fliC (CT<29). IgM and IgG ELISA against four S. Typhi antigens was also performed. In total, 643 children (median age 1.3 years) with nonspecific febrile disease were enrolled; 31 (4.8%) were BC positive for Salmonella (n = 13 S. Typhi, n = 16 S. Typhimurium, and n = 2 S. Enteritidis). Pre-enrichment culture of blood followed by PCR identified a further 8 S. Typhi and 15 S. Typhimurium positive children. IgM and IgG titres to the S. Typhi antigen STY1498 (haemolysin) were significantly higher in children that were PCR positive but blood culture negative compared to febrile children with all other non-typhoid illnesses. The addition of pre-enrichment culture and PCR increased the case ascertainment of invasive Salmonella disease in children by 62–94%. These data support recent burden estimates that highlight the insensitivity of blood cultures and support the targeting of pre-school children for typhoid vaccine prevention in Africa. Blood culture with real-time PCR following pre-enrichment should be used to further refine estimates of vaccine effectiveness in typhoid vaccine trials. [ABSTRACT FROM AUTHOR]
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- 2019
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3. One hypervirulent clone, sequence type 283, accounts for a large proportion of invasive Streptococcus agalactiae isolated from humans and diseased tilapia in Southeast Asia.
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Barkham, Timothy, Zadoks, Ruth N., Azmai, Mohammad Noor Amal, Baker, Stephen, Bich, Vu Thi Ngoc, Chalker, Victoria, Chau, Man Ling, Dance, David, Deepak, Rama Narayana, van Doorn, H. Rogier, Gutierrez, Ramona A., Holmes, Mark A., Huong, Lan Nguyen Phu, Koh, Tse Hsien, Martins, Elisabete, Mehershahi, Kurosh, Newton, Paul, Ng, Lee Ching, Phuoc, Nguyen Ngoc, and Sangwichian, Ornuma
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STREPTOCOCCUS ,TREPONEMA pallidum ,STREPTOCOCCUS agalactiae ,FOODBORNE diseases ,TILAPIA ,INFECTIOUS arthritis ,FRESHWATER fishes - Abstract
Background: In 2015, Singapore had the first and only reported foodborne outbreak of invasive disease caused by the group B Streptococcus (GBS; Streptococcus agalactiae). Disease, predominantly septic arthritis and meningitis, was associated with sequence type (ST)283, acquired from eating raw farmed freshwater fish. Although GBS sepsis is well-described in neonates and older adults with co-morbidities, this outbreak affected non-pregnant and younger adults with fewer co-morbidities, suggesting greater virulence. Before 2015 ST283 had only been reported from twenty humans in Hong Kong and two in France, and from one fish in Thailand. We hypothesised that ST283 was causing region-wide infection in Southeast Asia. Methodology/Principal findings: We performed a literature review, whole genome sequencing on 145 GBS isolates collected from six Southeast Asian countries, and phylogenetic analysis on 7,468 GBS sequences including 227 variants of ST283 from humans and animals. Although almost absent outside Asia, ST283 was found in all invasive Asian collections analysed, from 1995 to 2017. It accounted for 29/38 (76%) human isolates in Lao PDR, 102/139 (73%) in Thailand, 4/13 (31%) in Vietnam, and 167/739 (23%) in Singapore. ST283 and its variants were found in 62/62 (100%) tilapia from 14 outbreak sites in Malaysia and Vietnam, in seven fish species in Singapore markets, and a diseased frog in China. Conclusions: GBS ST283 is widespread in Southeast Asia, where it accounts for a large proportion of bacteraemic GBS, and causes disease and economic loss in aquaculture. If human ST283 is fishborne, as in the Singapore outbreak, then GBS sepsis in Thailand and Lao PDR is predominantly a foodborne disease. However, whether transmission is from aquaculture to humans, or vice versa, or involves an unidentified reservoir remains unknown. Creation of cross-border collaborations in human and animal health are needed to complete the epidemiological picture. [ABSTRACT FROM AUTHOR]
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- 2019
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4. Hospital-acquired colonization and infections in a Vietnamese intensive care unit.
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Thuy, Duong Bich, Campbell, James, Nhat, Le Thanh Hoang, Hoang, Nguyen Van Minh, Hao, Nguyen Van, Baker, Stephen, Geskus, Ronald B., Thwaites, Guy E., Chau, Nguyen Van Vinh, and Thwaites, C. Louise
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NOSOCOMIAL infections ,INTENSIVE care units ,HOSPITAL sanitation ,METHICILLIN-resistant staphylococcus aureus ,ESCHERICHIA coli diseases - Abstract
Data concerning intensive care unit (ICU)-acquired bacterial colonization and infections are scarce from low and middle-income countries (LMICs). ICU patients in these settings are at high risk of becoming colonized and infected with antimicrobial-resistant organisms (AROs). We conducted a prospective observational study at the Ho Chi Minh City Hospital for Tropical Diseases, Vietnam from November 2014 to January 2016 to assess the ICU-acquired colonization and infections, focusing on the five major pathogens in our setting: Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Klebsiella spp., Pseudomonas spp. and Acinetobacter spp., among adult patients with more than 48 hours of ICU stay. We found that 61.3% (223/364) of ICU patients became colonized with AROs: 44.2% (161/364) with rectal ESBL-producing E. coli and Klebsiella spp.; 30.8% (40/130) with endotracheal carbapenemase-producing Acinetobacter spp.; and 14.3% (52/364) with nasal methicillin-resistant S. aureus. The incidence rate of ICU patients becoming colonized with AROs was 9.8 (223/2,276) per 100 patient days. Significant risk factor for AROs colonization was the Charlson Comorbidity Index score. The proportion of ICU patients with HAIs was 23.4% (85/364), and the incidence rate of ICU patients contracting HAIs was 2.3 (85/3,701) per 100 patient days. The vascular catheterization (central venous, arterial and hemofiltration catheter) was significantly associated with hospital-acquired bloodstream infection. Of the 77 patients who developed ICU-acquired infections with one of the five specified bacteria, 44 (57.1%) had prior colonization with the same organism. Vietnamese ICU patients have a high colonization rate with AROs and a high risk of subsequent infections. Future research should focus on monitoring colonization and the development of preventive measures that may halt spread of AROs in ICU settings. [ABSTRACT FROM AUTHOR]
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- 2018
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5. Diagnostic metabolite biomarkers of chronic typhoid carriage.
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Näsström, Elin, Jonsson, Pär, Johansson, Anders, Dongol, Sabina, Karkey, Abhilasha, Basnyat, Buddha, Tran Vu Thieu, Nga, Trinh Van, Tan, Thwaites, Guy E., Antti, Henrik, and Baker, Stephen
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TYPHOID fever diagnosis ,SALMONELLA typhi ,GALLBLADDER ,BIOLOGICAL tags ,METABOLITES - Abstract
Background: Salmonella Typhi and Salmonella Paratyphi A are the agents of enteric (typhoid) fever; both can establish chronic carriage in the gallbladder. Chronic Salmonella carriers are typically asymptomatic, intermittently shedding bacteria in the feces, and contributing to disease transmission. Detecting chronic carriers is of public health relevance in areas where enteric fever is endemic, but there are no routinely used methods for prospectively identifying those carrying Salmonella in their gallbladder. Methodology/Principal findings: Here we aimed to identify biomarkers of Salmonella carriage using metabolite profiling. We performed metabolite profiling on plasma from Nepali patients undergoing cholecystectomy with confirmed S. Typhi or S. Paratyphi A gallbladder carriage (and non-carriage controls) using two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GCxGC-TOFMS) and supervised pattern recognition modeling. We were able to significantly discriminate Salmonella carriage samples from non-carriage control samples. We were also able to detect differential signatures between S. Typhi and S. Paratyphi A carriers. We additionally compared carriage metabolite profiles with profiles generated during acute infection; these data revealed substantial heterogeneity between metabolites associated with acute enteric fever and chronic carriage. Lastly, we found that Salmonella carriers could be significantly distinguished from non-carriage controls using only five metabolites, indicating the potential of these metabolites as diagnostic markers for detecting chronic Salmonella carriers. Conclusions/Significance: Our novel approach has highlighted the potential of using metabolomics to search for diagnostic markers of chronic Salmonella carriage. We suggest further epidemiological investigations of these potential biomarkers in alternative endemic enteric fever settings. [ABSTRACT FROM AUTHOR]
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- 2018
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6. Molecular characterization of hepatitis B virus in Bangladesh reveals a highly recombinant population.
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Munshi, Saif Ullah, Tran, Thanh Thi Thanh, Vo, Truc Nhu Thanh, Tabassum, Shahina, Sultana, Nahida, Nguyen, Trang Hoa, Jahan, Munira, Le, Chau Ngoc, Baker, Stephen, and Rahman, Motiur
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HEPATITIS B treatment ,RECOMBINANT viruses ,MICROBIAL virulence ,DISEASE prevalence ,GENETIC mutation - Abstract
The natural history and treatment outcome of hepatitis B viruses (HBV) infection is largely dependent on genotype, subgenotype, and the presence or absence of virulence associated mutations. We have studied the prevalence of genotype and subgenotype as well as virulence and drug resistance associated mutations and prevalence of recombinant among HBV from Bangladesh. A prospective cross-sectional study was conducted among treatment naïve chronic HBV patients attending at Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh for HBV viral load assessment between June and August 2015. Systematical selected 50% of HBV DNA positive patients (every second patient) were enrolled. Biochemical and serological markers for HBV infection and whole genome sequencing (WGS) was performed on virus positive sample. Genotype, subgenotype, virulence, nucleos(t)ide analogue (NA) resistance (NAr) mutations, and the prevalence of recombinant isolates were determined. Among 114 HBV DNA positive patients, 57 were enrolled in the study and 53 HBV WGS were generated for downstream analysis. Overall, 38% (22/57) and 62% (35/57) of patients had acute and chronic HBV infections, respectively. The prevalence of genotypes A, C, and D was 18.9% (10/53), 45.3% (24/53), and 35.8% (19/53), respectively. Among genotype A, C and D isolates subgenotype A1 (90%; 9/10), C1 (87.5%; 21/24) and D2 (78.9%; 15/19) predominates. The acute infection, virulence associated mutations, and viral load was higher in the genotype D isolates. Evidence of recombination was identified in 22.6% (12/53) of the HBV isolates including 20.0% (2/10), and 16.7% (4/24) and 31.6% (6/19) of genotype A, C and D isolates, respectively. The prevalence of recombination was higher in chronic HVB patients (32.2%; 10/31 versus 9.1%; 2/22); p<0.05. NAr mutations were identified in 47.2% (25/53) of the isolates including 33.9% novel mutations (18/53). HBV genotype C and D predominated in this population in Bangladesh; a comparatively high prevalence of recombinant HBV are circulating in this setting. [ABSTRACT FROM AUTHOR]
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- 2017
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7. A 23-year retrospective investigation of Salmonella Typhi and Salmonella Paratyphi isolated in a tertiary Kathmandu hospital.
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Zellweger, Raphaël M., Basnyat, Buddha, Shrestha, Poojan, Prajapati, Krishna G., Dongol, Sabina, Sharma, Paban K., Koirala, Samir, Darton, Thomas C., Dolecek, Christiane, Thompson, Corinne N., Thwaites, Guy E., Baker, Stephen G., and Karkey, Abhilasha
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SALMONELLA typhi ,DISEASE susceptibility ,ANTI-infective agents ,TYPHOID fever treatment ,RETROSPECTIVE studies - Abstract
Background: Salmonella serovars Typhi (S. Typhi) and Paratyphi A (S. Paratyphi A), the causative agents of enteric fever, have been routinely isolated organisms from the blood of febrile patients in the Kathmandu Valley since the early 1990s. Susceptibility against commonly used antimicrobials for treating enteric fever has gradually changed throughout South Asia since this time, posing serious treatment challenges. Here, we aimed to longitudinally describe trends in the isolation of Salmonella enterica and assess changes in their antimicrobial susceptibility in Kathmandu over a 23-year period. Methods: We conducted a retrospective analysis of standardised microbiological data from April 1992 to December 2014 at a single healthcare facility in Kathmandu, examining time trends of Salmonella-associated bacteraemia and the corresponding antimicrobial susceptibility profiles of the isolated organisms. Results: Over 23 years there were 30,353 positive blood cultures. Salmonella enterica accounted for 65.4% (19,857/30,353) of all the bacteria positive blood cultures. S. Typhi and S. Paratyphi A were the dominant serovars, constituting 68.5% (13,592/19,857) and 30.5% (6,057/19,857) of all isolated Salmonellae. We observed (i) a peak in the number of Salmonella-positive cultures in 2002, a year of heavy rainfall and flooding in the Kathmandu Valley, followed by a decline toward pre-flood baseline by 2014, (ii) an increase in the proportion of S. Paratyphi in all Salmonella-positive cultures between 1992 and 2014, (iii) a decrease in the prevalence of MDR for both S. Typhi and S. Paratyphi, and (iv) a recent increase in fluoroquinolone non-susceptibility in both S. Typhi and S. Paratyphi isolates. Conclusions: Our work describes significant changes in the epidemiology of Salmonella enterica in the Kathmandu Valley during the last quarter of a century. We highlight the need to examine current treatment protocols for enteric fever and suggest a change from fluoroquinolone monotherapy to combination therapies of macrolides or cephalosporins along with older first-line antimicrobials that have regained their efficacy. [ABSTRACT FROM AUTHOR]
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- 2017
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8. A one-year prospective study of colonization with antimicrobial-resistant organisms on admission to a Vietnamese intensive care unit.
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Thuy, Duong Bich, Campbell, James, Hoang, Nguyen Van Minh, Trinh, Truong Thi Thuy, Duong, Ha Thi Hai, Hieu, Nguyen Chi, Duy, Nguyen Hoang Anh, Hao, Nguyen Van, Baker, Stephen, Thwaites, Guy E., Chau, Nguyen Van Vinh, and Thwaites, C. Louise
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BACTERIAL disease risk factors ,INTENSIVE care units ,STAPHYLOCOCCUS aureus ,BACTERIAL colonies ,ACINETOBACTER ,DRUG resistance in bacteria - Abstract
There is a paucity of data regarding initial bacterial colonization on admission to Intensive Care Units (ICUs) in low and middle-income countries (LMICs). Patients admitted to ICUs in LMICs are at high-risk of subsequent infection with antimicrobial-resistant organisms (AROs). We conducted a prospective, observational study at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam from November 2014 to January 2016 to assess the colonization and antimicrobial susceptibility of Staphylococcus aureus, Escherichia coli, Klebsiella spp., Pseudomonas spp. and Acinetobacter spp. among adult patients within 48 hours of ICU admission. We found the admission colonization prevalence (with at least one of the identified organisms) was 93.7% (785/838) and that of AROs was 63.1% (529/838). The colonization frequency with AROs among patients admitted from the community was comparable to those transferred from other hospitals (62.2% vs 63.8%). Staphylococcus aureus was the most commonly isolated bacteria from nasal swabs (13.1%, 110/838) and the methicillin-resistant Staphylococcus aureus nasal colonization prevalence was 8.6% (72/838). We isolated Escherichia coli from rectal swabs from almost all enrolled patients (88.3%, 740/838) and 52.1% (437/838) of patients were colonized by extended spectrum β-lactamase producing Escherichia coli. Notably, Klebsiella pneumoniae was the most frequently isolated bacteria from the tracheal swabs (11.8%, 18/153). Vietnamese ICU patients have a high rate of colonization with AROs and are thus at risk of subsequent infections with these organisms if good infection control practices are not in place. [ABSTRACT FROM AUTHOR]
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- 2017
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9. A cross-sectional seroepidemiological survey of typhoid fever in Fiji.
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Watson, Conall H., Baker, Stephen, Lau, Colleen L., Rawalai, Kitione, Taufa, Mere, Coriakula, Jerimaia, Thieu, Nga Tran Vu, Van, Tan Trinh, Ngoc, Dung Tran Thi, Hens, Niel, Lowry, John, de Alwis, Ruklanthi, Cano, Jorge, Jenkins, Kylie, Mulholland, E. Kim, Nilles, Eric J., Kama, Mike, and Edmunds, W. John
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TYPHOID fever , *SALMONELLA enterica serovar Typhi , *IMMUNOGLOBULIN G , *IMMUNE system , *MULTIVARIABLE calculus - Abstract
Fiji, an upper-middle income state in the Pacific Ocean, has experienced an increase in confirmed case notifications of enteric fever caused by Salmonella enterica serovar Typhi (S. Typhi). To characterize the epidemiology of typhoid exposure, we conducted a cross-sectional sero-epidemiological survey measuring IgG against the Vi antigen of S. Typhi to estimate the effect of age, ethnicity, and other variables on seroprevalence. Epidemiologically relevant cut-off titres were established using a mixed model analysis of data from recovering culture-confirmed typhoid cases. We enrolled and assayed plasma of 1787 participants for anti-Vi IgG; 1,531 of these were resident in mainland areas that had not been previously vaccinated against S. Typhi (seropositivity 32.3% (95%CI 28.2 to 36.3%)), 256 were resident on Taveuni island, which had been previously vaccinated (seropositivity 71.5% (95%CI 62.1 to 80.9%)). The seroprevalence on the Fijian mainland is one to two orders of magnitude higher than expected from confirmed case surveillance incidence, suggesting substantial subclinical or otherwise unreported typhoid. We found no significant differences in seropositivity prevalences by ethnicity, which is in contrast to disease surveillance data in which the indigenous iTaukei Fijian population are disproportionately affected. Using multivariable logistic regression, seropositivity was associated with increased age (odds ratio 1.3 (95% CI 1.2 to 1.4) per 10 years), the presence of a pit latrine (OR 1.6, 95%CI 1.1 to 2.3) as opposed to a septic tank or piped sewer, and residence in settlements rather than residential housing or villages (OR 1.6, 95% CI 1.0 to 2.7). Increasing seropositivity with age is suggestive of low-level endemic transmission in Fiji. Improved sanitation where pit latrines are used and addressing potential transmission routes in settlements may reduce exposure to S. Typhi. Widespread unreported infection suggests there may be a role for typhoid vaccination in Fiji, in addition to public health management of cases and outbreaks. [ABSTRACT FROM AUTHOR]
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- 2017
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10. Comparative genomics of Cryptococcus neoformans var. grubii associated with meningitis in HIV infected and uninfected patients in Vietnam.
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Day, Jeremy N., Qihui, Seet, Thanh, Lam Tuan, Trieu, Phan Hai, Van, Anh Duong, Thu, Nha Hoang, Chau, Tran Thi Hong, Lan, Nguyen P. H., Chau, Nguyen Van Vinh, Ashton, Philip M., Thwaites, Guy E., Boni, Maciej F., Wolbers, Marcel, Nagarajan, Niranjan, Tan, Patrick B. O., and Baker, Stephen
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GENOMICS ,CRYPTOCOCCUS neoformans ,MENINGITIS ,HIV infections ,LYMPHOCYTES - Abstract
The vast burden of cryptococcal meningitis occurs in immunosuppressed patients, driven by HIV, and is caused by Cryptococcus neoformans var. grubii. We previously reported cryptococcal meningitis in Vietnam arising atypically in HIV uninfected, apparently immunocompetent patients, caused by a single amplified fragment length polymorphism (AFLP) cluster of C. neoformans var. grubii (VNIγ). This variant was less common in HIV infected individuals; it remains unclear why this lineage is associated with apparently immunocompetent patients. To study this host tropism we aimed to further our understanding of clinical phenotype and genomic variation within Vietnamese C. neoformans var. grubii. After performing MLST on C. neoformans clinical isolates we identified 14 sequence types (STs); ST5 correlated with the VNIγ cluster. We next compared clinical phenotype by lineage and found HIV infected patients with cryptococcal meningitis caused by ST5 organisms were significantly more likely to have lymphadenopathy (11% vs. 4%, p = 0.05 Fisher’s exact test) and higher blood lymphocyte count (median 0.76 versus 0.55 X10
9 cells/L, p = 0.001, Kruskal-Wallis test). Furthermore, survivors of ST5 infections had evidence of worse disability outcomes at 70 days (72.7% (40/55) in ST5 infections versus 57.1% (52/91) non-ST5 infections (OR 2.11, 95%CI 1.01 to 4.41), p = 0.046). To further investigate the relationship between strain and disease phenotype we performed genome sequencing on eight Vietnamese C. neoformans var. grubii. Eight genome assemblies exhibited >99% nucleotide sequence identity and we identified 165 kbp of lineage specific to Vietnamese isolates. ST5 genomes harbored several strain specific regions, incorporating 19 annotated coding sequences and eight hypothetical proteins. These regions included a phenolic acid decarboxylase, a DEAD-box ATP-dependent RNA helicase 26, oxoprolinases, a taurine catabolism dioxygenase, a zinc finger protein, membrane transport proteins and various drug transporters. Our work outlines the complexity of genomic pathogenicity in cryptococcal infections and identifies a number of gene candidates that may aid the disaggregation of the pathways associated with the pathogenesis of Cryptococcus neoformans var. grubii. [ABSTRACT FROM AUTHOR]- Published
- 2017
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11. The impact of migration and antimicrobial resistance on the transmission dynamics of typhoid fever in Kathmandu, Nepal: A mathematical modelling study.
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Saad, Neil J., Bowles, Cayley C., Grenfell, Bryan T., Basnyat, Buddha, Arjyal, Amit, Dongol, Sabina, Karkey, Abhilasha, Baker, Stephen, and Pitzer, Virginia E.
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TYPHOID fever ,ANTI-infective agents ,DRUG resistance in microorganisms ,INFECTIOUS disease transmission - Abstract
Background: A substantial proportion of the global burden of typhoid fever occurs in South Asia. Kathmandu, Nepal experienced a substantial increase in the number of typhoid fever cases (caused by Salmonella Typhi) between 2000 and 2003, which subsequently declined but to a higher endemic level than in 2000. This epidemic of S. Typhi coincided with an increase in organisms with reduced susceptibility against fluoroquinolones, the emergence of S. Typhi H58, and an increase in the migratory population in Kathmandu. Methods: We devised a mathematical model to investigate the potential epidemic drivers of typhoid in Kathmandu and fit this model to weekly data of S. Typhi cases between April 1997 and June 2011 and the age distribution of S. Typhi cases. We used this model to determine if the typhoid epidemic in Kathmandu was driven by heightened migration, the emergence of organisms with reduced susceptibility against fluoroquinolones or a combination of these factors. Results: Models allowing for the migration of susceptible individuals into Kathmandu alone or in combination with the emergence of S. Typhi with reduced susceptibility against fluoroquinolones provided a good fit for the data. The emergence of organisms with reduced susceptibility against fluoroquinolones organisms alone, either through an increase in disease duration or increased transmission, did not fully explain the pattern of S. Typhi infections. Conclusions: Our analysis is consistent with the hypothesis that the increase in typhoid fever in Kathmandu was associated with the migration of susceptible individuals into the city and aided by the emergence of reduced susceptibility against fluoroquinolones. These data support identifying and targeting migrant populations with typhoid immunization programmes to prevent transmission and disease. [ABSTRACT FROM AUTHOR]
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- 2017
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12. Whole Genome Sequence Analysis of Salmonella Typhi Isolated in Thailand before and after the Introduction of a National Immunization Program.
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Dyson, Zoe A., Holt, Kathryn E., Thanh, Duy Pham, Vinh, Phat Voong, Thanh, Tuyen Ha, Rabaa, Maia A., Thwaites, Guy E., Baker, Stephen, Bodhidatta, Ladaporn, Mason, Carl Jeffries, and Srijan, Apichai
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SALMONELLA genetics ,NUCLEOTIDE sequencing ,SALMONELLA typhi ,TYPHOID fever ,TYPHOID vaccines ,IMMUNIZATION ,MEDICAL care ,GOVERNMENT policy ,DISEASE risk factors - Abstract
Vaccines against Salmonella Typhi, the causative agent of typhoid fever, are commonly used by travellers, however, there are few examples of national immunization programs in endemic areas. There is therefore a paucity of data on the impact of typhoid immunization programs on localised populations of S. Typhi. Here we have used whole genome sequencing (WGS) to characterise 44 historical bacterial isolates collected before and after a national typhoid immunization program that was implemented in Thailand in 1977 in response to a large outbreak; the program was highly effective in reducing typhoid case numbers. Thai isolates were highly diverse, including 10 distinct phylogenetic lineages or genotypes. Novel prophage and plasmids were also detected, including examples that were previously only reported in Shigella sonnei and Escherichia coli. The majority of S. Typhi genotypes observed prior to the immunization program were not observed following it. Post-vaccine era isolates were more closely related to S. Typhi isolated from neighbouring countries than to earlier Thai isolates, providing no evidence for the local persistence of endemic S. Typhi following the national immunization program. Rather, later cases of typhoid appeared to be caused by the occasional importation of common genotypes from neighbouring Vietnam, Laos, and Cambodia. These data show the value of WGS in understanding the impacts of vaccination on pathogen populations and provide support for the proposal that large-scale typhoid immunization programs in endemic areas could result in lasting local disease elimination, although larger prospective studies are needed to test this directly. [ABSTRACT FROM AUTHOR]
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- 2017
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13. Molecular Surveillance Identifies Multiple Transmissions of Typhoid in West Africa.
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null, null, Wong, Vanessa K., Holt, Kathryn E., Okoro, Chinyere, Baker, Stephen, Pickard, Derek J., Marks, Florian, Page, Andrew J., Olanipekun, Grace, Munir, Huda, Alter, Roxanne, Fey, Paul D., Feasey, Nicholas A., Weill, Francois-Xavier, Le Hello, Simon, Hart, Peter J., Kariuki, Samuel, Breiman, Robert F., Gordon, Melita A., and Heyderman, Robert S.
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TYPHOID fever diagnosis ,TYPHOID fever ,PUBLIC health ,CHILDREN'S health ,PATIENTS ,MANAGEMENT - Abstract
Background: The burden of typhoid in sub-Saharan African (SSA) countries has been difficult to estimate, in part, due to suboptimal laboratory diagnostics. However, surveillance blood cultures at two sites in Nigeria have identified typhoid associated with Salmonella enterica serovar Typhi (S. Typhi) as an important cause of bacteremia in children. Methods: A total of 128 S. Typhi isolates from these studies in Nigeria were whole-genome sequenced, and the resulting data was used to place these Nigerian isolates into a worldwide context based on their phylogeny and carriage of molecular determinants of antibiotic resistance. Results: Several distinct S. Typhi genotypes were identified in Nigeria that were related to other clusters of S. Typhi isolates from north, west and central regions of Africa. The rapidly expanding S. Typhi clade 4.3.1 (H58) previously associated with multiple antimicrobial resistances in Asia and in east, central and southern Africa, was not detected in this study. However, antimicrobial resistance was common amongst the Nigerian isolates and was associated with several plasmids, including the IncHI1 plasmid commonly associated with S. Typhi. Conclusions: These data indicate that typhoid in Nigeria was established through multiple independent introductions into the country, with evidence of regional spread. MDR typhoid appears to be evolving independently of the haplotype H58 found in other typhoid endemic countries. This study highlights an urgent need for routine surveillance to monitor the epidemiology of typhoid and evolution of antimicrobial resistance within the bacterial population as a means to facilitate public health interventions to reduce the substantial morbidity and mortality of typhoid. [ABSTRACT FROM AUTHOR]
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- 2016
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14. Invasive Non-typhoidal Salmonella Infections in Asia: Clinical Observations, Disease Outcome and Dominant Serovars from an Infectious Disease Hospital in Vietnam.
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Phu Huong Lan, Nguyen, Le Thi Phuong, Tu, Nguyen Huu, Hien, Thuy, Le, Mather, Alison E., Park, Se Eun, Marks, Florian, Thwaites, Guy E., Van Vinh Chau, Nguyen, Thompson, Corinne N., and Baker, Stephen
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SALMONELLA diseases ,HIV infections ,TROPICAL medicine ,BACTEREMIA ,INSTITUTIONAL review boards - Abstract
Invasive non-typhoidal Salmonella (iNTS) infections are now a well-described cause of morbidity and mortality in children and HIV-infected adults in sub-Saharan Africa. In contrast, the epidemiology and clinical manifestations of iNTS disease in Asia are not well documented. We retrospectively identified >100 cases of iNTS infections in an infectious disease hospital in Southern Vietnam between 2008 and 2013. Clinical records were accessed to evaluate demographic and clinical factors associated with iNTS infection and to identify risk factors associated with death. Multi-locus sequence typing and antimicrobial susceptibility testing was performed on all organisms. Of 102 iNTS patients, 71% were HIV-infected, >90% were adults, 71% were male and 33% reported intravenous drug use. Twenty-six/92 (28%) patients with a known outcome died; HIV infection was significantly associated with death (p = 0.039). S. Enteritidis (Sequence Types (ST)11) (48%, 43/89) and S. Typhimurium (ST19, 34 and 1544) (26%, 23/89) were the most commonly identified serovars; S. Typhimurium was significantly more common in HIV-infected individuals (p = 0.003). Isolates from HIV-infected patients were more likely to exhibit reduced susceptibility against trimethoprim-sulfamethoxazole than HIV-negative patients (p = 0.037). We conclude that iNTS disease is a severe infection in Vietnam with a high mortality rate. As in sub-Saharan Africa, HIV infection was a risk factor for death, with the majority of the burden in this population found in HIV-infected adult men. [ABSTRACT FROM AUTHOR]
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- 2016
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15. The Molecular and Spatial Epidemiology of Typhoid Fever in Rural Cambodia.
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Pham Thanh, Duy, Thompson, Corinne N., Rabaa, Maia A, Sona, Soeng, Sopheary, Sun, Kumar, Varun, Moore, Catrin, Tran Vu Thieu, Nga, Wijedoru, Lalith, Holt, Kathryn E., Wong, Vanessa, Pickard, Derek, Thwaites, Guy E., Day, Nicholas, Dougan, Gordon, Turner, Paul, Parry, Christopher M., and Baker, Stephen
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MOLECULAR epidemiology ,TYPHOID fever ,SALMONELLA typhi ,NUCLEOTIDE sequencing ,EPIDEMIOLOGY - Abstract
Typhoid fever, caused by the bacterium Salmonella Typhi, is an endemic cause of febrile disease in Cambodia. The aim of this study was to better understand the epidemiology of pediatric typhoid fever in Cambodia. We accessed routine blood culture data from Angkor Hospital for Children (AHC) in Siem Reap province between 2007 and 2014, and performed whole genome sequencing (WGS) on the isolated bacteria to characterize the S. Typhi population. The resulting phylogenetic information was combined with conventional epidemiological approaches to investigate the spatiotemporal distribution of S. Typhi and population-level risk factors for reported disease. During the study period, there were 262 cases of typhoid within a 100 km radius of AHC, with a median patient age of 8.2 years (IQR: 5.1–11.5 years). The majority of infections occurred during the rainy season, and commune incidences as high as 11.36/1,000 in children aged <15 years were observed over the study period. A population-based risk factor analysis found that access to water within households and increasing distance from Tonle Sap Lake were protective. Spatial mapping and WGS provided additional resolution for these findings, and confirmed that proximity to the lake was associated with discrete spatiotemporal disease clusters. We confirmed the dominance of MDR H58 S. Typhi in this population, and found substantial evidence of diversification (at least seven sublineages) within this single lineage. We conclude that there is a substantial burden of pediatric typhoid fever in rural communes in Cambodia. Our data provide a platform for additional population-based typhoid fever studies in this location, and suggest that this would be a suitable setting in which to introduce a school-based vaccination programme with Vi conjugate vaccines. [ABSTRACT FROM AUTHOR]
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- 2016
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16. A Phylogenetic and Phenotypic Analysis of Salmonella enterica Serovar Weltevreden, an Emerging Agent of Diarrheal Disease in Tropical Regions.
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Makendi, Carine, Page, Andrew J., Wren, Brendan W., Le Thi Phuong, Tu, Clare, Simon, Hale, Christine, Goulding, David, Klemm, Elizabeth J., Pickard, Derek, Okoro, Chinyere, Hunt, Martin, Thompson, Corinne N., Phu Huong Lan, Nguyen, Tran Do Hoang, Nhu, Thwaites, Guy E., Le Hello, Simon, Brisabois, Anne, Weill, François-Xavier, Baker, Stephen, and Dougan, Gordon
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SALMONELLA enterica ,BACTERIA phylogeny ,VIRULENCE of bacteria ,BACTERIAL genomes ,LABORATORY mice - Abstract
Salmonella enterica serovar Weltevreden (S. Weltevreden) is an emerging cause of diarrheal and invasive disease in humans residing in tropical regions. Despite the regional and international emergence of this Salmonella serovar, relatively little is known about its genetic diversity, genomics or virulence potential in model systems. Here we used whole genome sequencing and bioinformatics analyses to define the phylogenetic structure of a diverse global selection of S. Weltevreden. Phylogenetic analysis of more than 100 isolates demonstrated that the population of S. Weltevreden can be segregated into two main phylogenetic clusters, one associated predominantly with continental Southeast Asia and the other more internationally dispersed. Subcluster analysis suggested the local evolution of S. Weltevreden within specific geographical regions. Four of the isolates were sequenced using long read sequencing to produce high quality reference genomes. Phenotypic analysis in Hep-2 cells and in a murine infection model indicated that S. Weltevreden were significantly attenuated in these models compared to the classical S. Typhimurium reference strain SL1344. Our work outlines novel insights into this important emerging pathogen and provides a baseline understanding for future research studies. [ABSTRACT FROM AUTHOR]
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- 2016
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17. An age-stratified serosurvey against purified Salmonella enterica serovar Typhi antigens in the Lao People´s Democratic Republic
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Lisa Hefele, Antony P. Black, Trinh Van Tan, Nguyen Tri Minh, Nguyen Duc Hoang, Siriphone Virachith, Claude P. Muller, Judith M. Hübschen, Paula Russell, Josefin Bartholdson Scott, Chau Nguyen Ngoc Minh, Tran Vu Thieu Nga, Stephen Baker, Tri Minh, Nguyen [0000-0002-1819-2296], Duc Hoang, Nguyen [0000-0003-2437-3568], Virachith, Siriphone [0000-0001-5049-0544], Hübschen, Judith M [0000-0002-5001-2128], Russell, Paula [0000-0003-2389-6631], Bartholdson Scott, Josefin [0000-0003-3380-4446], Thieu Nga, Tran Vu [0000-0003-3672-9867], Baker, Stephen [0000-0003-1308-5755], and Apollo - University of Cambridge Repository
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Bacterial Diseases ,Male ,Physiology ,Epidemiology ,RC955-962 ,Fevers ,Pathology and Laboratory Medicine ,Biochemistry ,Cohort Studies ,Medical Conditions ,Salmonella ,Immune Physiology ,Arctic medicine. Tropical medicine ,Typhoid ,Ethnicities ,Enzyme-Linked Immunoassays ,Child ,Immune System Proteins ,Age Factors ,Antibodies, Bacterial ,Bacterial Pathogens ,Infectious Diseases ,Serology ,Medical Microbiology ,Laos ,Child, Preschool ,Lao People ,Female ,Pathogens ,Public aspects of medicine ,RA1-1270 ,Research Article ,Adult ,Adolescent ,Immunology ,Enzyme-Linked Immunosorbent Assay ,Microbiology ,Antibodies ,Young Adult ,Signs and Symptoms ,Asian People ,Enterobacteriaceae ,Humans ,Typhoid Fever ,Immunoassays ,Microbial Pathogens ,Medicine and health sciences ,Antigens, Bacterial ,Bacteria ,Biology and life sciences ,Public Health, Environmental and Occupational Health ,Organisms ,Proteins ,Infant ,Salmonella typhi ,Research and analysis methods ,Immunoglobulin G ,Immunologic Techniques ,Population Groupings ,Clinical Medicine ,People and places - Abstract
The epidemiology of typhoid fever in Lao People`s Democratic Republic is poorly defined. Estimating the burden of typhoid fever in endemic countries is complex due to the cost and limitations of population-based surveillance; serological approaches may be a more cost-effective alternative. ELISAs were performed on 937 serum samples (317 children and 620 adults) from across Lao PDR to measure IgG antibody titers against Vi polysaccharide and the experimental protein antigens, CdtB and HlyE. We measured the significance of the differences between antibody titers in adults and children and fitted models to assess the relationship between age and antibody titers. The median IgG titres of both anti-HylE and CdtB were significantly higher in children compared to adults (anti-HylE; 351.7 ELISA Units (EU) vs 198.1 EU, respectively; p, Author summary Typhoid fever is a serious bloodstream infection caused by the bacterium Salmonella Typhi. Estimating the burden of typhoid fever is complex due to the limitations, cost, and scalability of current diagnostic surveillance methods. The detection of specific antibody responses against the organism may be a more sustainable manner of measuring exposure and disease burden in endemic location. We measured antibody (IgG) in 937 serum samples (317 children and 620 adults) from across the Lao People`s Democratic Republic against a polysaccharide (Vi) and two experimental protein antigens, CdtB and HlyE, that may more appropriate markers of disease exposure. We measured the significance of the differences between antibody titers in adults and children and fitted models to assess the relationship between age and antibody titers. The median IgG titres against HylE and CdtB were significantly higher in children than adults. Conversely, the median IgG titres against Vi was significantly higher in adults than children. We identified a significant association between a peak in IgG titres against CdtB and HlyE in children aged under 5 years. These data are indicative of high level of typhoid fever exposure in children under 5 years of age in Lao PDR and we surmise that IgG titres against HylE and CdtB may be a superior measure of typhoid disease burden than IgG titres against Vi. Our approach is scalable and can be further validated to assess the burden of typhoid fever in countries where the disease may be endemic, and evidence is required for the introduction of typhoid vaccines.
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- 2022
18. A genomic snapshot of Salmonella enterica serovar Typhi in Colombia
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To Nguyen Thi Nguyen, Duy Pham Thanh, Paula Diaz Guevara, Megan E Carey, Enrique Perez, Thanh Ho Ngoc Dan, Edna Catering Rodríguez, Mailis Maes, Stephen Baker, Carolina Duarte, Isabel Chinen, Lucy Angeline Montaño, Josefina Campos, Maes, Mailis [0000-0002-0266-6557], Thanh, Duy Pham [0000-0001-7029-9210], Duarte, Carolina [0000-0001-7596-8292], Rodriguez, Edna Catering [0000-0001-5537-1923], Montaño, Lucy Angeline [0000-0002-0083-211X], Carey, Megan E. [0000-0002-7797-9080], Campos, Josefina [0000-0003-1409-0441], Perez, Enrique [0000-0002-7730-899X], Apollo - University of Cambridge Repository, Baker, Stephen [0000-0003-1308-5755], and Carey, Megan E [0000-0002-7797-9080]
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Bacterial Diseases ,Epidemiology ,Single Nucleotide Polymorphisms ,RC955-962 ,Salmonella typhi ,Pathology and Laboratory Medicine ,Salmonella Typhi ,Geographical locations ,0302 clinical medicine ,Medical Conditions ,Salmonella ,Arctic medicine. Tropical medicine ,Typhoid ,030212 general & internal medicine ,Clade ,Data Management ,Genetics ,0303 health sciences ,Computer and information sciences ,Genomics ,3. Good health ,Bacterial Pathogens ,Anti-Bacterial Agents ,Phylogenetics ,Infectious Diseases ,Medical Microbiology ,Population Surveillance ,Pathogens ,Public aspects of medicine ,RA1-1270 ,Research Article ,Biology ,Colombia ,Disease Surveillance ,Microbiology ,complex mixtures ,Typhoid fever ,03 medical and health sciences ,Antibiotic resistance ,Enterobacteriaceae ,Microbial Control ,Drug Resistance, Bacterial ,Pulsed-field gel electrophoresis ,medicine ,Evolutionary Systematics ,Typhoid Fever ,Genotyping ,Microbial Pathogens ,030304 developmental biology ,Taxonomy ,Whole genome sequencing ,Pharmacology ,Medicine and health sciences ,Genetic diversity ,Evolutionary Biology ,Bacteria ,Biology and life sciences ,Public Health, Environmental and Occupational Health ,Organisms ,South America ,medicine.disease ,bacterial infections and mycoses ,Antimicrobial Resistance ,People and places - Abstract
Little is known about the genetic diversity of Salmonella enterica serovar Typhi (S. Typhi) circulating in Latin America. It has been observed that typhoid fever is still endemic in this part of the world; however, a lack of standardized blood culture surveillance across Latin American makes estimating the true disease burden problematic. The Colombian National Health Service established a surveillance system for tracking bacterial pathogens, including S. Typhi, in 2006. Here, we characterized 77 representative Colombian S. Typhi isolates collected between 1997 and 2018 using pulse field gel electrophoresis (PFGE; the accepted genotyping method in Latin America) and whole genome sequencing (WGS). We found that the main S. Typhi clades circulating in Colombia were clades 2.5 and 3.5. Notably, the sequenced S. Typhi isolates from Colombia were closely related in a global phylogeny. Consequently, these data suggest that these are endemic clades circulating in Colombia. We found that AMR in S. Typhi in Colombia was uncommon, with a small subset of organisms exhibiting mutations associated with reduced susceptibility to fluoroquinolones. This is the first time that S. Typhi isolated from Colombia have been characterized by WGS, and after comparing these data with those generated using PFGE, we conclude that PFGE is unsuitable for tracking S. Typhi clones and mapping transmission. The genetic diversity of pathogens such as S. Typhi is limited in Latin America and should be targeted for future surveillance studies incorporating WGS., Author summary Salmonella Typhi is the causative agent of typhoid fever, with between 9–13 million cases and 116,800 associated deaths annually. Typhoid fever is still a public health problem mainly in low and middle-income countries (LMICs), including in Latin America, which has a modelled incidence of up to 169 (32–642) cases per 100,000 person-years. Several international studies have aimed to fill data gaps regarding the global distribution and genetic landscape of typhoid; however, in spite of these efforts Latin America is still underrepresented. The globally dominant lineages of S. Typhi (e.g., H58), which often carry multi-drug resistance (MDR) plasmids, decreased fluoroquinolone susceptibility, and now azithromycin resistance, are not detectable by the accepted method (PFGE) used to track outbreaks of typhoid in Latin America. We compared PFGE with whole genome sequence (WGS) and found it correlated poorly, resulting in the over clustering of cases. We additionally found that unlike in most endemic countries, S. Typhi in Colombia are highly antimicrobial susceptible and restricted to a limited number of genotypes that are not as commonly identified in other S. Typhi endemic countries. Our study provides the first enhanced insights into the molecular epidemiology of S. Typhi in Colombia, using WGS data for the first time to investigate the population structure in Colombia and identifying predominant circulating genotypes. Our work demonstrates that routine surveillance with the integration of WGS is necessary not only to improve disease burden estimates, but also to track the national and regional transmission dynamics of S. Typhi.
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- 2021
19. Spatiotemporal persistence of multiple, diverse clades and toxins of Corynebacterium diphtheriae
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Eva Heinz, Karthick Vasudevan, Thandavarayan Ramamurthy, Stephen Baker, Ankur Mutreja, Naresh Chand Sharma, Gordon Dougan, Agila Kumari Pragasam, Pradeep Haldar, Robert C. Will, Balaji Veeraraghavan, Bhabatosh Das, Lucky Sangal, Vyacheslav Melnikov, Vartul Sangal, Dhirendra Kumar, Will, Robert C. [0000-0002-4230-5182], Kumar, Dhirendra [0000-0002-8014-2521], Das, Bhabatosh [0000-0002-2447-5380], Heinz, Eva [0000-0003-4413-3756], Melnikov, Vyacheslav [0000-0002-0825-7930], Baker, Stephen [0000-0003-1308-5755], Sangal, Vartul [0000-0002-7405-8446], Mutreja, Ankur [0000-0002-1118-8075], Apollo - University of Cambridge Repository, and Will, Robert C [0000-0002-4230-5182]
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0301 basic medicine ,Bacterial toxins ,Diphtheria Toxoid ,General Physics and Astronomy ,medicine.disease_cause ,Bacterial evolution ,Anti-Infective Agents ,Diphtheria Toxin ,Clade ,Phylogeny ,Genetics ,Multidisciplinary ,biology ,article ,Diphtheria ,C500 ,Genomics ,C700 ,humanities ,3. Good health ,Pathogens ,wc_320 ,Science ,030106 microbiology ,631/326/41/2529 ,631/326/41/1319 ,qw_125 ,India ,45/22 ,45/23 ,Microbial Sensitivity Tests ,complex mixtures ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,qw_805 ,03 medical and health sciences ,Antibiotic resistance ,Phylogenetics ,Drug Resistance, Bacterial ,medicine ,Humans ,Gene ,631/326/41/2530 ,Bacterial genomics ,Corynebacterium diphtheriae ,45 ,Toxin ,631/326/421 ,qu_500 ,Genetic Variation ,General Chemistry ,biology.organism_classification ,medicine.disease ,030104 developmental biology ,Bacteria ,Genome, Bacterial - Abstract
Diphtheria is a respiratory disease caused by the bacterium Corynebacterium diphtheriae. Although the development of a toxin-based vaccine in the 1930s has allowed a high level of control over the disease, cases have increased in recent years. Here, we describe the genomic variation of 502 C. diphtheriae isolates across 16 countries and territories over 122 years. We generate a core gene phylogeny and determine the presence of antimicrobial resistance genes and variation within the tox gene of 291 tox+ isolates. Numerous, highly diverse clusters of C. diphtheriae are observed across the phylogeny, each containing isolates from multiple countries, regions and time of isolation. The number of antimicrobial resistance genes, as well as the breadth of antibiotic resistance, is substantially greater in the last decade than ever before. We identified and analysed 18 tox gene variants, with mutations estimated to be of medium to high structural impact., Cases of diphtheria have increased in recent years. Here, the authors analyse the genomes of 502 Corynebacterium diphtheriae isolates across 16 countries and territories over 122 years, describing an increase in antimicrobial resistance genes and identifying toxin variants.
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- 2021
20. Gallbladder carriage generates genetic variation and genome degradation in Salmonella Typhi
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To Nguyen Thi Nguyen, Maia A. Rabaa, Ho Ngoc Dan Thanh, Buddha Basnyat, Gordon Dougan, Sabina Dongol, Megan E Carey, Pham Thanh Duy, Abhilasha Karkey, Stephen Baker, Nga Tran Vu Thieu, Thanh Duy, Pham [0000-0001-7029-9210], Karkey, Abhilasha [0000-0002-5179-650X], Carey, Megan [0000-0002-7797-9080], Basnyat, Buddha [0000-0002-1125-2743], Rabaa, Maia A [0000-0003-0529-2228], Baker, Stephen [0000-0003-1308-5755], Apollo - University of Cambridge Repository, and Rabaa, Maia A. [0000-0003-0529-2228]
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Bacterial Diseases ,Male ,Single Nucleotide Polymorphisms ,Adaptation, Biological ,Pathology and Laboratory Medicine ,Salmonella typhi ,Biochemistry ,Medical Conditions ,Salmonella ,Genotype ,Typhoid ,Biology (General) ,Phylogeny ,Data Management ,0303 health sciences ,education.field_of_study ,Vi capsular polysaccharide vaccine ,Computer and information sciences ,030302 biochemistry & molecular biology ,Gallbladder ,Nonsense Mutation ,Phylogenetic Analysis ,Middle Aged ,Bacterial Pathogens ,3. Good health ,Anti-Bacterial Agents ,Phylogenetics ,Infectious Diseases ,medicine.anatomical_structure ,Liver ,Medical Microbiology ,Female ,Anatomy ,Pathogens ,medicine.drug ,Research Article ,Adult ,QH301-705.5 ,Immunology ,Population ,Biology ,Microbiology ,Typhoid fever ,03 medical and health sciences ,Enterobacteriaceae ,Virology ,DNA-binding proteins ,Genetic variation ,Genetics ,medicine ,Humans ,Evolutionary Systematics ,Genetic variability ,Typhoid Fever ,education ,Microbial Pathogens ,Molecular Biology ,Taxonomy ,030304 developmental biology ,Aged ,Medicine and health sciences ,Evolutionary Biology ,Bacteria ,Biology and life sciences ,Whole Genome Sequencing ,Organisms ,Proteins ,Genetic Variation ,RC581-607 ,medicine.disease ,Biliary System ,Mutation ,Parasitology ,Immunologic diseases. Allergy - Abstract
Despite recent advances in typhoid fever control, asymptomatic carriage of Salmonella Typhi in the gallbladder remains poorly understood. Aiming to understand if S. Typhi becomes genetically adapted for long-term colonisation in the gallbladder, we performed whole genome sequencing on a collection of S. Typhi isolated from the gallbladders of typhoid carriers. These sequences were compared to contemporaneously sampled sequences from organisms isolated from the blood of acute patients within the same population. We found that S. Typhi carriage was not restricted to any particular genotype or conformation of antimicrobial resistance genes, but was largely reflective of S. Typhi circulating in the general population. However, gallbladder isolates showed a higher genetic variability than acute isolates, with median pairwise SNP distances of 21 and 13 SNPs (p = 2.8x10-9), respectively. Within gallbladder isolates of the predominant H58 genotype, variation was associated with a higher prevalence of nonsense mutations. Notably, gallbladder isolates displayed a higher frequency of non-synonymous mutations in genes encoding hypothetical proteins, membrane lipoproteins, transport/binding proteins, surface antigens, and carbohydrate degradation. Specifically, we identified several gallbladder-specific non-synonymous mutations involved in LPS synthesis and modification, with some isolates lacking the Vi capsular polysaccharide vaccine target due to the 134Kb deletion of SPI-7. S. Typhi is under strong selective pressure in the human gallbladder, which may be reflected phylogenetically by long terminal branches that may distinguish organisms from chronic and acute infections. Our work shows that selective pressures asserted by the hostile environment of the human gallbladder generate new antigenic variants and raises questions regarding the role of carriage in the epidemiology of typhoid fever., Author summary Salmonella Typhi is the bacterium that causes typhoid. Salmonella Typhi is infamous for being able to be carried in the gallbladder, with Typhoid Mary being the best-known example of a typhoid carrier. Despite having new tools for typhoid control, we have made little progress in understanding this disease process. Aiming to understand if Salmonella Typhi is adapted for long-term survival in the gallbladder, we sequenced the genomes of 24 Salmonella Typhi isolated from the gallbladders of typhoid carriers. We compared these genomes to Salmonella Typhi from acute typhoid patients within the same population. The carriage of Salmonella Typhi was not restricted to any specific genotype or resistance to antibiotics, but reflective of the organisms causing acute disease. However, gallbladder isolates had higher genetic variability than acute isolates, with a higher frequency of mutations changing the amino acid sequences of hypothetical proteins, membrane lipoproteins, transport/binding proteins, surface antigens, and carbohydrate degradation. We identified several gallbladder-specific mutations involved in polysaccharide synthesis on the bacterial surface. Our work shows that selective pressures asserted by the hostile environment of the human gallbladder generates genetic variation, which is not observed in acute isolates, raising questions regarding the role of carriage in the epidemiology of typhoid.
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- 2020
21. A novel therapeutic antibody screening method using bacterial high-content imaging reveals functional antibody binding phenotypes of Escherichia coli ST131
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Stephen Baker, Catherine Ludden, Zoe A. Dyson, Stephen Reece, David Goulding, Josefin Bartholdson Scott, Gordon Dougan, Sarah E. Smith, Mailis Maes, Paul Kellam, Baker, Stephen [0000-0003-1308-5755], Dougan, Gordon [0000-0003-0022-965X], Bartholdson Scott, Josefin [0000-0003-3380-4446], and Apollo - University of Cambridge Repository
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0301 basic medicine ,lcsh:Medicine ,medicine.disease_cause ,Antimicrobial resistance ,631/154/51/1568 ,631/154/1435/2417 ,Insertion sequence ,lcsh:Science ,631/326 ,Escherichia coli Infections ,Phylogeny ,Multidisciplinary ,biology ,Virulence ,Chemistry ,631/326/41 ,High-throughput screening ,article ,O Antigens ,Phenotype ,Anti-Bacterial Agents ,Antibody ,Pathogens ,Phenotypic screening ,medicine.drug_class ,030106 microbiology ,Microbial Sensitivity Tests ,Monoclonal antibody ,Antibodies, Monoclonal, Humanized ,Microbiology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Drug Resistance, Bacterial ,medicine ,Escherichia coli ,Humans ,Gene ,Bacteria ,631/326/421 ,lcsh:R ,High-Throughput Screening Assays ,Interspersed Repetitive Sequences ,Microscopy, Electron ,030104 developmental biology ,631/326/22/1434 ,biology.protein ,Feasibility Studies ,lcsh:Q ,Antibody therapy ,631/154/1435/2163 - Abstract
Funder: National Institute for Health Research; doi: http://dx.doi.org/10.13039/501100000272, Funder: MRC Proximity to Discovery: Industry Engagement Fund Biomedical Research Exchange Programme, The increase of antimicrobial resistance (AMR), and lack of new classes of licensed antimicrobials, have made alternative treatment options for AMR pathogens increasingly attractive. Recent studies have demonstrated anti-bacterial efficacy of a humanised monoclonal antibody (mAb) targeting the O25b O-antigen of Escherichia coli ST131. To evaluate the phenotypic effects of antibody binding to diverse clinical E. coli ST131 O25b bacterial isolates in high-throughput, we designed a novel mAb screening method using high-content imaging (HCI) and image-based morphological profiling to screen a mAb targeting the O25b O-antigen. Screening the antibody against a panel of 86 clinical E. coli ST131 O25:H4 isolates revealed 4 binding phenotypes: no binding (18.60%), weak binding (4.65%), strong binding (69.77%) and strong agglutinating binding (6.98%). Impaired antibody binding could be explained by the presence of insertion sequences or mutations in O-antigen or lipopolysaccharide core biosynthesis genes, affecting the amount, structure or chain length of the O-antigen. The agglutinating binding phenotype was linked with lower O-antigen density, enhanced antibody-mediated phagocytosis and increased serum susceptibly. This study highlights the need to screen candidate mAbs against large panels of clinically relevant isolates, and that HCI can be used to evaluate mAb binding affinity and potential functional efficacy against AMR bacteria.
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- 2020
22. Surveillance of Salmonella enterica serovar Typhi in Colombia, 2012-2015
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Mailis Maes, Stephen Baker, Julio Cesar Martinez Angarita, Duy Pham Thanh, Carolina Duarte, Gabriela Zabaleta, William León-Quevedo, Miriam Moroni, Enrique Perez, Jaime Guerrero, Carlos Castañeda-Orjuela, Lucy Angeline Montaño, Paula Díaz-Guevara, Josefina Campos, Claudia Jimena Alvarez Alvarez, Diaz-Guevara, Paula [0000-0002-8252-5622], Baker, Stephen [0000-0003-1308-5755], and Apollo - University of Cambridge Repository
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Bacterial Diseases ,0301 basic medicine ,Male ,Epidemiology ,RC955-962 ,Fevers ,Drug resistance ,Pathology and Laboratory Medicine ,Salmonella typhi ,Geographical locations ,0302 clinical medicine ,Public health surveillance ,Salmonella ,Ampicillin ,Arctic medicine. Tropical medicine ,Typhoid ,Ethnicities ,Public and Occupational Health ,Child ,Aged, 80 and over ,Disease surveillance ,Geography ,Transmission (medicine) ,Population groupings ,Middle Aged ,Bacterial Pathogens ,Phylogeography ,Infectious Diseases ,Biogeography ,Medical Microbiology ,Child, Preschool ,Epidemiological Monitoring ,Female ,Pathogens ,Public aspects of medicine ,RA1-1270 ,medicine.drug ,Research Article ,Adult ,medicine.medical_specialty ,Adolescent ,Genotype ,Ecology and environmental sciences ,030231 tropical medicine ,Microbial Sensitivity Tests ,Disease Surveillance ,Biology ,Colombia ,Microbiology ,Typhoid fever ,03 medical and health sciences ,Young Adult ,Signs and Symptoms ,Age Distribution ,Enterobacteriaceae ,Diagnostic Medicine ,Environmental health ,Drug Resistance, Bacterial ,Genetics ,medicine ,Humans ,Sex Distribution ,Typhoid Fever ,Microbial Pathogens ,Aged ,Retrospective Studies ,Medicine and health sciences ,Evolutionary Biology ,Bacteria ,Population Biology ,Biology and life sciences ,Organisms ,Public Health, Environmental and Occupational Health ,Genetic Variation ,Infant ,Latin American people ,South America ,medicine.disease ,bacterial infections and mycoses ,Molecular Typing ,Earth sciences ,030104 developmental biology ,People and places ,Population Genetics - Abstract
Funder: Instituto Nacional de Salud, Bogotá, Colombia, Salmonella Typhi (S. Typhi) is the causative agent of typhoid fever; a systemic disease affecting ~20 million people per year globally. There are little data regarding the contemporary epidemiology of typhoid in Latin America. Consequently, we aimed to describe some recent epidemiological aspects of typhoid in Colombia using cases reported to the National Public Health Surveillance System (Sivigila) between 2012 and 2015. Over the four-year reporting period there were 836 culture confirmed cases of typhoid in Colombia, with the majority (676/836; 80.1%) of reported cases originated from only seven departments. We further characterized 402 S. Typhi isolates with available corresponding data recovered from various departments of Colombia through antimicrobial susceptibility testing and molecular subtyping. The majority (235/402; 58.5%) of these typhoid cases occurred in males and were most commonly reported in those aged between 10 and 29 years (218/402; 54.2%); there were three (0.74%) reported fatalities. The overwhelming preponderance (339/402; 84.3%) of S. Typhi were susceptible to all tested antimicrobials. The most common antimicrobial to which the organisms exhibited non-susceptibility was ampicillin (30/402;7.5%), followed by nalidixic acid (23/402, 5.7%). Molecular subtyping identified substantial genetic diversity, which was well distributed across the country. Despite the diffuse pattern of S. Typhi genotypes, we identified various geographical hotspots of disease associated with local dominant genotypes. Notably, we found limited overlap of Colombian genotypes with organisms reported in other Latin American countries. Our work highlights a substantial burden of typhoid in Colombia, characterized by sustained transmission in some regions and limited epidemics in other departments. The disease is widely distributed across the country and associated with multiple antimicrobial susceptible genotypes that appear to be restricted to Colombia. This study provides a current perspective for typhoid in Latin America and highlights the importance of pathogen-specific surveillance to add insight into the limited epidemiology of typhoid in this region.
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- 2020
23. Dissecting the molecular evolution of fluoroquinolone-resistant Shigella sonnei
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Stephen Baker, To Nguyen Thi Nguyen, Ryan R. Wick, Paul Turner, Pieter-Jan Ceyssens, Vinh Phat Voong, Claire Jenkins, Vu Thuy Duong, François-Xavier Weill, Tuyen Ha Thanh, Guy E. Thwaites, Ladaporn Bodhidatta, Duy Pham Thanh, Martin Cormican, Kathryn E. Holt, Nicholas R. Thomson, Maia A. Rabaa, Sonam Wangchuk, Phu H. Nguyen, Christine J. Boinett, Mary Valcanis, Benjamin P Howden, Carl J. Mason, Niall De Lappe, Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), Public Health England [London], Centre National de Référence - National Reference Center Escherichia coli, Shigella et Salmonella (CNR-ESS), Institut Pasteur [Paris], The Peter Doherty Institute for Infection and Immunity [Melbourne], University of Melbourne-The Royal Melbourne Hospital, University Hospital Galway, National University of Ireland [Galway] (NUI Galway), Ministry of Health [Bhoutan], Armed Forces Research Institute of Medical Sciences [Bangkok] (AFRIMS), Hospital for Tropical Diseases, Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Angkor Hospital for Children (AHC), Monash University [Melbourne], Sciensano [Bruxelles], Réseau International des Instituts Pasteur (RIIP), London School of Hygiene and Tropical Medicine (LSHTM), The Wellcome Trust Sanger Institute [Cambridge], University of Cambridge [UK] (CAM), H.C.T. received a DPhil scholarship from the Tropical Network Fund, Nuffield Department of Medicine, University of Oxford. S.B. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (100087/Z/12/Z). We thank I. Carle, M. Lejay-Collin, and C. Ruckly from the Institut Pasteur for their excellent technical assistance. F.X.W is funded by the Institut Pasteur, Santé Publique France, and by the French Government 'Investissement d’Avenir' program (Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence, grant no. ANR-10-LABX-62-IBEID)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Chung The, Hao [0000-0002-4028-4074], Weill, Francois-Xavier [0000-0001-9941-5799], Howden, Benjamin P [0000-0003-0237-1473], Mason, Carl J [0000-0002-3676-2811], Turner, Paul [0000-0002-1013-7815], Wick, Ryan [0000-0001-8349-0778], Holt, Kathryn E [0000-0003-3949-2471], Rabaa, Maia A [0000-0003-0529-2228], Baker, Stephen [0000-0003-1308-5755], Apollo - University of Cambridge Repository, Howden, Benjamin P. [0000-0003-0237-1473], Mason, Carl J. [0000-0002-3676-2811], Holt, Kathryn E. [0000-0003-3949-2471], Rabaa, Maia A. [0000-0003-0529-2228], Institut Pasteur [Paris] (IP), and University of Oxford-University of Oxford
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0301 basic medicine ,General Physics and Astronomy ,Drug resistance ,Antimicrobial resistance ,Ciprofloxacin ,Bacterial genetics ,Shigella sonnei ,lcsh:Science ,Asia, Southeastern ,Phylogeny ,Genetics ,Experimental evolution ,education.field_of_study ,Molecular Epidemiology ,Multidisciplinary ,article ,3. Good health ,Anti-Bacterial Agents ,Europe ,DNA Gyrase ,Pathogens ,Fluoroquinolones ,DNA Topoisomerase IV ,Shigellosis ,Science ,030106 microbiology ,Population ,45/22 ,631/208/325/2482 ,45/23 ,Biology ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Evolution, Molecular ,03 medical and health sciences ,Molecular evolution ,Phylogenetics ,Drug Resistance, Bacterial ,medicine ,Asia, Western ,Humans ,education ,Dysentery, Bacillary ,Molecular epidemiology ,45 ,631/326/421 ,Bayes Theorem ,General Chemistry ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,bacterial infections and mycoses ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,digestive system diseases ,030104 developmental biology ,692/699/255/1318 ,631/326/22/1434 ,Mutation ,bacteria ,lcsh:Q ,Bacterial infection ,Directed Molecular Evolution ,Genome, Bacterial - Abstract
Shigella sonnei increasingly dominates the international epidemiological landscape of shigellosis. Treatment options for S. sonnei are dwindling due to resistance to several key antimicrobials, including the fluoroquinolones. Here we analyse nearly 400 S. sonnei whole genome sequences from both endemic and non-endemic regions to delineate the evolutionary history of the recently emergent fluoroquinolone-resistant S. sonnei. We reaffirm that extant resistant organisms belong to a single clonal expansion event. Our results indicate that sequential accumulation of defining mutations (gyrA-S83L, parC-S80I, and gyrA-D87G) led to the emergence of the fluoroquinolone-resistant S. sonnei population around 2007 in South Asia. This clone was then transmitted globally, resulting in establishments in Southeast Asia and Europe. Mutation analysis suggests that the clone became dominant through enhanced adaptation to oxidative stress. Experimental evolution reveals that under fluoroquinolone exposure in vitro, resistant S. sonnei develops further intolerance to the antimicrobial while the susceptible counterpart fails to attain complete resistance., Shigella sonnei is one of the main species causing shigellosis worldwide. Here the authors analyse nearly 400 S. sonnei genome sequences and carry out experimental evolution experiments to shed light into the evolutionary processes underlying the recent emergence of fluoroquinolone resistance in this pathogen.
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- 2019
24. Development of ELISAs for diagnosis of acute typhoid fever in Nigerian children
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Binta W. Jibir, Stephen K. Obaro, Jiin Felgner, Safiya Gambo, Algis Jasinskas, Aarti Jain, Fabio Miyajima, Fatimah Hassan-Hanga, Rie Nakajima, Kudirat Eyinade Olateju, Li Liang, Philip L. Felgner, Joseph M. Vinetz, Eduardo Gotuzzo, D. Huw Davies, Munir Pirmohamed, Dominic Umoru, and Baker, Stephen
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Immunoglobulin A ,Salmonella ,Febre Tifoide ,Salmonellosis ,Pathology and Laboratory Medicine ,Pediatrics ,Salmonella Typhi ,Immunoglobulin G ,Hemolysin Proteins ,0302 clinical medicine ,Immunoglobulin A/blood ,Typhoid ,Public and Occupational Health ,Child ,Child Health ,Bacterial ,Antibodies, Bacterial/blood ,3. Good health ,Bacterial Pathogens ,Blood ,Medical Microbiology ,Child, Preschool ,Pediatric Infections ,Infection ,purl.org/pe-repo/ocde/ford#3.03.06 [https] ,lcsh:RC955-962 ,Ensaio de Imunoadsorção Enzimática ,Nigeria ,Microbiology ,Sensitivity and Specificity ,03 medical and health sciences ,Clinical Research ,Biodefense ,Humans ,Lipopolysaccharides/immunology ,Serologic Tests ,Typhoid Fever ,Microbial Pathogens ,Serologic Tests/methods ,Bacteria ,Prevention ,Public Health, Environmental and Occupational Health ,Organisms ,Biology and Life Sciences ,Infant ,lcsh:RA1-1270 ,Salmonella typhi ,Immunoglobulin M/blood ,medicine.disease ,Tropical Diseases ,Immunoglobulin G/blood ,Immunoglobulin M ,Immunology ,Digestive Diseases ,Hemolysin Proteins/immunology ,Bacterial Diseases ,Lipopolysaccharides ,Physiology ,medicine.disease_cause ,Medical and Health Sciences ,Serology ,Zoonoses ,Medicine and Health Sciences ,030212 general & internal medicine ,Pediatric ,Salmonella typhi/immunology ,biology ,lcsh:Public aspects of medicine ,Biological Sciences ,Antibodies, Bacterial ,Body Fluids ,Infectious Diseases ,Typhoid Fever/diagnosis ,Pathogens ,Anatomy ,Research Article ,Neglected Tropical Diseases ,lcsh:Arctic medicine. Tropical medicine ,030231 tropical medicine ,Enzyme-Linked Immunosorbent Assay ,Typhoid fever ,Brucellosis ,Antibodies ,Vaccine Related ,Rare Diseases ,Enterobacteriaceae ,Tropical Medicine ,medicine ,Preschool ,Enzyme-Linked Immunosorbent Assay/methods ,business.industry ,Emerging Infectious Diseases ,Good Health and Well Being ,ROC Curve ,biology.protein ,business - Abstract
Improved serodiagnostic tests for typhoid fever (TF) are needed for surveillance, to facilitate patient management, curb antibiotic resistance, and inform public health programs. To address this need, IgA, IgM and IgG ELISAs using Salmonella enterica serovar Typhi (S. Typhi) lipopolysaccharide (LPS) and hemolysin E (t1477) protein were conducted on 86 Nigerian pediatric TF and 29 non-typhoidal Salmonella (NTS) cases, 178 culture-negative febrile cases, 28 “other” (i.e., non-Salmonella) pediatric infections, and 48 healthy Nigerian children. The best discrimination was achieved between TF and healthy children. LPS-specific IgA and IgM provided receiver operator characteristic areas under the curve (ROC AUC) values of 0.963 and 0.968, respectively, and 0.978 for IgA+M combined. Similar performance was achieved with t1477-specific IgA and IgM (0.968 and 0.968, respectively; 0.976 combined). IgG against LPS and t1477 was less accurate for discriminating these groups, possibly as a consequence of previous exposure, although ROC AUC values were still high (0.928 and 0.932, respectively). Importantly, discrimination between TF and children with other infections was maintained by LPS-specific IgA and IgM (AUC = 0.903 and 0.934, respectively; 0.938 combined), and slightly reduced for IgG (0.909), while t1477-specific IgG performed best (0.914). A similar pattern was seen when comparing TF with other infections from outside Nigeria. The t1477 may be recognized by cross-reactive antibodies from other acute infections, although a robust IgG response may provide some diagnostic utility in populations where incidence of other infections is low, such as in children. The data are consistent with IgA and IgM against S. Typhi LPS being specific markers of acute TF., Author summary In many African countries, clinical management of children that present with symptoms of bacterial sepsis, such as typhoid fever (TF) caused by Salmonella Typhi, consists of empiric broad spectrum antibiotics. Blood culture remains the gold-standard for diagnosis, but is slow, suffers from poor sensitivity, and often unavailable. Consequently multi-drug resistant bacteria have emerged that are difficult to manage with antibiotics. There is an urgent need to develop rapid, sensitive and affordable tests for patient diagnosis, help curb antibiotic resistance, and inform public health preventive strategies such as the deployment of vaccines. Here, we have assessed antibodies to S. Typhi lipopolysaccharide (LPS) and hemolysin E (HylE, t1477) in the sera of Nigerian children with acute TF and compared them with heathy children, children with other febrile infections, and adults from around the world with a variety of other bacterial infections. The key finding concerns LPS. This is a common cell-wall component present in many bacterial species. Yet despite this, S. Typhi LPS-specific IgA and IgM are excellent markers of acute TF in Nigerian children, and insensitive to other non-salmonelloses. This surprising finding suggests a rapid point-of-care test for TF can be developed based on detection of LPS-specific IgA+IgM.
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- 2017
25. Molecular Surveillance Identifies Multiple Transmissions of Typhoid in West Africa
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Ben Amos, Roxanne Alter, Samuel Kariuki, Elizabeth de Pinna, Robert F. Breiman, Anthony M. Smith, Calman A. MacLennan, Nicholas A. Feasey, Peter J. Hart, Stephen K. Obaro, Gordon Dougan, Chinyere K. Okoro, Huda Munir, Melita A. Gordon, Andrew J. Page, Vanessa K. Wong, Octavie Lunguya, Paul D. Fey, Simon Le Hello, Robert S. Heyderman, Chisomo L. Msefula, Robert S. Onsare, Kathryn E. Holt, Florian Marks, Derek Pickard, Karen H. Keddy, Stephen Baker, François-Xavier Weill, Satheesh Nair, Grace Olanipekun, Jan Jacobs, The Wellcome Trust Sanger Institute [Cambridge], Addenbrooke's Hospital, Cambridge University NHS Trust, Bio21 Molecular Science & Biotechnology Institute [Melbourne] (School of Chemistry), Faculty of Science [Melbourne], University of Melbourne-University of Melbourne, University of Melbourne, Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), Nuffield Department of Clinical Medicine [Oxford], University of Oxford [Oxford], London School of Hygiene and Tropical Medicine (LSHTM), Department of Epidemiology, International Vaccine Institute (IVI), International Foundation Against Infectious Diseases in Nigeria (IFAIN), Department of Medical Microbiology, Aminu Kano Teaching Hospital, University of Nebraska Medical Center, University of Nebraska System, Liverpool School of Tropical Medicine (LSTM), Centre National de Référence - National Reference Center Escherichia coli, Shigella et Salmonella (CNR-ESS), Institut Pasteur [Paris], Institut National de Recherche Biomédicale [Kinshasa] (INRB), St. George’s, University of London, Kenya Medical Research Institute (KEMRI), Global Disease Detection Division, Centers for Disease Control and Prevention, Emory Global Health Institute [Atlanta] (EGHI), Emory University [Atlanta, GA], University of Liverpool, University College of London [London] (UCL), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Malawi, National Institute for Communicable Diseases [Johannesburg] (NICD), St Augustine’s Hospital, Division of Pediatric Infectious Diseases, University of Nebraska System-University of Nebraska System, University of Abuja, Bingham University, This work was supported by a number of organizations. The Wellcome Trust Sanger Institute authors were funded by Wellcome Trust Award 098051, NAF was supported by the Wellcome Trust Research Fellowship WT092152MA. NAF, RSH and this work were supported by a strategic award from the Wellcome Trust for the MLW Clinical Research Programme (101113/Z/13/Z). KEH was supported by the NHMRC of Australia (fellowship #1061409) and the Victorian Life Sciences Computation Initiative (VLSCI) (grant #VR0082). CAM was supported by a Clinical Research Fellowship from GlaxoSmithKline and PJH by a UK Medical Research Council PhD studentship. This work forms part of an EU FP7 Marie Curie Actions Industry Academia Partnerships and Pathways (IAPP) Consortium Programme, entitled GENDRIVAX (Genome-driven vaccine development for bacterial infections), involving the Wellcome Trust Sanger Institute, KEMRI Nairobi and Novartis Vaccines Institute for Global Health. The Institut Pasteur (IP) authors were funded by the IP, the Institut de Veille Sanitaire, and by the French Government 'Investissement d'Avenir' program(Integrative Biology of Emerging Infectious Diseases' Laboratory of Excellence, grant no. ANR-10-LABX-62-IBEID). CO was supported by Society in Science, The Branco Weiss Fellowship, administered by the ETH Zurich. JJ was supported by the antibioticresistance surveillance project in DR Congo, funded by Project 2.01 of the Third Framework Agreement between the Belgian Directorate General of Development Cooperation and the Institute of Tropical Medicine, Antwerp, Belgium. FM was supported by a research grant from the Bill & Melinda Gates Foundation. The findings and conclusions contained within this publication are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation. SK was supported by the NIH Grant Number R01 AI099525-02. SB is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society(100087/Z/12/Z). SO was supported by the National Institute Of Allergy And Infectious Diseases (NIAID) of the National Institutes of Health (#R01AI097493). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis,decision to publish, or preparation of the manuscript., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Baker, Stephen [0000-0003-1308-5755], Marks, Florian [0000-0002-6043-7170], Dougan, Gordon [0000-0003-0022-965X], Apollo - University of Cambridge Repository, University of Oxford, Institut Pasteur [Paris] (IP), and Ryan, E
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0301 basic medicine ,Bacterial Diseases ,Veterinary medicine ,Salmonella typhi ,Pathology and Laboratory Medicine ,Global Health ,Salmonella Typhi ,Geographical Locations ,0302 clinical medicine ,Salmonella ,Epidemiology ,Global health ,Medicine and Health Sciences ,Typhoid ,Medicine ,Public and Occupational Health ,Clade ,Mammals ,lcsh:Public aspects of medicine ,International Typhoid Consortium ,3. Good health ,Bacterial Pathogens ,Europe ,Infectious Diseases ,Medical Microbiology ,Vertebrates ,Pathogens ,Research Article ,medicine.medical_specialty ,lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,030231 tropical medicine ,Nigeria ,Microbiology ,complex mixtures ,Typhoid fever ,wa_110 ,03 medical and health sciences ,Antibiotic resistance ,Enterobacteriaceae ,Environmental health ,Microbial Control ,Animals ,Microbial Pathogens ,QR355 ,Pharmacology ,Bacteria ,business.industry ,qw_138 ,wc_270 ,Public Health, Environmental and Occupational Health ,Organisms ,Biology and Life Sciences ,lcsh:RA1-1270 ,medicine.disease ,bacterial infections and mycoses ,R1 ,United Kingdom ,030104 developmental biology ,Carriage ,Parasitology ,Amniotes ,People and Places ,Africa ,Cats ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Antimicrobial Resistance ,business - Abstract
Background The burden of typhoid in sub-Saharan African (SSA) countries has been difficult to estimate, in part, due to suboptimal laboratory diagnostics. However, surveillance blood cultures at two sites in Nigeria have identified typhoid associated with Salmonella enterica serovar Typhi (S. Typhi) as an important cause of bacteremia in children. Methods A total of 128 S. Typhi isolates from these studies in Nigeria were whole-genome sequenced, and the resulting data was used to place these Nigerian isolates into a worldwide context based on their phylogeny and carriage of molecular determinants of antibiotic resistance. Results Several distinct S. Typhi genotypes were identified in Nigeria that were related to other clusters of S. Typhi isolates from north, west and central regions of Africa. The rapidly expanding S. Typhi clade 4.3.1 (H58) previously associated with multiple antimicrobial resistances in Asia and in east, central and southern Africa, was not detected in this study. However, antimicrobial resistance was common amongst the Nigerian isolates and was associated with several plasmids, including the IncHI1 plasmid commonly associated with S. Typhi. Conclusions These data indicate that typhoid in Nigeria was established through multiple independent introductions into the country, with evidence of regional spread. MDR typhoid appears to be evolving independently of the haplotype H58 found in other typhoid endemic countries. This study highlights an urgent need for routine surveillance to monitor the epidemiology of typhoid and evolution of antimicrobial resistance within the bacterial population as a means to facilitate public health interventions to reduce the substantial morbidity and mortality of typhoid., Author Summary Typhoid fever, a serious bloodstream infection caused by the bacterium Salmonella Typhi, is a major cause of disease and death around the world. There have been limited data on the epidemiology of typhoid in many countries in sub-Saharan African, including Nigeria. Recent evidence, however, showed that typhoid was an important cause of bacteraemia in children residing in two regions of Nigeria. Here, we analyzed the whole genome sequences of 128 S. Typhi isolates from two studies in order to elucidate the population structure and characterize the genetic components of antimicrobial resistance. We found that the multiple S. Typhi genotypes identified were closely related to other S. Typhi from neighboring regions of Africa and that multidrug resistance (MDR) was common among these isolates, and in many cases was associated with the IncHI1 plasmid known to cause MDR typhoid. These results provide evidence that typhoid was established in Nigeria as a result of several independent introductions into the country and that there has been extensive exchange of S. Typhi in and around the region of West Africa. This study emphasizes the importance of surveillance to improve our understanding of the epidemiology of typhoid, which is needed to underpin public health measures to reduce the spread of disease and facilitate patient management.
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- 2016
26. Invasive Non-typhoidal Salmonella Infections in Asia: Clinical Observations, Disease Outcome and Dominant Serovars from an Infectious Disease Hospital in Vietnam
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Le Thuy, Se Eun Park, Florian Marks, Tu Le Thi Phuong, Stephen Baker, Corinne N. Thompson, Nguyen Van Vinh Chau, Alison E. Mather, Hien Nguyen Huu, Guy E. Thwaites, Nguyen Phu Huong Lan, Small, P, Marks, Florian [0000-0002-6043-7170], Baker, Stephen [0000-0003-1308-5755], and Apollo - University of Cambridge Repository
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Bacterial Diseases ,Male ,0301 basic medicine ,Salmonellosis ,HIV Infections ,Disease ,Pathology and Laboratory Medicine ,Salmonella Typhi ,Geographical Locations ,Anti-Infective Agents ,Salmonella ,Epidemiology ,Medicine and Health Sciences ,Medicine ,education.field_of_study ,Antimicrobials ,Mortality rate ,lcsh:Public aspects of medicine ,Ceftriaxone ,Drugs ,Salmonella enterica ,Middle Aged ,Hospitals ,Bacterial Pathogens ,3. Good health ,Infectious Diseases ,Vietnam ,Medical Microbiology ,Salmonella Typhimurium ,Salmonella Infections ,Drug Therapy, Combination ,Female ,Pathogens ,Research Article ,Fluoroquinolones ,medicine.drug ,Adult ,medicine.medical_specialty ,Asia ,lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,030106 microbiology ,Population ,Viral diseases ,Serogroup ,Microbiology ,Typhoid fever ,03 medical and health sciences ,Sex Factors ,Enterobacteriaceae ,Microbial Control ,Internal medicine ,Trimethoprim, Sulfamethoxazole Drug Combination ,Humans ,Typhoid Fever ,education ,Microbial Pathogens ,Aged ,Retrospective Studies ,Pharmacology ,Bacteria ,business.industry ,Organisms ,Public Health, Environmental and Occupational Health ,Biology and Life Sciences ,lcsh:RA1-1270 ,medicine.disease ,Trimethoprim ,Logistic Models ,Infectious disease (medical specialty) ,People and Places ,Multivariate Analysis ,Immunology ,Antimicrobial Resistance ,business ,Multilocus Sequence Typing - Abstract
Invasive non-typhoidal Salmonella (iNTS) infections are now a well-described cause of morbidity and mortality in children and HIV-infected adults in sub-Saharan Africa. In contrast, the epidemiology and clinical manifestations of iNTS disease in Asia are not well documented. We retrospectively identified >100 cases of iNTS infections in an infectious disease hospital in Southern Vietnam between 2008 and 2013. Clinical records were accessed to evaluate demographic and clinical factors associated with iNTS infection and to identify risk factors associated with death. Multi-locus sequence typing and antimicrobial susceptibility testing was performed on all organisms. Of 102 iNTS patients, 71% were HIV-infected, >90% were adults, 71% were male and 33% reported intravenous drug use. Twenty-six/92 (28%) patients with a known outcome died; HIV infection was significantly associated with death (p = 0.039). S. Enteritidis (Sequence Types (ST)11) (48%, 43/89) and S. Typhimurium (ST19, 34 and 1544) (26%, 23/89) were the most commonly identified serovars; S. Typhimurium was significantly more common in HIV-infected individuals (p = 0.003). Isolates from HIV-infected patients were more likely to exhibit reduced susceptibility against trimethoprim-sulfamethoxazole than HIV-negative patients (p = 0.037). We conclude that iNTS disease is a severe infection in Vietnam with a high mortality rate. As in sub-Saharan Africa, HIV infection was a risk factor for death, with the majority of the burden in this population found in HIV-infected adult men., Author Summary Invasive non-typhoidal Salmonella (iNTS) infections occur when Salmonella bacteria, which normally cause diarrhea, enter the bloodstream and spread through the body. Invasive NTS infections have become a common cause of infection and death in children with malaria and adults with HIV in sub-Saharan Africa. However, it is unknown whether iNTS is as common or as severe outside sub-Saharan Africa. We evaluated over 100 iNTS cases from an infectious disease hospital in southern Vietnam admitted between 2008–2013. We used hospital records to determine the clinical features of iNTS disease and to identify risk factors associated with death and performed typing of the isolated organisms. The majority of patients were HIV positive (72/102, 71%), >90% of patients were adults, 71% were male and 33% reported intravenous drug use. The mortality rate of iNTS patients was 28% (26/92), and HIV infection was a significant risk factor for fatal outcome (p = 0.039). The serovars most commonly identified were S. Enteritidis and S. Typhimurium; S. Typhimurium was found more frequently in HIV-positive individuals (p = 0.003). We report that iNTS disease is a severe infection in Vietnam with a high mortality rate. Similar to sub-Saharan Africa, HIV infection was a strong risk factor for death.
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- 2016
27. Diagnostic metabolite biomarkers of chronic typhoid carriage
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Sabina Dongol, Henrik Antti, Tan Trinh Van, Buddha Basnyat, Guy E. Thwaites, Pär Jonsson, Anders Johansson, Elin Näsström, Abhilasha Karkey, Nga Tran Vu Thieu, Stephen Baker, Näsström, Elin [0000-0001-6499-3281], Baker, Stephen [0000-0003-1308-5755], and Apollo - University of Cambridge Repository
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Male ,Bacterial Diseases ,0301 basic medicine ,Salmonella ,Metabolite ,medicine.medical_treatment ,Fevers ,Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ,Pathology and Laboratory Medicine ,Salmonella typhi ,medicine.disease_cause ,Biochemistry ,Salmonella Typhi ,Plasma ,chemistry.chemical_compound ,Mathematical and Statistical Techniques ,fluids and secretions ,Metabolites ,Medicine and Health Sciences ,Prospective Studies ,Principal Component Analysis ,lcsh:Public aspects of medicine ,Salmonella paratyphi A ,Gallbladder ,food and beverages ,Middle Aged ,Bacterial Pathogens ,3. Good health ,Infectious Diseases ,medicine.anatomical_structure ,Liver ,Medical Microbiology ,Carrier State ,Physical Sciences ,Female ,Pathogens ,Anatomy ,Statistics (Mathematics) ,Research Article ,Adult ,lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,030106 microbiology ,Surgical and Invasive Medical Procedures ,Research and Analysis Methods ,Microbiology ,complex mixtures ,Gas Chromatography-Mass Spectrometry ,Typhoid fever ,Young Adult ,Digestive System Procedures ,03 medical and health sciences ,Signs and Symptoms ,Nepal ,Enterobacteriaceae ,Diagnostic Medicine ,medicine ,Humans ,Metabolomics ,Cholecystectomy ,Typhoid Fever ,Statistical Methods ,Microbial Pathogens ,Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ,Aged ,Bacteria ,business.industry ,Organisms ,Public Health, Environmental and Occupational Health ,Biology and Life Sciences ,lcsh:RA1-1270 ,bacterial infections and mycoses ,medicine.disease ,Metabolism ,030104 developmental biology ,Carriage ,chemistry ,Biliary System ,Multivariate Analysis ,Immunology ,bacteria ,business ,Biomarkers ,Mathematics - Abstract
Background Salmonella Typhi and Salmonella Paratyphi A are the agents of enteric (typhoid) fever; both can establish chronic carriage in the gallbladder. Chronic Salmonella carriers are typically asymptomatic, intermittently shedding bacteria in the feces, and contributing to disease transmission. Detecting chronic carriers is of public health relevance in areas where enteric fever is endemic, but there are no routinely used methods for prospectively identifying those carrying Salmonella in their gallbladder. Methodology/Principal findings Here we aimed to identify biomarkers of Salmonella carriage using metabolite profiling. We performed metabolite profiling on plasma from Nepali patients undergoing cholecystectomy with confirmed S. Typhi or S. Paratyphi A gallbladder carriage (and non-carriage controls) using two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GCxGC-TOFMS) and supervised pattern recognition modeling. We were able to significantly discriminate Salmonella carriage samples from non-carriage control samples. We were also able to detect differential signatures between S. Typhi and S. Paratyphi A carriers. We additionally compared carriage metabolite profiles with profiles generated during acute infection; these data revealed substantial heterogeneity between metabolites associated with acute enteric fever and chronic carriage. Lastly, we found that Salmonella carriers could be significantly distinguished from non-carriage controls using only five metabolites, indicating the potential of these metabolites as diagnostic markers for detecting chronic Salmonella carriers. Conclusions/Significance Our novel approach has highlighted the potential of using metabolomics to search for diagnostic markers of chronic Salmonella carriage. We suggest further epidemiological investigations of these potential biomarkers in alternative endemic enteric fever settings., Author summary Enteric fever, caused by typhoidal Salmonella serovars, remains a substantial public health problem in many low- and middle-income countries. The human-restricted nature of these organisms combined with the development of new vaccines suggests that regional elimination of enteric fever should be possible. However, individuals that chronically carry Salmonella in their gallbladder, such as the notorious Typhoid Mary, complicates enteric fever transmission and maintain circulation of the organisms. The prospective detection of chronic Salmonella carriers is therefore a critical step for regional enteric fever elimination. However, there are currently no diagnostic methods routinely in use for this purpose. Here, we used a novel method for identifying chronic Salmonella carriers by comparing metabolite patterns in plasma samples from patients with chronic Salmonella carriage against non-carriage controls. We could significantly distinguish Salmonella carriers from non-carriers based on a large set of metabolites. Five metabolites were then highlighted, after comparing metabolite patterns obtained during chronic Salmonella carriage and acute enteric fever respectively, which could significantly distinguish Salmonella carriers from non-carriers. These potential biomarkers require further evaluation in epidemiological investigations of enteric fever in alternative endemic settings but this study provides a first step towards improved detection of Salmonella carriers.
- Published
- 2018
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