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Typhoid conjugate vaccine (TCV) has recently been introduced in the expanded program for immunization (EPI) in Pakistan. Before its introduction in routine immunization, a onetime catchup campaign among children 9 months to 15 years old was conducted in November 2019. We performed field evaluation of TCV against culture confirmed Salmonella Typhi (S. Typhi) among 9 months to 15 years old children during the catch up campaign in Karachi and Hyderabad.A rapid assessment of blood culture confirmed S. Typhi was performed. Age eligible cases of culture confirmed S. Typhi were identified from the laboratory networks of Aga Khan University Hospital Karachi and Hyderabad, Kharadar General Hospital Karachi, and Liaqat University of MedicalHealth Sciences (LUMHS) Hyderabad. Information on sociodemographic, typhoid vaccination history and antimicrobial resistance was collected using a structured questionnaire. Patient medical records and lab reports were also reviewed to collect information on diagnosis and antimicrobial susceptibility information. Information about the population vaccination coverage during catch-up campaign was obtained from the provincial EPI office. Field performance of TCV in catchup campaign was measured by calculating the effectiveness using rapid screening method which is less resource-intensive technique of calculating vaccine effectiveness (VE).Overall, 968 culture confirmed typhoid cases were enrolled. Among them, 82% (793/968) were from Karachi and 18% (175/968) from Hyderabad. The average age of the participants was 5.68 years, and 54% (523/968) were male. 6% (62/968) of the culture confirmed S. Typhi cases were multidrug resistant (MDR), and 61% (586/968) were extensively drug resistant (XDR). The VE using the TCV coverage data provided by EPI was 98%.TCV is effective against culture confirmed S. Typhi among children aged 9 months to 15 years in the catch-up campaign setting. While typhoid vaccination can significantly decrease the burden of typhoid disease, improvements in sanitation and hygiene are necessary for the prevention of spread of enteric fever. Longer term follow up will be needed to assess the duration of protection and requirement for booster doses of TCV.

We aimed to detect typhoid carriers by performing duodenal fluid culture in patients in a tertiary care hospital in Pakistan. A cross-sectional study was conducted during 2017 at the Aga Khan University Hospital, Karachi. Patients who underwent upper gastrointestinal endoscopy were included. Participants were interviewed, and duodenal fluid samples were taken for culture to detect Salmonella typhi (S. typhi) and paratyphi. A polymerase chain reaction on 100 randomly selected sub-samples was also conducted. A total of 477 participants were enrolled. The mean age was 42.4±15.5 years. History of typhoid fever was present in 73 (15.3%) participants. Out of the 477 duodenal fluid cultures tested for various micro-organisms, 250 (52.4%) were positive. Neither S. typhi nor paratyphi were isolated. S. typhi was also not detected by PCR. To better detect S. typhi carriage in general population, future studies should target people with gall bladder diseases and screen them using culture and PCR based methods.

BackgroundAntimicrobial therapy is essential for the treatment of enteric fever, the infection caused by Salmonella serovars Typhi and Paratyphi A. However, an increase in resistance to key antimicrobials and the emergence of MDR and XDR in Salmonella Typhi poses a major threat for efficacious outpatient treatments.ObjectivesWe recently identified tebipenem, an oral carbapenem licensed for use for respiratory tract infections in Japan, as a potential alternative treatment for MDR/XDR Shigella spp. Here, we aimed to test the in vitro antibacterial efficacy of this drug against MDR and XDR typhoidal Salmonella.MethodsWe determined the in vitro activity of tebipenem in time–kill assays against a collection of non-XDR and XDR Salmonella Typhi and Salmonella Paratyphi A (non-XDR) isolated in Nepal and Bangladesh. We also tested the efficacy of tebipenem in combination with other antimicrobials.ResultsWe found that both XDR and non-XDR Salmonella Typhi and Salmonella Paratyphi A are susceptible to tebipenem, exhibiting low MICs, and were killed within 8–24 h at 2–4×MIC. Additionally, tebipenem demonstrated synergy with two other antimicrobials and could efficiently induce bacterial killing.ConclusionsSalmonella Paratyphi A and XDR Salmonella Typhi display in vitro susceptibility to the oral carbapenem tebipenem, while synergistic activity with other antimicrobials may limit the emergence of resistance. The broad-spectrum activity of this drug against MDR/XDR organisms renders tebipenem a good candidate for clinical trials.

Background: \ud The emergence of increasingly antimicrobial-resistant Salmonella enterica serovar Typhi (S Typhi) threatens to undermine effective treatment and control. Understanding where antimicrobial resistance in S Typhi is emerging and spreading is crucial towards formulating effective control strategies.\ud \ud Methods: \ud In this genomic epidemiology study, we sequenced the genomes of 3489 S Typhi strains isolated from prospective enteric fever surveillance studies in Nepal, Bangladesh, Pakistan, and India (between 2014 and 2019), and combined these with a global collection of 4169 S Typhi genome sequences isolated between 1905 and 2018 to investigate the temporal and geographical patterns of emergence and spread of antimicrobial-resistant S Typhi. We performed non-parametric phylodynamic analyses to characterise changes in the effective population size of fluoroquinolone-resistant, extensively drug-resistant (XDR), and azithromycin-resistant S Typhi over time. We inferred timed phylogenies for the major S Typhi sublineages and used ancestral state reconstruction methods to estimate the frequency and timing of international and intercontinental transfers.\ud \ud Findings: \ud Our analysis revealed a declining trend of multidrug resistant typhoid in south Asia, except for Pakistan, where XDR S Typhi emerged in 2016 and rapidly replaced less-resistant strains. Mutations in the quinolone-resistance determining region (QRDR) of S Typhi have independently arisen and propagated on at least 94 occasions, nearly all occurring in south Asia. Strains with multiple QRDR mutations, including triple mutants with high-level fluoroquinolone resistance, have been increasing in frequency and displacing strains with fewer mutations. Strains containing acrB mutations, conferring azithromycin resistance, emerged in Bangladesh around 2013 and effective population size of these strains has been steadily increasing. We found evidence of frequent international (n=138) and intercontinental transfers (n=59) of antimicrobial-resistant S Typhi, followed by local expansion and replacement of drug-susceptible clades.\ud \ud Interpretation: \ud Independent acquisition of plasmids and homoplastic mutations conferring antimicrobial resistance have occurred repeatedly in multiple lineages of S Typhi, predominantly arising in south Asia before spreading to other regions.\ud \ud Funding: \ud Bill & Melinda Gates Foundation.

Omphalitis is a mild medical condition that can turn severe in exceptional situations leading to necrotising fasciitis. The most common cause of omphalitis is umbilical vein catheterisation (UVC) where the cleanliness measures can be compromised. The treatment options for omphalitis include antibiotics, debridement and supportive care. Sadly, the fatality rate in such cases is high. This report is about a premature female baby who was admitted to a neonatal intensive care unit after her birth at 34 weeks of gestation. UVC was performed on her which led to abnormal changes in the skin around her umbilicus. Further tests revealed that she had omphalitis and was treated with antibiotics and supportive care. Unfortunately, her condition quickly worsened and she was diagnosed with necrotising fasciitis which ultimately resulted in her death. This report provides details about the patient’s symptoms, course of illness and treatment for necrotising fasciitis.

BackgroundThe Surveillance for Enteric Fever in Asia Project (SEAP) is a multicenter, multicountry study conducted in Pakistan, Nepal, and Bangladesh. The objectives of the study were to characterize disease incidence among patients with enteric fever. We report the burden of enteric fever at selected sites of Karachi, Pakistan.MethodsDuring September 2016 to September 2019, prospective surveillance was conducted at inpatient, outpatient, surgical departments, and laboratory networks of Aga Khan University Hospital, Kharadar General Hospital, and surgery units of National Institute of Child Health and Jinnah Postgraduate Medical Centre. Socio-demographic, clinical, and laboratory data were obtained from all suspected or confirmed enteric fever cases.ResultsOverall, 22% (2230/10 094) of patients enrolled were culture-positive for enteric fever. 94% (2093/2230) of isolates were Salmonella Typhi and 6% (137/2230) were S. Paratyphi. 15% of isolates multi-drug resistant (MDR) to first-line antibiotics and 60% were extensively drug-resistant (XDR), resistant to first-line antibiotics, fluoroquinolones and third generation cephalosporin.ConclusionEnteric fever cases have increased during the last 3 years with large proportion of drug resistant S. Typhi cases. However, the burden of paratyphoid is still relatively low. Strengthening the existing surveillance system for enteric fever and antimicrobial resistance at the national level is recommended in Pakistan to inform prevention measures. While typhoid vaccination can significantly decrease the burden of typhoid and may also impact antimicrobial resistance, water, sanitation, and hygiene improvement is highly recommended to prevent the spread of enteric fever.

Background Typhoid fever is caused by Salmonella enterica subspecies enterica serovar Typhi (S. Typhi) and can lead to systemic illness and complications. We aimed to characterize typhoid-related ileal perforation in the context of the population-based Surveillance of Enteric Fever in Asia Project (SEAP) in Bangladesh, Nepal and Pakistan. Methods Between September 2016 and September 2019, all cases of nontraumatic ileal perforation with a clinical diagnosis of typhoid were enrolled from 4 tertiary care hospitals in Karachi, 2 pediatric hospitals in Bangladesh, and 2 hospitals in Nepal. Sociodemographic data were collected from patients or their caregivers, and clinical and outcome data were retrieved from medical records. Tissue samples were collected for histopathology and blood cultures where available. Results Of the 249 enrolled cases, 2 from Bangladesh, 5 from Nepal and 242 from Pakistan. In Pakistan, most of the cases were in the 0–15 (117/242; 48%) and 16–30 (89/242; 37%) age groups. In all countries, males were most affected: Pakistan 74.9% (180/242), Nepal 80% (4/5), and Bangladesh 100% (2/2). Blood culture was done on 76 cases; 8 (11%) were positive for S. Typhi, and all were extensively drug resistant (XDR) S. Typhi. Tissue cultures was done on 86 patients; 3 (3%) were positive for S. Typhi, and all were XDR S. Typhi, out of 86 samples tested for histopathology 4 (5%) revealed ileal perforation with necrosis. Culture or histopathology confirmed total 15 (11%) enteric fever cases with ileal perforation are similar to the clinically diagnosed cases. There were 16/242 (7%) deaths from Pakistan. Cases of ileal perforation who survived were more likely to have sought care before visiting the sentinel hospital (P = .009), visited any hospital for treatment (P = .013) compared to those who survived. Conclusions Although surveillance differed substantially by country, one reason for the higher number of ileal perforation cases in Pakistan could be the circulation of XDR strain of S. Typhi in Karachi.

Background Characterizing healthcare-seeking patterns for acute febrile illness is critical for generating population-based enteric fever incidence estimates from facility-based surveillance data. Methods We used a hybrid model in the Surveillance for Enteric Fever in Asia Project (SEAP) to assess incidence of enteric fever at 6 study hospitals in 3 countries. We recruited individuals presenting to the hospitals and obtained blood cultures to evaluate for enteric fever. For this analysis, we undertook cluster random household surveys in Dhaka, Bangladesh (2 sites); Karachi, Pakistan; Kathmandu, Nepal; and Kavrepalanchok, Nepal between January 2017 and February 2019, to ascertain care-seeking behavior for individuals with 1) fever for ≥3 consecutive days within the past 8 weeks; or 2) fever resulting in hospitalization within the past year. We also collected data about disease severity and household demographics and assets. We used mixed-effect multivariable logistic regression models to identify determinants of healthcare seeking at study hospitals and determinants of culture-confirmed enteric fever. Results We enrolled 31 841 households (53 926 children) in Bangladesh, 25 510 households (84 196 children and adults) in Nepal, and 21 310 households (108 031 children and adults) in Pakistan. Children Conclusions Age, household wealth, and disease severity are important determinants of healthcare seeking for acute febrile illness and enteric fever risk in these communities, and should be incorporated into estimation models for enteric fever incidence.

Background Clinicians have limited therapeutic options for enteric as a result of increasing antimicrobial resistance, and therefore typhoid vaccination is recommended as a preventive measure. As a part of the Surveillance for Enteric Fever in Asia Project (SEAP), we investigated the extent measured the burden of antimicrobial resistance (AMR) among confirmed enteric fever cases in Bangladesh, Nepal, and Pakistan. Methods From September 2016–September 2019, SEAP recruited study participants of all age groups from its outpatient, inpatient, hospital laboratory, laboratory network, and surgical sites who had a diagnosis of febrile illness that was either suspected or blood culture confirmed for enteric fever. Antimicrobial resistance of isolates was determined by disc diffusion using Clinical and Laboratory Standard Institute cut-off points. We reported the frequency of multidrug resistance (MDR)(resistance to ampicillin, cotrimoxazole, and chloramphenicol), extensive drug resistance (XDR) (MDR plus non-susceptible to fluoroquinolone and any 3rd generation cephalosporins), and fluoroquinolone (FQ) and azithromycin non-susceptibility. Results We enrolled 8,705 blood culture confirmed enteric fever cases: 4,873 (56%) from Bangladesh, 1,602 (18%) from Nepal and 2,230 (26%) from Pakistan. Of these, 7,591 (87%) were Salmonella Typhi and 1114 (13%) were S. Paratyphi. MDR S. Typhi was identified in 17% (701/4065) of isolates in Bangladesh, and 1% (19/1342) in Nepal. In Pakistan, 16 % (331/2084) of S. Typhi isolates were MDR, and 64% (1319/2074) were XDR. FQ nonsusceptibility among S. Typhi isolates was 98% in Bangladesh, 87% in Nepal, and 95% in Pakistan. Azithromycin non-susceptibility was detected in 77 (2%) in Bangladesh, 9 (.67%) in Nepal and 9 (.59%) isolates in Pakistan. In Pakistan, three (2%) S. Paratyphi isolates were MDR; no MDR S. Paratyphi was reported from Bangladesh or Nepal. Conclusions Although AMR against S. Paratyphi was low across the three countries, there was widespread drug resistance among S. Typhi, including FQ non-susceptibility and the emergence of XDR S. Typhi in Pakistan, limiting treatment options. As typhoid conjugate vaccine (TCV) is rolled out, surveillance should continue to monitor changes in AMR to inform policies and to monitor drug resistance in S. Paratyphi, for which there is no vaccine.

Background Blood culture is the current standard for diagnosing bacteremic illnesses, yet it is not clear how physicians in many low- and middle-income countries utilize blood culture for diagnostic purposes and to inform treatment decisions. Methods We screened suspected enteric fever cases from 6 hospitals in Bangladesh, Nepal, and Pakistan, and enrolled patients if blood culture was prescribed by the treating physician. We used generalized additive regression models to analyze the probability of receiving blood culture by age, and linear regression models to analyze changes by month to the proportion of febrile cases prescribed a blood culture compared with the burden of febrile illness, stratified by hospital. We used logistic regression to analyze predictors for receiving antibiotics empirically. We descriptively reviewed changes in antibiotic therapy by susceptibility patterns and coverage, stratified by country. Results We screened 30 809 outpatients resulting in 1819 enteric fever cases; 1935 additional cases were enrolled from other hospital locations. Younger outpatients were less likely to receive a blood culture. The association between the number of febrile outpatients and the proportion prescribed blood culture varied by hospital. Antibiotics prescribed empirically were associated with severity and provisional diagnoses, but 31% (1147/3754) of enteric fever cases were not covered by initial therapy; this was highest in Pakistan (50%) as many isolates were resistant to cephalosporins, which were commonly prescribed empirically. Conclusions Understanding hospital-level communication between laboratories and physicians may improve patient care and timeliness of appropriate antibiotics, which is important considering the rise of antimicrobial resistance.

Background Shigella is a leading cause of childhood diarrhea and target for vaccine development. Microbiologic and clinical case definitions are needed for pediatric field vaccine efficacy trials. Methods We compared characteristics of moderate to severe diarrhea (MSD) cases in the Global Enteric Multicenter Study (GEMS) between children with culture positive Shigella to those with culture-negative, quantitative polymerase chain reaction (qPCR)-attributable Shigella (defined by an ipaH gene cycle threshold, Molecular methods identified Shigella more commonly than microbiologic culture in younger and stunted children. A simplified clinical score containing dehydration, hospitalization, and diarrhea duration could be used to stratify vaccine trial endpoints by severity based on its ability to predict death.

Highlights • Post licensure safety data of Typbar-TCV® is not available from a population wide campaign setting. • 207,000 doses of Typbar-TCV were administered in a campaign setting of Hyderabad, Pakistan. • No death, disability or hospitalization associated with Typbar-TCV during 14 days of vaccination was observed. • Fever and local reactogenicity were the frequently observed adverse events., Pakistan is facing the world's largest outbreak of extensively drug-resistant (XDR) Typhoid. Vaccination campaign for children aged 6 months to 10 years old with Typhoid Conjugate Vaccine (Typbar-TCV®) was conducted in high-risk areas of Hyderabad during 2018. About 207,000 children were vaccinated. Here we report the adverse events following immunization (AEFI) during the campaign. The campaign was carried out using outreach and fixed centre strategy. Community mobilizers visited each household to perform line listing and mobilize parents with age-eligible children. Children were observed for 30 min post-vaccination. Two-pronged strategy was used for ascertainment of AEFI. A 24/7 hotline number was provided to all parents/caretakers (n = 199,861) to report AEFI during 14 days following immunization. An age-stratified (n = 7139 children) were actively followed at days 7 and 14 for the ascertainment of AEFI. All AEFI were examined by three trained medical officers. A structured questionnaire using Brighton collaboration criteria with level 3 diagnostic certainty was used for the recording of AEFI. Data were analysed using Microsoft Excel Office 365. Overall, 499 AEFI (433 in the subset actively followed and 66 self-reported through hotline) were observed. The rate of AEFI was significantly higher among very young children (age group 6 to 12 months) as compared to 2 to 3 years old children (0.54% vs. 0.33% respectively; p-value

Background: Typhoid and paratyphoid fever (enteric fever) is a common cause of non-specific febrile infection in adults and children presenting to health care facilities in low resource settings such as the South Asia. A 7-day course of a single oral antimicrobial such as ciprofloxacin, cefixime, or azithromycin is commonly used for its treatment. Increasing antimicrobial resistance threatens the effectiveness of these treatment choices. We hypothesize that combined treatment with azithromycin (active mainly intracellularly) and cefixime (active mainly extracellularly) will be a better option for the treatment of clinically suspected and culture-confirmed typhoid fever in South Asia. Methods: This is a phase IV, international multi-center, multi-country, comparative participant-and observer-blind, 1:1 randomised clinical trial. Patients with suspected uncomplicated typhoid fever will be randomized to one of the two interventions: Arm A: azithromycin 20mg/kg/day oral dose once daily (maximum 1gm/day) and cefixime 20mg/kg/day oral dose in two divided doses (maximum 400mg bd) for 7 days, Arm B: azithromycin 20mg/kg/day oral dose once daily (max 1gm/day) for 7 days AND cefixime-matched placebo for 7 days. We will recruit 1500 patients across sites in Bangladesh, India, Nepal, and Pakistan. We will assess whether treatment outcomes are better with the combination after one week of treatment and at one- and three-months follow-up. Discussion: Combined treatment may limit the emergence of resistance if one of the components is active against resistant sub-populations not covered by the other antimicrobial activity. If the combined treatment is better than the single antimicrobial treatment, this will be an important result for patients across South Asia and other typhoid endemic areas. Clinicaltrials.gov registration: NCT04349826 (16/04/2020)

Background: Enteric fever, caused by Salmonella Typhi and S. Paratyphi, is a cause of high morbidity and mortality among children in South Asia. Rising antimicrobial resistance presents an additional challenge. Typhoid Conjugate Vaccines (TCV) are recommended by the World Health Organization for use among people 6 months to 45 years old living in endemic settings. This study aimed to assess the effectiveness of TCV against culture-confirmed S. Typhi in Lyari Town, Karachi, Pakistan. This peri-urban town was one of the worst affected by the outbreak of extensively drug resistant (XDR) typhoid that started in November 2016. Methods: A matched case-control study was conducted following a mass immunization campaign with TCV at three key hospitals in Lyari Town Karachi, Pakistan. Children aged 6 months to 15 years presenting with culture-confirmed S. Typhi were enrolled as cases. For each case, at least 1 age-matched hospital control and two age-matched community controls were enrolled. Adjusted odds ratios with 95% confidence intervals (CIs) were calculated using conditional logistic regression. Results: Of 82 typhoid fever patients enrolled from August 2019 through December 2019, 8 (9·8%) had received vaccine for typhoid. Of the 164 community controls and 82 hospital controls enrolled, 38 (23·2%) community controls and 27 (32·9%) hospital controls were vaccinated for typhoid. The age and sex-adjusted vaccine effectiveness was found to be 72% (95% CI: 34% − 88%). The consumption of meals prepared outside home more than once per month (adjusted odds ratio: 3·72, 95% CI: 1·55- 8·94; p-value: 0·003) was associated with the development of culture-confirmed typhoid. Conclusion: A single dose of TCV is effective against culture confirmed typhoid among children aged 6 months to 15 years old in an XDR typhoid outbreak setting of a peri-urban community in Karachi, Pakistan. acceptedVersion

Typhoid fever is endemic in Pakistan, with high annual incidence rates. An outbreak of extensively drug-resistant typhoid fever that first started in the Hyderabad district of Sindh province in November 2016 immediately spread to the whole province. We conducted an age-matched case–control study to assess the risk factors of typhoid fever in an outbreak setting of Lyari Town, Karachi. We enrolled 82 patients with blood culture-confirmed Salmonella typhi between August 2019 to December 2019, 82 age-matched hospital and 164 age-matched community control subjects. In a matched conditional logistic regression model, consumption of meals outside the home more than once per month was associated significantly with developing culture-confirmed typhoid fever compared with no consumption of food outside the home (odds ratio, 4.11). Hygiene of the environment in which food is prepared, practices of adult food handlers, access to clean water, and food legislation play significant roles in the spread of typhoid fever.

IntroductionA significant number of patients continue to recover from COVID-19; however, little is known about the lung function capacity among survivors. We aim to determine the long-term impact on lung function capacity in patients who have survived moderate or severe COVID-19 disease in a resource-poor setting.Methods and analysisThis prospective cohort study will include patients aged 15 years and above and have reverse transcriptase-polymerase chain reaction (RT-PCR) positive for COVID 19 (nasopharyngeal or oropharyngeal). Patients with a pre-existing diagnosis of obstructive or interstitial lung disease, lung fibrosis and cancers, connective tissue disorders, autoimmune conditions affecting the lungs, underlying heart disease, history of syncope and refuse to participate will be excluded. Pulmonary function will be assessed using spirometry and diffusion lung capacity for carbon monoxide (DLCO) at three- and six-months interval. A chest X-ray at three and six-month follow-up and CT-chest will be performed if clinically indicated after consultation with the study pulmonologist or Infectious Disease (ID) physician. Echocardiogram (ECHO) to look for pulmonary hypertension at the three months visit and repeated at six months if any abnormality is identified initially. Data analysis will be performed using standard statistical software.Ethics and disseminationThe proposal was reviewed and approved by ethics review committee (ERC) of the institution (ERC reference number 2020-4735-11311). Informed consent will be obtained from each study participant. The results will be disseminated among study participants, institutional, provincial and national level through seminars and presentations. Moreover, the scientific findings will be published in high-impact peer-reviewed medical journals.Strengths and Limitations of this study-The study has the potential to develop context-specific evidence on the long-term impact on lung function among COVID-19 survivors-Findings will play key role in understanding the impact of the disease on vital functions and help devise rehabilitative strategies to best overcome the effects of disease-This is a single-center, study recruiting only a limited number of COVID-19 survivors-The study participants may loss-to-follow up due to uncertain conditions and disease reemergence

Salmonella is a gram-negative, motile, nonsporulating, facultative anaerobic bacillus, belongs to the family Enterobacteriaceae. The bacteria were first identified in 1884. It is transmitted through direct contact with an infected person or indirect contact by the consumption of contaminated food and water. More than 2500 serotypes of Salmonella enterica have been identified but less than 100 serotypes are known to cause infections in humans. S. enterica serovar typhi (S. typhi) and S. enterica serovar paratyphi (S. paratyphi A B C) cause enteric fever, whereas nontyphoidal Salmonella serotypes (NTS) cause diarrhea. NTS commonly presents with gastroenteritis and is a self-limiting disease. Enteric fever is a potentially life-threatening acute febrile systemic infection and is diagnosed by isolating a pathogen on culture. With the emergence of the extensive drug-resistant (XDR) S. typhi clone, limited treatment options are available. Vaccination of persons at risk, improvement of sanitation, promotion of food hygiene, and detection and control of chronic carriers are essential preventive control measures of enteric fever.

BackgroundSalmonella enterica serovar Paratyphi A (Salmonella Paratyphi A) is the primary causative agent of paratyphoid fever, which is responsible for an estimated 3.4 million infections annually. However, little genomic information is available on population structure, antimicrobial resistance (AMR), and spatiotemporal distribution of the pathogen. With rising antimicrobial resistance and no licensed vaccines, genomic surveillance is important to track the evolution of this pathogen and monitor transmission.ResultsWe performed whole-genome sequencing of 817 Salmonella Paratyphi A isolates collected from Bangladesh, Nepal, and Pakistan and added publicly available 562 genomes to build a global database representing 37 countries, covering 1917-2019. To track the evolution of Salmonella Paratyphi A, we used the existing lineage scheme, developed earlier based on a small dataset, but certain sub-lineages were not homologous, and many isolates could not be assigned a lineage. Therefore, we developed a single nucleotide polymorphism based genotyping scheme, Paratype, a tool that segregates Salmonella Paratyphi A into three primary and nine secondary clades, and 18 genotypes. Each genotype has been assigned a unique allele definition located on a conserved gene. Using Paratype, we identified genomic variation between different sampling locations and specific AMR markers, and mutations in the O2-polysaccharide synthesis locus, a candidate for vaccine development.ConclusionsThis large-scale global analysis proposes the first genotyping tool for Salmonella Paratyphi A. Paratype has already been released (https://github.com/CHRF-Genomics/Paratype) as an open-access, command-line tool and is being adopted for large scale genomic analysis. This tool will assist future genomic surveillance and help inform prevention and treatment strategies.

The incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae (Salmonella enterica serovars Typhi and Paratyphi), is largely unknown in regions without blood culture surveillance. The aim of this study was to evaluate whether new diagnostic serological markers for typhoidal Salmonella can reliably estimate population-level incidence.We collected longitudinal blood samples from patients with blood culture-confirmed enteric fever enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana between 2016 and 2021 and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to hemolysin E and S Typhi lipopolysaccharide. We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titres and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.The longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children younger than 5 years ranged between 58·5 per 100 person-years (95% CI 42·1-81·4) in Dhaka, Bangladesh, to 6·6 per 100 person-years (4·3-9·9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates.The approach described here has the potential to expand the geographical scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographical regions and time.BillMelinda Gates Foundation.For the Nepali, Bengali and Urdu translations of the abstract see Supplementary Materials section.

BackgroundThe incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae, is largely unknown in regions lacking blood culture surveillance. New serologic markers have proven accurate in diagnosing enteric fever, but whether they could be used to reliably estimate population-level incidence is unknown.MethodsWe collected longitudinal blood samples from blood culture-confirmed enteric fever cases enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to Hemolysin E (HlyE) and S. Typhi lipopolysaccharide (LPS). We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titers and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.FindingsThe longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children InterpretationThe approach described here has the potential to expand the geographic scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographic regions and time.FundingThis work was supported by the Bill and Melinda Gates Foundation (INV-000572).Research in contextEvidence before this studyPrevious studies have identified serologic responses to two antigens (Hemolysin E [HlyE] and Salmonella lipopolysaccharide [LPS]) as promising diagnostic markers of acute typhoidal Salmonella infection. We reviewed the evidence for seroepidemiology tools for enteric fever available as of November 01, 2021, by searching the National Library of Medicine article database and medRxiv for preprint publications, published in English, using the terms “enteric fever”, “typhoid fever”, “Salmonella Typhi”, “Salmonella Paratyphi”, “typhoidal Salmonella”, “Hemolysin E”, “Salmonella lipopolysaccharide”, “seroconversion”, “serosurveillance”, “seroepidemiology”, “seroprevalence” and “seropositivity.” We found no studies using HlyE or LPS as markers to measure the incidence or prevalence of enteric fever in a population. Anti-Vi IgG responses were used as a marker of population seroprevalence in cross-sectional studies conducted in South Africa, Fiji, and Nepal, but were not used to calculate population-based incidence estimates.Added value of this studyWe developed and validated a method to estimate typhoidal Salmonella incidence in cross-sectional population samples using antibody responses measured from dried blood spots. First, using longitudinal dried blood spots collected from over 1400 blood culture-confirmed cases in four countries, we modeled the longitudinal dynamics of antibody responses for up to two years following infection, accounting for heterogeneity in antibody responses and age-dependence. We found that longitudinal antibody responses were highly consistent across four countries on two continents and did not differ by clinical severity. We then used these antibody kinetic parameters to estimate incidence in population-based samples in six communities across the four countries, where concomitant population-based incidence was measured using blood cultures. Seroincidence estimates were much higher than blood-culture-based case estimates across all six sites, suggestive of a high incidence of asymptomatic or unrecognized infections. Still, the rank order of seroincidence and culture-based incidence rates were the same, with the highest rates in Bangladesh and lowest in Ghana.Implications of all the available evidenceMany at-risk low- and middle-income countries lack data on typhoid incidence needed to inform and evaluate vaccine introduction. Even in countries where incidence estimates are available, data are typically geographically and temporally sparse due to the resources necessary to initiate and sustain blood culture surveillance. We found that typhoidal Salmonella infection incidence can be estimated from community-based serosurveys using dried blood spots, representing an efficient and scalable approach for generating the typhoid burden data needed to inform typhoid control programs in resource-constrained settings.

Enteric fever infections remain a significant public health issue, with up to 20 million infections per year. Increasing rates of antibiotic resistant strains have rendered many first-line antibiotics potentially ineffective. Genotype 4.3.1 (H58) is the main circulating lineage of S. Typhi in many South Asian countries and is associated with high levels of antibiotic resistance. The emergence and spread of extensively drug resistant (XDR) typhoid strains has increased the need for a rapid molecular test to identify and track these high-risk lineages for surveillance and vaccine prioritisation. Current methods require samples to be cultured for several days, followed by DNA extraction and sequencing to determine the specific lineage. We designed and evaluated the performance of a new multiplex PCR assay, targeting S. Paratyphi A as well as the H58 and XDR lineages of S. Typhi on a collection of bacterial strains. Our assay was 100% specific for the identification of lineage specific S. Typhi and S. Paratyphi A, when tested with a mix of non-Typhi Salmonella and non-Salmonella strains. With additional testing on clinical and environmental samples, this assay will allow rapid lineage level detection of typhoid of clinical significance, at a significantly lower cost to whole-genome sequencing. To our knowledge, this is the first report of a SNP-based multiplex PCR assay for the detection of lineage specific serovars of Salmonella Typhi.Data StatementAll supporting data, code and protocols have been provided within the article or through supplementary data files.

The emergence of increasingly antimicrobial-resistant (AMR) Salmonella enterica serovar Typhi (S. Typhi) threatens to undermine effective treatment and control. Here, aiming to investigate the temporal and geographic patterns of emergence and spread of AMR S. Typhi, we sequenced 3,489 S. Typhi isolated from prospective surveillance in South Asia and combined these with a global collection of 4,169 S. Typhi genomes. Our analysis revealed that independent acquisition of plasmids and homoplastic mutations conferring AMR have occurred repeatedly in multiple lineages of S. Typhi, predominantly arising in South Asia. We found evidence of frequent international and intercontinental transfers of AMR S. Typhi, followed by rapid expansion and replacement of antimicrobial-susceptible clades.

Enteric fever remains a major cause of morbidity in developing countries with poor sanitation conditions that enable fecal contamination of water distribution systems. Historical evidence has shown that contamination of water systems used for household consumption or agriculture are key transmission routes for Salmonella Typhi and Salmonella Paratyphi A. The World Health Organization now recommends that typhoid conjugate vaccines (TCV) be used in settings with high typhoid incidence; consequently, governments face a challenge regarding how to prioritize typhoid against other emerging diseases. A key issue is the lack of typhoid burden data in many low- and middle-income countries where TCV could be deployed. Here we present an argument for utilizing environmental sampling for the surveillance of enteric fever organisms to provide data on community-level typhoid risk. Such an approach could complement traditional blood culture-based surveillance or even replace it in settings where population-based clinical surveillance is not feasible. We review historical studies characterizing the transmission of enteric fever organisms through sewage and water, discuss recent advances in the molecular detection of typhoidal Salmonella in the environment, and outline challenges and knowledge gaps that need to be addressed to establish environmental sampling as a tool for generating actionable data that can inform public health responses to enteric fever.

Background: Intravascular catheters are susceptible to infections, thus requiring catheter removal and leading to increased morbidity and costs. Antibiotic lock therapy (ALT) is a therapeutic technique that is used to salvage the catheter. The aim of this study was to evaluate the outcome of antibiotic lock therapy in bloodstream infections in pediatric hematology/oncology patients in a tertiary care hospital, Karachi. Methods: A retrospective review was performed from January 2013 to December 2017 of pediatric hematology/oncology patients with bloodstream infections and who received ALT at Aga Khan University Hospital. All cases of polymicrobial infections, catheter removal, or malfunction before the completion of ALT were excluded. Descriptive analysis was carried out using SPSS version 20. Results: A total of nine hematology/oncology patients were eligible. The catheter was salvaged in 7/9 (77.8%) children, and in 2/9 (22.2%) cases, catheter was removed because of persistent bacteremia. The most common organism isolated was Staphylococcus non-aureus species (33.3%). Relapse with a similar pathogen occurred in 2 (22.2%) patients and 2 (22.2%) of them developed an exit-site infection. Conclusion: In our experience, in almost two thirds of the cases, the catheter was salvaged, but disappointingly, relapses were high when the infection was due to Staphylococcus spp. Although this is a small study, our results show that ALT can be a potential safe adjunctive strategy to treat catheter-related bloodstream infections (CRBSI). However, we need larger prospective studies to test the safety and efficacy of ALT to develop specific ALT recommendations and guidelines particularly in children. Keywords: Antibiotic lock therapy, Bloodstream infections, Pediatric hematology/oncology patients

Background This review assessed the case definitions, diagnostic criteria, antimicrobial resistance, and methods used for enteric fever outbreaks and utilization of any unified outbreak score or checklist for early identification and response in Asia and Africa from 1965-2019. Methods We searched enteric fever outbreaks using PubMed, Google Scholar, and the Cochrane library. Studies describing a single outbreak event of enteric fever in Asia and Africa from 1965-2019 were reviewed. We excluded case reports, letter to editors, studies reporting typhoid in conjunction with other diseases, the Centers for Disease Control and Prevention (CDC) trip reports, the World Health Organization (WHO) bulletins report, data from mathematical modeling and simulation studies, reviews and ProMed alert. Also, non-typhoidal salmonella outbreaks were excluded. Results A total of 5063 articles were identified using the key terms and 68 studies were selected for data extraction. Most (48, 71%) outbreaks were from Asian countries, 20 (29%) were reported from Africa. Only 15 studies reported the case definition used for case identification during an outbreak and 8 of those were from Asia. A third (20, 29%) of the studies described antibiotic resistance pattern. 43 (63%) studies contained information regarding the source of the outbreak. Outcomes (hospitalization and deaths) were reported in a quarter of studies. Only 23 (29%) of the studies reported outbreak control strategies while none reported any unified outbreak score or a checklist to identify the outbreak. Conclusion This review highlights the variability in detection and reporting methods for enteric fever outbreaks in Asia and Africa. No standardized case definitions or laboratory methods were reported. Only a few studies reported strategies for outbreak control. There is a need for the development of a unified outbreak score or a checklist to identify and report enteric fever outbreaks globally.

Introduction: Job satisfaction is vital for the optimal functioning of medical practitioners. Herein, we report our experience of restructuring the internship program by identifying the gaps, developing, implementing strategies to overcome gaps and sharing the results of the pre-implementation and post-implementation audit, as an example for establishing a system for improving intern’s work-based learning and satisfaction in a university hospital setting. Methods: Using Kern’s six-step instructional model, a prospective mixed-method study was conducted at Aga Khan University Hospital. In phase 1 (2013) gaps were identified by evaluating various aspects of the internship program. Strategies were developed and implemented to overcome the identified gaps. In phase 2 (2014-2016) the impact of these developmental strategies was assessed. Results: A total of 65 interns, 30 residents, and 22 faculty members participated in phase I, while 71 interns participated in phase II. The reformation of orientation sessions, including practical exposure and content of sessions, opportunities to enhance hands-on experience and supervision in inpatient areas, operating rooms, supervision by fellows, supervision for hands-on procedures, career counseling, and mentorship, led to significant improvement in satisfaction. It was identified that the lack of hands-on opportunities can be overcome by surgical skills-based workshops. These reforms led to an overall rise in intern satisfaction (50% vs 75.4%, p=0.02). Conclusion: Periodic restructuring of an existing program helps to improve the work-based learning experience and overall satisfaction among interns. This not only maximizes learning but also eases interns into their postgraduate life and workload subsequently enabling them to become more competent and well-rounded health practitioners.

The COVID-19 pandemic has exposed weaknesses in disease surveillance in nearly all countries. Early identification of COVID-19 cases and clusters for rapid containment was hampered by inadequate diagnostic capacity, insufficient contact tracing, fragmented data systems, incomplete data insights for public health responders, and suboptimal governance of all these elements. Once SARS-CoV-2 became widespread, interventions to control community transmission were undermined by weak surveillance of cases and insufficient national capacity to integrate data for timely adjustment of public health measures.1, 2 Although some countries had little or no reliable data, others did not share data consistently with their own populations and with WHO and other multilateral agencies. The emergence of SARS-CoV-2 variants has highlighted inadequate national pathogen genomic sequencing capacities in many countries and led to calls for expanded virus sequencing. However, sequencing without epidemiological and clinical surveillance data is insufficient to show whether new SARS-CoV-2 variants are more transmissible, more lethal, or more capable of evading immunity, including vaccine-induced immunity.

The emergence of multi-drug (MDR) and extensive-drug resistance (XDR) in Salmonella Typhi and Paratyphi A hinder efficacious out-patient enteric fever treatment. We show that non-XDR and XDR S. Typhi and S. Paratyphi A are susceptible to the carbapenem tebipenem in vitro. Tebipenem demonstrated partial synergy with antimicrobials including azithromycin, signifying combination therapy may limit the emergence of resistance. Given recent evidence on tebipenem inhibitory activity against MDR Shigella, its broad-spectrum activity against MDR/XDR organisms renders it a good clinical trial candidate.

Diarrhoea is an important cause of morbidity and mortality in children from low-income and middle-income countries (LMICs), despite advances in the management of this condition. Understanding of the causes of diarrhoea in children in LMICs has advanced owing to large multinational studies and big data analytics computing the disease burden, identifying the important variables that have contributed to reducing this burden. The advent of the mobile phone has further enabled the management of childhood diarrhoea by providing both clinical support to health-care workers (such as diagnosis and management) and communicating preventive measures to carers (such as breastfeeding and vaccination reminders) in some settings. There are still challenges in addressing the burden of diarrhoeal diseases, such as incomplete patient information, underrepresented geographical areas, concerns about patient confidentiality, unequal partnerships between study investigators, and the reactive approach to outbreaks. A transparent approach to promote the inclusion of researchers in LMICs could address partnership imbalances. A big data umbrella encompassing cloud-based centralised databases to analyse interlinked human, animal, agricultural, social, and climate data would provide an informative solution to the development of appropriate management protocols in LMICs.

Summary Background Salmonella enterica serotype Typhi (S Typhi) is a major public health problem in low-income and middle-income countries. We aimed to investigate the effectiveness and impact of the typhoid conjugate vaccine Typbar-TCV against S Typhi among children in an outbreak setting of extensively drug-resistant (XDR) S Typhi in Pakistan. Methods This cohort study was done from Feb 21, 2018, to Dec 31, 2019. A census survey of all households located in the Qasimabad and Latifabad subdistricts of Hyderabad, Pakistan, was done at baseline, and 174 005 households were registered in the census. The Typbar-TCV immunisation campaign was initiated at temporary vaccination centres and 207 000 children aged 6 months to 10 years were vaccinated from Feb 21, 2018, to Dec 31, 2018. Social mobilisers informed parents about the vaccination process. Vaccination records were maintained electronically and linked with the household census surveys. Active surveillance for suspected and blood-culture-confirmed S Typhi was established in hospitals, clinics, and laboratories to assess the following outcomes: cases of suspected typhoid fever, culture-confirmed S Typhi, and antimicrobial resistance. An age-stratified cohort of 1100 vaccinated children was randomly selected from the vaccination registry, tested for Vi-IgG antibodies (data not reported), and followed up fortnightly (via telephone calls or household visits) until Dec 31, 2019, for ascertainment of outcomes during the study period. 20 847 vaccinated and unvaccinated children were randomly selected from the census registry as a quality control cohort and followed up from Oct 1 to Dec 31, 2019, for ascertainment of outcomes. Vaccine effectiveness against suspected, culture-confirmed, and XDR S Typhi was calculated. Findings 23 407 children from the census registry and surveillance system were included in the vaccine effectiveness analysis. 13 436 (57·4%) children were vaccinated, 12 214 (52·2%) were male, and 10 168 (43·4%) were aged 6–59 months. 5378 (23·0%) of 23 407 children had suspected S Typhi, among whom 775 (14·4%) had culture-confirmed S Typhi and 361 (68·6%) of 526 had XDR S Typhi. Vaccine effectiveness was 55% (95% CI 52–57) against suspected S Typhi (regardless of culture confirmation), 95% (93–96) against culture-confirmed S Typhi, and 97% (95–98) against XDR S Typhi. Interpretation Typbar-TCV is effective in protecting children against S Typhi infection in an outbreak setting, and was able, with moderate deployment, to curtail a major XDR S Typhi outbreak in a densely populated setting. The vaccine shows efficacy against S Typhi irrespective of antimicrobial resistance. Funding Bill & Melinda Gates Foundation.

Background: Precise enteric fever disease burden data are needed to inform prevention and control measures, including the use of newly available typhoid vaccines. To inform these strategies, the Surveillance for Enteric Fever in Asia Project (SEAP) conducted prospective, facility-based surveillance for Salmonella Typhi and S . Paratyphi A from 2016-2019. Methods: To generate population-based incidence estimates of enteric fever, we conducted prospective clinical surveillance at five hospitals in pre-determined catchment areas in Dhaka, Bangladesh, Kathmandu and Kavrepalanchok, Nepal, and Karachi, Pakistan. We employed a hybrid surveillance model, pairing facility-based blood culture surveillance with community surveys of healthcare utilization. Blood cultures were performed for enrolled patients. We calculated overall and age-specific typhoid and paratyphoid incidence estimates for each study site. Adjusted estimates accounted for the sensitivity of blood culture, the proportion of eligible individuals who consented and provided blood, the probability of care-seeking at a study facility, and the influence of wealth and education on care-seeking. Findings: Of the 33,136 blood cultures performed on enrolled patients, 8,705 (26%) were positive for typhoidal Salmonella . Adjusted incidence of S . Typhi, expressed per 100,000 person-years, was 1,110 (95% CI: 949-1,305) in Dhaka. In Nepal, the adjusted typhoid incidence rates were 330 (95% CI: 232-476) in Kathmandu and 271 (95% CI:205-365) in Kavrepalanchok. In Pakistan, the adjusted incidence rates per hospital site were 195 (95% CI:163-236) and 126 (95% CI:106-151). Although lower than the rates of typhoid, the adjusted incidence rates of paratyphoid were 150 ( 95% CI: 127-177) in Bangladesh, 49 (95% CI: 38-65) and 82 (95% CI: 57-116) in the Nepal sites, and 25 (95% CI: 21-31) and 1 (95% CI: 1-1) in the Pakistan sites. Adjusted incidence of hospitalization was high across sites, and overall 32% of case patients were hospitalized. Interpretation: Across diverse communities in three South Asian countries, adjusted incidence exceeded the threshold for “high burden” of enteric fever (100 per 100,000 person-years). Incidence was highest among children, although age patterns differed across sites. The substantial disease burden identified highlights the need for control measures, including improvements to water and sanitation infrastructure and the implementation of typhoid vaccines. Funding: This work was supported by a grant from the Bill and Melinda Gates Foundation (grant number INV-008335). Declaration of Interest: None to declare. Ethical Approval: We obtained written informed consent from all eligible participants and the parents/guardians of participants aged

Background: We aim to report the effectiveness and impact evaluation of typhoid conjugate vaccine (TCV) against Salmonella Typhi (S.Typhi) among 6 months to 10 years old children in an outbreak setting of extensively drug resistant (XDR) Typhoid in Pakistan. Methods: A cohort and nested case-cohort studies conducted from March 01, 2018 to December 31, 2019. All households located in Qasimabad and Latifabad sub-districts were registered through electronic registry at baseline and age eligible children were offered free vaccination. Typhoid surveillance was established. 1058 randomly selected vaccinated cohort was followed till December 31, 2019 for additional S.Typhi cases. Besides, a case-cohort of 20,090 children were surveyed during Oct-Dec 2019 for any missed cases of S.Typhi. TCV vaccination status was available from baseline registry. Incidence rate ratio (IRR) and vaccine effectiveness (VE) against S.Typhi was calculated using 1-IRR. Findings: A total 23,407 children, 13436 (57·4%) were vaccinated, 12214 (52·2%) were male, and 10168 (43·4%) were 6-59 months old. 5378 (23%) children had suspected S.Typhi, among whom 775 (14·4%) were culture confirmed and 361/526 (68·6%) were XDR. The VE (95% CI) against suspected (regardless of cultures), culture confirmed and XDR S.Typhi, was 55% (52% to 57%), 95% (93% to 96%), and 97% (94% to 98%), respectively. The adjusted hazard ratio (aHR) of contracting culture confirmed S.Typhi among vaccinated children was 0·053; 95% CI 0·039 to 0·071; p

BackgroundImplementation of population-based surveys is resource intensive and logistically demanding, especially in areas with rapidly changing demographics and incomplete or no enumeration of the underlying population and their residences. To remove the need for pre-enumeration and to simplify field logistics for the population healthcare utilization survey used for the Surveillance for Enteric Fever in Asia Project in Nepal, we incorporated a geographic information system–based geosurvey and field mapping system into a single-stage cluster sampling approach.MethodsA survey was administered to ascertain healthcare-seeking behavior in individuals with recent suspected enteric fever. Catchment areas were based on residential addresses of enteric fever patients using study facilities; clusters were randomly selected from digitally created grids using available satellite images and all households within clusters were offered enrollment. A tablet-compatible geosurvey and mapping system that allowed for data-syncing and use in areas without cellular data was created using the ArcGIS suite of software.ResultsBetween January 2017 and November 2018, we surveyed 25 521 households in Nepal (16 769 in urban Kathmandu and 8752 in periurban Kavrepalanchok), representing 84 202 individuals. Overall, the survey participation rate was 90.9%, with geographic heterogeneity in participation rates within each catchment area. Areas with higher average household wealth had lower participation rates.ConclusionA geographic information system–based geosurvey and field mapping system allowed creation of a virtual household map at the same time as survey administration, enabling a single-stage cluster sampling method to assess healthcare utilization in Nepal for the Surveillance for Enteric Fever in Asia Project . This system removed the need for pre-enumeration of households in sampling areas, simplified logistics and could be replicated in future community surveys.

Background Typhoid fever is endemic in the urban Kathmandu Valley of Nepal; however, there have been no population-based studies of typhoid outside of this community in the past 3 decades. Whether typhoid immunization should be prioritized in periurban and rural communities has been unclear. Methods We performed population-based surveillance for enteric fever in 1 urban catchment (Kathmandu) and 1 periurban and rural catchment (Kavrepalanchok) as part of the Surveillance for Enteric Fever in Asia Project (SEAP). We recruited individuals presenting to outpatient and emergency departments at 2 study hospitals with suspected enteric fever and performed blood cultures. Additionally, we conducted a household survey in each catchment area to characterize care seeking for febrile illness. We evaluated spatial heterogeneity in febrile illness, care seeking, and enteric fever incidence. Results Between September 2016 and September 2019, we enrolled 5736 participants with suspected enteric fever at 2 study hospitals. Among these, 304 (5.3%) were culture positive for Salmonella Typhi (249 [81.9%]) or Paratyphi A (55 [18.1%]). Adjusted typhoid incidence in Kathmandu was 484 per 100 000 person-years and in Kavrepalanchok was 615 per 100 000 person-years. While all geographic areas for which estimates could be made had incidence >200 per 100 000 person-years, we observed spatial heterogeneity with up to 10-fold variation in incidence between communities. Conclusions In urban, periurban, and rural communities in and around Kathmandu, we measured a high but heterogenous incidence of typhoid. These findings provide some support for the introduction of conjugate vaccines in Nepal, including outside urban areas, alongside other measures to prevent enteric fever.