Blood Culture-confirmed Typhoid Fever Research Articles

Efficacy of typhoid conjugate vaccine: final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children

Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection beyond 2 years are sparse. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up, with the aim of investigating vaccine efficacy over time and by age group. In this phase 3, double-blind, randomised controlled efficacy trial in Blantyre, Malawi, healthy children aged 9 months to 12 years were randomly assigned (1:1) by an unmasked statistician to receive a single dose of Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT) or meningococcal capsular group A conjugate (MenA) vaccine. Children had to have no previous history of typhoid vaccination and reside in the study areas for inclusion and were recruited from government schools and health centres. Participants, their parents or guardians, and the study team were masked to vaccine allocation. Nurses administering vaccines were unmasked. We did surveillance for febrile illness from vaccination until follow-up completion. The primary outcome was first occurrence of blood culture-confirmed typhoid fever. Eligible children who were randomly assigned and vaccinated were included in the intention-to-treat analyses. This trial is registered at ClinicalTrials.gov, NCT03299426. Between Feb 21, 2018, and Sept 27, 2018, 28 130 children were vaccinated; 14 069 were assigned to receive Vi-TT and 14 061 to receive MenA. After a median follow-up of 4·3 years (IQR 4·2-4·5), 24 (39·7 cases per 100 000 person-years) children in the Vi-TT group and 110 (182·7 cases per 100 000 person-years) children in the MenA group were diagnosed with a first episode of blood culture-confirmed typhoid fever. In the intention-to-treat population, efficacy of Vi-TT was 78·3% (95% CI 66·3-86·1), and 163 (129-222) children needed to be vaccinated to prevent one case. Efficacies by age group were 70·6% (6·4-93·0) for children aged 9 months to 2 years; 79·6% (45·8-93·9) for children aged 2-4 years; and 79·3% (63·5-89·0) for children aged 5-12 years. A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years and shows efficacy in all age groups, including children younger than 2 years. These results support current WHO recommendations in typhoid-endemic areas for mass campaigns among children aged 9 months to 15 years, followed by routine introduction in the first 2 years of life. Bill & Melinda Gates Foundation.

The Identification of Enteric Fever-Specific Antigens for Population-Based Serosurveillance.

Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi A, is a major public health problem in low- and middle-income countries. Moderate sensitivity and scalability of current methods likely underestimate enteric fever burden. Determining the serological responses to organism-specific antigens may improve incidence measures. Plasma samples were collected from blood culture-confirmed enteric fever patients, blood culture-negative febrile patients over the course of 3 months, and afebrile community controls. A panel of 17 Salmonella Typhi and Paratyphi A antigens was purified and used to determine antigen-specific antibody responses by indirect ELISAs. The antigen-specific longitudinal antibody responses were comparable between enteric fever patients, patients with blood culture-negative febrile controls, and afebrile community controls for most antigens. However, we found that IgG responses against STY1479 (YncE), STY1886 (CdtB), STY1498 (HlyE), and the serovar-specific O2 and O9 antigens were greatly elevated over a 3-month follow up period in S. Typhi/S. Paratyphi A patients compared to controls, suggesting seroconversion. We identified a set of antigens as good candidates to demonstrate enteric fever exposure. These targets can be used in combination to develop more sensitive and scalable approaches to enteric fever surveillance and generate invaluable epidemiological data for informing vaccine policies. ISRCTN63006567.

Typhoid conjugate vaccine effectiveness in Malawi: evaluation of a test-negative design using randomised, controlled clinical trial data

Typhoid conjugate vaccines are being introduced in low-income and middle-income countries to prevent typhoid illness in children. Vaccine effectiveness studies assess vaccine performance after introduction. The test-negative design is a commonly used method to estimate vaccine effectiveness that has not been applied to typhoid vaccines because of concerns over blood culture insensitivity. The overall aim of the study was to evaluate the appropriateness of using a test-negative design to assess typhoid Vi polysaccharide-tetanus toxoid conjugate vaccine (Vi-TT) effectiveness using a gold standard randomised controlled trial database. Using blood culture data from a randomised controlled trial of Vi-TT in Malawi, we simulated a test-negative design to derive vaccine effectiveness estimates using three different approaches and compared these to randomised trial efficacy results. In the randomised trial, 27 882 children aged 9 months to 12 years were randomly assigned (1:1) to receive a single dose of Vi-TT or meningococcal capsular group A conjugate vaccine between Feb 21 and Sept 27, 2018, and were followed up for blood culture-confirmed typhoid fever until Sept 30, 2021. For all three test-negative design approaches, vaccine effectiveness estimates (test-negative design A, 80·3% [95% CI 66·2 to 88·5] vs test-negative design B, 80·5% [66·5 to 88·6] vs test-negative design C, 80·4% [66·9 to 88·4]) were almost identical to the randomised trial results (80·4% [95% CI 66·4 to 88·5]). Receipt of Vi-TT did not affect the risk of non-typhoid fever (vaccine efficacy against non-typhoid fever -0·4% [95% CI -4·9 to 3·9] vs -1% [-5·6 to 3·3] vs -2·5% [-6·4 to 1·3] for test-negative design A, test-negative design B, and test-negative design C, respectively). This study validates the test-negative design core assumption for typhoid vaccine effectiveness estimation and shows the accuracy and precision of the estimates compared with the randomised controlled trial. These results show that the test-negative design is suitable for assessing typhoid conjugate vaccine effectiveness in post-introduction studies using blood culture surveillance. Bill & Melinda Gates Foundation.

Estimating typhoid incidence from community-based serosurveys: a multicohort study

SummaryBackgroundThe 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.MethodsWe 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.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 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.InterpretationThe 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.FundingBill & Melinda Gates Foundation.TranslationsFor the Nepali, Bengali and Urdu translations of the abstract see Supplementary Materials section.

Incidence of typhoid and paratyphoid fever in Bangladesh, Nepal, and Pakistan: results of the Surveillance for Enteric Fever in Asia Project

SummaryBackgroundPrecise enteric fever disease burden data are needed to inform prevention and control measures, including the use of newly available typhoid vaccines. We established the Surveillance for Enteric Fever in Asia Project (SEAP) to inform these strategies.MethodsFrom September, 2016, to September, 2019, we conducted prospective clinical surveillance for Salmonella enterica serotype Typhi (S Typhi) and Paratyphi (S Paratyphi) A, B, and C at health facilities in predetermined catchment areas in Dhaka, Bangladesh; Kathmandu and Kavrepalanchok, Nepal; and Karachi, Pakistan. Patients eligible for inclusion were outpatients with 3 or more consecutive days of fever in the last 7 days; inpatients with suspected or confirmed enteric fever; patients with blood culture-confirmed enteric fever from the hospital laboratories not captured by inpatient or outpatient enrolment and cases from the laboratory network; and patients with non-traumatic ileal perforation under surgical care. We used a hybrid surveillance model, pairing facility-based blood culture surveillance with community surveys of health-care use. 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. We additionally calculated incidence of hospitalisation due to typhoid and paratyphoid.FindingsA total of 34 747 patients were enrolled across 23 facilitates (six tertiary hospitals, surgical wards of two additional hospitals, and 15 laboratory network sites) during the study period. Of the 34 303 blood cultures performed on enrolled patients, 8705 (26%) were positive for typhoidal Salmonella. Adjusted incidence rates of enteric fever considered patients in the six tertiary hospitals. Adjusted incidence of S Typhi, expressed per 100 000 person-years, was 913 (95% CI 765–1095) in Dhaka. In Nepal, the adjusted typhoid incidence rates were 330 (230–480) in Kathmandu and 268 (202–362) in Kavrepalanchok. In Pakistan, the adjusted incidence rates per hospital site were 176 (144–216) and 103 (85–126). The adjusted incidence rates of paratyphoid (of which all included cases were due to S Paratyphi A) were 128 (107–154) in Bangladesh, 46 (34–62) and 81 (56–118) in the Nepal sites, and 23 (19–29) and 1 (1–1) in the Pakistan sites. Adjusted incidence of hospitalisation was high across sites, and overall, 2804 (32%) of 8705 patients with blood culture-confirmed enteric fever were hospitalised.InterpretationAcross 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.FundingBill & Melinda Gates Foundation.

Salmonella Typhi Shedding and Household Transmission by Children With Blood Culture-Confirmed Typhoid Fever in Vellore, South India.

BackgroundChildren suffer the highest burden of the typhoid fever, with a considerable proportion shedding Salmonella Typhi in stool, potentially resulting in transmission of S Typhi.MethodsWe enrolled 70 children with blood culture-confirmed typhoid fever (index cases), from 63 households, during community-based fever surveillance in India. The index cases and their household contacts were followed up with stool samples at multiple time points over 3 weeks and 1 week, respectively. S Typhi was detected using quantitative real-time polymerase chain reaction.ResultsFifteen of 70 (21.4%) children with culture-confirmed typhoid fever shed S Typhi in stool after onset of fever. Ten of 15 children shed S Typhi for a median of 11.5 (range, 3–61) days from the day of completion of antibiotics. Of 172 household contacts from 56 of the 63 index case households, 12 (7%) contacts in 11 (19.6%) households had S Typhi in stool. Five of the 12 contacts who were shedding S Typhi were asymptomatic, whereas 7 reported recent fever.ConclusionsOne in 5 children with typhoid fever shed S Typhi, with shedding persisting even after antibiotics. One in 5 households had at least 1 contact of the child shedding S Typhi, highlighting potential concurrent typhoid infections in households in settings with poor water and sanitation.

Cost of Illness Due to Severe Enteric Fever in India.

Background Lack of robust data on economic burden due to enteric fever in India has made decision making on typhoid vaccination a challenge. Surveillance for Enteric Fever network was established to address gaps in typhoid disease and economic burden.MethodsPatients hospitalized with blood culture-confirmed enteric fever and nontraumatic ileal perforation were identified at 14 hospitals. These sites represent urban referral hospitals (tier 3) and smaller hospitals in urban slums, remote rural, and tribal settings (tier 2). Cost of illness and productivity loss data from onset to 28 days after discharge from hospital were collected using a structured questionnaire. The direct and indirect costs of an illness episode were analyzed by type of setting.ResultsIn total, 274 patients from tier 2 surveillance, 891 patients from tier 3 surveillance, and 110 ileal perforation patients provided the cost of illness data. The mean direct cost of severe enteric fever was US$119.1 (95% confidence interval [CI], US$85.8–152.4) in tier 2 and US$405.7 (95% CI, 366.9–444.4) in tier 3; 16.9% of patients in tier 3 experienced catastrophic expenditure.ConclusionsThe cost of treating enteric fever is considerable and likely to increase with emerging antimicrobial resistance. Equitable preventive strategies are urgently needed.

Case-Fatality Ratio of Enteric Fever: Estimates From Multitiered Surveillance in India.

BackgroundThe case-fatality ratio (CFR) for enteric fever is essential for estimating disease burden and calibrating measures that balance the likely health gains from interventions against social and economic costs.MethodsWe aimed to estimate the CFR for enteric fever using multiple data sources within the National Surveillance System for Enteric Fever in India. This surveillance (2017–2020) was established as a multitiered surveillance system including community cohorts (tier 1), facility-based (tier 2), and tertiary care surveillance (tier 3) for estimating the burden of enteric fever in India. The CFR was calculated after accounting for healthcare-seeking behavior for enteric fever and deaths occurring outside the hospital.ResultsA total of 1236 hospitalized patients with blood culture–confirmed enteric fever were enrolled, of which 9 fatal cases were identified, for an estimated hospitalized CFR of 0.73% (95% confidence interval [CI], .33%–1.38%). After adjusting for severity, healthcare-seeking behavior, and deaths occurring out-of-hospital, the CFR was estimated to be 0.16% (95% CI, .07%–.29%) for all enteric fevers.ConclusionsOur estimates of the CFR are relatively lower than previously estimated, accounting for care-seeking behavior and deaths outside the hospital.

Efficacy of typhoid conjugate vaccine in Nepal: final results of a phase 3, randomised, controlled trial

SummaryBackgroundTyphoid fever is a major public health problem in low-resource settings. Vaccination can help curb the disease and might reduce transmission. We have previously reported an interim analysis of the efficacy of typhoid conjugate vaccine (TCV) in Nepali children. Here we report the final results after 2 years of follow-up.MethodsWe did a participant-masked and observer-masked individually randomised trial in Lalitpur, Nepal, in which 20 019 children aged 9 months to younger than 16 years were randomly assigned in a 1:1 ratio to receive a single dose of TCV (Typbar TCV, Bharat Biotech International, India) or capsular group A meningococcal conjugate vaccine (MenA). Participants were followed up until April 9, 2020. The primary outcome was blood culture-confirmed typhoid fever. Cases were captured via passive surveillance and active telephone surveillance followed by medical record review. The trial is registered at ISRCTN registry, ISRCTN43385161 and is ongoing.FindingsFrom Nov 20, 2017, to April 9, 2018, of 20 119 children screened, 20 019 participants were randomly assigned to receive TCV or MenA vaccine. There were 75 cases of blood culture-confirmed typhoid fever included in the analysis (13 in the TCV group and 62 in the MenA group) over the 2-year period. The protective efficacy of TCV against blood culture-confirmed typhoid fever at 2 years was 79·0% (95% CI 61·9–88·5; p<0·0001). The incidence of typhoid fever was 72 (95% CI 38–123) cases per 100 000 person-years in the TCV group and 342 (95% CI 262–438) cases per 100 000 person-years in the MenA group. Adverse events occurring within the first 7 days post-vaccination were reported previously.InterpretationThe final results of this randomised, controlled trial are in keeping with the results of our published interim analysis. There is no evidence of waning protection over a 2-year period. These findings add further support for the WHO recommendations on control of enteric fever.FundingBill & Melinda Gates Foundation.

Typhoid Conjugate Vaccines: Advancing the Research and Public Health Agendas.

The disease burden of typhoid fever remains high in endemic areas in Asia and Africa, especially in children. Recent clinical trials conducted by the Typhoid Vaccine Acceleration Consortium show typhoid conjugate vaccine (TCV) to be safe, immunogenic, and efficacious at preventing blood culture-confirmed typhoid fever in African and Asian children. Pakistan, Liberia, and Zimbabwe recently introduced TCV through campaigns and routine childhood immunizations, providing protection for this vulnerable population. It is essential to continue this momentum while simultaneously filling data gaps—including typhoid complications—to inform decision-making on TCV introduction. A multidisciplinary approach including surveillance, water, sanitation, and hygiene investments, and large-scale TCV introduction is needed to decrease the burden and mortality of typhoid fever.

Stool shedding of Salmonella Typhi in children with blood culture-confirmed typhoid fever

Background: Shedding of Salmonella Typhi in stool following symptomatic or asymptomatic infections may play a substantial role in the transmission of typhoid fever. This study estimated the proportion of children shedding S. Typhi in stool during and after an episode of typhoid fever, as well as shedding among members of their household. Methods and materials: The study was nested within a paediatric cohort of the Surveillance for Enteric Fever in India (SEFI) study, Vellore, where 6000 children are under active surveillance for fever. As per the study protocol, children with fever for ≥3 days receive a blood culture and receive azithromycin therapy, if the culture grew S. Typhi. Children positive for S.Typhi were requested to provide stool samples (3 samples/week) over the next three weeks. Concurrently, three stool samples were also collected from each of the household contacts of these children, for screening S. Typhi. The STY0201 gene was detected using Real-time Polymerase Chain Reaction (RT-PCR). Clinical characteristics of children with blood culture-confirmed typhoid fever who shed S. Typhi and did not were compared. Results: Of 65 children with blood culture-confirmed typhoid fever between November 2018 to July 2019, 58(89.2%) children from 53 households consented to provide stool samples. Of these 58 children, 15(25.9%) shed S. Typhi, with a median time (IQR) of shedding at 17(11-24) days from the onset of fever and three of these 15, shed S. Typhi again at a median interval of 30 days from the onset of fever. History of hospitalization during the typhoid fever episode was associated with shedding S. Typhi [OR: 6.6(95% CI:1.5-29)]. Eight(15.1%) of the 53 households with a case of typhoid fever had at least one family member shedding S. Typhi, of whom five were asymptomatic and remaining three had a recent history of fever. Conclusion: One in four children shed S.Typhi during and after the typhoid fever and severity of illness was associated with shedding. About 15% of the households with a child with typhoid fever had a family member shedding S. Typhi concurrently. Thus, it is recommended to consider these parameters while studying disease transmission in endemic settings.

Healthcare Utilization Patterns for Acute Febrile Illness in Bangladesh, Nepal, and Pakistan: Results from the Surveillance for Enteric Fever in Asia Project.

BackgroundCharacterizing healthcare-seeking patterns for acute febrile illness is critical for generating population-based enteric fever incidence estimates from facility-based surveillance data.MethodsWe 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.ResultsWe 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 <5 years were most likely to be taken to the study hospitals for febrile illness at all sites. Household wealth was positively correlated with healthcare seeking in 4 of 5 study sites, and at least one marker of disease severity was positively associated with healthcare seeking in 3 of 5 catchment areas. Wealth and disease severity were variably predictive of blood culture-confirmed enteric fever.ConclusionsAge, 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.

Illness Severity and Outcomes Among Enteric Fever Cases From Bangladesh, Nepal, and Pakistan: Data From the Surveillance for Enteric Fever in Asia Project, 2016-2019.

BackgroundEnteric fever can lead to prolonged hospital stays, clinical complications, and death. The Surveillance for Enteric Fever in Asia Project (SEAP), a prospective surveillance study, characterized the burden of enteric fever, including illness severity, in selected settings in Bangladesh, Nepal, and Pakistan. We assessed disease severity, including hospitalization, clinical complications, and death among SEAP participants.MethodsWe analyzed clinical and laboratory data from blood culture–confirmed enteric fever cases enrolled in SEAP hospitals and associated network laboratories from September 2016 to September 2019. We used hospitalization and duration of hospital stay as proxies for severity. We conducted a follow-up interview 6 weeks after enrollment to ascertain final outcomes.ResultsOf the 8705 blood culture-confirmed enteric fever cases enrolled, we identified 6 deaths (case-fatality ratio, .07%; 95% CI, .01–.13%), 2 from Nepal, 4 from Pakistan, and none from Bangladesh. Overall, 1.7% (90/5205) of patients recruited from SEAP hospitals experienced a clinical complication (Bangladesh, 0.6% [18/3032]; Nepal, 2.3% [12/531]; Pakistan, 3.7% [60/1642]). The most identified complications were hepatitis (n = 36), septic shock (n = 22), and pulmonary complications/pneumonia (n = 13). Across countries, 32% (2804/8669) of patients with hospitalization data available were hospitalized (Bangladesh, 27% [1295/4868]; Nepal, 29% [455/1595]; Pakistan, 48% [1054/2206]), with a median hospital stay of 5 days (IQR, 3–7).ConclusionsWhile defined clinical complications and deaths were uncommon at the SEAP sites, the high proportion of hospitalizations and prolonged hospital stays highlight illness severity and the need for enteric fever control measures, including the use of typhoid conjugate vaccines.

Pathogen genomic surveillance of typhoidal Salmonella infection in adults and children reveals no association between clinical outcomes and infecting genotypes

BackgroundIndia is endemic for enteric fever, and it is not known whether the variations in clinical manifestations between patients are due to host, environmental or pathogen factors.Blood culture surveillance was conducted at St. John’s Medical College Hospital, Bangalore, between July 2016 and June 2017. Clinical, laboratory and demographic data were collected from each case, and bacterial isolates were subjected to whole genome sequencing. Comparative analysis between adults and paediatric patients was carried out to ascertain differences between adult and paediatric disease.ResultsAmong the 113 cases of blood culture-confirmed enteric fever, young adults (16–30 years) and children < 15 years accounted for 47% and 37% of cases, respectively. Anaemia on presentation was seen in 46% of cases, and 19% had an abnormal leucocyte count on presentation. The majority received treatment as inpatients (70%), and among these, adults had a significantly longer duration of admission when compared with children (p = 0.002). There were atypical presentations including arthritis, acute haemolysis and a case of repeated typhoid infection with two separate S. Typhi genotypes. There was no association between infecting genotype/serovar and treatment status (outpatient vs inpatient), month of isolation, duration of admission, patient age (adult or child), antimicrobial susceptibility, Widal positivity or haematologic parameters.ConclusionsAmidst the many public health concerns of South India, enteric fever continues to contribute substantially to hospital burden with non-specific as well as uncommon clinical features in both paediatric and adult populations likely driven by host and environmental factors. Robust clinical surveillance as well monitoring of pathogen population structure is required to inform treatment and preventive strategies.

ANALYSIS OF COST-OF-ILLNESS DUE TO TYPHOID FEVER IN TERTIARY HEALTH CARE HOSPITALS AND PHARMACEUTICAL EVALUATION OF DIFFERENT BRANDS USED IN THE TREATMENT

The objectives of the current study were to estimate the out-of-pocket costs of illness of blood culture-confirmed typhoid fever, as well as to evaluate the different brands of ciprofloxacin HCl used in the treatment of typhoid fever. Therefore, a comparative study was designed for the assessment of costs of treatment at sixteen public (Government sector) and private tertiary health care hospitals located in Rawalpindi and Islamabad, Pakistan. On the basis of prescriptions collected from the hospitals, seven different brands of ciprofloxacin HCl prescribed in the treatment of typhoid fever were purchased from retail pharmacies for quality assessment. The mean costs for fourteen days and seven days treatment were analyzed and the overall costs of treatment were high at private health care sectors than public sectors. Model independent approach like similarity factor (f2) was also applied to assess the similarity between the dissolution profiles of different brands, and result indicated that three brands were found to be similar with reference product, while, three were dissimilar. It can be concluded that this cost-effective analysis of antibiotics used in the typhoid fever, will help to the local regularity body as well as WHO to update typhoid fever immunization recommendations. Ciprofloxacin was found an effective antibacterial agent in the treatment of typhoid fever and all brands met the pharmaceutical quality parameters. Thus, physicians, pharmacists and patients can select most appropriate quality brand for the therapy of typhoid fever.

ANALYSIS OF COST-OF-ILLNESS DUE TO TYPHOID FEVER IN TERTIARY HEALTH CARE HOSPITALS AND PHARMACEUTICAL EVALUATION OF DIFFERENT BRANDS USED IN THE TREATMENT

The objectives of the current study were to estimate the out-of-pocket costs of illness of blood culture-confirmed typhoid fever, as well as to evaluate the different brands of ciprofloxacin HCl used in the treatment of typhoid fever. Therefore, a comparative study was designed for the assessment of costs of treatment at sixteen public (Government sector) and private tertiary health care hospitals located in Rawalpindi and Islamabad, Pakistan. On the basis of prescriptions collected from the hospitals, seven different brands of ciprofloxacin HCl prescribed in the treatment of typhoid fever were purchased from retail pharmacies for quality assessment. The mean costs for fourteen days and seven days treatment were analyzed and the overall costs of treatment were high at private health care sectors than public sectors. Model independent approach like similarity factor (f2) was also applied to assess the similarity between the dissolution profiles of different brands, and result indicated that three brands were found to be similar with reference product, while, three were dissimilar. It can be concluded that this cost-effective analysis of antibiotics used in the typhoid fever, will help to the local regularity body as well as WHO to update typhoid fever immunization recommendations. Ciprofloxacin was found an effective antibacterial agent in the treatment of typhoid fever and all brands met the pharmaceutical quality parameters. Thus, physicians, pharmacists and patients can select most appropriate quality brand for the therapy of typhoid fever.

Persistent circulation of a fluoroquinolone-resistant Salmonella enterica Typhi clone in the Indian subcontinent.

BackgroundThe molecular structure of circulating enteric fever pathogens was studied using hospital-based genomic surveillance in a tertiary care referral centre in South India as a first genomic surveillance study, to our knowledge, of blood culture-confirmed enteric fever in the region.MethodsBlood culture surveillance was conducted at St John’s Medical College Hospital, Bengaluru, between July 2016 and June 2017. The bacterial isolates collected were linked to demographic variables of patients and subjected to WGS. The resulting pathogen genomic data were also globally contextualized to gauge possible phylogeographical patterns.ResultsHospital-based genomic surveillance for enteric fever in Bengaluru, India, identified 101 Salmonella enterica Typhi and 14 S. Paratyphi A in a 1 year period. Ninety-six percent of isolates displayed non-susceptibility to fluoroquinolones. WGS showed the dominant pathogen was S. Typhi genotype 4.3.1.2 (H58 lineage II). A fluoroquinolone-resistant triple-mutant clone of S. Typhi 4.3.1.2 previously associated with gatifloxacin treatment failure in Nepal was implicated in 18% of enteric fever cases, indicating ongoing inter-regional circulation.ConclusionsEnteric fever in South India continues to be a major public health issue and is strongly associated with antimicrobial resistance. Robust microbiological surveillance is necessary to direct appropriate treatment and preventive strategies. Of particular concern is the emergence and expansion of the highly fluoroquinolone-resistant triple-mutant S. Typhi clone and its ongoing inter- and intra-country transmission in South Asia, which highlights the need for regional coordination of intervention strategies, including vaccination and longer-term strategies such as improvements to support hygiene and sanitation.

A retrospective study of patients with blood culture-confirmed typhoid fever in Fiji during 2014-2015: epidemiology, clinical features, treatment and outcome.

BackgroundTyphoid fever is endemic in Fiji. We sought to describe the epidemiology, clinical features and case fatality risk of blood culture-confirmed typhoid fever from January 2014 through December 2015.MethodsBlood culture-positive patients were identified from a typhoid surveillance line list. A standardised case investigation form was used to record data from patients’ medical records.ResultsOf 542 patients, 518 (95.6%) were indigenous Fijians (iTaukei) and 285 (52.6%) were male. The median (IQR) age was 25 (16–38) y. Mean (SD) time from the onset of illness to admission was 11.1 (6.9) d. Of 365 patients with clinical information, 346 (96.9%) had fever, 239 (66.9%) diarrhoea, 113 (33.5%) vomiting, and 72 (30.2%) abdominal pain. There were 40 (11.0%) patients with complications, including 17 (4.7%) with shock, and 11 (3.0%) with hepatitis. Nine patients died for a case fatality risk of 1.7%. Of the 544 Salmonella Typhi isolates tested, none were resistant to first line antimicrobials; 3(0.8%) were resistant to ciprofloxacin and 5(1.4%) to nalidixic acid.ConclusionsIn Fiji, most blood culture-confirmed typhoid fever cases were in young adults. Common clinical manifestations were fever and gastrointestinal symptoms. Further studies are required to elucidate the factors associated with complications and death.

Logistics of Implementing a Large-scale Typhoid Vaccine Trial in Kathmandu, Nepal.

Typhoid fever is estimated to affect over 20 million people per year worldwide, with infants, children, and adolescents in south-central and southeast Asia experiencing the greatest burden of disease. The Typhoid Vaccine Acceleration Consortium (TyVAC) aims to support the introduction of typhoid conjugate vaccines into Gavi-eligible countries in an effort to reduce morbidity and mortality from typhoid. TyVAC-Nepal is a large-scale, participant- and observer-blind, individually randomized, controlled trial evaluating the efficacy of a newly developed typhoid conjugate vaccine in an urban setting in Nepal. In order to effectively deliver the trial, a number of key elements required meticulous planning. Public engagement strategies were considered early, and involved the implementation of a tiered approach. Approximately 300 staff were employed and trained in order to achieve the mass vaccination of 20 000 children aged 9 months to ≤16 years old over a 4-month period. There were 19 vaccination clinics established across the Lalitpur metropolitan city in the Kathmandu valley. Participants will be followed for 2 years post-vaccination to measure the rate reduction of blood culture–confirmed typhoid fever in the vaccination arm as compared to the control arm. The experience of conducting this large-scale vaccine trial suggests that comprehensive planning, continuous monitoring, and an ability to adapt plans in response to feedback are key.

Enteric Fever in Cambodia: Community Perceptions and Practices Concerning Disease Transmission and Treatment

.Enteric fever is a systemic bacterial infection in humans that is endemic in Cambodia and for which antibiotic resistance is increasingly reported. To guide public health programs, this qualitative study sought to explore community perceptions on transmission and treatment. Participant observation was carried out in hospital settings, pharmacies, and at a community level in Phnom Penh. In-depth interviews 39 and one focus group discussion were carried out with blood culture–confirmed enteric fever patients and purposively selected key informants. Informants were theoretically sampled based on initial themes identified using abductive analysis. Nvivo 11 was used for thematic coding. An urgent need to address health literacy concerning the transmission of enteric fever was identified, as lay informants did not link the disease and its symptoms to bacterial contamination of foods and drinks but rather to foods considered “bad” following humoral illness interpretations. As a result, lay informants considered recurrence of enteric fever preventable with appropriate dietary restrictions and Khmer traditional medicines. This study also reveals pluralistic health-care–seeking behavior. For initial and mild symptoms, patients preferred home treatment or traditional healing practices; limited household finances delayed treatment seeking. When symptoms persisted, patients first visited drug outlets or private practitioners, where they received a mix of nonessential medicines and one or more antibiotics often without prescription or confirmation of diagnosis. Inappropriate use of antibiotics was common and was related to diagnostic uncertainty and limited finances, factors which should be addressed during future efforts to improve the uptake of appropriate diagnostics and treatment of enteric fever.