Tracking the shift in enteric fever trends and evolving antibiotic sensitivity patterns.

Objective: This study aims to examine the frequency of Salmonella Paratyphi found in blood cultures and evaluate the antibiotic susceptibility pattern of Salmonella isolates to different antibiotics. Additionally, the study aims to assess the paradigm shift in the trend of enteric fever caused by Salmonella Typhi (S. Typhi) to Salmonella Paratyphi(S. Paratyphi) . Study Design: Retrospective study. Participant: The study enrolled patients aged 12 years and above diagnosed with enteric fever (positive blood culture) and admitted to Peelamedu Samanaidu Govindasamy Naidu (PSG) Hospital. Interventions: The study analyzed demographic and antibiotic susceptibility profiles of Salmonella isolates collected from 106 enteric fever patients in the hospital between 2010 and 2022. The susceptibility profiles of Salmonella isolates to multiple antibiotics were assessed. Results: There were 106 participants, and 95 (89.62%) of them had enteric fever linked to Salmonella Typhi, while only 11 (10.38%) had enteric fever linked to Salmonella Paratyphi A. From 2010 to 2022, the study discovered a general decline in the prevalence of enteric fever caused by Salmonella species. But between 2014 and 2022, the incidence of enteric fever linked to S. Typhi rapidly increased. Azithromycin (100% , n = 106) and ceftriaxone (99% , n = 105) were highly effective against the Salmonella isolates, whereas nalidixic acid was resisted by 3 isolates (4.72%, n = 3). Conclusion: The study observed a higher incidence of Salmonella Typhi in comparison to Paratyphi A and a greater susceptibility of males to enteric fever. Funding: None declared.

Extensively drug-resistant Salmonella typhi Infection in Adults; Experience from A Tertiary Care Hospital.

Objectives: This study aimed to determine the epidemiology, clinical features, and complications of extensively drug-resistant Salmonella typhi (XDR S. typhi) infection in adults. Method: This cross-sectional study enrolled adults with culture-proven XDR S. typhi admitted to Hayatabad Medical Complex, Peshawar from 1st March to 10th September 2022. Their demographic characteristics, clinical features, treatment, and complications were recorded. Results: Out of 84 patients, 68 (80.9%) were male. The mean age of enrolled patients was 25.2 ± 11.3 years. The mean duration of fever at the time of admission was 13.6 ± 8.2 days, respectively. The most common symptom was loose stools (n=25, 29.8%). Most of the patients (n=69, 82.1%) had received empirical treatment before hospitalization. The majority of the patients (n=42, 50%) received meropenem and a combination of meropenem and azithromycin (n=35, 41.7%) during the study. The time to defervescence for both regimens was similar. Five patients (6%) developed complications of enteric fever. There was no mortality among the participants. Conclusions: Diarrhea was the most common associated clinical feature in XDR typhoid fever. Most of the patients received meropenem alone or in combination with azithromycin with a comparable time to defervescence. The majority of the patients recovered uneventfully and there was no mortality among the study participants.

Colonoscopy Findings of Uncomplicated Enteric Fever Mimicking Koch's Disease.

Enteric fever is a common occurrence in Southeast Asia with a myriad of presentations. Partial treatment often leads to prolonged illness. Along with this, bowel imaging often confounds the picture with tuberculosis. Colonoscopy and biopsy may help to differentiate from tuberculosis. The data on colonoscopy is scarce in enteric fever and is mostly available from case reports of gastrointestinal (GI) bleeding. We have described three cases of enteric fever with GI involvement mimicking tuberculosis. The colonoscopy picture is characteristic of pinkish-bluish ileal mucosa, with edema and decreased distensibility, along with multiple superficial ulcers. The ileocecal valve was involved in all three cases. The ascending colon was involved in two cases. There was complete resolution of lesions after treatment on follow-up. How to cite this article: Verma A, Dahale AS, Gopal P, et al. Colonoscopy Findings of Uncomplicated Enteric Fever Mimicking Koch's Disease. Euroasian J Hepato-Gastroenterol 2024;14(1):120-123.

Epidemiology of non-travel enteric fever cases in England: insights from 10 years of surveillance.

OBJECTIVES: In non-endemic countries, surveillance of non-travel cases of enteric fever is important to identify carriers and reduce secondary transmission. We characterised these cases in England between 2012 and 2021 and assessed potential sources of infection to inform guidance revision. STUDY DESIGN: Retrospective case-case. METHODS: We identified enteric fever cases from the national surveillance dataset. Non-travel cases were defined as no travel to an endemic country or travel but onset of >60 days after return. Multivariable logistic regression was used to identify factors associated with non-travel cases. We reviewed the case records of cases with unknown source of infection. RESULTS: Compared to travel cases, non-travel cases (7%; 225/3075) were older (odds ratio [OR] = 1.02, 95% confidence interval [CI]: 1.02-1.04), asymptomatic (OR = 9.3: 95% CI: 4.3-20.3), and confirmed with Salmonella typhi infection (OR = 1.74, 95% CI: 1.26-2.4). Non-travel cases had lower odds of being of Indian (OR = 0.27, 95% CI: 0.16-0.45) or Pakistani ethnicity (OR = 0.34, 95% CI: 0.16-0.45) than White British. Surveillance questionnaires identified a possible infection source for 53%: case records review identified a further 23%: 33% secondary transmission, mostly household; 21% had overseas visitors, or travelling family; 12% were carriers (cases with enteric fever in the past), 12% travelled to endemic country outside of the 60-day window, and 22% had other possible sources. Case records differentiated between travel 60-90 days (5%) vs travel years prior to onset (7%), suggesting carrier status. CONCLUSION: Not all possible carriers were identified through the surveillance questionnaire. Therefore, we recommend additional questions to systematically capture travel history beyond 60 days to assist in classifying carrier status and to updating the source of infection.

Clinical presentation and outcome of enteric fever in adult patients with cancer: a perspective from Pakistan.

Introduction. Enteric fever is a significant health concern in endemic countries. While extensive research has been conducted to understand its presentation and outcomes in non-cancer patients, limited data exist on its impact on cancer patients. This descriptive study aims to investigate the clinical presentation and outcome in cancer patients. Methodology. This retrospective observational study analysed 90 adult cancer patients from a single centre in Pakistan from January 2017 to December 2022. Inclusion criteria involved documented blood culture infections with Salmonella typhi or paratyphi A, B, or C. We examined clinical presentation, laboratory parameters, antimicrobial resistance, complications, and outcomes. Additionally, we explored the effects of chemotherapy, comorbidities, type of malignancy, and patient age on complications and mortality. Results. Salmonella typhi was the most prevalent organism (72.2 %), followed by Salmonella paratyphi A (22.2 %) and B (5.5 %). Variably-resistant isolates constituted 51.5 %, multi-drug resistant (MDR) isolates accounted for 20 %, extensively drug-resistant (XDR) for 14.4 % and ESBL-producers for 15.5 %, of all enteric fever infections. Enteric fever-associated complications were observed in 21.1 % of cases. Chemotherapy in the preceding month did not affect mortality, nor did age, gender, or malignancy type. However, comorbidities were statistically significant for mortality (p-value 0.03). A total of 8.8 % of patients required ICU care, and the all-cause 30 day mortality rate was 13.3 % Conclusion. Enteric fever remains prevalent in our geographical region. Unlike non-typhoidal Salmonella (NTS), enteric fever does not behave differently in an immunocompromised population, including cancer patients.

Prevalence and Influencing Factor Analysis of Typhoid/Paratyphoid Fever - China, 2011-2020.

Introduction: Over the last 12 years, there has been a consistent decline in the cases of typhoid/paratyphoid fever in China. Studying the epidemiological patterns of these diseases in various provincial-level administrative divisions (PLADs) and examining potential influencing factors can provide crucial information for implementing successful control strategies. Methods: In this study, we analyzed the cases and incidence rates of typhoid/paratyphoid fever reported in various PLADs of China from 2011 to 2022, along with exploring potential influencing factors. We initially studied spatial shifts in the incidence rates through centroid shift analysis. Seasonal variations in typhoid/paratyphoid fever onset were examined using heatmaps. Spatial autocorrelation analysis was utilized to understand the spatial correlations among different PLADs. To assess potential factors, we utilized a generalized estimating equations model that integrated spatial lag effects and sequence comparison analysis. Results: The study identified significant geographical clustering of typhoid/paratyphoid fever cases in southwestern China. A decrease in incidence rates in the west resulted in a movement of the disease center towards the east. Higher incidence occurred during warmer seasons, highlighting the seasonal pattern of the diseases. Factors such as meteorological conditions and socioeconomic status were probable influencers of typhoid/paratyphoid fever. Conclusions: The geographical and temporal spread of typhoid/paratyphoid fever can be impacted by meteorological and socioeconomic factors. Enhancing economic conditions, particularly in regions with high disease prevalence, could aid in the prevention and management of these fevers.

Enteric Fever in Children: An Epidemiological and Clinical Review of Cases in Southeast Texas.

Extensively drug-resistant (XDR) strains of Salmonella enterica serotype Typhi have emerged in Pakistan and Iraq. We report 13 children with enteric fever in Southeast Texas seen over 3.5 years, of whom 23.1% had XDR isolates.

Antibiotic Resistance in Salmonella typhi Strains Isolated From Patients in Pakistan: A Hospital Database Study.

BACKGROUND: The surge in antibiotic-resistant Salmonella enterica serotype Typhi strains has led to heightened morbidity, mortality, and treatment expenses. This study aims to assess the resistance patterns of Salmonella Typhi to diverse antibiotics among patients seeking care at a tertiary hospital in Pakistan. METHODS: A database from a tertiary care hospital in Pakistan was reviewed, and data on blood cultures that isolated Salmonella enterica serotype Typhi were collected. Data were collected and analyzed using Microsoft Excel (Microsoft Corporation, USA) and IBM SPSS software (IBM Corp., Armonk, NY). RESULTS: Demographic information of the selected data was retrieved from the hospital database, and the results showed that 63.7% were male, 36.1% were female, and 0.2% were categorized as neutered. Regarding antibiotic resistance, ampicillin exhibited the highest resistance rate (91.50%), while meropenem demonstrated the lowest (3.00%). Antibiotic sensitivity patterns also varied across different age groups, although statistical analysis indicated no significant differences. Significant associations were found between antibiotic resistance and comorbidities, as well as previous antibiotic use. CONCLUSION:  Salmonella enterica serotype Typhi showed a high resistance to ampicillin and fluoroquinolones, such as ciprofloxacin. The emergence of resistance and decreased sensitivity to current first-line antibiotics necessitates a shift towards alternative options, such as third-generation cephalosporins, azithromycin, and newer antibiotics like meropenem.

Lower gastrointestinal bleeding as a complication of enteric fever: A case report.

Enteric fever is a systemic bacterial infection caused by enteroinvasive, gram-negative bacilli, named Salmonella enterica serovar typhi and Salmonella enterica serovar paratyphi. It presents with hectic fever, headache, malaise, bowel habit changes, and abdominal pain. Diagnosis is usually confirmed by blood culture. Gastrointestinal complications of enteric fever include intestinal bleeding, bowel perforation, pancreatitis, and cholecystitis. We encountered a case of lower gastrointestinal bleeding (hematochezia) as a complication of enteric fever. A 35-year-old male patient presented to Aster CMI hospital, India, with an intermittent fever of 2-week duration associated with dry cough, loss of appetite, abdominal pain, and generalized body weakness. Four days after admission, he experienced three episodes of lower gastrointestinal bleeding. Upon physical examination, he was hemodynamically stable and had a high-grade fever, mild hepatomegaly, tipped splenomegaly, and lower abdominal tenderness. Blood culture grew Salmonella typhi. Abdominal ultrasound showed ileocolonic thickening with enlarged mesenteric lymph nodes. Abdominal computed tomography scan displayed enlarged mesenteric lymph nodes with surrounding fat strands. A colonoscopy revealed multiple shallow, punched-out, and punctate ileocolonic ulcerative lesions, with stigmata of active bleeding at caecal ulcers. Colonoscopy-guided biopsy suggested multifocal active colitis favoring infective etiology. Diagnosis of blood culture-confirmed enteric ulcer was made. He was treated with ceftriaxone 1 g iv twice daily for 10 days and rehydrated with intravenous fluids. Adrenaline injection was done at the site of bleeding ulcers, and hemostasis was secured. Other additional medications were antipyretics, anti-emetics, multivitamins, and proton pump inhibitors. He was fever-free on the third day of admission and discharged after 10 days of hospital stay. He was appointed to follow-up clinic after a week. He was completely healthy on the day of the first follow-up clinic visit and planned to resume his duties. Enteric fever remains a common public health problem in most developing countries. Early suspicion and prompt institution of appropriate antibiotics are crucial in the reduction of systemic and local complications of enteric fever. Since gastrointestinal complications of enteric fever are less often encountered in the antibiotic era, clinicians should be cognizant of an enteric ulcer as a cause of lower gastrointestinal bleeding.

Acute non-immune hemolytic anemia in enteric fever due to nalidixic acid-resistant Salmonella enterica serotype Typhi: A case report.

Nalidixic acid-resistant Salmonella enterica serotype Typhi is a well-known cause of enteric fever, and its prevalence is increasing worldwide. However, the incidence of enteric fever complicated by non-immune hemolytic anemia without co-existing thalassemia or glucose-6-phosphate dehydrogenase deficiency is rare. In this case report, we present a case of acute non-immune hemolytic anemia in enteric fever caused by nalidixic acid-resistant Salmonella enterica serotype Typhi.

Comprehensive Analysis of Salmonella Species Antibiogram and Evolving Patterns in Empirical Therapy: Insights From Tertiary Care Hospitals in Peshawar, Pakistan.

Background Typhoid fever presents a significant challenge in developing nations, exacerbated by the emergence of antibiotic-resistant strains due to widespread prevalence and overuse of antibiotics. This study seeks to assess the antibiogram profiles of Salmonella species isolated from blood cultures of patients hospitalized at two prominent tertiary care hospitals in Peshawar, Pakistan: Khyber Teaching Hospital (KTH) and Hayatabad Medical Complex (HMC). By examining these profiles, the research aims to provide valuable insights into the evolving landscape of antibiotic resistance in the context of typhoid fever management. Materials and Methods This retrospective cross-sectional study utilized data gathered from two hospitals in Peshawar, KTH and HMC. Cases of enteric fever were identified based on positive blood cultures for Salmonella species. The study encompasses demographic information, seasonal prevalence, and antibiogram profiles of 3,137 cases that were presented between 2017 and 2023. Results Among the total 3,137 cases, males accounted for the majority, comprising 63% (2,044 cases). Particularly notable was the clustering of cases among children and adolescents aged one to 24 years. The incidence peaked during the months of summer and spring, from April to September. In terms of Salmonella Typhi isolates, considerable resistance was noted against first-line antibiotics such as amoxicillin/clavulanate (80.1%), co-trimoxazole/trimethoprim-sulfamethoxazole (66.6%), and chloramphenicol (86.9%), as well as against ceftriaxone (79.7%) and ciprofloxacin (51.6%). Conversely, certain antibiotics displayed higher sensitivity patterns, including meropenem (97.8%), doripenem (99.5%), imipenem (97.7%), ertapenem (96.5%), polymyxin B (99.4%), colistin (98.1%), and tigecycline (97.3%). Despite a limited sample size of 214 specimens, fosfomycin demonstrated a remarkable sensitivity of 93.4%. Sensitivities of amikacin and gentamicin were 90.7% and 81.5%, respectively. However, the sensitivity of azithromycin was concerning, standing at 66.5%. The antibiogram pattern for Salmonella exhibited significant and drastic changes. Conclusion In conclusion, this study sheds light on a higher prevalence of typhoid fever among males, with a notable seasonal peak observed during the summer and spring months. The age group most affected spans from one to 24 years. Salmonella isolates displayed significant resistance to conventional first-line antibiotics, alongside ciprofloxacin and third-generation cephalosporins. Azithromycin exhibited lower sensitivity compared to amikacin, gentamicin, and fosfomycin. The research advocates for the empirical use of amikacin, gentamicin, fosfomycin, and meropenem in the treatment of typhoid fever in Pakistan. Urgent measures, including regular Salmonella antibiogram surveillance, antibiotic stewardship, public health education, and Salmonella vaccination programs, are deemed crucial for primary disease prevention.

The increasing healthcare burden of enteric fever in a low-incidence setting.

OBJECTIVES: Enteric fever carries appreciable morbidity in non-endemic settings, particularly in returned travelers. This study aimed to characterize the healthcare burden of enteric fever in a low-incidence setting and to identify risk factors and opportunities for preventative interventions. METHODS: Analysis of a retrospective case series from a tertiary pediatric center (2015-2019), augmented by public health notification and microbiological laboratory data (2018-2019), from Western Sydney, Australia, a region with frequent travel links to South Asia. RESULTS: Eighty-nine (89) patients were diagnosed with enteric fever, including 43 children with complete demographic and travel data. Enteric fever cases increased over time (by 4.9 % per year) and incidence was three times higher in the pediatric population (<15 years old) compared to adults. Travel to India and visiting friends and relatives (VFR) travel were risk factors. Few children received enteric fever vaccination prior to travel, as pre-travel advice most commonly was not sought. CONCLUSIONS: Children visiting relatives in high-incidence countries are increasingly at risk for enteric fever, particularly when travelling to South Asia. Targeted health advice to travelers visiting friends and relatives is warranted to mitigate the healthcare burden of enteric fever in low-incidence settings.

Acute Cerebillitis Due to Salmonella typhimurium Infection in an Adult: A Report of an Unusual Case.

Acute cerebellitis is an inflammatory illness that may manifest as a primary, para-infectious, or post-infectious disease. The clinical manifestations of acute cerebellitis are traditionally characterized by fever, vomiting, headache, and altered sensorium, accompanied by impaired cerebellar function corroborated by neuroradiography alterations. Acute cerebellitis may lead to a potentially fatal increase in pressure within the skull, requiring immediate and critical neurosurgical surgery. It is important to note that cerebellar symptoms may not be evident initially. This report provides a comprehensive analysis of a case of a 57-year-old male patient who had been diagnosed with acute cerebellitis caused by an infection with Salmonella typhimurium.

Asymptomatic Salmonella Myocarditis: A Case Report of a Rare Entity.

Enteric fever typically displays symptoms like high fever, abdominal pain, constipation, and headaches, primarily affecting the digestive system. While it is commonly seen as a gastrointestinal infection, it can also lead to rare but significant cardiovascular issues. There have been only a few reported cases of enteric fever causing heart manifestations. We present a case of a young male with enteric fever-induced myocarditis, which, due to its rarity, can be challenging to diagnose and is essentially a diagnosis of exclusion. Cardiac MRI (CMR) is crucial for diagnosis, supported by ECG, echocardiograms, and troponin levels. The treatment involves standard approaches for cardiomyopathy, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and diuretics. However, our patient presented as a case of asymptomatic myocarditis and fully recovered with treatment without any long-lasting heart problems. Our study aims to contribute to the limited body of knowledge on heart-related complications of enteric fever, raising awareness among clinicians of such presentations in enteric fever cases.

Cost-effectiveness and public health impact of typhoid conjugate vaccine introduction strategies in Bangladesh.

PURPOSE: Typhoid fever causes substantial morbidity and mortality in Bangladesh. The government of Bangladesh plans to introduce typhoid conjugate vaccines (TCV) in its expanded program on immunization (EPI) schedule. However, the optimal introduction strategy in addition to the costs and benefits of such a program are unclear. METHODS: We extended an existing mathematical model of typhoid transmission to integrate cost data, clinical incidence data, and recently conducted serosurveys in urban, semi-urban, and rural areas. In our primary analysis, we evaluated the status quo (i.e., no vaccination) and eight vaccine introduction strategies including routine and 1-time campaign strategies, which differed by age groups targeted and geographic focus. Model outcomes included clinical incidence, seroincidence, deaths, costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for each strategy. We adopted a societal perspective, 10-year model time horizon, and 3 % annual discount rate. We performed probabilistic, one-way, and scenario sensitivity analyses including adopting a healthcare perspective and alternate model time horizons. RESULTS: We projected that all TCV strategies would be cost saving compared to the status quo. The preferred strategy was a nationwide introduction of TCV at 9-12 months of age with a single catch-up campaign for children ages 1-15, which was cost saving compared to all other strategies and the status quo. In the 10 years following implementation, we projected this strategy would avert 3.77 million cases (95 % CrI: 2.60 - 5.18), 11.31 thousand deaths (95 % CrI: 3.77 - 23.60), and save $172.35 million (95 % CrI: -14.29 - 460.59) compared to the status quo. Our findings were broadly robust to changes in parameter values and willingness-to-pay thresholds. CONCLUSIONS: We projected that nationwide TCV introduction with a catch-up campaign would substantially reduce typhoid incidence and very likely be cost saving in Bangladesh.

Persistent fever in acute hepatitis: think beyond acute viral hepatitis.

BACKGROUND: Acute hepatitis due to various tropical infections can mimic the clinical picture of acute viral hepatitis(AVH), leading to increased morbidity and mortality. We aimed to identify clinical and laboratory parameters that could help to distinguish acute hepatitis due to tropical infections from AVH. METHODS: We retrospectively analyzed our database of 150 children (107 boys) with AVH and 50 children(34 boys)with acute hepatitis due to tropical infections between January 2013 and March 2023. Clinical features, investigations, complications and outcomes were compared. RESULTS: Hepatitis A (75%) was the commonest etiology of AVH while enteric fever (34%), dengue (26%), scrub typhus (20%) and leptospirosis (16%) constituted the majority of tropical infections. Persistent fever and skin rashes were found in 88% and 16% of patients respectively in the tropical infection group and none in the AVH group (p < 0.001). On univariate analysis, prodromal symptoms, clinically detectable jaundice, cholestatic pattern, total and direct bilirubin and liver enzymes were significantly higher in AVH while headache, myalgia, leukopoenia, thrombocytopenia, hyponatremia were significantly higher in tropical infections group (all p < 0.05). Multivariate analysis identified thrombocytopenia (Odds ratio [OR] 4.237) as an independent positive predictive factor and markedly elevated total bilirubin (OR 0.575), direct bilirubin (OR 0.498), aspartate aminotransferase (OR 0.841) and alanine aminotransferase (OR 0.863) as independent negative predictive factors for acute hepatitis due to tropical infections. CONCLUSION: High index of suspicion for tropical infections is warranted in patients with persistent fever after the onset of jaundice, especially in the presence of skin rash and thrombocytopenia.SUMMARYAcute viral hepatitis and acute hepatitis due to tropical infections can have similar clinical and biochemical parameters. Milder degree of jaundice, lower elevation of serum transaminases and thrombocytopenia can be useful predictors for acute hepatitis due to tropical infections.

A Prolonged Outbreak of Enteric Fever Associated With Illegal Miners in the City of Matlosana, South Africa, November 2020-September 2022.

Background: In South Africa, the annual incidence of enteric fever averaged 0.1 per 100 000 persons between 2003 and 2018. During 2021 an increase in the number of enteric fever cases was observed. An outbreak investigation was conducted to determine the magnitude and source of the outbreak. Methods: We performed a cross-sectional descriptive study. Data were collected through telephonic or face-to-face interviews with cases or proxies via a standardized case investigation form. Whole genome sequencing was performed on all Salmonella Typhi isolates. Drinking water samples were collected, tested, and analyzed. Descriptive analysis was performed with Microsoft Excel. Results: Between January 2020 and September 2022, a cluster of 53 genetically highly related Salmonella Typhi isolates was identified from 5 provinces in South Africa. Isolates associated with the cluster showed ≤5 allelic differences, as determined following core genome multilocus sequence typing analysis. Most cases (60%, 32/53) were in the North West province. Males represented 68% (36/53). Of these, 72% (26/36) were aged 15 to 49 years, with a median age of 31 years. Where occupation was known within this age group, 78% (14/18) were illegal gold miners. Illegal miners reported illness onset while working underground. Five municipal tap water samples were tested and showed no evidence of fecal contamination. Conclusions: This outbreak predominantly affected illegal gold miners, likely due to the consumption of contaminated groundwater while working in a gold mine shaft. In addition, this investigation highlights the value of whole genome sequencing to detect clusters and support epidemiologic investigation of enteric fever outbreaks.

Computational study of the piperidine and FtsZ interaction in Salmonella Typhi: implications for disrupting cell division machinery.

FtsZ, a bacterial cell division protein, is essential for assembling the contractile Z-ring crucial in bacterial cytokinesis. Consequently, inhibiting FtsZ could impede proto-filaments, disrupting FtsZ and other associated proteins vital for cell division machinery. Conduct an in-silico drug interaction study to identify novel drug candidates that inhibit the FtsZ protein, aiming to prevent Multi-Drug Resistant (MDR) Salmonella Typhi. Data mining was performed based on piperidine compounds, which were subsequently screened for safe pharmacokinetic profiles. Compounds that met favorable drug-likeness criteria underwent virtual screening against the FtsZ drug target. Two compounds were chosen for molecular docking and molecular dynamic simulation to verify the binding affinity and stability between the target protein and the potential compounds. The 400 isoforms of piperidine analogues were curated, among them potent compound ZINC000000005416 found to possess high binding affinity (-8.49 kcal/mol) and low dissociation constant (0.597 µM). The highest binding affinity shown by ZINC000000005416 was validated by hydrogen bonds, hydrophobic interaction, and salt bridges with the functional domain of the cell division regulatory protein. Docking profiles, when correlated with molecular dynamic simulation (MDS) depicted stable trajectories and compatible conformational changes in the FtsZ-ZINC000000005416 complex. The stable simulated trajectories were validated through free-energy calculations using the Molecular Mechanics-Poisson Boltzmann Surface Area (MM/PBSA) module. Low energy conformations, although the simulation trajectory confirmed the stable ZINC000000005416-FtsZ interaction, which encouraged experimental validations. This study encourages further exploration of the compound ZINC000000005416 as a drug candidate inhibiting FtsZ protein against MDR Salmonella Typhi.Communicated by Ramaswamy H. Sarma.

Host transcriptional meta-signatures reveal diagnostic biomarkers for Plasmodium falciparum malaria.

BACKGROUND: Transcriptomics has been used to evaluate immune responses during malaria in diverse cohorts worldwide. However, the high heterogeneity of cohorts and poor generalization of transcriptional signatures reported in each study limit their potential clinical applications. METHODS: We compiled 28 public datasets containing 1,556 whole blood or peripheral blood mononuclear cells (PBMC) transcriptome samples. We estimated effect sizes with Hedges´ g and DerSimonian-Laird random effects model for meta-analyses of uncomplicated malaria. Random forest models identified gene signatures that discriminate malaria from bacterial infections or malaria severity. Parasitological, hematological, immunological, and metabolomics data were used for validation. RESULTS: We identified three gene signatures denominated the uncomplicated Malaria Meta-Signature (uMMS), which discriminates P. falciparum malaria from uninfected controls; the Malaria or Bacteria Signature (MoBS), that distinguishes malaria from sepsis and enteric fever; and the cerebral Malaria Meta-Signature (cMMS), which characterizes individuals with cerebral malaria. These signatures correlate with clinical hallmark features of malaria. Blood transcription modules (BTM) indicate immune regulation by glucocorticoids, whereas cell development and adhesion are associated with cerebral malaria. CONCLUSION: Transcriptional meta-signatures reflecting immune cell responses provide potential biomarkers for translational innovation and suggest critical roles for metabolic regulators of inflammation during malaria.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: ISRCTN63006567.