Controlling the bacterial load of Salmonella Typhi in an experimental mouse model by a lytic Salmonella phage STWB21: a phage therapy approach.

BACKGROUND: Salmonella enterica serotype Typhi is one of the major pathogens causing typhoid fever and a public health burden worldwide. Recently, the increasing number of multidrug-resistant strains of Salmonella spp. has made this utmost necessary to consider bacteriophages as a potential alternative to antibiotics for S. Typhi infection treatment. Salmonella phage STWB21, isolated from environmental water, has earlier been reported to be effective as a safe biocontrol agent by our group. In this study, we evaluated the efficacy of phage STWB21 in reducing the burden of salmonellosis in a mammalian host by inhibiting Salmonella Typhi invasion into the liver and spleen tissue. RESULTS: Phage treatment significantly improved the survival percentage of infected mice. This study also demonstrated that oral administration of phage treatment could be beneficial in both preventive and therapeutic treatment of salmonellosis caused by S. Typhi. Altogether the result showed that the phage treatment could control tissue inflammation in mice before and after Salmonella infection. CONCLUSIONS: To the best of our knowledge, this is the first report of phage therapy in a mouse model against a clinically isolated Salmonella Typhi strain that includes direct visualization of histopathology and ultrathin section microscopy images from the liver and spleen sections.

Salmonellosis Including Enteric Fever.

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.

Increasingly limited options for the treatment of enteric fever in travellers returning to England, 2014-2019: a cross-sectional analytical study.

Introduction. Enteric fever (caused by Salmonella enterica serovars Typhi and Paratyphi) frequently presents as an acute, undifferentiated febrile illness in returning travellers, requiring timely empirical antibiotics.Gap Statement. Determining which empirical antibiotics to prescribe for enteric fever requires up-to-date knowledge of susceptibility patterns.Aim. By characterising factors associated with antimicrobial resistance in cases of S. Typhi and S. Paratyphi imported to England, we aim to guide effective empirical treatment.Methodology. All English isolates of S. Typhi and S. Paratyphi 2014-2019 underwent antimicrobial susceptibility testing; results were compared to a previous survey in London 2005-2012. Risk factors for antimicrobial resistance were analysed with logistic regression models to predict adjusted odds ratios (aOR) for resistance to individual antibiotics and multi-drug resistance.Results. We identified 1088 cases of S. Typhi, 729 S. Paratyphi A, 93 S. Paratyphi B, and one S. Paratyphi C. In total, 93 % were imported. Overall, 90 % of S. Typhi and 97 % of S. Paratyphi A isolates were resistant to ciprofloxacin; 26 % of S. Typhi were multidrug resistant to ciprofloxacin, amoxicillin, co-trimoxazole, and chloramphenicol (MDR+FQ). Of the isolates, 4 % of S. Typhi showed an extended drug resistance (XDR) phenotype of MDR+FQ plus resistance to third-generation cephalosporins, with cases of XDR rising sharply in recent years (none before 2017, one in 2017, six in 2018, 32 in 2019). For S. Typhi isolates, resistance to ciprofloxacin was associated with travel to Pakistan (aOR=32.0, 95 % CI: 15.4-66.4), India (aOR=21.8, 95 % CI: 11.6-41.2), and Bangladesh (aOR=6.2, 95 % CI: 2.8-13.6) compared to travel elsewhere, after adjusting for rising prevalence of resistance over time. MDR+FQ resistance in S. Typhi isolates was associated with travel to Pakistan (aOR=3.5, 95 % CI: 2.4-5.2) and less likely with travel to India (aOR=0.07, 95 % CI 0.04-0.15) compared to travel elsewhere. All XDR cases were imported from Pakistan. No isolate was resistant to azithromycin. Comparison with the 2005-2012 London survey indicates substantial increases in the prevalence of resistance of S. Typhi isolates to ciprofloxacin associated with travel to Pakistan (from 79-98 %) and Africa (from 12-60 %).Conclusion. Third-generation cephalosporins and azithromycin remain appropriate choices for empirical treatment of enteric fever in most returning travellers to the UK from endemic countries, except from Pakistan, where XDR represents a significant risk.

Salmonella Typhi: a rare cause of parotid abscess.

The incidence of extraintestinal infection caused by Salmonella spp has been increased during the past decade. Here we report a case of a parotid abscess caused by Salmonella enterica subspecies enterica serotype Typhi (S Typhi) in an individual without any significant abnormality of the parotid gland. A 68-year-old man presented to the surgical department with high-grade intermittent fever associated with painful swelling over the right side of the face, extending into the neck. An ultrasound of the neck revealed an abscess of the right parotid gland. S Typhi was isolated from the pus drained from the parotid gland. The patient was treated with intravenous followed by oral cephalosporin for a period of 7 days. This case gives an insight into one of the rarer aetiological agents causing parotid abscess.

Estudio de problemas de enfermedades causados ​​por Salmonella y relación con la fiebre tifoidea / Study of Illness Problems Caused By Salmonella and Relation with Typhoid

There is urgent need to address illness problems caused by Salmonella enteric serotype Typhibacteria. The bacteria are deposited in water or food by human carrier and are then spread to other people in the area. In this research, a blood specimens were collected from typhoid fever patients, and serum levels of IFN-γ and IL-6 during the chronic and acute phase in typhoid patients group was determined according protocol kit and calculation, results were higher levels in chronic phase (137.187 ± 0.703.427 ± 206.545pg/ml respectively) and in acute phase were 128.787 ± 2.522, 137.733 ± 23.424 pg/ml, respectively with highly significant (P ≤ 0.01) than those in healthy control group. Salmonella infects hosts as diversified as human, animal, and plant

Typhoidal Salmonella human challenge studies: ethical and practical challenges and considerations for low-resource settings.

Typhoidal Salmonella is a major global problem affecting more than 12 million people annually. Controlled human infection models (CHIMs) in high-resource settings have had an important role in accelerating the development of conjugate vaccines against Salmonella Typhi.The typhoidal Salmonella model has an established safety profile in over 2000 volunteers in high-income settings, and trial protocols, with modification, could be readily transferred to new study sites. To date, a typhoidal Salmonella CHIM has not been conducted in a low-resource setting, although it is being considered.Our article describes the challenges posed by a typhoidal Salmonella CHIM in the high-resource setting of Oxford and explores considerations for an endemic setting.Development of CHIMs in endemic settings is scientifically justifiable as it remains unclear whether findings from challenge studies performed in high-resource non-endemic settings can be extrapolated to endemic settings, where the burden of invasive Salmonella is highest. Volunteers are likely to differ across a range of important variables such as previous Salmonella exposure, diet, intestinal microbiota, and genetic profile. CHIMs in endemic settings arguably are ethically justifiable as affected communities are more likely to gain benefit from the study. Local training and research capacity may be bolstered.Safety was of primary importance in the Oxford model. Risk of harm to the individual was mitigated by careful inclusion and exclusion criteria; close monitoring with online diary and daily visits; 24/7 on-call staffing; and access to appropriate hospital facilities with capacity for in-patient admission. Risk of harm to the community was mitigated by exclusion of participants with contact with vulnerable persons; stringent hygiene and sanitation precautions; and demonstration of clearance of Salmonella infection from stool following antibiotic treatment.Safety measures should be more stringent in settings where health systems, transport networks, and sanitation are less robust.We compare the following issues between high- and low-resource settings: scientific justification, risk of harm to the individual and community, benefits to the individual and community, participant understanding, compensation, and regulatory requirements.We conclude that, with careful consideration of country-specific ethical and practical issues, a typhoidal Salmonella CHIM in an endemic setting is possible.

[CME: Typhoid Fever - Clinical Manifestation, Diagnosis, Therapy and Prevention]. / CME: Typhus abdominalis ­ Klinik, Diagnostik, Therapie und Prävention.

CME: Typhoid Fever - Clinical Manifestation, Diagnosis, Therapy and Prevention Abstract. Thypoid fever is rare in Western countries. It is, however, among the most common etiologies for febrile illness in the traveller returning from tropical areas (especially South(east) Asia and Sub-Saharan Africa). There are several signs that have been described as classical findings in typhoid fever: i) febrile temperatures with relative bradycardia, ii) eosinopenia, iii) slow defervescence, and iv) systemic manifestations (e.g. hepatitis). Diagnosis is confirmed by positive blood cultures. Pretravel vaccination and safe food and water practices can prevent typhoid fever.

Burden of typhoid fever and cholera: similarities and differences. Prevention strategies for European travelers to endemic/epidemic areas.

The burden of diarrheal diseases is very high, accounting for 1.7 to 5 billion cases per year worldwide. Typhoid fever (TF) and cholera are potentially life-threatening infectious diseases, and are mainly transmitted through the consumption of food, drink or water that have been contaminated by the feces or urine of subjects excreting the pathogen. TF is mainly caused by Salmonella typhi, whereas cholera is caused by intestinal infection by the toxin-producing bacterium Vibrio cholerae. These diseases typically affect low- and middle-income countries where housing is overcrowded and water and sanitation are poor, or where conflicts or natural disasters have led to the collapse of the water, sanitation and healthcare systems. Mortality is higher in children under 5 years of age. Regarding their geographical distribution, TF has a high incidence in sub-Saharan Africa, India and south-east Asia, while cholera has a high incidence in a few African countries, particularly in the Horn of Africa and the Arabian Peninsula. In the fight against these diseases, preventive measures are fundamental. With modern air travel, transmissible diseases can spread across continents and oceans in a few days, constituting a threat to global public health. Nowadays, people travel for many reasons, such as tourism and business. Several surveys have shown that a high proportion of travelers lack adequate information on safety issues, such as timely vaccination and prophylactic medications. The main objective of this overview is to provide information to help European travelers to stay healthy while abroad, and thus also to reduce the potential importation of these diseases and their consequent implications for public health and society. The preventive measures to be implemented in the case of travel to countries where these diseases are still endemic are well known: the adoption of safe practices and vaccinations. It is important to stress that an effective preventive strategy should be based both on vaccinations and on hygiene travel guidelines. Furthermore, the emergence of multidrug-resistant strains is becoming a serious problem in the clinical treatment of these diseases. For this reason, vaccination is the main solution.

Integrating Qualitative Techniques in Model Development: A Case Study Using the Framework Approach.

BACKGROUND: Despite their potential, there is limited uptake of formal qualitative methods in model development by modellers and health economists. The aim of this case study was to highlight in a real-world context how a qualitative approach has been applied to gain insight into current practice (delineating existing care pathways) for typhoid fever in Ghana, which can then assist in model structure conceptualisation in a model-based cost-effectiveness analysis. METHODS: The perspectives of a range of healthcare professionals working in different settings and across different practices in the Eastern region of Ghana were captured with a self-administered survey using open-ended questions and analysed using the framework method. RESULTS: A total of 51 completed questionnaires were retrieved representing a 73% response rate. It was found that two main care pathways for typhoid fever exist in Ghana and there was no consensus on how a new test might be applied to the existing pathways. CONCLUSION: The two settings in Ghana have different care pathways and any cost-effectiveness analysis should consider the alternative pathways separately. This study demonstrated that framework analysis is a qualitative methodology that is likely to be accessible and feasible across a wide range of health economic settings.

Selection of Potential Therapeutic Bacteriophages that Lyse a CTX-M-15 Extended Spectrum ß-Lactamase Producing Salmonella enterica Serovar Typhi Strain from the Democratic Republic of the Congo.

Recently, a Salmonella Typhi isolate producing CTX-M-15 extended spectrum ß-lactamase (ESBL) and with decreased ciprofloxacin susceptibility was isolated in the Democratic Republic of the Congo. We have selected bacteriophages that show strong lytic activity against this isolate and have potential for phage-based treatment of S. Typhi, and Salmonella in general.

Assessing the potential impact of limited public health resources on the spread and control of typhoid.

Typhoid fever is a systemic infection caused by Salmonella Typhi and occurs predominantly in association with poor sanitation and lack of clean drinking water. Despite recent progress in water and sanitation coverage, the disease remains a substantial public health problem in many developing countries. A mathematical model for the spread of typhoid has been formulated using non linear ordinary differential equations. The model includes a special treatment function to assess the effects of limited treatment resources on the spread of typhoid. It is shown that the model has multiple equilibria and using the center manifold theory, the model exhibits the phenomenon of backward bifurcation whose implications are discussed. The results suggest the need for comprehensive and accessible treatment facilities to curtail typhoid infection.

Pneumonia with pleural empyema caused by Salmonella Typhi in an immunocompetent child living in a non-endemic country.

Extra-intestinal complications of Salmonella Typhi (S. Typhi) infections usually occur in endemic countries and in patients with underlying risk conditions. A 14-year-old immunocompetent girl was admitted with respiratory distress owing to S. Typhi pneumonia and pleural empyema. She was a native of Ivory Coast but had lived in France for 4 years and had not travelled abroad for several years. There were no gastro-intestinal symptoms and no S. Typhi carriage was detected in her family. She recovered completely with ceftriaxone and ciprofloxacin and pleural drainage was not required. An atypical presentation of S. Typhi should be considered even in settings where there are no risk factors.

Biofilm Producing Salmonella Typhi: Chronic Colonization and Development of Gallbladder Cancer.

Salmonella enterica subspecies enterica serovar Typhi is the aetiological agent of typhoid or enteric fever. In a subset of individuals, S. Typhi colonizes the gallbladder causing an asymptomatic chronic infection. Nonetheless, these asymptomatic carriers provide a reservoir for further spreading of the disease. Epidemiological studies performed in regions where S. Typhi is endemic, revealed that the majority of chronically infected carriers also harbour gallstones, which in turn, have been indicated as a primary predisposing factor for the onset of gallbladder cancer (GC). It is now well recognised, that S. Typhi produces a typhoid toxin with a carcinogenic potential, that induces DNA damage and cell cycle alterations in intoxicated cells. In addition, biofilm production by S. Typhi may represent a key factor for the promotion of a persistent infection in the gallbladder, thus sustaining a chronic local inflammatory response and exposing the epithelium to repeated damage caused by carcinogenic toxins. This review aims to highlight the putative connection between the chronic colonization by highly pathogenic strains of S. Typhi capable of combining biofilm and toxin production and the onset of GC. Considering the high risk of GC associated with the asymptomatic carrier status, the rapid identification and profiling of biofilm production by S. Typhi strains would be key for effective therapeutic management and cancer prevention.

Modifiable risk factors for typhoid intestinal perforations during a large outbreak of typhoid fever, Kampala Uganda, 2015.

BACKGROUND: Between January and June, 2015, a large typhoid fever outbreak occurred in Kampala, Uganda, with 10,230 suspected cases. During the outbreak, area surgeons reported a surge in cases of typhoid intestinal perforation (TIP), a complication of typhoid fever. We conducted an investigation to characterize TIP cases and identify modifiable risk factors for TIP. METHODS: We defined a TIP case as a physician-diagnosed typhoid patient with non-traumatic terminal ileum perforation. We identified cases by reviewing medical records at all five major hospitals in Kampala from 2013 to 2015. In a matched case-control study, we compared potential risk factors among TIP cases and controls; controls were typhoid patients diagnosed by TUBEX TF, culture, or physician but without TIP, identified from the outbreak line-list and matched to cases by age, sex and residence. Cases and controls were interviewed using a standard questionnaire from 1st -23rd December 2015. We used conditional logistic regression to assess risk factors for TIP and control for confounding. RESULTS: Of the 88 TIP cases identified during 2013-2015, 77% (68/88) occurred between January and June, 2015; TIPs sharply increased in January and peaked in March, coincident with the typhoid outbreak. The estimated risk of TIP was 6.6 per 1000 suspected typhoid infections (68/10,230). The case-fatality rate was 10% (7/68). Cases sought care later than controls; Compared with 29% (13/45) of TIP cases and 63% (86/137) of controls who sought treatment within 3 days of onset, 42% (19/45) of cases and 32% (44/137) of controls sought treatment 4-9 days after illness onset (ORadj = 2.2, 95%CI = 0.83-5.8), while 29% (13/45) of cases and 5.1% (7/137) of controls sought treatment ≥10 days after onset (ORadj = 11, 95%CI = 1.9-61). 68% (96/141) of cases and 23% (23/100) of controls had got treatment before being treated at the treatment centre (ORadj = 9.0, 95%CI = 1.1-78). CONCLUSION: Delay in seeking treatment increased the risk of TIPs. For future outbreaks, we recommended aggressive community case-finding, and informational campaigns in affected communities and among local healthcare providers to increase awareness of the need for early and appropriate treatment.

Typhoid intestinal perforation in developing countries: Still unavoidable deaths?

Typhoid fever is a public health challenge mostly concentrated in impoverished, overcrowded areas of the developing world, with lack of safe drinking and sanitation. The most serious complication is typhoid intestinal perforation (TIP), observed in 0.8% to 39%, with a striking rate difference between high-income and low-middle-income countries. Although the mortality rate consequent to TIP in resource-poor countries is improved in the last decades, it is still fluctuating from 5% to 80%, due to surgical- and not surgical-related constraints. Huge economic costs and long timelines are required to provide a short- to middle-term solution to the lack of safe water and sanitation. Inherent limitations of the currently available diagnostic tools may lead to under-evaluation as well as over-evaluation of the disease, with consequent delayed treatment or inappropriate, excessive antibiotic use, hence increasing the likelihood of bacterial resistance. There is a need for immunization programs in populations at greatest risk, especially in sub-Saharan Africa. Uniform surgical strategies and guidelines, on the basis of sound or prospective surgical studies and adapted to the local realities, are still lacking. Major drawbacks of the surgical treatment are the frequent delays to surgery, either for late diagnosis or for difficult transports, and the unavailable appropriate intensive care units in most peripheral facilities. As a consequence, poor patient's conditions at presentation, severe peritoneal contamination and unsuitable postoperative care are the foremost determinant of surgical morbidity and mortality.

Emerging insights into the biology of typhoid toxin.

Typhoid toxin is a unique A2B5 exotoxin and an important virulence factor for Salmonella Typhi, the cause of typhoid fever. In the decade since its initial discovery, great strides have been made in deciphering the unusual biological program of this toxin, which is fundamentally different from related toxins in many ways. Purified typhoid toxin administered to laboratory animals causes many of the symptoms of typhoid fever, suggesting that typhoid toxin is a central factor in this disease. Further advances in understanding the biology of this toxin will help guide the development of badly needed diagnostics and therapeutic interventions that target this toxin to detect, prevent or treat typhoid fever.

Enteric Fever.

Enteric fever is an important public-health problem in India. The clinical presentation of typhoid fever is very variable, ranging from fever with little other morbidities to marked toxemia and associated multisystem complications. Fever is present in majority of patients (>90 %) irrespective of their age group. Mortality is higher in younger children. Blood culture remains gold standard for diagnosis. Widal test has low sensitivity and specificity but may be used in second week to support the diagnosis. Emerging resistance to several antibiotics should be kept in mind when selecting antibiotics or revising the treatment. The key preventive strategies are safe water, safe food, personal hygiene, and appropriate sanitation. Vaccination is an additional effective tool for prevention.

Sufficient Sample Size and Power in Multilevel Ordinal Logistic Regression Models.

For most of the time, biomedical researchers have been dealing with ordinal outcome variable in multilevel models where patients are nested in doctors. We can justifiably apply multilevel cumulative logit model, where the outcome variable represents the mild, severe, and extremely severe intensity of diseases like malaria and typhoid in the form of ordered categories. Based on our simulation conditions, Maximum Likelihood (ML) method is better than Penalized Quasilikelihood (PQL) method in three-category ordinal outcome variable. PQL method, however, performs equally well as ML method where five-category ordinal outcome variable is used. Further, to achieve power more than 0.80, at least 50 groups are required for both ML and PQL methods of estimation. It may be pointed out that, for five-category ordinal response variable model, the power of PQL method is slightly higher than the power of ML method.