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.

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.

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.

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.

Utilization of Healthcare in the Typhoid Fever Surveillance in Africa Program.

BACKGROUND: Assessing healthcare utilization is important to identify weaknesses of healthcare systems, to outline action points for preventive measures and interventions, and to more accurately estimate the disease burden in a population. METHODS: A healthcare utilization survey was developed for the Typhoid Fever Surveillance in Africa Program (TSAP) to adjust incidences of salmonellosis determined through passive, healthcare facility-based surveillance. This cross-sectional survey was conducted at 11 sites in 9 sub-Saharan African countries. Demographic data and healthcare-seeking behavior were assessed at selected households. Overall and age-stratified percentages of each study population that sought healthcare at a TSAP healthcare facility and elsewhere were determined. RESULTS: Overall, 88% (1007/1145) and 81% (1811/2238) of the population in Polesgo and Nioko 2, Burkina Faso, respectively, and 63% (1636/2590) in Butajira, Ethiopia, sought healthcare for fever at any TSAP healthcare facility. A far smaller proportion-namely, 20%-45% of the population in Bissau, Guinea-Bissau (1743/3885), Pikine, Senegal (1473/4659), Wad-Medani, Sudan (861/3169), and Pietermaritzburg, South Africa (667/2819); 18% (483/2622) and 9% (197/2293) in Imerintsiatosika and Isotry, Madagascar, respectively; and 4% (127/3089) in Moshi, Tanzania-sought healthcare at a TSAP healthcare facility. Patients with fever preferred to visit pharmacies in Imerintsiatosika and Isotry, and favored self-management of fever in Moshi. Age-dependent differences in healthcare utilization were also observed within and across sites. CONCLUSIONS: Healthcare utilization for fever varied greatly across sites, and revealed that not all studied populations were under optimal surveillance. This demonstrates the importance of assessing healthcare utilization. Survey data were pivotal for the adjustment of the program's estimates of salmonellosis and other conditions associated with fever.

A Qualitative Study Investigating Experiences, Perceptions, and Healthcare System Performance in Relation to the Surveillance of Typhoid Fever in Madagascar.

BACKGROUND: The burden of typhoid fever (TF) in sub-Saharan Africa is largely unknown but is increasingly thought to be high, given that water and sanitary conditions remain unimproved in many countries. To address this gap in information, the Typhoid Fever Surveillance in Africa Program (TSAP) founded a surveillance system for TF in 10 African countries. This study was a component of the TSAP surveillance project in Madagascar. METHODS: The study entailed a qualitative assessment of patients' experiences and perceptions of services for febrile symptoms at the studies' rural and urban sentinel public health clinics. The study examined influences on the use of these facilities, alternative sources of care, and providers' descriptions of medical consultations and challenges in providing services. Data were collected through semistructured and open-ended individual interviews and a focus group with patients, caregivers, and medical personnel. RESULTS: Thirty-three patients and 12 healthcare providers participated in the data collection across the 2 healthcare facilities. The quality of services, cost, and travel distance were key factors that enabled access to and use of these clinics. Divergent healthcare-seeking patterns were related to variability in the care utilized, socioeconomic status, and potential distance from the facilities : These factors influenced delivery of care, patient access, and the health facilities' capacity to identify cases of febrile illness such as TF. CONCLUSIONS: This approach provided an in-depth investigation and understanding of healthcare-seeking behavior at the study facilities, and factors that facilitated or acted as barriers to their use. Our findings demonstrate the relevance of these public health clinics as sites for the surveillance of TF in their role as central healthcare sources for families and communities within these rural and urban areas of Madagascar.

Pyonephrosis Caused by Salmonella Typhi: A Case Report.

INTRODUCTION: Salmonella is a rare cause of urinary tract infections. We report here a unique case of pyonephrosis due to Salmonella Typhi (S. Typhi) complication, a stone-related obstructive pyelonephritis. CASE REPORT: A 47-year-old man, without any history of typhoid fever or gastrointestinal symptoms, presented with a pyonephrosis and life-threatening bacteremia following an acute obstructive right pyelonephritis caused by S. Typhi. The patient was treated by urinary drainage (ureteral stent), antibiotics, and delayed right nephrectomy. We postulated that urolithiasis could explain asymptomatic chronic urinary carriage of S. Typhi. CONCLUSION: S. Typhi is one possible cause of life-threatening urinary tract infection, especially in the context of urolithiasis.

Immunomodulatory and antimicrobial efficacy of Lactobacilli against enteropathogenic infection of Salmonella typhi: In-vitro and in-vivo study.

Salmonellosis-induced diarrhea, is one of the commonest cause of childhood mortality in developing countries. Using of probiotics is viewed as a promising means for reducing the pathogenic loads of bacterial infection. The current study aimed to evaluate the potential antimicrobial and immunomodulatory efficacy of isolated lactobacillus strains against the enteropathogenic effect of S. Typhi. Different Lactobacillus strains were isolated from 13 dairy products. Their antimicrobial activities were tested against different bacterial strains. Six groups of CD1 mice were treated for 8 days as follows: group (1) untreated control; group (2) was challenged with single inoculation S. typhi, and groups (3) and (4) were treated with Lactobacillus plantarum (LA5) or Lactobacillus paracsi (LA7) for 7 days, respectively. Groups (5) and (6) were challenged with S. typhi, and then treated with either LA5 or LA 7 for 7 days, respectively. Isolated Lactobacillus showed antimicrobial activity against wide range of bacterial strains. Salmonellosis showed high widal titer, induced significant disturbance of TNF and IL-1ß, while sever changes of the histological patterns of the intestinal villi and hepatocytes have been illustrated. LA5 or LA7 succeeded to eradicate typhoid infection, restore the values of inflammatory cytokines to typical levels of control group, and improve histological pictures of intestinal and hepatic tissues. It can be concluded that lactobacilli are promising candidate in protection and eradication against bacterial infection induced by S. Typhi due to its antimicrobial, anti-inflammatory, and immunomodulatory activities.

Prolonged Care for Presumed Typhoid Encephalitis in Indonesia.

Despite advancements in military medical treatment and evacuation, soldiers in austere environments remain vulnerable to disease and non-battle injury and may face prolonged evacuation before receiving definitive care. In particular, arranging care for a soldier presenting with a conditions that has a wide differential diagnosis, such as acute altered mental status (AMS), can be especially challenging. We highlight the case of an otherwise young, healthy U.S. Soldier serving in Indonesia, who presented with acute AMS concerning for undifferentiated infection. Subsequent workup at the receiving hospital following evacuation revealed Salmonella enterica infection, more commonly known as typhoid. However, even with clinical findings of typhoid encephalitis and initiation of empiric treatment, medical care proved challenging in the resource-limited local facilities, despite multiple escalations of care. Ultimately, the patient was evacuated to a tertiary facility in Singapore, where his condition improved, and 4 days after initial presentation the patient had no definitive findings of infections on lumbar puncture. This case not only highlights the threat of typhoid and other infectious diseases in modern operations but also the challenges of suboptimal medical care in both the prehospital and hospital settings when utilizing host nation facilities.

[Understanding current practice of clinical medicine in the tropics (II). Bacterial and viral diseases. Malnutrition]. / Aspectos básicos en la práctica actual de la medicina clínica en el trópico (II). Enfermedades bacterianas y virales. Malnutrición.

In recent years, a significant number of physicians want to spend part of their medical training in health facilities in developing countries. In this setting, clinical skills are extremely important due to the limited available diagnostic resources. Bacterial diseases are common, but bacterial cultures are rarely accessible. In Africa, tuberculosis affects over 200 cases per 100,000 persons, and more than 22 million people live with HIV infection; both diseases are a serious public health problem. Malnutrition is endemic in many countries in Africa and is compounded by the continuous humanitarian and food crisis. In this paper, basic concepts of epidemiology, clinical features, diagnosis and treatment of major diseases that can be found in a rural health post in the tropics are discussed.

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.

Cost of illness due to typhoid fever in five Asian countries.

OBJECTIVE: To generate community-based estimates of the public (paid by the government) and private (paid by households) costs of blood culture-confirmed typhoid fever in Hechi, China; North Jakarta, Indonesia; Kolkata, India; Karachi, Pakistan and Hue, Vietnam. METHODS: To measure out-of-pocket costs of illness and lost earnings, families with culture-proven cases were surveyed 7, 14 and 90 days after onset of illness. Public costs of treatment were measured at local health facilities using a micro costing (bottom-up) method. RESULTS: The costs of hospitalized cases ranged from USD 129 in Kolkata to USD 432 in North Jakarta (hospitalization rates varied from 2% in Kolkata to 40% in Hechi) and the costs of non-hospitalized cases ranged from USD 13 in Kolkata to USD 67 in Hechi. Where costs were highest (Hechi, North Jakarta and Karachi), the bulk of the costs of hospitalized cases was borne by families, comprising up to 15% of annual household income. CONCLUSION: Although these estimates may understate true costs due to the fact that higher quality treatment may have been provided earlier-than-usual, this multi-country community-based study contributes to evidence on the public and private costs of typhoid fever in developing countries. These cost estimates were used in a cost-effectiveness analysis of typhoid vaccines and will help policymakers respond to World Health Organization's updated typhoid fever immunization recommendations.

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.

Treatment cost for typhoid fever at two hospitals in Kolkata, India.

The purpose of this study was to estimate treatment cost for typhoid fever at two hospitals in Kolkata, India. This study was an incidence-based cost-of-illness analysis from the providers' perspective. Micro-costing approach was employed for calculating patient-specific data. Unit costs of medical services used in the calculation were directly measured from the study hospital by standard method. The study hospitals were selected based on accessibility to data and cooperation. Eighty-three Widal-positive and/or culture-confirmed patients with typhoid fever during November 2003-April 2006 were included in the study. Most (93%) patients were children. Eighty-one percent was treated at the outpatient department. The average duration of hospitalization for child and adult patients was 8.4 and 4.2 days respectively. The average cost of treating children, adults, and all patients was US$ 16.72, 72.71, and 20.77 respectively (in 2004 prices). Recalculation based on 80% occupancy rate in inpatient wards (following the recommendation of the World Health Organization) found that the cost of treating children, adults, and all patients was US$ 14.53, 36.44, and 16.11 respectively.

[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.

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.