What Should We Be Recommending for the Treatment of Enteric Fever?

Patients with suspected enteric (typhoid and paratyphoid) fever are predominantly managed as outpatients in endemic regions. Nonspecific clinical presentation, lack of accurate diagnostic tools, and widespread antimicrobial resistance makes management challenging. Resistance has been described for all antimicrobials including chloramphenicol, amoxycillin, trimethoprim-sulfamethoxazole, ciprofloxacin, ceftriaxone, and azithromycin. No significant differences have been demonstrated between these antimicrobials in their ability to treat enteric fever in systematic reviews of randomized controlled trials (RCTs). Antimicrobial choice should be guided by local resistance patterns and national guidance. Extensively drug-resistant typhoid isolates require treatment with azithromycin and/or meropenem. Combining antimicrobials that target intracellular and extracellular typhoid bacteria is a strategy being explored in the Azithromycin and Cefixime in Typhoid Fever (ACT-SA) RCT, in progress in South Asia. Alternative antimicrobials, such as the oral carbapenem, tebipenem, need clinical evaluation. There is a paucity of evidence to guide the antimicrobial management of chronic fecal carriers.

Accelerating clinical development of a live attenuated vaccine against Salmonella Paratyphi A (VASP): study protocol for an observer-participant-blind randomised control trial of a novel oral vaccine using a human challenge model of Salmonella Paratyphi A infection in healthy adult volunteers.

INTRODUCTION: This is the first efficacy study of an oral live attenuated vaccine against Salmonella Paratyphi A using a human challenge model of paratyphoid infection. S. Paratyphi A is responsible for 3.3 million cases of enteric fever every year, with over 19 000 deaths. Although improvements to sanitation and access to clean water are vital to reduce the burden of this condition, vaccination offers a cost-effective, medium-term solution. Efficacy trials of potential S. Paratyphi vaccine candidates in the field are unlikely to be feasible given the large number of participants required. Human challenge models therefore offer a unique, cost-effective solution to test efficacy of such vaccines. METHODS AND ANALYSIS: This is an observer-blind, randomised, placebo-controlled trial phase I/II of the oral live-attenuated vaccine against S. Paratyphi A, CVD 1902. Volunteers will be randomised 1:1 to receive two doses of CVD 1902 or placebo, 14 days apart. One month following second vaccination all volunteers will ingest S. Paratyphi A bacteria with a bicarbonate buffer solution. They will be reviewed daily in the following 14 days and diagnosed with paratyphoid infection if the predefined microbiological or clinical diagnostic criteria are met. All participants will be treated with antibiotics on diagnosis, or at day 14 postchallenge if not diagnosed. The vaccine efficacy will be determined by comparing the relative attack rate, that is, the proportion of those diagnosed with paratyphoid infection, in the vaccine and placebo groups. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the Berkshire Medical Research Ethics Committee (REC ref 21/SC/0330). The results will be disseminated via publication in a peer-reviewed journal and presentation at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN15485902.

Typhoid fever control in the 21st century: where are we now?

PURPOSE OF REVIEW: Momentum for achieving widespread control of typhoid fever has been growing over the past decade. Typhoid conjugate vaccines represent a potentially effective tool to reduce the burden of disease in the foreseeable future and new data have recently emerged to better frame their use-case. RECENT FINDINGS: We describe how antibiotic resistance continues to pose a major challenge in the treatment of typhoid fever, as exemplified by the emergence of azithromycin resistance and the spread of Salmonella Typhi strains resistant to third-generation cephalosporins. We review efficacy and effectiveness data for TCVs, which have been shown to have high-level efficacy (≥80%) against typhoid fever in diverse field settings. Data from randomized controlled trials and observational studies of TCVs are reviewed herein. Finally, we review data from multicountry blood culture surveillance studies that have provided granular insights into typhoid fever epidemiology. These data are becoming increasingly important as countries decide how best to introduce TCVs into routine immunization schedules and determine the optimal delivery strategy. SUMMARY: Continued advocacy is needed to address the ongoing challenge of typhoid fever to improve child health and tackle the rising challenge of antimicrobial resistance.

Antimicrobial agents for the treatment of enteric fever chronic carriage: A systematic review.

BACKGROUND: Chronic carriage of S. Typhi or S. Paratyphi is an important source of enteric fever transmission. Existing guidance and treatment options for this condition are limited. This systematic review aims to assess the evidence concerning the efficacy of different antimicrobials in treating enteric fever chronic carriage. METHODS: We searched major bibliographic databases using relevant keywords between 1946 and September 2021. We included all interventional studies that included patients with confirmed enteric fever chronic carriage and deployed an antimicrobial that remains in clinical practice today. Case reports and case series of under 10 patients were excluded. Two reviewers screened abstracts, selected articles for final inclusion and quality-assessed the included studies for risk of bias. Extracted data was analysed, with pooling of data and eradication rates for each antimicrobial calculated. As only one randomised controlled trial was identified, no meta-analysis was performed. RESULTS: Of the 593 papers identified by the initial search, a total of eight studies met the inclusion criteria and were included in the systematic review. Evidence was identified for the use of fluoroquinolones and amoxicillin/ampicillin in the treatment for enteric fever chronic carriage. Fluoroquinolones were superior to amoxicillin/ampicillin with 92% of patients achieving eradication after one antimicrobial course compared to 68% (p = 0.02). The quality of included studies was poor, and all were carried out before 1990. CONCLUSION: This review identified fluoroquinolones and amoxicillin/ampicillin as treatment options for enteric fever chronic carriage, with fluoroquinolones the more effective option. However, this evidence pre-dates rises in antimicrobial resistance in enteric fever and therefore the significance of these findings to today's practice is unclear. Further research is needed to investigate whether these antimicrobials remain appropriate treatment options or whether alternative interventions are more effective.

Viral vector vaccines.

Over the past two years, the SARS-CoV-2 pandemic has highlighted the impact that emerging pathogens can have on global health. The development of new and effective vaccine technologies is vital in the fight against such threats. Viral vectors are a relatively new vaccine platform that relies on recombinant viruses to deliver selected immunogens into the host. In response to the SARS-CoV-2 pandemic, the development and subsequent rollout of adenoviral vector vaccines has shown the utility, impact, scalability and efficacy of this platform. Shown to elicit strong cellular and humoral immune responses in diverse populations, these vaccine vectors will be an important approach against infectious diseases in the future.

Seroprevalence of SARS-CoV-2 antibodies in healthcare workers at a London NHS Trust.

Healthcare workers (HCWs) have a theoretically increased risk of contracting severe acute respiratory coronavirus virus 2 (SARS-CoV-2) given their occupational exposure. We tested 2,167 HCWs in a London Acute Integrated Care Organisation for antibodies to SARS-CoV-2 in May and June 2020 to evaluate seroprevalence. We found a seropositivity rate of 31.6% among HCWs.

An aggressive form of Haemophilus parainfluenzae infective endocarditis presenting with limb weakness.

We present the case of a 49-year-old man with a bicuspid aortic valve who presented to the emergency department with limb weakness and a fever. Blood tests revealed a fulminant septic process with Haemophilus parainfluenzae bacteraemia, anaemia and thrombocytopenia. Imaging revealed a cervical spinal abscess and discitis causing spinal cord compression, in addition to multiple cerebral septic emboli, pleural effusions and ascites. A transoesophageal echocardiogram (TOE) performed post decompression of his spinal collection showed native aortic valve endocarditis with an associated large aortic root abscess. He underwent successful aortic valve surgery and a 6-week course of antibiotic therapy and made an excellent clinical recovery with no long-term complications from his condition.