Protocol for the challenge non-typhoidal Salmonella (CHANTS) study: a first-in-human, in-patient, double-blind, randomised, safety and dose-escalation controlled human infection model in the UK

Treatment of Salmonella infection in healthy immunocompetent adults poses a number of specific challenges. Antimicrobial therapy is indicated for invasive disease but may prolong shedding in patients with paucisymptomatic gastroenteritis. We have elected to offer rescue treatment in specific circumstances. The rationale for this decision is discussed elsewhere.21 Antibiotic therapy will be initiated in all participants who fulfil criteria for Salmonella diagnosis through reaching either or both of the defined primary endpoints of persistent fever or BSI. Treatment will also be commenced in participants who do not achieve the primary outcome measures but reach any of the other prespecified treatment criteria outlined in box 1. Treatment for BSI will comprise oral ciprofloxacin 500 mg two times per day for 10–14 days, or second-line therapy of intravenous ceftriaxone 1 g once daily for up to 14 days. All other treatment indications (systemic illness, gastroenteritis, asymptomatic/paucisymptomatic shedding) will be treated with oral ciprofloxacin 500 mg two times per day for 5 days, or with second-line oral azithromycin 500 mg once daily for 5 days. Antibiotic treatment will not be routinely offered to participants who do not fulfil any prespecified treatment criteria. The full antibiotic treatment decision algorithm is illustrated in online supplemental figure 1.

Box 1

Criteria for commencing antibiotic therapy following oral bacterial challenge

Antibiotics are commenced if any of the following apply.

Any participant with Salmonella Typhimurium bacteraemia.

Fever ≥38°C for ≥12 hours.

Any participant with severe gastroenteritis*.

Moderate gastroenteritis** plus:

Any participant with three or more of the following symptoms on the same day at grade 2 or higher.

  • Headache.

  • Fatigue/malaise.

  • Anorexia.

  • Abdominal pain.

  • Nausea.

  • Vomiting.

  • Myalgia.

  • Arthralgia.

  • Cough.

Any participant from whom Salmonella has been detected from at least two stool culture/PCR and 24 hours apart who has not received antibiotics by day 14 postchallenge.

Any participant in whom antibiotic use is felt to be clinically necessary (as decided by a medically qualified study doctor).

*Severe gastroenteritis: ≥6 loose/liquid stools (Bristol types 6–7) and/or >800 g of loose/liquid stools in a rolling 24-hour period and/or ≥2 stools with gross blood in 24 hours.

**Moderate gastroenteritis: 4–5 loose/liquid stools (Bristol types 6–7) and/or 400–800 g in a rolling 24-hour period.

***Grade 0=not present; grade 1=present but no interference with activity; grade 2=some interference with activity; grade 3=significant; prevents daily activity; grade 4: Emergency department (ED) visit or hospitalisation.

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