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Evaluation of the Clinical and Microbiological Response to Salmonella Paratyphi A Infection in the First Paratyphoid Human Challenge Model.

ABSTRACT: To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of Salmonella enterica serovar Paratyphi A infection.Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pretreatment at 1 of 2 dose levels (group 1: 1-5 × 103 colony-forming units [CFU] and group 2: 0.5-1 × 103 CFU). Participants were monitored in an outpatient setting with daily clinical review and collection of blood and stool cultures. Antibiotic treatment was started when prespecified diagnostic criteria were met (temperature ?38°C for ?12 hours and/or bacteremia) or at day 14 postchallenge.The primary study objective was achieved following challenge with 1-5 × 103 CFU (group 1), which resulted in an attack rate of 12 of 20 (60%). Compared with typhoid challenge, paratyphoid was notable for high rates of subclinical bacteremia (at this dose, 11/20 [55%]). Despite limited symptoms, bacteremia persisted for up to 96 hours after antibiotic treatment (median duration of bacteremia, 53 hours [interquartile range, 24-85 hours]). Shedding of S. Paratyphi A in stool typically preceded onset of bacteremia.Challenge with S. Paratyphi A at a dose of 1-5 × 103 CFU was well tolerated and associated with an acceptable safety profile. The frequency and persistence of bacteremia in the absence of clinical symptoms was notable, and markedly different from that seen in previous typhoid challenge studies. We conclude that the paratyphoid challenge model is suitable for the assessment of vaccine efficacy using endpoints that include bacteremia and/or symptomatology.NCT02100397.

SUBMITTER: Dobinson HC

PROVIDER: S-EPMC5439345 | biostudies-other | 2017 Apr

REPOSITORIES: biostudies-other

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Evaluation of the Clinical and Microbiological Response to Salmonella Paratyphi A Infection in the First Paratyphoid Human Challenge Model.

Dobinson Hazel C HC Gibani Malick M MM Jones Claire C Thomaides-Brears Helena B HB Voysey Merryn M Darton Thomas C TC Waddington Claire S CS Campbell Danielle D Milligan Iain I Zhou Liqing L Shrestha Sonu S Kerridge Simon A SA Peters Anna A Stevens Zoe Z Podda Audino A Martin Laura B LB D'Alessio Flavia F Thanh Duy Pham DP Basnyat Buddha B Baker Stephen S Angus Brian B Levine Myron M MM Blohmke Christoph J CJ Pollard Andrew J AJ

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20170401 8

<h4>Background</h4>To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of Salmonella enterica serovar Paratyphi A infection.<h4>Methods</h4>Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pretreatment at 1 of 2 dose levels (group 1: 1-5 × 103 colony-forming units [CFU] and group 2: 0.5-1 × 103 CFU). Participants were monitored in an outpatient setting with daily clinical revi ...[more]

PMID: 28158395

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Project description:BackgroundThe treatment of enteric fever is complicated by the emergence of antimicrobial resistant Salmonella Typhi. Azithromycin is commonly used for first-line treatment of uncomplicated enteric fever, but the response to treatment may be sub-optimal in some patient groups when compared with fluoroquinolones.MethodsWe performed an analysis of responses to treatment with azithromycin (500mg once-daily, 14 days) or ciprofloxacin (500mg twice-daily, 14 days) in healthy UK volunteers (18-60 years) enrolled into two Salmonella controlled human infection studies. Study A was a single-centre, open-label, randomised trial. Participants were randomised 1:1 to receive open-label oral ciprofloxacin or azithromycin, stratified by vaccine group (Vi-polysaccharide, Vi-conjugate or control Men-ACWY vaccine). Study B was an observational challenge/re-challenge study, where participants were randomised to challenge with Salmonella Typhi or Salmonella Paratyphi A. Outcome measures included fever clearance time, blood-culture clearance time and a composite measure of prolonged treatment response (persistent fever ≥38.0°C for ≥72 hours, persistently positive S. Typhi blood cultures for ≥72 hours, or change in antibiotic treatment). Both trials are registered with ClinicalTrials.gov (NCT02324751 and NCT02192008).FindingsIn 81 participants diagnosed with S. Typhi in two studies, treatment with azithromycin was associated with prolonged bacteraemia (median 90.8 hours [95% CI: 65.9-93.8] vs. 20.1 hours [95% CI: 7.8-24.3], p<0.001) and prolonged fever clearance times <37.5°C (hazard ratio 2.4 [95%CI: 1.2-5.0]; p = 0.02). Results were consistent when studies were analysed independently and in a sub-group of participants with no history of vaccination or previous challenge. A prolonged treatment response was observed significantly more frequently in the azithromycin group (28/52 [54.9%]) compared with the ciprofloxacin group (1/29 [3.5%]; p<0.001). In participants treated with azithromycin, observed systemic plasma concentrations of azithromycin did not exceed the minimum inhibitory concentration (MIC), whilst predicted intracellular concentrations did exceed the MIC. In participants treated with ciprofloxacin, the observed systemic plasma concentrations and predicted intracellular concentrations of ciprofloxacin exceeded the MIC.InterpretationAzithromycin at a dose of 500mg daily is an effective treatment for fully sensitive strains of S. Typhi but is associated with delayed treatment response and prolonged bacteraemia when compared with ciprofloxacin within the context of a human challenge model. Whilst the cellular accumulation of azithromycin is predicted to be sufficient to treat intracellular S. Typhi, systemic exposure may be sub-optimal for the elimination of extracellular circulating S. Typhi. In an era of increasing antimicrobial resistance, further studies are required to define appropriate azithromycin dosing regimens for enteric fever and to assess novel treatment strategies, including combination therapies.Trial registrationClinicalTrials.gov (NCT02324751 and NCT02192008).

Project description:Non-typhoidal Salmonella (NTS) bacteremia is a significant cause of morbidity and mortality worldwide. It is considered to be an emerging and neglected tropical disease in Africa. We studied this in two tertiary hospitals-Al Farwaniya and Al Amiri-in Kuwait, a subtropical country, from April 2013-May 2016. NTS bacteremia was present in 30 of 53,860 (0.75%) and 31 of 290,36 (1.33%) blood cultures in the two hospitals respectively. In Al Farwaniya hospital, one-third of the patients were from some tropical developing countries of Asia. About 66% of all patients (40/61) had diarrhea, and of these, 65% had the corresponding blood serovar isolated from stool culture. A few patients had Salmonella cultured from urine. Patients were either young or old. Most of the patients had co-morbidities affecting the immune system. Two patients each died in both hospitals. The number of different serovars cultured in each hospital was 13, and most infections were due to S. Enteritidis (all sequence type [ST]) 11) and S. Typhimurium (all ST19) except in a subgroup of expatriate patients from tropical developing countries in Al Farwaniya hospital. About a quarter of the isolates were multidrug-resistant. Most patients were treated with a cephalosporin with or without other antibiotics. S. Enteritidis and S. Typhimurium isolates were typed by pulsed field-gel electrophoresis (PFGE) and a selected number of isolates were whole-genome sequenced. Up to four different clades were present by PFGE in either species. Whole-genome sequenced isolates showed antibiotic-resistance genes that showed phenotypic correlation, and in some cases, phenotypes showed absence of specific genes. Whole-genome sequenced isolates showed presence of genes that contributed to blood-stream infection. Phylogeny by core genome analysis showed a close relationship with S. Typhimurium and S. Enteritidis from other parts of the world. The uniqueness of our study included the finding of a low prevalence of infection, mortality and multidrug-resistance, a relatively high prevalence of gastrointestinal infection in patients, and the characterization of selected isolates of S. Typhimurium and S. Enteritidis serovars by whole-genome sequencing that shed light on phylogeny, virulence and resistance. Similarities with studies from developing countries especially Africa included infection in patients with co-morbidities affecting the immune system, predominance of S. Typhimurium and S. Enteritidis serovars and presence of drug-resistance in isolates.

Project description:Enteric fever is a systemic infection caused by Salmonella Typhi or Paratyphi A. In many endemic areas, these serovars co-circulate and can cause multiple infection-episodes in childhood. Prior exposure is thought to confer partial, but incomplete, protection against subsequent attacks of enteric fever. Empirical data to support this hypothesis are limited, and there are few studies describing the occurrence of heterologous-protection between these closely related serovars. We performed a challenge-re-challenge study using a controlled human infection model (CHIM) to investigate the extent of infection-derived immunity to Salmonella Typhi or Paratyphi A infection. We recruited healthy volunteers into two groups: naïve volunteers with no prior exposure to Salmonella Typhi/Paratyphi A and volunteers previously-exposed to Salmonella Typhi or Paratyphi A in earlier CHIM studies. Within each group, participants were randomised 1:1 to oral challenge with either Salmonella Typhi (104 CFU) or Paratyphi A (103 CFU). The primary objective was to compare the attack rate between naïve and previously challenged individuals, defined as the proportion of participants per group meeting the diagnostic criteria of temperature of ≥38°C persisting for ≥12 hours and/or S. Typhi/Paratyphi bacteraemia up to day 14 post challenge. The attack-rate in participants who underwent homologous re-challenge with Salmonella Typhi was reduced compared with challenged naïve controls, although this reduction was not statistically significant (12/27[44%] vs. 12/19[63%]; Relative risk 0.70; 95% CI 0.41-1.21; p = 0.24). Homologous re-challenge with Salmonella Paratyphi A also resulted in a lower attack-rate than was seen in challenged naïve controls (3/12[25%] vs. 10/18[56%]; RR0.45; 95% CI 0.16-1.30; p = 0.14). Evidence of protection was supported by a post hoc analysis in which previous exposure was associated with an approximately 36% and 57% reduced risk of typhoid or paratyphoid disease respectively on re-challenge. Individuals who did not develop enteric fever on primary exposure were significantly more likely to be protected on re-challenge, compared with individuals who developed disease on primary exposure. Heterologous re-challenge with Salmonella Typhi or Salmonella Paratyphi A was not associated with a reduced attack rate following challenge. Within the context of the model, prior exposure was not associated with reduced disease severity, altered microbiological profile or boosting of humoral immune responses. We conclude that prior Salmonella Typhi and Paratyphi A exposure may confer partial but incomplete protection against subsequent infection, but with a comparable clinical and microbiological phenotype. There is no demonstrable cross-protection between these serovars, consistent with the co-circulation of Salmonella Typhi and Paratyphi A. Collectively, these data are consistent with surveillance and modelling studies that indicate multiple infections can occur in high transmission settings, supporting the need for vaccines to reduce the burden of disease in childhood and achieve disease control. Trial registration NCT02192008; clinicaltrials.gov.

Dataset Information

Evaluation of the Clinical and Microbiological Response to Salmonella Paratyphi A Infection in the First Paratyphoid Human Challenge Model.

Publications

Evaluation of the Clinical and Microbiological Response to Salmonella Paratyphi A Infection in the First Paratyphoid Human Challenge Model.

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