Rifaximin Fails to Prevent Campylobacteriosis in the Human Challenge Model: A Randomized, Double-Blind, Placebo-Controlled Trial

Rimmer, Joanna E.; Harro, Clayton; Sack, David A.; Talaat, Kawsar R.; Gutiérrez, Ramiro L.; DeNearing, Barbara; Brubaker, Jessica; Laird, Renée M.; Poly, Frédéric; Maue, Alexander C.; Jaep, Kayla; Alcala, Ashley; Mochalova, Yelizaveta; Gariepy, Christina L.; Chakraborty, Subhra; Guerry, Patricia; Tribble, David R.; Porter, Chad K.; Riddle, Mark S.

doi:10.1093/cid/cix1014

Cited by 16 publications

(19 citation statements)

References 34 publications

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“…2a ). This rate of recrudescence is higher than previous trials likely due to enhanced culture techniques, such as not refrigerating stool before culturing, that were employed specifically for increased vigilance of recrudescence 15 . Recrudescent infection isolates were confirmed to be the inoculum strain and, in all cases, were sensitive to azithromycin and ciprofloxacin.…”

Section: Gene Variants Associated With Treatment or Human Disease Stamentioning

confidence: 73%

“…Samples were obtained from a previously described 15 controlled human infection model ( ClinicalTrials.gov Identifier NCT02280044, Navy Medical Research Center IRB NMRC.2014.0013, and Western Institutional Review Board study number WIRB 1147996). Volunteers were healthy adults recruited from the mid-Atlantic area, signed informed consent prior to participating in the study, and allowed for all future use of the samples obtained during the study.…”

Section: Methodsmentioning

confidence: 99%

“…In the challenge, a single liquid inoculum of C. jejuni strain CG8421 was used to simultaneously infect a group of human volunteers, making this study a highly-controlled pathogen adaptation experiment in humans. The challenge was designed to evaluate the prophylactic efficacy of rifaximin on C. jejuni infection in humans and is described elsewhere ( ClinicalTrials.gov Identifier NCT02280044) 15 . Briefly, rifaximin treatment had no effect on the primary clinical outcome of campylobacteriosis.…”

Section: Introductionmentioning

confidence: 99%

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Campylobacter jejuni transcriptional and genetic adaptation during human infection

et al. 2018

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Campylobacter jejuni infections are a leading cause bacterial food-borne diarrheal illness worldwide, and Campylobacter infections in children are associated with stunted growth and therefore long-term deficits into adulthood. Despite this global impact on health and human capital, how zoonotic C. jejuni responds to the human host remains unclear. Unlike other intestinal pathogens, C. jejuni does not harbor pathogen-defining toxins that explicitly contribute to disease in humans. This makes understanding Campylobacter pathogenesis challenging and supports a broad examination of bacterial factors that contribute to C. jejuni infection. Here we use a controlled human infection model to characterize C. jejuni transcriptional and genetic adaptations in vivo, along with a non-human primate infection model to validate our approach. We found variation in 11 genes is associated with either acute or persistent human infections and include products involved in host cell invasion, bile sensing, and flagella modification, plus additional potential therapeutic targets. Particularly, a functional version of the cell invasion protein A (cipA) gene product is strongly associated with persistently infecting bacteria and we went on to identify its biochemical role in flagella modification. These data characterize the adaptive C. jejuni response to primate infections and suggest therapy design should consider the intrinsic differences between acute and persistently infecting bacteria. Additionally, RNA-sequencing revealed conserved responses during natural host commensalism and human infections. 39 genes were differentially regulated in vivo across hosts, lifestyles, and C. jejuni strains. This conserved in vivo response highlights important C. jejuni survival mechanisms such as iron acquisition and evasion of the host mucosal immune response. These advances highlight pathogen adaptability across host species and demonstrate the utility of multidisciplinary collaborations in future clinical trials to study pathogens in vivo.

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Section: Gene Variants Associated With Treatment or Human Disease Stamentioning

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Campylobacter jejuni transcriptional and genetic adaptation during human infection

et al. 2018

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“…Briefly, the currently CHIM utilizes an HS23/36 strain, named CG8421, isolated from a US solder in Thailand with acute febrile dysentery in 1999 97 The strain has been safely administered to 68 "naïve" subjects at 3 clinical sites at doses ranging from 2 × 10 4 to 1 × 10 colony forming units. [103][104][105] In the most recent randomized, doubleblind, placebo-controlled trial, the strain induced campylobacteriosis in 85.7% (24/28) of all subjects. 103 Importantly, microbial recrudescence has been observed with this strain, a phenomenon that may be specific to this model or may be reflective of natural Campylobacter infection.…”

Section: Summary and Looking Towards The Futurementioning

confidence: 99%

“…[103][104][105] In the most recent randomized, doubleblind, placebo-controlled trial, the strain induced campylobacteriosis in 85.7% (24/28) of all subjects. 103 Importantly, microbial recrudescence has been observed with this strain, a phenomenon that may be specific to this model or may be reflective of natural Campylobacter infection. 103,104,106,107 While the CG8421 appears to be sufficiently robust to assess current vaccine candidates, other vaccine strategies (or other capsule-types) may require the development of new C. jejuni CHIMs.…”

Section: Summary and Looking Towards The Futurementioning

confidence: 99%

Update on Campylobacter vaccine development

Poly

Noll

Riddle

et al. 2018

Human Vaccines & Immunotherapeutics

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Background: Acute diarrheal disease caused by viral, bacterial and parasitic infections are a major global health problem with substantial mortality and morbidity in children under five years of age in lower and middle income countries. However, a number of these infections also impact large segments of populations in upper income countries, as well as individuals who travel overseas for work, business or pleasure. Campylobacter has been and continues to be a leading cause of disease burden globally across all income countries. Aims: The aim of this review is to describe recent understanding in burden of disease, consider the current landscape of Campylobacter vaccine development, and address the challenges that need to be overcome. Sources: Relevant data from the literature as well as clinical trials described in European and US registries were used to conduct this review. Content: Despite advances in population health, food security, improved sanitation, water quality and the reduction of poverty, Campylobacter infections continue to plague global populations. The emerging recognition of chronic health consequences attributed to this pathogen is changing the potential valuation of preventive interventions. Advancing development of new vaccines is a present opportunity and holds promise.

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