The use of oral prophylactics for the maintenance of gut health in travellers and the effect on development of antimicrobial resistance.

Troth, Thomas (2025). The use of oral prophylactics for the maintenance of gut health in travellers and the effect on development of antimicrobial resistance. University of Birmingham. M.D.

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Abstract

BACKGROUND

Travellers’ Diarrhoea (TD) is a significant issue for deployed troops. Antibiotic prophylaxis can be effective, but raises antimicrobial resistance (AMR) concerns. We aimed to evaluate the risk of extended-spectrum ß -lactamase (ESBL) acquisition in the PREVENT TD trial, a double-blind, randomised, placebo-controlled trial comparing once- and twice-daily rifaximin 550mg against placebo (ClinicalTrials.gov: NCT02498301). Volunteers were from UK Armed Forces personnel in British Army Training Unit Kenya (BATUK) This dissertation presents results on the acquisition of ESBL-producing Enterobacteriaceae in PREVENT TD participants. It also uses bioinformatic techniques and command line interfaces to analyse the presence of antimicrobial resistance genes, virulence factors and construct phylogenetic trees. It also attempts to identify transmission of strains between individuals. It then moves on to a further study of TD prevention using an over-the-counter product, Travelan, an anti-E. coli immunoglobulin and the conduct of an ongoing randomised control trial including the regulatory approval processes.

MATERIALS

Enrolled UK subjects deployed to BATUK for 6-week periods. 121 participants provided stool samples upon arrival and prior to departure. Approximately 100mg of stool was incubated in Luria Broth with cefotaxime (10μg/ml) at 37°C for 18 hours. These cultures were then spread onto ESBL Chromoselect agar (Merck) and incubated for 24 hours at 40°C. The presence of growth, was taken as positive for ESBL bacteria. The two rifaximin intervention arms were compared to placebo using Fisher’s exact test. A selection of resistant E. coli strains that grew on ESBL Chromoselect agar and sensitive strains that grew on UTI Chromoselect agar were sent for short read sequencing and bioinformatic analysis performed.

RESULTS

A total of 84 of 121 (69.4%) subjects had no ESBL present on arrival in BATUK and were eligible for an assessment of ESBL acquisition. The highest incidence of ESBL acquisition was observed in subjects randomized to the placebo arm; however, the differences were not statistically significant. Analysis of those individuals whose first study visit in BATUK found that 30.6% had E. coli that grew on ESBL Chromoselect agar. This level is around twice what is seen in previous UK studies. Rifaximin resistance levels increased from 16.4% to 35.5% during the study. Azithromycin resistance increased from 11.5% to 36.4% Multi Locus Sequence Typing identified that Sequence Type (ST) 69 was the most common ST and the most frequent E. coli phylotype was A. There were Intestinal Pathogenic E. coli associated virulence factors identified in 49/51 (96.1%) genomes. This does not necessarily mean the strains are pathogenic, as many VF work in concert with others to cause clinical disease, The most common Extended-Spectrum-Beta-Lactamase gene was blaCTX-M-15. Other strains contained genes such as bla-DHA, blaOXA, blaTEM and blaEC, which do not always confer ESBL resistance. The reasons for this are discussed. Numerous strains had similarities in their plasmids, virulence factors and AMR genes, but were not sufficiently close in SNP distances to say they were the same strains.

CONCLUSIONS

This is the first study to assess risk of ESBL acquisition in travellers after rifaximin prophylaxis. While ESBL acquisition rate was relatively high (26.5%), rifaximin was not associated with an increase in ESBL acquisition. This may be a significant advantage as a prophylactic agent. Additional trials are needed to corroborate these findings. A follow on randomised controlled trial comparing Travelan and placebo in the maintenance of gut health is underway.

Type of Work:

Thesis (Doctorates > M.D.)

Award Type:

Doctorates > M.D.

Supervisor(s):