What’s new in travellers’ diarrhoea: updates on epidemiology, diagnostics, treatment and long-term consequences

Abstract

Background

Travellers’ diarrhoea (TD) is the most common clinical syndrome affecting travellers. This narrative review summarizes key discoveries reported in the last two years related to TD and suggests areas for future research.

Methods

A PubMed literature search was conducted for novel data in TD research published between 12 January 2018 and 12 January 2020. Inclusion was based on contribution to epidemiology, aetiology, diagnostics, management and long-term consequences and relevance to public health, discovery and clinical practice.

Results

The initial literature search yielded 118 articles. We retrieved 72 and reviewed 31 articles for inclusion. The findings support our understanding that TD incidence varies by traveller group and environment with students and military-travel remaining moderately high risk, and control of food and water in mass gathering events remain an important goal. The growth of culture-independent testing has led to a continued detection of previously known pathogens, but also an increased detection frequency of norovirus. Another consequence is the increase in multi-pathogen infections, which require consideration of clinical, epidemiological and diagnostic data. Fluoroquinolone resistant rates continue to rise. New data on non-absorbable antibiotics continue to emerge, offering a potential alternative to current recommendations (azithromycin and fluoroquinolones), but are not recommended for febrile diarrhoea or dysentery or regions/itineraries where invasive pathogens are likely to cause illness. Recent studies investigated the interaction of the microbiome in TD prevention and consequences, and while discriminating features were identified, much uncertainty remains. The prevalence of extended-spectrum beta-lactamase–producing Enterobacteriaceae (ESBL-PE) acquisition and carriage is increasing. Finally, continued research documents the post-infectious consequences, whereas mechanisms of reactive arthritis and post-infectious IBS necessitate further investigation.

Conclusions

Globally, TD remains an important travel health issue and advances in our understanding continue. More research is needed to mitigate risk factors where possible and develop risk-based management strategies to reduce antibiotic usage and its attendant consequences.

Antimicrobial resistance, PCR, antibiotics, irritable bowel syndrome (IBS), microbiome, reactive arthritis

Introduction

Prior to the global SARS-CoV-2 pandemic, 500–600 million people travelled annually to low- and middle-income countries (LMICs).¹ It is well known that of all travel-associated risks, travellers’ diarrhoea (TD) continues to be an important problem with per trip attack rate estimates of 10–40%.^2,3 The impacts to the individual traveller and destinations are significant and include lost time, productivity, medical expenses and averted spending.⁴ While the perennial threat of TD continues, so too do advances in research tools and methods to understand the problem and develop novel solutions to mitigate this priority health concern. Thus, the purpose of this review was to consider and highlight new research reported in the last two years related to TD and summarize important research gaps.

Methods

We conducted a PubMed literature search of English-language articles published between 12 January 2018 and 12 January 2020 that included the terms ‘travelers diarrhea’ (including spelling variations travellers and diarrhoea) in the title or abstract fields. The search strategy included novel data from observational studies and non-human randomized controlled trials. Articles were chosen for inclusion based on relevance to public health, discovery and clinical practice specific to TD. Findings were organized by epidemiology, aetiology, diagnostics, management and long-term consequences.

Epidemiology

Incidence and Risk Factors

In recent research, updates to trends in TD incidence and risk factors varied according to traveller type and environment. A pair of studies of Hajj pilgrims supported the declining trend noted in recent decades among this population.^5–9 The self-reported TD incidence was 5.4% in a cross-sectional survey⁵ and 13.8% in a 3-year prospective cohort study.⁶ This trend likely reflects measures at the Hajj to improve food and water quality, sanitary conditions and restrictions on fresh food importation.^5,10 Of note, there was no evidence supporting the protective role of handwashing in either study. These data offer pertinent findings to the new discipline of mass gathering medicine, which aims to guide development of optimal public health at mass gathering events.⁸

While these findings support prior research that has observed a declining TD incidence in some countries following trends of improved sanitation and hygiene infrastructure globally,² additional reports would suggest that these trends do not apply to all travel populations or environments similarly. This was the case among students participating in international travel electives where TD was a frequent ailment.^11–13 Travel from high to LMICs was a particular risk. In separate studies of European medical students travelling to LMICs, the per trip TD incidence was 46.3 and 48.1% (average trip durations of 67 and 41 days).^11,12 The greatest observed risk was in Africa, Asia (specifically the Indian subcontinent) and South America.

Likewise, reports of military populations revealed that TD remains prevalent among this traveller group, although the infrastructure made a difference. Ashley et al. compared adult and paediatric U.S. military beneficiaries and found per trip TD incidence of 22 and 15%, respectively, for median trip duration of 15 and 16 days.¹⁴ Destinations represented trips lacking built-up base infrastructure and travel regions included Southeast Asia/North Asia/Oceania, South America/Central America/Caribbean and Africa. The incidence rates supported prior work that TD incidence is not decreasing in military populations.^15,16

Alternatively, at a forward frontline military base in Honduras, Walters et al. observed an incidence rate of around 3% per month,¹⁷ which was much lower than previous work.¹⁵ Along similar lines, among British military personnel at a 6-week exercise in Nanyuki, Kenya, a reported TD incidence of 21.9% represented a decline relative to estimates in 1999–2000 of 40–60%.¹⁸ These data would appear to offer evidence of risk reduction afforded by improved infrastructure in forward deployed bases with onsite dining options and improved sanitation.¹⁹ While it is often difficult to establish such infrastructure early on in deployment scenarios, prioritization of infrastructure in both permanent and mission operations could serve to alleviate TD burden among this traveller population.

Research in TD also investigated travel-related risk factors. Vlot et al. observed a greater risk among students in accommodations without running water or refrigerator (both P < 0.001).¹¹ In Ecuador, Smith et al. found treatment of household drinking water protective against TD, (aOR = 0.72; P = 0.03) even in houses that reported improved drinking water sources.²⁰ On the other hand, there was little evidence for the protective role of personal risk behaviour counselling on food and water hygiene, supporting previous work.^12,21 Furthermore, separate studies of Hajj pilgrims and students found no association with dietary indiscretion.^5,13 Only one study observed an association with local food consumption.¹⁸ These findings support a major tenant that factors outside of a travellers’ control such as poor restaurant hygiene are more likely to have a greater impact on TD prevention.^2,21,22

Overall, the role of the environment was a prominent theme. Thus, research aiming to further understand the association between TD and global sanitation improvement to substantiate its impact on both host–nation residents as well as travellers is valuable. In the meantime, providers should continue counselling patients on food and water precautions during travel, as supported by a recent retrospective cohort study in the United States that found TD pre-travel consultations associated with shorter hospital stays and reduced gastroenterology consultant rates,²³ but with caution not to overestimate its effect, and research should continue exploring other modifiable factors protective against TD.

Aetiology

Etiologic research continued highlighting trends and geographic variations in pathogens associated with TD. Eight articles were recently published that analysed the prevalence of pathogens from diarrhoeal illness due to travel (Table 1). These recent studies confirmed that TD aetiology is predominantly bacterial.^2,17,24–29 Also consistent with prior work, globally enterotoxigenic Escherichia coli (ETEC) remains one of the most common pathogens and was especially prevalent in Latin America and African countries, but less so in Southeast Asia.^{2,24–27,29–32} Separate studies investigated ETEC toxins. While a prospective case–control in Thailand found no difference in the distribution of heat-labile (LT) and heat-stabile (ST) toxins between symptomatic and asymptomatic travellers,³¹ a prospective study of Finnish travellers in various LMICs found that moderate/severe TD was associated with STh (human) subtype and that LT was the most frequently identified toxin.³³

Table 1

Prevalence of enteric pathogens from travellers’ diarrhoea according to travel destination

Region of travel destination	Location of travel destination	Prevalence of pathogensa,b	Number of samples	Study population  c,d	Timing of testing	Study type	Study period	Diagnostic method	Study author
Asia	East Asia	Campylobacter (29%) EAEC (14%) ETEC (14%) Norovirus GI/GII (14%) Rotavirus A (14%) CD toxin A/B (14%)	7	Civilian travellers presenting to travel clinic in Japan	Post-travel	Prospective case–control	2016	• Multiplex PCR	Kutsuna30
Asia	Indian Subcontinent (Nepal)	EAEC (26%) *Campylobacter (20%) *Norovirus (17%) *ETEC (12%) EPEC (11%) *Rotavirus (9%) *Shigella (8%) Giardia (6%)	433e	Civilian travellers from developed countries	Acute illness	Prospective case–control	2012–2014	• Culture • Microscopy • Commercial ELISA • Real-time PCR • Multiplex PCR	Murphy31
Asia	Indian Subcontinent (Nepal)	Norovirus (32%) ETEC (21%) Campylobacter jejuni (18%) EAEC (11%) EPEC (10%) Shigella/EIEC (10%)	165	Military and civilian travellers from developed countries	Acute illness	Observational	2012–2018	• Culture • Real-time PCR • Multiplex PCR	Ashbaugh25
Asia	South Asia	EAEC (73%) EPEC (55%) ETEC (41%) Campylobacter (36%) Shigella/EIEC (36%) STEC stc1/stx2 (23%) E. coli O157 (18%) Giardia lamblia (14%) Norovirus GI/GII (14%) Cryptosporidium (9%) Plesiomonas (9%)	22	Civilian travellers presenting to travel clinic in Japan	Post-travel	Prospective case–control	2016	• Multiplex PCR	Kutsuna30
Asia	Southeast Asia (Thailand)	*Campylobacter (14%) *Plesiomonas (14%) *Vibrio (14%) *Norovirus (12%) Salmonella (12%) *ETEC (8%)	389f	Civilian travellers from developed countries	Acute illness	Prospective case–control	2001–2003	• Culture • Microscopy • Real-time PCR • ELISA	Bodhidatta26
Asia	Southeast Asia (Thailand)	Norovirus (44%) Campylobacter jejuni (31%) EPEC (31%) Salmonella (19%) EAEC (6%) ETEC (6%)	16	Military and civilian travellers from developed countries	Acute illness	Observational	2012–2018	• Culture • Real-time PCR • Multiplex PCR	Ashbaugh25
Asia	Southeast Asia	EAEC (51%) ETEC (51%) EPEC (29%) Plesiomonas (29%) Campylobacter (24%) STEC stc1/stx2 (20%) E. coli O157 (11%) Shigella/EIEC (11%) Vibrio (7%) Cryptosporidium (6%) Salmonella (6%)	55	Civilian travellers presenting to travel clinic in Japan	Post-travel	Prospective case–control	2016	• Multiplex PCR	Kutsuna30
Africa	Kenya	ETEC (29%) Norovirus (17%) EAEC (15%) Shigella/EIEC (6%)	87	Military personnel	Acute illness	Retrospective analysis	2013–2015	• Multiplex PCR	Ashbaugh25
Africa	Africa	EAEC (55%) EPEC (46%) ETEC (36%) Norovirus GI/GII (18%) Shigella/EIEC (18%) STEC stc1/stx2 (18%) E. coli O157 (9%) Giardia lamblia (9%) Salmonella (9%)	11	Civilian travellers presenting to travel clinic in Japan	Post-travel	Prospective case–control	2016	• Multiplex PCR	Kutsuna30
Middle East	Egypt	ETEC (43%) Shigella/EIEC (29%) Campylobacter jejuni (7%) EAEC (7%) EPEC (7%) Norovirus (7%)	14	Military and civilian travellers from developed countries	Acute illness	Observational	2012–2018	• Culture • Real-time PCR • Multiplex PCR	Ashbaugh25
South/Central America	Honduras	Norovirus (20%) ETEC (14%) Campylobacter jejuni (11%) Shigella/EIEC (9%)	44	Military and civilian travellers from developed countries	Acute illness	Observational	2012–2018	• Culture • Real-time PCR • Multiplex PCR	Ashbaugh25
South/Central America	Honduras	EAEC (34%) ETEC (33%) EPEC (23%) STEC (13%) Shigella/EIEC (12%) Norovirus (8%)	152	Military personnel at a forward operating military base	Acute illness	Passive surveillance	2014–2016	• Multiplex PCR	Walters17
South/Central America	Honduras	EAEC (44%) EPEC (44%) ETEC (38%) STEC (19%) Campylobacter (6%) Cyclospora (6%) Rotavirus (6%) Shigella (6%)g	16	Military personnel at a forward operating military base	Acute illness	Active longitudinal surveillance	2015–2016	• Multiplex PCR	Walters17
South/Central America	Peru	Norovirus (16%) Campylobacter jejuni (9%) ETEC (9%) Shigella/EIEC (9%) EPEC (6%)	171	Military and civilian travellers from developed countries	Acute illness	Observational	2012–2018	• Culture • Real-time PCR • Multiplex PCR	Ashbaugh25
South/Central America	Latin America	EAEC (33%) ETEC (33%) Norovirus GI/GII (33%)	3	Civilian travellers presenting to travel clinic in Japan	Post-travel	Prospective case–Control	2016	• Multiplex PCR	Kutsuna30
Tropical or subtropical areas	Africa and Asia	EAEC (54%) EPEC (44%) ETEC (32%) EIEC/Shigella (27%) Salmonella spp (27%) Cryptosporidium (18%) Sapovirus (18%) Campylobacter jejuni (17%) Norovirus (17%) Rotavirus (15%) Giardia (13%) Astrovirus (6%) STEC (6%)	59	Paediatric travellers presenting to hospital in France	Post-travel	Prospective study	2014–2015	• Multiplex PCR	Pouletty27
Mixed	All continents excluding Antarctica	E. coli (31%) Giardia (28%) Campylobacter spp (9%) Salmonella spp (8%)	194	Patients referred to travel clinic in Germany	Post-travel	Retrospective analysis	2009–2017	• Culture • Microscopy • Real-time PCR • Multiplex PCR	Brehm28
Mixed	All continents excluding Australia and Antarctica	EAEC (46%) *EPEC (43%) *ETEC (41%) STEC (16%) Plesiomonas (8%) Shigella/EIEC (7%)	61	Civilian travellers	Acute illness, self-collected stool samples during travel	Ancillary nested case–control	Not reported	• Culture • Multiplex PCR	Schaumburg29

^aBolded text with asterisk indicates that pathogen was significantly associated with TD in cases compared with controls (P > 0.05)

^bIncluded pathogens detected at a prevalence greater than 5%

^cAll travellers in the study population were considered adults unless paediatric noted

^dTesting of samples was completed at the location of travel for the studies that collected samples during acute illness. In post-travel testing, location sites are included in Study Population.

^eSample size varied for several pathogens: EAEC, EPEC n = 420; ETEC n = 402

^fSample size varied for several pathogens: ETEC n = 325; Norovirus n = 259

^gShigella was detected by culture instead of multiplex PCR methods

KEY:  E. coli: Escherichia coli, EAEC: enteroaggregative E. coli, EPEC: enteropathogenic E. coli, ETEC: enterotoxigenic E. coli, Shigella/EIEC: Shigella/Enteroinvasive E. coli, STEC: Shiga-toxin-producing Escherichia coli or Shiga-like toxin producing E. coli, CD toxin A/B: Clostridium difficile toxins A and B

Although enteroaggregative E. coli (EAEC) and enteropathogenic E. coli (EPEC) were commonly isolated pathogens,^25,26,29,31 both recent findings and previous work have challenged their pathogenic significance due to high prevalence in asymptomatic travellers.^34,35 In a case–control study in Nepal, no significant difference was observed for either pathogen (EAEC P = 0.560; EPEC P = 0.370).³¹ Similarly, in Thailand, the isolation frequency of EPEC was the same in cases and controls (5%; P = 0.860); EAEC was not included in testing.²⁶ In an ancillary nested case–control study of prospectively collected stool samples during global travel, EPEC isolation was significantly associated with TD (P = 0.01), while EAEC was not (P = 0.08).²⁹ Additionally, among 59 children returning from travel to tropical and subtropical countries, EAEC was always detected as a co-infection.²⁷ Yet, on the other hand, previous work that reported EAEC and EPEC isolation more frequently in current TD cases compared with resolved cases supports pathogenesis.³⁶ Additionally, recent EAEC research continued to support its pathogenicity through the identification of specific genetic and virulence profiles associated with disease and disease severity, thus suggesting that heterogeneity contributes to differences in clinical presentation^37–39 Less evidence currently exists for EPEC. Thus, research should continue exploring significant genetic and virulence profiles of both pathogens (Table 2).

Table 2

Future directions for travellers’ diarrhoea research

Area of research	Future directions
Epidemiology	• Public health initiatives and global sanitation programs associated with TD reduction • Pathogenic significance of EAEC, EPEC and norovirus in acute TD • Antimicrobial resistance to azithromycin • Clinical resistance implications of azithromycin and travel-associated quinolone non-susceptibility
Diagnostics	• Differentiation between asymptomatic colonization from pathogenic infection • Clinical utility of PCR diagnostics • Multiple microbe interactions and impact on disease progression
Treatment	• Rifamycin • Doxycycline prophylaxis • PDX myoviridae
Long-term consequences	• Quality of life (PI-IBS, reactive arthritis) • Potential pre-travel microbiome modifications for colonization resistance • Mechanisms of ESBL-PE acquisition and carriage

Another trend was the increased detection frequency of norovirus relative to other pathogens.^25,26,31 In the multi-site global study by Ashbaugh et al., norovirus was the most commonly identified pathogen (24%).²⁵ While there continues to be concern that norovirus may not be attributable to the cause of illness due to its proclivity towards prolonged shedding in paediatric diarrhoeal studies,⁴⁰ it was the sole pathogen in 81% of norovirus-detected cases. Similarly, in Thailand, norovirus was detected in a significantly greater number of cases than controls (P = 0.000) strongly suggesting disease attribution.²⁶ As with other enteropathogens, it will likely be important to quantitate detection of the amount of pathogens to fully discriminate disease attribution. More data should be forthcoming as Lindsay et al. has written a prospective cohort study protocol to estimate the incidence of norovirus acute gastroenteritis among US and European travellers to areas of moderate to high TD risk.⁴¹

Epidemiology of Antimicrobial Resistance

Tracking antimicrobial resistance (AMR) in pathogens causing TD is critical to monitor global infectious disease threats. Murphy et al. reported changes in AMR among TD related pathogens in Nepal and observed near total resistance to fluoroquinolones among Campylobacter and Shigella isolates at 97 and 78% resistance, respectively, and also ETEC at 23%. Furthermore, among 47 of 433 cases willing to follow-up, 7 had persistent symptoms.³¹ Possible explanations included treatment failure, drug–bug mismatch or irritable bowel syndrome, calling for the need to continue monitoring for the advent of treatment failure. These findings support recent guidelines that do not recommend fluoroquinolones for moderate to severe TD in Southeast Asia specifically, although globally they remain a treatment option.^31,42

Additionally, they observed an increase in AMR to azithromycin. Compared with a previous report where no Campylobacter azithromycin-resistant isolates were detected between 2001 and 2003 in Nepal,⁴³ 8% resistance was observed between 2012 and 2014. Azithromycin resistance to ETEC and Shigella also increased (ETEC complete resistance 0–10% and Shigella intermediate susceptibility 35–39%). Both trends are consistent with increasing resistance patterns against macrolides and fluoroquinolones among Shigella spp globally²⁴ and E. coli in Asia/India.^24,44,45 These findings are concerning because azithromycin is the drug of choice for TD treatment in Southeast Asia (and globally). Future research should continue monitoring AMR to azithromycin and the incidence of clinical resistance (e.g. treatment failures).

Supporting these data in destination travel settings, Grass et al. investigated the susceptibility of enteric bacterial infections to quinolones among individuals in the United States by linking data from the U.S. Antimicrobial Resistance Monitoring System to enteric infections reported to Foodborne Diseases Active Surveillance Network.⁴⁶ International travel was associated with more than 10-fold increased odds of acquisition of isolates not susceptible to quinolones. These findings support work from the past 10–15 years that high rates of fluoroquinolone resistance in diarrhoeal patients are associated with foreign travel in industrialized countries.²⁴ While previous literature suggests that patients infected with drug-resistant pathogens may experience more severe illness, hospitalizations or death,⁴⁶ further studies are needed to expound on the implications of quinolone non-susceptibility on patient outcomes in TD.

Clearly, vigilant monitoring of trends in AMR among TD pathogens and evidence for treatment failure are necessary given the trajectory of resistance that is supported by continued research.

Diagnostics

The increased sensitivity of PCR and its ability to detect more pathogens compared with stool culture diagnostic methods have continued to be reaffirmed.³⁰ This shift in diagnostics is changing our understanding of epidemiologic trends. For instance, the viral contribution to TD aetiology, which was previously thought to be predominantly bacterial, coincided with the use of molecular techniques for viral detection.³¹ This prospective shift in diagnostics, however, highlights the challenges of identifying disease-causing pathogens and determining clinical utility of these tests.

Determining Pathogenicity and Clinical Utility

Recent reports considered in this review found an average of 41.2% of TD cases resulted in multi-pathogen detection using various diagnostic methods.^{17,25–28,30,31,47} Moreover, data from case–control studies in this review showed an average of 44% of asymptomatic controls demonstrated pathogen detection.^26,29,31 This highlights the need for clearer understanding of pathological significance of detected microbes.

Overall, opinions regarding PCR’s clinical utility remained mixed. In one study, EPEC and ETEC were the only pathogens detected by PCR that significantly related to TD symptoms. Campylobacter, Salmonella and norovirus GI/GII were exclusively detected in TD cases but, due to a small sample size, were not statistically significant.²⁹ A clinical review by Clark et al. found that the use of multiplex-PCR on patients with diarrhoea only led to a change in clinical management in 5.2% of patients, and patients who were returning travellers did not show significantly more clinically relevant pathogens compared with the rest of the study group.⁴⁸ Other studies, however, suggested increased clinical utility since implementation of PCR diagnostics. For example, one study showed that since starting multiplex-PCR diagnostics for paediatric cases of TD, two hospitals optimized the number of treated patients by 27%.²⁷ Another study found that while the introduction of multiplex-PCR to an emergency department did not affect time to disposition or empiric antibiotics for diarrhoea cases, the length of hospital stay and time to optimal antibiotic treatment were significantly shortened.⁴⁹ Less patients were also discharged with antibiotics following the introduction of PCR. While this study did not target TD specifically, this type of research as it relates to TD would be useful in analysing the cost-effectiveness of implementing PCR for returning travellers.

Timing of symptoms was another factor when considering PCR’s utility. In a retrospective analysis of TD patients, multiplex-PCR results were consistent with previous findings in which bacteria were more commonly detected in those with symptoms for less than 14 days and protozoa and helminths were predominantly detected in those with symptoms for at least 30.²⁸ This finding led the authors to suggest an individualized diagnostic approach in which molecular diagnostic methods are withheld from those with longer-lasting symptoms, as no relevant bacterial pathogen in this study group would have been missed by performing stool microscopy only. Still, the authors suggested prospective diagnostic trials to validate the utility of this new approach. Currently, guidelines recommend microbiologic diagnosis in travellers with chronic or severe symptoms.⁴² In summary, these data suggest that the clinical utility of molecular diagnostic tests in outpatients with diarrhoea, including those with TD, needs further study.

Future Directions in Diagnostics

It was suggested that future studies use predefined PCR testing intervals and symptom surveillance to gain further understanding of persistent pathogen detection after treatment and resolution of symptoms.⁵⁰ It has also been suggested that quantitative PCR may help differentiate colonization from infection, and one study investigated whether biorepositories of diarrhoeal and non-diarrhoeal specimens could be used to explore this further.⁵⁰ Additionally, development and validation of self-collected stool samples, such as filter paper stool cards, represents an important tool that could be developed to advance understanding of epidemiology and support field trials for new vaccines and therapeutics.⁵¹ Finally, the co-pathogen issue continues to warrant further understanding.

At this time, determining treatment based on the clinical presentation of TD cases combined with detected pathogens remains important. Overall, future research is needed to continue to identify which etiologic agents are truly of pathogenic significance. An important step is furthering our understanding of how the timing of testing relative to the onset of diarrhoea influences pathogens detected. Similarly, more research on the shedding times of different pathogens will help differentiate prior or asymptomatic colonization from current infections. Etiologic and diagnostic research should collaborate to identify diagnostic methods and protocols that would optimize the increased sensitivity of modern testing with the ability to differentiate disease causative versus non-causative pathogens.

Treatment

Antibiotics

The current first-line treatment for moderate and severe TD is antibiotic use, though the individual choice of when to use antibiotics given the risk–benefit for acute clinical relief versus the increased risk for antimicrobial-resistant colonization continues to drive debate. Recently, Rifamycin SV MMX^® (Aemcolo™; Relafalk™) (henceforth: rifamycin) joined rifaximin at the forefront of potential TD antibiotic treatments for non-invasive pathogens. Non-invasive pathogens account for the majority of TD, so non-absorptive antibiotics that target the colon or small-intestine (i.e. rifamycin and rifaximin, respectively) are very appealing as treatments.⁵² While rifamycin was shown to have comparable efficacy to ciprofloxacin in treating non-invasive pathogens, the trial report from Steffen et al. did not find a significant difference in time to last unformed stool (TLUS) between ciprofloxacin and rifamycin (average of around 55 h for each).

An appealing characteristic of rifamycin SV MMX (and possibly rifaximin⁵³) in the context of TD treatment is the potential to cause less microbiome disturbance and a resultant decrease in acquisition of multi-drug resistant (MDR) organisms during travel. There was no significant difference in acquisition of MDR organisms in stool after treatment with azithromycin vs rifamycin SV MMX, but there was shown to be significantly less acquisition of MDR organisms in stool after treatment with rifamycin SV MMX when compared with ciprofloxacin.^52,54 A decrease in MDR organisms after treatment with rifamycin SV MMX could potentially reduce complications post-infection, and further studies on this topic are recommended. Further research is needed to evaluate the potential benefits of these non-absorbables on their reduction of post-antibiotic consequences, balanced with their apparent decreased efficacy against severe and invasive disease. Furthermore, while the eubiotic effects of rifaximin have been detailed in a number of clinical contexts,⁵³ such effects have not been directly shown in the context of TD. Finally, the combination of these non-absorbable antibiotics with loperamide and in single-dose regimens, which also appear to have a decreased risk of MDRO acquisition,⁵⁵ is needed in comparison with current first-line agent, azithromycin.

Research advancing novel therapeutics has emerged such as the use of phages and engineered bacteriocins.⁵⁶ Recent animal model data on a phage called PDX offer a non-traditional antibiotic therapy against EAEC.⁵⁷ PDX was shown to be efficacious in killing EAEC both in vitro in human faeces and in vivo in mouse models. PDX is a Myoviridae strain that kills EAEC without disruption of the human microbiota. PDX has not yet been put through human trials but represents a new strategy for non-antibiotic therapies.⁵⁸ In addition to PDX, Microcin J25 (MccJ25) offers an oral non-antibiotic treatment for ETEC and was shown to significantly improve ETEC-caused clinical symptoms in mice, including body weight loss, diarrhoea scores, rectal temperature and survival rate, with the added benefit of gut anti-inflammatory properties.⁵⁹

Prophylaxis

The idea of antibiotic prophylaxis for TD prevention has little appeal, due to antibiotic stewardship, the unknown responsiveness of the pathogen and a broad geographical variety in pathogen species. The application of antibiotic prophylaxis has its place in individuals at risk for severe TD and subsequent severe complications according to current guidelines.⁴² Currently, in the supported use of prophylactic antibiotics, rifaximin is the preferred drug. Recently, however, a study from Lago et al. observed a relationship between the use of doxycycline for malaria prophylaxis and a TD relative risk of 0.62 (95% CI: 0.47–0.82).⁶⁰ While antibiotic prophylaxis for TD is still discouraged, this study presented the notion of potential benefit in travellers prescribed doxycycline for malaria prophylaxis. Important considerations for such a benefit would be to know the susceptibility of common TD pathogens to a given area, as well as the recommendation of doxycycline for antimalarial chemoprophylaxis to these same regions and balancing the potential adverse drug reaction risk in a given traveler.⁶⁰

With respect to treatment, the current guidelines for initial treatment of TD remain relevant. The current recommended OTC treatment for mild TD remains maintenance and/or replacement of hydration as well as therapy with loperamide or bismuth salicylate, with more severe forms of TD resistant to these therapies empirically treated by a pharmacist with antibiotics such as a fluoroquinolone, azithromycin or rifaximin (in areas where diarrhoeagenic E. coli predominate).⁴² While we are hopeful for a non-drug preventative measure such as personal protective behaviour counselling, there has not so far been significant data to suggest this is effective in preventing TD. Knowing this, the search for TD prophylaxis continues. In the meantime, new antibiotics such as rifamycin warrant further study. New developments in treatments outside of traditional antibiotics include the use of phages such as PDX, which was shown to be effective in mouse models for the treatment of EAEC without disruption of the gut microbiota but has insufficient data in human studies, as well as the use of microcins such as MccJ25, which was shown to be effective in mouse models for the treatment of ETEC.

Long-term Consequences

Microbiome Changes

When it comes to TD and its long-term effects, new research has started to examine the role of the microbiome. A recent study from Leo et al. found that in comparison to individuals who did not experience TD (n = 34) during a trip abroad, diversity decreased in all individuals who did (n = 9).⁶¹ These individuals saw increased levels of the phyla Proteobacteria and Bacteroidetes, as well as decreased levels of the phylum Firmicutes. However, all travellers, regardless of TD infection, saw an increase in the family Enterobacteriaceae. Travellers who experienced TD and did not take antibiotics (n = 17) had microbiota that returned to basal/pre-travel levels within their first month of returning from travel. These data support the potential to further understand colonization resistance in the traveller setting as defined by the capacity of the intestinal microbiota to resist long-term settlement of exogenous bacteria.

Another study from Walters et al. also explored the association between the microbiome and travel.¹⁷ Among deployed military with TD, they found the relative abundance of the specific families Lachnospiraceae and Verrucomicrobia was increased. Studies continue to find changes in microbiome composition among travellers with TD, but these compositions are not necessarily similar among populations or destinations. More research is needed in order to fully understand the relationship between the two, specifically when it comes to the mechanisms of colonization resistance and the potential to prevent infection through various methods.

Reactive Arthritis

One of the growing topics of interest surrounding the long-term impacts of TD is the development of reactive arthritis and other arthritides that may be linked to infection. In 2020, Tuompo et al. was the first prospective study that investigated whether reactive musculoskeletal (MSK) symptoms were associated with the acquisition of diarrhoeagenic E. coli, especially EAEC and EPEC.⁶² Symptoms included arthralgia, low back pain, joint swelling and synovitis. In total, 224 volunteers, out of the 526 initially contacted, returned all three questionnaires (pre-travel, post-travel and 3-week follow-up), and pre-travel and post-travel stool specimens. Of those volunteers, 155 reported experiencing TD during their travels, while 69 did not experience TD. Using a multivariate analysis, the researchers found that 18.7% of those with and 13.0% of those without TD reported MSK symptoms (95% CI 0.7–3.4; P = 0.3). While MSK symptoms were generally mild, they appeared 21.5 days (SD 23.5, range 0–56) after TD and lasted 82.8 days (SD 92.9, range 2–300). During their analysis, they also concluded that the acquisition of diarrhoeagenic E. coli was connected to the risk of developing MSK symptoms, independent of TD symptom severity. Importantly, this study also found that among all travellers with reactive MSK symptoms and diarrhoeagenic E. coli in their post-travel stools, the diarrhoeagenic E. coli were travel acquired since none was identified in their pre-travel stools. Overall, this topic needs to be further explored and larger studies need to be conducted in order to determine if MSK symptoms and reactive arthritis have a high incidence among travellers with TD caused by diarrhoeagenic E. coli.

Post-infectious Chronic Gastrointestinal Disorders

Although a connection between TD and post-infectious IBS (PI-IBS) has already been established, there has been some new research concerning its incidence and a possible mechanism behind the persistent immune activation involved in PI-IBS and other non–IBS-persistent abdominal complaints (PI-AC). In a 2018 prospective study, 101 participants were asked about gastrointestinal symptoms pre-travel and again post-travel at the intervals of 2 weeks, 6 months and 1 year.⁶³ While overall rates of PI-IBS and PI-AC were low, there was a higher rate of PI-AC (but not PI-IBS) in those who experienced TD compared with those who did not. In exploration of underlying mechanisms that could explain differences, they found that the psychological factors preceding infection and severity of symptoms associated with TD infection (but not immunological or gene expression differences) were associated with the development of PI-AC. More research is needed focusing on the role of TD in the development of PI-IBS and other PI-AC, underlying mechanisms and interventions to mitigate these sequelae.

Antibiotic Resistance and Extended-Spectrum Beta-Lactamase–Producing Enterobacteriaceae

Research continues to advance our understanding of the acquisition risk of antibiotic-resistant bacteria and of extended-spectrum beta-lactamase–producing Enterobacteriaceae (ESBL-PE), as well as potential underlying mechanisms. In a cohort study conducted between 2016 and 2017, among 230 German volunteers traveling mainly to Southeastern Asia (26%), South America (23%) and Eastern Africa (23%) that tested ESBL-PE negative before travelling, researchers found that 36% of the travellers reported experiencing TD symptoms and 23% returned ESBL-PE positive. Their multivariate analyses identified that age, accommodation type and traveling to Asia were associated with ESBL-PE colonization. From the group of 53 travellers that tested ESBL-PE positive after travel, 42 were examined again 6 months later, and 7 tested ESBL-PE positive.⁶⁴ There were several additional studies published about the epidemiology of ESBL-PE. Ljungquist et al. determined the prevalence of ESBL-PE carriage among Swedish patients with TD following international travel. They reported a prevalence of 28%, which was not significantly increased from a similar study done 10 years earlier,⁶⁵ despite the doubling of international travel in the past decade and rising ESBL-PE prevalence.⁶⁶ ESBL-PE prevalence was highest for travellers from Africa (54%), Asia (45%) and North America and the Caribbean (22%).⁶⁶

With respect to understanding mechanisms and explaining the variability noted in ESBL-PE acquisition, Leo et al. explored the host microbiome and the association with ESBL-PE acquisition and found acquisition was not associated with a specific microbiome before or after travel. There was also no significant impact on the microbiota when acquired MRE were not treated with antibiotics.⁶¹ However, the acquisition and carriage of MRE still need to be further addressed and researched in a larger context.

Overall, recent research has explored the long-term consequences of TD in relation to the microbiome and finds that TD infection is associated with decreased overall diversity, increased levels of Proteobacteria and Bacteroidetes, and decreased levels of Firmicutes. However, further investigation is still needed surrounding the microbiome, as well as the development and mechanisms of reactive arthritis and post-infectious IBS.

Author Contributions

A.A., H.C., S.T. and R.W. performed literature search, prepared the manuscript, contributed to revisions and approved final submission. A.A. and M.R. provided feedback of the manuscript, contributed to revisions and approved final submission. All the authors have seen and approved the final version of the manuscript.

Conflicts of interest

None declared.