This systematic review summarizes the findings of several studies showing a comparative advantage of antibiotic chemoprophylaxis for the prevention of TD. With respect to rifaximin chemoprophylaxis, two studies (Flores et al. and Armstrong et al.) did not show that chemoprophylaxis with rifaximin reached a statistically significant difference in preventing TD compared to placebo [25, 27]. In both studies, the incidence of TD in the control group was relatively low (8 of 48 (17%) and 9 of 47 (19%), respectively), which could have explained the findings given that the sample size calculations were based on the expected incidence of TD of 40% and thus may have been too small to detect the true effect of rifaximin in preventing TD. Furthermore, though studies utilizing rifaximin were limited to only two regions, there appeared to be a consistent effect of protection at 67% (D&L 95% CI = 55% to 76%) with little heterogeneity (heterogeneity χ2 = 3.09, P = 0.377; I
2 =3.1%), and the study by Taylor et al. suggests that rifaximin may be effective against more invasive pathogens occurring in other common travel destinations . However, until such studies are done in field settings (and against a broader range of invasive pathogens to include nontyphoid Salmonella and Campylobacter), routine chemoprophylaxis against TD with rifaximin may not be appropriate if a traveler is going to destinations where diarrheagenic Escherichia coli are less common.
The effectiveness of fluoroquinolone antibiotics would appear to be greater than rifaximin, which is not surprising, given the broader spectrum of coverage and systemic distribution of this drug class. Pooled estimates of fluoroquinolone efficacy were 88% (95% CI 80% to 93%) with little evidence of heterogeneity (heterogeneity χ2 = 1.25, P = 0.87; I
2 = 0.0%), though less effective when moderate to severe TD as an outcome is considered (summary D&L efficacy of 49%). It is important to note that studies examining fluoroquinolones were not as current as the studies that examined rifaximin (publication 1986 to 1994 vs. 2005 to 2011). As sanitation and hygiene conditions improve, resistance to fluoroquinolones emerges, and geographical patterns of resistance change (and keep evolving), older data citing fluoroquinolone use for chemoprophylaxis may become obsolete. The data from older studies of the use of fluoroquinolones may be less contemporaneous, but it is still valuable as it adds perspective and places newer data from rifaximin studies into context.
Although such a meta-analysis of the efficacy of antibiotics for TD prevention is interesting, the results do not necessarily compel one to embrace chemoprophylaxis as a potential solution. Even in the face of efficacy data for safer antibiotics such as rifaximin, the prevailing consensus is against widespread use exemplified by Dr. Gorbach, Chairman of the 1985 NIH Consensus Development Panel, who wrote an accompanying editorial to the first report of rifaximin diarrhea prophylactic efficacy in 2005 . Gorbach’s concerns included potential unintended adverse consequences, such as safety issues, uncertain protection against invasive pathogens, and microbiologic adverse effects, that may not yet be apparent in the small number of studied individuals. Dr. Gorbach concluded with the statement, “Rapid and judicious treatment of diarrhea, not antibiotic prophylaxis, is the best recommendation for most travelers.”
Although these concerns still prevail today, a new consideration regarding the potential risk of postinfectious chronic health consequences of TD has arisen. Serious sequelae such as reactive arthritis  and Guillain-Barré syndrome  have long been known to be associated with infections causing TD, but they are relatively infrequent. Most notable has been the accumulating evidence associating TD with postinfectious irritable bowel syndrome. Two separate systematic reviews have now been published which conclude that roughly 1 of 11 people who develop acute diarrheal infection may go on to develop PI-IBS [15, 16]. Other studies are also reporting TD risk with other common postinfectious functional gastrointestinal disorders [37–40]. With TD specifically, there have been six studies among traveler populations, all of which have shown an increased risk of PI-IBS among travelers who develop TD compared to those who do not develop TD [39–44]. Factors which appear to be associated with increased risk of PI-IBS include fever, illness severity, duration, infection with an invasive pathogen, and concomitant acute stress. Furthermore, this risk remains elevated for at least 3 years after the infection  and has been described to persist in 57% after 6 years in one study and 76% after 5 years in another [45, 46].
Thus, the recognition of both the acute and chronic consequences associated with TD diarrhea may change the risk-balance and value equation for antibiotic chemoprophylaxis. A recent economic analysis by Lundkvist et al., who evaluated the potential cost-effectiveness of a vaccine against enterotoxigenic E. coli, described the cost of a TD event of $1,460 or $1,996 for a leisure or business traveler, respectively (including value of travel, value of time, and medical costs) . With regard to IBS, in a review of 18 economic studies conducted in the United States and United Kingdom, direct and indirect cost per patient-year were estimated between $700 and $12,000 (2002) . In this systematic review, we found a NNT with chemoprophylaxis to prevent TD during travel of 2.8 (95% CI = 2.0 to 4.7) for fluoroquinolones and 4.5 (95% CI = 2.6 to 15.9) for rifaximin. A back-of-the-envelope calculation would suggest that to prevent the cost of acute disease, a single-dose, 14-day regimen of rifaximin 550 mg (at $22.61 per dose, $316.58 regimen) would provide a net benefit of $35 for a leisure traveler ($1,460 – (4.5 × $316.58)) and a $571 net benefit for the average business traveler to an average-risk region. Fluoroquinolones at less than $1.00 per dose (ciprofloxacin) would appear to be even more cost-effective using a simplistic calculation. However, such cost savings need to be balanced by the cost of potential AEs associated with antibiotics. Interestingly, in this systematic review, there were no treatment emergent-related AEs reported for any of the studies, though the inclusion of risk of Clostridium difficile infection and fluoroquinolone-related tendonopathies ought to be considered more formally in an economic analysis. If one were to more comprehensively consider the value added in preventing PI-IBS and other chronic health consequences, the benefits of chemoprophylaxis in acute and chronic disease prevention may appear to outweigh the risks associated with chemoprophylaxis. Clearly, future studies are needed to better define the economic cost associated with PI-IBS and whether chemoprophylaxis with rifaximin or fluoroquinolones can be used safely to prevent such sequelae.
The present review includes a comprehensive literature search, a priori inclusion and exclusion criteria, standardized data abstraction, risk of bias scoring, and current analytic methods, all of which reduce the potential bias in the resultant population of studies used for analysis. However, the small number of studies and the lack of studies conducted among a variety of study population types and geographic regions limit the broad application of these results beyond young healthy travelers and, for rifaximin, to regions outside Central America, where diarrheagenic E. coli may not predominate. Though comprehensive, our search strategy might not have identified all eligible studies. We did not find heterogeneity in study effect estimates, but the studies evaluating fluoroquinolones were not current and thus may have been subject to changes in traveler population demographics and secular trends of antimicrobial resistance. Therefore, translation of results from this type of controlled setting to other populations who may be less healthy or subject to different travel or treatment environments need to be validated by additional studies. This systematic review afforded an objective assessment of study design and risk of bias for the population of chemoprophylaxis trials included. Although the risk of bias for most domains was considered low, the authors felt that there was incomplete data reporting for some studies, which could have included important secondary outcomes related to per-protocol or efficacy evaluable analyses and efficacy against moderate to severe disease. In addition, it was noted that not all studies included information on how they ensured or measured treatment adherence and what potential effect such nonadherence may have had on study results. Given the known problem of medication adherence with malaria chemoprophylaxis, such an assessment for TD adherence within these trial settings would be informative [49, 50]. Last, some studies had significant lost to follow-up rates, which, though generally balanced across treatment arms, raises further concern about self-selection bias and the generalizability of these results. Future studies ought to consider better methods to ensure avoidance of dropouts and losses to follow-up, which can be a challenge in a travel setting.