By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

Dr. Fischer reports no financial relationships relevant to this field of study.

SYNOPSIS: International travel carries a risk of colonization by antimicrobial-resistant intestinal flora. The use of a quinolone, but not a macrolide, during travel further increases the risk of acquisition of extended-spectrum beta-lactamase-producing Enterobacteriaceae.

SOURCE: Wuerz TC, Kassim SS, Atkins KE. Acquisition of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) carriage after exposure to systemic antimicrobials during travel: Systematic review and meta-analysis. Travel Med Infect Dis 2020;37:101823.

International travel prompts changes in the intestinal flora, and colonization by extended-spectrum beta-lactamase producing-Enterobacteriaceae (ESBL-PE) is associated with travel alone. The use of antibiotics during travel is thought to further increase the risk of becoming colonized by these resistant microbes. ESBL-PE-colonized individuals usually have no symptoms but are at some risk of developing symptomatic illness that carries financial costs as well as risks of morbidity and mortality.

Using standard systematic review techniques, Wuerz and colleagues identified 15 prospective cohort studies published from 2010 to 2017 that evaluated ESBL-PE acquisition associated with international travel and noted whether the traveler had been exposed to antibiotics during the trip. A total of 5,283 travelers were included in the 15 studies.

Asia was the most common destination continent, followed by Africa. Diarrhea was reported in 38% of travelers, and 10% received antibiotics. The antibiotics received were beta-lactams (30%), fluoroquinolones (25%), doxycycline (20%), and macrolides (8%). Overall, 31% of travelers acquired ESBL-PE during their travel.

As determined by meta-analysis, antibiotic use increased the risk of ESBL-PE acquisition 2.37-fold. Fluoroquinolones, as compared to no antibiotic use, increased ESBL-PE acquisition 4.68-fold. Tetracyclines (which are used for malaria prevention as well as for diarrhea treatment) increased ESBL-PE acquisition 1.68-fold. Beta-lactams and macrolides did not increase the risk of acquisition of these organisms.

COMMENTARY

We and our patients imagine, anticipate, and dream of the opportunity to travel internationally again. Eventually, we again will confront the possibility of providing presumptive antibiotic therapy for travelers who might develop bothersome traveler’s diarrhea. Even during the pandemic, though, science is advancing. The helpful systematic review by Wuerz and colleagues provides clear evidence that the use of antibiotics for healthy travelers with mild diarrhea should be questioned and, likely, avoided.

Traveler’s diarrhea is common, affecting one-third or more of short-term visitors to less-resourced countries in tropical regions. In fact, a recent study showed that 46% of medical students on overseas rotations developed traveler’s diarrhea.1 Typically, the diarrhea is self-limited, resolving within a few days. Nonetheless, the illness can be uncomfortable, inconvenient, and, rarely, severe. Bacteria, often enterotoxigenic Escherichia coli, are the usual cause of diarrhea in travelers from more-resourced to less-resourced countries, and antibiotics such as azithromycin and quinolones significantly shorten the duration of illness.2

Thus, it has been common practice to provide travelers with a course of oral antibiotics to use in the event that they develop diarrhea. The cost and side effects (rare allergic reactions) seemed minimal compared to the benefit of salvaging a day or two of lost activity and altered travel plans. It was assumed that the number of treated travelers would be small compared to the total population numbers and that a few days of antibiotic use would not contribute significantly to population-level alterations in antimicrobial resistance. However, as previously reported in Infectious Disease Alert (2015;34:67-69) and proposed by an expert panel of the International Society of Travel Medicine,2 there has been growing concern that antibiotic use can increase the acquisition of resistant germs significantly, with resultant spread of these germs in new regions following the return from travel. Now, there are enough data on specific risks related to extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) to warrant the systematic review provided by Wuerz and colleagues.

Wuerz’s review is extremely useful. Clearly, ESBL-PE acquisition is common with international travel, with about one-third of travelers from North America and Europe to Asia or Africa becoming colonized. And, antibiotics increase the risk. However, as this meta-analysis clearly shows, it is not just any antibiotic that increases the risk; fluoroquinolones are problematic, and macrolides are not.

Of course, the data from Wuerz et al are not new, even if the systematic review and meta-analysis are new uses of previously published data. The prescribing patterns of experts at 20 United States travel clinics were followed from 2009-2018 as they provided care to more than 100,000 travelers prior to trip departure.3 As new data and expert guidelines and governmental concerns about antimicrobial use were published, antibiotic use dropped significantly, and quinolones, in particular, became used much less frequently.2,3

Overuse of antibiotics likely also relates to the changing resistance patterns of more serious infections such as typhoid fever. A recent report of international travelers who acquired typhoid during their trips showed quinolone resistance in 78% of South Asian S. typhi isolates and in 60% of isolates from sub-Saharan Africa.4

In terms of avoiding increases in both general antimicrobial resistance and ESBL-PE acquisition, antibiotics should not be used to treat uncomplicated traveler’s diarrhea in most healthy patients.2 Rather, oral hydration and, perhaps, an anti-motility agent such as loperamide (except in young children) can be effective in facilitating recovery and reducing poor outcomes. For immunocompromised patients, travelers with bloody diarrhea, and, possibly, those with very tight travel itineraries, an antibiotic could be considered, with preference for a macrolide over a quinolone.

REFERENCES

  1. Vlot JA, Blanter AI, Jonker EFF, et al. Travel preparation and health risks in Dutch and Belgian medical students during an elective in low- or middle-income countries: A prospective self-reporting cohort study. Travel Med Infect Dis 2020;37:101779.
  2. Riddle MS, Connor BA, Beeching NJ, et al. Guidelines for the prevention and treatment of travelers’ diarrhea: A graded expert panel report. J Travel Med 2017;24(Suppl 1):S57-S74.
  3. Gandhi AR, Rao SR, Chen LH, et al. Prescribing patterns of antibiotics for the self-treatment of travelers’ diarrhea in Global TravEpiNet, 2009-2018. Open Forum Infect Dis 2020;7:ofaa376.
  4. Hagmann SHF, Angelo KM, Huits R, et al. Epidemiological and clinical characteristics of international travelers with enteric fever and antibiotic resistance profiles of their isolates: A GeoSentinel analysis. Antimicrob Agents Chemother 2020;64:e01084-20.