Author(s): D. Cal Ham, Joseph Lutgring, Diya Surie, Louise Francois Watkins, Cindy Friedman

Antimicrobial resistance enables microbes to avoid or diminish the effects of antimicrobial agents and is acquired through either genetic mutation or the acquisition of resistance genes. Antimicrobial-resistant organisms can cause infections that are difficult to treat, often requiring the use of agents that are more expensive, less effective, or more toxic.

Resistance can occur in bacterial, viral, parasitic, and fungal pathogens. The epidemiology of resistant organisms can vary from country to country (and region to region) and might differ from that seen in the United States. International travelers should be aware of their risk of acquiring resistant organisms when abroad, and medical professionals should consider travel history when caring for patients, both to identify effective treatments for infections and to ensure infection-control interventions are in place to prevent the spread of antimicrobial resistance.

This chapter discusses resistant bacteria and an emerging fungal pathogen; these microbes can be acquired from community and health care exposures during international travel and can cause illness or asymptomatic colonization. Additional information about organism-specific resistance is available in the disease-specific chapters of Section 5, Travel-Associated Infections & Diseases. The topic of antimicrobial resistance is also addressed in Sec. 6, Ch. 4, Medical Tourism.

Infectious Agents & Epidemiology

Antimicrobial-Resistant Organisms in the Community

Globally, the emergence and spread of resistance have been linked to widespread use of antimicrobials in agriculture and in animal (veterinary) and human health care. Inadequate sanitation and water purification infrastructure also plays a role. At the community level, antimicrobial resistance can take many forms; two of relevance to travelers are diarrhea-causing bacteria, and bacteria that result in long-term intestinal colonization and (sometimes) extraintestinal infections.

Diarrhea-Causing Bacteria

Bacteria that cause diarrhea include a variety of enteric pathogens (e.g., Campylobacter jejuni, enterotoxigenic Escherichia coli, E. coli O157, Salmonella spp., Shigella spp.). Among these enteric pathogens, resistance to recommended treatment agents has risen worldwide in recent years, posing challenges for medical management. Refer to Section 5 for details of antimicrobial resistance in specific bacterial species.

Intestinal Colonization & Extraintestinal Infections

Bacterial colonization of the intestine is influenced and facilitated by a person’s diet; their use of agents that disrupt normal microbial flora (e.g., antacids, antibiotics); and their interactions with animals, other humans, and the environment. Enteric bacteria that commonly inhabit the human intestine (e.g., E. coli, Klebsiella pneumoniae) can be transmitted between close contacts (e.g., household members). Similarly, people who become colonized with antimicrobial-resistant bacteria during international travel can pass these to others. If present, intestinal colonization with antibiotic-resistant bacteria can last from a few weeks to >1 year posttravel; rates of colonization typically decline after 2–3 months, however.

Intestinal colonization with bacteria resistant to carbapenems, extended-spectrum cephalosporins, or colistin can also result in a range of difficult-to-treat extraintestinal infections.

Sources of Infection

Bacteria resistant to critically important antibiotics (e.g., carbapenems, extended-spectrum cephalosporins, colistin, macrolides, quinolones) have been isolated from a wide range of community sources, including animals and people, drinking water, meat, and produce. Consuming foods prepared by street vendors, taking antibiotics during travel, and having travelers’ diarrhea have all been associated with intestinal colonization with antibiotic-resistant bacteria. People with comorbidities (e.g., chronic bowel disease) also are more likely to become colonized with resistant bacteria during travel.

Risk to Travelers

The risk for intestinal colonization with antimicrobial-resistant enteric bacteria during travel is related to the prevalence of resistant organisms in the countries visited. Studies have identified that travelers returning from countries in East Africa, northern Africa, South America, South Asia, Southeast Asia, and the Middle East are at risk for colonization with bacteria resistant to extended-spectrum cephalosporins; risk for acquisition was greatest, however, after travel to India, Peru, and Vietnam. Acquisition of carbapenem-resistant Enterobacterales (CRE) has been reported in travelers returning from South Asia and Southeast Asia.

Colonization with E. coli carrying a novel gene that confers colistin resistance has been reported in travelers returning from countries in northwest Africa, South America and the Caribbean, East and Southeast Asia, Europe, and the Middle East. Although not used routinely to treat gram-negative infections in the United States, colistin is one of few remaining therapeutic options for extensively resistant infections. Emergence of colistin resistance, then, is of public health concern. In a study of 412 US international travelers, the rate of acquisition of bacteria with the mobile colistin resistance (mcr) gene was ≈5%. Bacteria harboring an mcr gene (e.g., mcr-1) appear to be primarily community-associated; mcr genes are often found in extended-spectrum β-lactamase (ESBL)–producing Enterobacterales.

Antimicrobial-Resistant Organisms in Health Care Settings

This section describes organisms of concern associated with overseas health care exposures (e.g., hospitalization, surgery). Recent hospitalization in another country can put travelers and medical tourists at risk for colonization or infection with organisms (bacteria, fungi) that possess antimicrobial resistance mechanisms that are rare in the United States. See resistance reports for specific organisms by country.

Gram-negative bacteria resistant to broad-spectrum antibiotics can cause difficult-to-treat infections. Some of the more concerning genetically mediated mechanisms of antibiotic resistance (mechanisms that can confer resistance to carbapenems, extended-spectrum cephalosporins, or colistin) have the potential for rapid spread to other bacteria. ESBL-producing gram-negative bacteria, for example, originally described in health care settings, are now present outside of health care globally, including in the United States.

Carbapenemase-Producing Bacteria

Carbapenemase-producing bacteria inactivate all or nearly all β-lactam antibiotics and are often highly antibiotic-resistant, making them difficult to treat. In some countries, as compared to the United States, carbapenemase production is the more frequent mechanism of carbapenem resistance, especially for Pseudomonas aeruginosa. Around the world, New Delhi Metallo-β-lactamase (NDM) is the most common carbapenemase; in the United States, however, where K. pneumoniae carbapenemase (KPC) predominates, NDM is still relatively uncommon.

In the United States, infections with carbapenemase-producing bacteria occur almost exclusively in people who were recently hospitalized or who had other health care exposures, and in residents of long-term care facilities. Among international travelers, infection with carbapenemase-producing bacteria similarly has been linked to hospitalizations and to medical tourism. In 2018, for example, a large outbreak of carbapenem-resistant P. aeruginosa occurred among medical tourists from several countries, including the United States, who traveled to Tijuana, Mexico, for elective bariatric surgery. The mechanism of antibiotic resistance was identified as Verona Integron-encoded Metallo-β-lactamase (VIM) carbapenemase. Also in 2018, the European Centre for Disease Prevention and Control reported an outbreak of carbapenem-resistant K. pneumoniae among travelers from 3 countries hospitalized in Gran Canaria, Spain; in this instance, resistance was due to bacterial production of the oxacillinase-48-like (OXA-48-like) carbapenemase.

In some countries, carbapenemase-producing bacteria cause both health care–associated and community-associated infections. In the aforementioned study of 412 US international travelers, the authors identified a low rate (<1%) of carbapenemase-producing CRE acquisition among travelers to South and Southeast Asia who did not have health care exposure.

Mobile Colistin Resistance

While bacteria harboring the mcr gene appear to be primarily community-associated, 2 hospital-based outbreaks of K. pneumoniae with mcr have been reported (one in China, the other in Portugal); the strain in the Portugal outbreak also produced a carbapenemase. Cases of colistin-resistant, carbapenemase-producing Enterobacterales have been associated with health care in other countries as well. Emergence of mcr in carbapenemase-producing CRE might result in the rapid spread of strains with extremely limited treatment options in health care settings.

Antimicrobial-Resistant Gram-Positive Bacteria

Antimicrobial-resistant gram-positive bacteria are a major cause of health care–associated infections. Methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (VRE) are endemic to the United States, and travelers hospitalized outside the United States also can become colonized or infected by these organisms. Transmissible linezolid resistance has been identified in gram-positive bacilli, including S. aureus, coagulase-negative Staphylococcus, and Enterococcus spp. from several countries worldwide, particularly in South America. This resistance is of particular concern in VRE, for which treatment options are already limited.

Candida Auris

The fungal pathogen Candida auris has rapidly emerged worldwide; >40 countries have reported cases, but broader spread is suspected. C. auris is distinct from other Candida species because it tends to cause outbreaks in health care facilities, can result in long-term asymptomatic skin colonization, persists in health care environments, and has high levels of resistance to multiple classes of antifungal agents. Strains of C. auris resistant to the 3 main classes of antifungal medications have been identified in several countries, including the United States.

Since C. auris was first reported in 2016, the number of cases in the United States has increased greatly. Many of the initial cases reported in the United States occurred in patients who had received health care previously in countries with documented C. auris transmission. Currently, however, most cases are the result of local spread in US health care settings, particularly long-term care facilities for high-acuity patients.

C. auris can be misidentified by some laboratory diagnostics, which might contribute to under-detection of cases, both domestically and outside the United States. Improved laboratory detection and targeted colonization screening, especially among health care contacts of known cases, can facilitate earlier identification of C. auris and its spread. Notify public health agencies and implement infection-control measures if C. auris is identified or suspected.

Prevention

In the Community

Contaminated food is the most common source of enteric pathogen exposures among travelers. Foods grown or prepared under unhygienic conditions can be a source of enteric bacteria. Bacteria harboring mcr genes have been identified in foods and food animals (e.g., camels, cattle, pigs, poultry) in multiple countries. Contaminated water is another potential source of antibiotic-resistant enteric bacteria (e.g., Campylobacter spp., E. coli, Salmonella spp., Shigella spp.). See Sec. 2, Ch. 9, Water Disinfection, for recommendations regarding water treatment. Insects (e.g., flies) also can serve as vectors in the spread of resistant bacteria.

Safe food choices and careful attention to good hand hygiene can reduce the risk for exposure to pathogens, including those that harbor antimicrobial resistance genes. See Sec. 2, Ch. 8, Food & Water Precautions, for recommendations regarding food consumption and guidance on hand hygiene. In addition, discourage travelers from purchasing or obtaining antibiotics for self-treatment in countries where drugs are available without prescription. Not only can these medications be ineffective for treating the traveler’s condition, but their use carries additional risks of unforeseen and untoward side effects. Antibiotics can disrupt the traveler’s healthy microbiota and promote acquisition of resistant organisms that can be carried in the traveler’s gastrointestinal tract for many months and transfer resistance to other organisms.

Management of mild cough, stomach upset, mild diarrhea, and other minor ailments usually does not require antibiotics. International travelers should include over-the-counter medications in their travel health kit (see Sec. 2, Ch. 10, Travel Health Kits), and clinicians can prescribe antibiotics during a pretravel clinic visit and instruct travelers on self-treatment of moderate diarrheal illness. Educate travelers about health issue warning signs that should prompt them to seek care. More information on management of travelers’ diarrhea during travel is available in Sec. 2, Ch. 6, Travelers’ Diarrhea.

Travelers and their treating clinicians should be aware that common bacterial infections in destination countries might be resistant to first-line antimicrobial drugs typically used in the United States. For example, fluoroquinolone-resistant enteric pathogens are now found globally. Therefore, if travelers need antibiotics to treat moderate to severe diarrhea, an alternative antibiotic (e.g., azithromycin) might be required. Evidence regarding effective therapies to prevent colonization or infection with resistant enteric organisms in travelers is lacking; investigations into the utility of probiotics and bismuth-containing compounds are under way.

In Health Care Settings

Patients admitted to health care facilities outside the United States, especially in low- and middle-income countries, might be at a greater risk for acquiring antimicrobial-resistant organisms due to a higher prevalence of these organisms and differences in infection-control standards and practices. Exposures can be facilitated by inadequate hand hygiene among staff and personnel, insufficient environmental cleaning, and irregular supply or use of personal protective equipment by health care workers. These gaps are more common in low-resource settings. In addition, access to newer combination therapies (e.g., ceftazidime-avibactam, imipenem-cilastatin- relebactam, meropenem-vaborbactam) used to treat infections caused by highly resistant carbapenemase-producing bacteria can be limited in some low- and middle-income countries.

Information about infection prevention and control services in international health care settings often is limited. When possible (e.g., for non-emergency procedures), people traveling overseas, particularly to low- and middle-income countries, can reduce their risk for health care–associated exposures by choosing facilities with active infection-prevention and control programs (see Sec. 6, Ch. 2, Obtaining Health Care Abroad, and Sec. 6, Ch. 4, Medical Tourism for more details and recommendations). Travelers should opt to receive health care at facilities that have been accredited for their infection-prevention and control programs by national and international authorities. Joint Commission International, an accreditation body used by US facilities, maintains a website of accredited hospitals globally. Although accredited health care facilities might have better infection-control practices than nonaccredited facilities, accreditation does not necessarily guarantee absence of risk for pathogen transmission.

Posttravel Considerations

Depending on their travel destination, some patients might be at greater risk for colonization and infection with resistant organisms. Strive to obtain an international travel history going back ≥12 months from patients presenting for care. Travel-related information can play an important role in the clinical care provided and infection control practices employed during clinical encounters.

Health Care Provider Guidance for Returning Travelers

For patients who recently stayed overnight in a health care facility outside the United States, the Centers for Disease Control and Prevention (CDC) has pathogen-specific guidance for CRE and C. auris.

Carbapenem-Resistant Enterobacterales

When CRE is identified in a patient with a history of an overnight stay in a health care facility outside the United States in the past 6 months, send the CRE isolate for confirmatory susceptibility testing and to determine the carbapenem-resistance mechanism. For patients admitted to health care facilities in the United States after hospitalization in facilities outside the United States within the past 6 months, consider rectal screening to detect CRE colonization; place patients in contact precautions while awaiting the screening cultures. Additional recommendations for patients infected or colonized with CRE can be found in the CRE Toolkit [PDF] and CDC Health Advisory [PDF].

Candida Auris

Consider screening for C. auris colonization in patients who have had an overnight stay in a health care facility outside the United States in the previous 12 months, especially if the stay occurred in a country with documented C. auris cases. See CDC recommendations on how to screen. All isolates of Candida collected from the bloodstream or other normally sterile sites should be identified to the species level. Also consider species identification for Candida isolates from nonsterile sites when the patient had an overnight stay in a health care facility outside the United States in the previous 12 months in a country with documented C. auris transmission.

Closely monitor patients being treated for C. auris for treatment failure. Susceptibility testing can help guide treatment selection. See additional recommendations for providers caring for patients infected or colonized with C. auris.