Increasing Globalization and the Movement of Antimicrobial Resistance between Countries

Abstract

Background:

Methods:

This review covers previously published studies examining how human movement contributes to the global spread of antimicrobial resistance, including between low- and middle-income and high-income countries.

Results:

The emergence of resistance in one country or part of the world can become a worldwide event quickly. Human movement, including travel, medical tourism, military service, and migration, results in the globalization of resistant bacterial strains.

Conclusions:

Increased surveillance, whole-genome sequencing, focused infection control, and effective stewardship practices are needed to maintain the efficacy of antibiotics.

Antibiotics remain one of the most important discoveries in the history of medicine, saving the lives of millions if not billions of people since their introduction in the mid-20^th Century. They have played a key role in the improvement in life expectancy, increasing rates of survival in everything from childhood illness to surgical site infection, and remain one of the most widely prescribed drug classes worldwide. Their introduction so revolutionized medical care that as early as the 1950s, bacterial infections were considered by some authors to be a subject not worthy of further extensive research, as described by Jawetz in 1956: “on the whole, the position of antimicrobial agents in medical therapy is highly satisfactory. The majority of bacterial infections can be cured simply, effectively and cheaply. The mortality and morbidity from bacterial diseases have fallen so low that they are no longer among the important unsolved problems of medicine. These accomplishments are widely known and appreciated” [1].

Unfortunately, the use of antibiotics was mirrored almost immediately by the development of antibiotic resistance. Selective pressure and genetic transmission of resistance factors between bacteria allow acquisition then spread of resistance traits, to the point where almost every known bacterial pathogen has developed resistance to at least one antibiotic [2]. Increasing resistance, coupled with the “discovery void” of new antibiotics, is leading to a rapidly progressive global health emergency as infections once easily treatable are becoming difficult or even impossible to eradicate in some patients. Given the slow pace of antibiotic development, preservation of our ability to treat serious infections now rests primarily on prevention of antibiotic resistance and control of its spread. Evidence-based practices of both antibiotic stewardship and infection control are vital.

Our efforts to understand the true scope of global antimicrobial resistance (AMR) continue to be hampered by limited surveillance, particularly in low- and middle-income countries (LMICs). Even in high-income countries, rates of AMR are usually based on samples taken from patients who are presumed or known to have infections rather than from the population as a whole, thus excluding asymptomatic carriers and potentially biasing results away from community-acquired organisms. The World Health Organization (WHO) continues its efforts to document worldwide resistance for a number of bacteria–antibacterial drug combinations of public health importance as well as to set initial standards for what information should be collected in a worldwide surveillance program [3]. Results from their initial report in 2014 were alarming, with the majority of WHO regions showing national rates of ≥50% resistance for Escherichia coli versus third-generation cephalosporins and fluoroquinolones, Klebsiella pneumoniae versus third-generation cephalosporins, Staphylococcus aureus versus methicillin (methicillin-resistant S. aureus, or MRSA), and Streptococcus pneumoniae versus penicillin. The U.S. Centers for Disease Control and Prevention (CDC) estimate that >2.8 million antibiotic-resistant infections occur in the United States each year, resulting in >35,000 deaths [4]. As progress is made in collecting worldwide data, the numbers will rise.

Considerations for Low- and Middle-Income Countries

The development and spread of antimicrobial resistance are multifactorial problems, which raises both difficulties in and opportunities for containment. Many of these issues are further complicated by resource limitations in LMICs. The main factor in de novo development of resistance is thought to be selective pressure: Bacteria are exposed to antibiotics, the susceptible succumb, whereas the surviving less susceptible or fully resistant bacteria then grow unopposed, increasing their chance of transmission to other hosts [4]. This selective pressure is the main impetus behind initiatives to increase provider and public education about the inappropriate use of antibiotics, and for efforts in antibiotic stewardship to prevent misuse; the goal being to treat the right patients with the right antibiotics, right dose, via the right route, and for the right amount of time.

One unintended side effect of the general success of antibiotics is increasing public demand for their use. It is well documented that many patients request antibiotic prescriptions for non-bacterial infections in high-income countries, or buy antibiotics over the counter themselves in countries with poor regulation [5]. Self-medication with shared or saved prescriptions may occur even in areas with strict prescription requirements [6, 7]. Physicians are also known to overprescribe antibiotics even when a bacterial infection is not confirmed, with 20%–50% of antibiotic prescriptions being inappropriate [8, 9]. The reasons for this are complex and include prescribing “just in case” the medication helps and perceived or actual patient pressure. Number-needed-to-treat estimates show that for every two or three patients given antibiotics, one will develop new colonization with a resistant organism [10]; even a modest improvement in prescribing practices thus can have a significant effect at the population level.

Many countries have increased public education in an effort to limit these practices, often starting education as early as school age years. This provides a general trend toward less antibiotic usage, particularly when educational campaigns were coupled with provider education; however, effects often are time limited and require continuing training [8,10]. However, even in high-income countries, the reach of education is limited, with disparate knowledge levels demonstrated in different socioeconomic and ethnic groups, particularly when language barriers are involved [11]. Adoption of educational efforts is particularly hampered in LMICs by obstacles such as poor literacy, limited media reach, few or no prescription requirements, lack of access to appropriately trained medical professionals, and competing governmental priorities. Additional issues such as limited laboratory and culture availability often impair efforts to separate infections from other diseases or to identify which organisms are causing disease, thus hindering treatment with appropriate antibiotics [12, 13].

Correct choice of treatment antibiotic, when indicated, is critical not only to prevent development of resistance but also to ensure that patients with significant infections are treated appropriately. In the United States and other high-income countries, this is aided by practice guidelines and local antibiograms, both of which may change frequently as antibiotic resistance grows. Few LMIC facilities know their local resistance patterns or have an established antibiogram, much less are able to carry out surveillance or national organism reporting. LMICs may face additional obstacles in treating with appropriate antibiotics because of limited and variable drug availability and poor drug quality [12], leading to incompletely or incorrectly treated infections.

Global Spread of Resistance

In addition to organism–organism transmission, antibiotic resistance spreads on a macroscopic scale. Whereas resistance factors may spread from one bacterium to another, enabling development of newly resistant organisms, individual resistant organisms and colonies also spread worldwide as colonized or infected patients travel. This mode of spread seems to be on the rise as globalization increases. Patients may transport resistant organisms through general travel, medical tourism, emigration, or military service. This risk of acquiring new resistant organisms is significantly increased if travelers come into contact with the healthcare system while abroad [14, 15], a situation estimated to impact approximately five of every 1,000 travelers [16]. This organism transport may be bidirectional, both to and from the visited country and between LMICs and high-income countries.

A classic example of global organism transport is the story of Acinetobacter baumannii. Known to cause infections in those with weakened immune systems, most commonly intensive care patients, multi-drug–resistant (MDR) Acinetobacter has been a rising global threat for many years. The 2019 CDC report on antibiotic resistance highlights carbapenem-resistant Acinetobacter as an urgent threat [4]. Most resistance in Acinetobacter arises from mobile genetic elements, such as a carbapenemase, that are shared easily with other bacteria. This increases the risk of spread to other organisms, particularly in hospital settings where Acinetobacter frequently contaminates surfaces and medical equipment. Multiple studies have documented Acinetobacter infections in the wounds of soldiers and civilians injured during combat in Iraq and Afghanistan; although the source of these infections remains controversial, there is concern that it is nosocomial [17 –21]. Strain typing has confirmed further monoclonal spread within U.S. hospitals after patient repatriation [22], as well as in Lebanon from civilians injured during the Syrian civil war [23]. Military conflict and soldier repatriation from the front also have been implicated in the spread of other resistant organisms, including other carbapenem-resistant organisms [24] and MRSA in >50% of patients from Libya transferred back to Germany [25].

Resistance spread via non-military travel is best exemplified by the history of NDM-1 Klebsiella pneumoniae, first isolated in 2008 in the urine of a 59-year old male patient of Indian descent then living in Sweden. Reports indicate that the patient had travelled to India, where he developed, and was treated in multiple hospitals for, a gluteal abscess, then was repatriated to Sweden for further care. Resistant Klebsiella was isolated from his urine the day after his return [26,27]. This strain ultimately was found to carry a novel metallo-β-lactamase conferring carbapenem resistance that was designated NDM-1. The same metallo-β-lactamase was isolated from stool E. coli in the same patient, raising concern for gene transfer. The theory that this novel determinant of resistance originated in the Indian subcontinent was later confirmed with documented occurrences of NDM-1-carrying Enterobacteriaceae throughout India, Pakistan, and Bangladesh [26]. NDM-1 now has spread to at least 40 countries [28]. Although not as dramatic, multiple other organisms have been shown to travel along with returning patients, spreading country to country in similar fashion [29 –32].

A rapidly rising niche of global medical care is medical tourism, where patients travel between high-income countries and LMICs to access care. The reasons for medical tourism differ, with the most common being cost, availability of new or experimental procedures, or decreased waiting times [33]. Many foreign hospitals court medical tourists, and the industry has grown rapidly. Quality of care in these hospitals can differ widely, with some developing expertise in advanced procedures whereas others provide sub-standard outcomes with little recourse for patients who develop complications [34]. Accreditation, monitoring, and infection control practices may be lacking, leading to a risk of hospital-acquired infection that is two- to 20-fold higher in LMICs than in high-income countries [15]. As an example, in January 2019, the CDC issued a Level 2 Travel Alert warning of surgical site infections caused by carbapenem-resistant Pseudomonas aeruginosa among U.S. residents who underwent surgery in Tijuana, Mexico. Most cases arose in patients who had bariatric surgery, and more than half of the reported cases were from a single Tijuana hospital [35]. Many of these patients subsequently required treatment in the United States for their infectious complications, bringing back resistant organisms and risking further person-to-person transmission. Additional cases of resistant organisms spreading between countries via medical tourism include rapidly growing Mycobacterium infections, MDR Enterobacter cloacae and Klebsiella pneumoniae, NDM-1-positive E. coli, and multiple carbapenem-resistant bacterial species [36 –41].

Rogers et al. reviewed risk factors for infection and colonization with MDR bacteria in medical tourists and aeromedical evacuees, identifying variable infection control and antibiotic use practices, procedures in unlicensed settings, transport through multiple facilities, and language barriers limiting information exchange [42]. Patient-specific factors such as traumatic injury, need for intensive care, and procedures requiring immunosuppression may also play a role in the spread of resistant infection.

Immigration, emigration, and the rising number of international refugees are also potential vectors of resistant organism transfer between countries. The International Labour Organization estimates that as of 2017 there were 258 million migrants worldwide, including 164 million migrant workers, with both groups increasing in number since 2015 [43]. Of these, approximately 32% of all migrants come from LMICs; though in immigrant workers this rises to >80%. Worldwide international refugee numbers also continue to increase, rising 2.8 million people in 2018 to an estimate of 25.9 million total worldwide [44]. The majority of refugees shelter in a neighboring country, although a small percentage travel farther from home. This massive global movement of people offers a continuing opportunity for transportation of resistant organisms. Both MDR malaria and tuberculosis are well documented in migrant and refugee populations [45 –49], with bidirectional spread between high-income countries and LMICs [50]. The AMR in other bacteria is less well studied, with data being primarily observational. However, a meta-analysis by Nellums et al. identified a reported pooled prevalence of AMR carriage or infection as high as 25.4% in migrants to Europe [51]. Rates tended to be higher in refugees and asylum seekers. Those investigators reported little evidence for high rates of transmission of AMR organisms to host populations, although the availability of these data in the studies evaluated likely is lacking. Conversely, Maltezou et al. have argued for routine screening of refugees for MDR organism carriage as a form of infection control [52,53]. Migration as a cause of international travel-related spread of resistance would benefit from further research to help determine optimal future surveillance and patient care.

Finally, international border regions represent a unique micro-environment in which to study antibiotic resistance and organism movement. Close proximity removes most if not all geographic factors influencing organism prevalence, leaving socio-economic factors such as sanitation, healthcare policy, prescription requirements, infection control practices, and antibiotic stewardship as the main drivers of differing prevalence patterns. These patterns may be muddled based on the porosity of the border; however, as high rates of cross-border traffic increase the theoretical risk of spread of resistant organisms. How frequently these organisms take hold within new communities or healthcare facilities is an area of ongoing investigation. Border region transmission is perhaps best studied in malaria and tuberculosis, particularly in endemic areas of Southeast Asia and Africa. Different policies and abilities to treat infections in neighboring countries alter the evolution of drug resistance, contribute to introduction or re-introduction into low-prevalence areas, and increase the numbers of patients with treatment interruptions or loss to follow-up [54 –57].

Cross-border transmission and resistance rates of other bacteria have been less well studied. Most research centers on the lengthy border between the United States and Mexico, where traffic is restricted but still frequent—the San Ysidro Land Port of Entry between San Diego, California, and Tijuana, Mexico, is the busiest land port of entry in the Western Hemisphere, with approximately 90,000 northbound travelers daily [58]. Many border communities include those who cross daily for work or school. Benoit et al. [59] and the CDC analyzed microbial data from eight U.S. hospitals along the border, focusing on common pathogens. After analyzing >140,000 clinical isolates, they identified resistance rates that differed by site, specimen, and hospital location, with the highest rates found for S. aureus (45.7% oxacillin resistance), P. aeruginosa (22.3% quinolone resistance), and E. coli (15.6% quinolone resistance). More than half of the antimicrobial–pathogen combinations studied showed increasing rates of resistance over the study time period. Notably, the rate of quinolone-resistant E. coli was significantly higher in these border region hospitals than reported for the country overall, raising the concern that this may be attributable to the influence of cross-border transmission.

Further evidence of high rates of cross-border transmission of resistant gram-negative organisms was demonstrated in a recent study evaluating trauma patients treated in Mexico prior to presenting in the United States [60]. Although this paper identified a higher rate of gram-negative infections in patients treated exclusively in the U.S., rates of resistance among those infections were significantly higher in patients who had been treated previously in Mexico (42.3% Mexico versus 9.6% United States). Overall, AMR was also higher in patients from Mexico at 26.9% of all infections versus 7.1% in patients from the United States. Most strikingly, MDR Klebsiella infections were found only in patients previously treated in Mexico (55.6% of all Klebsiella infections), with no resistant Klebsiella in patients treated only in the United States. When gram-negative organisms were evaluated for resistance to specific antibiotics, those from both countries remained sensitive to carbapenems, whereas organisms from Mexico demonstrated significantly lower sensitivity to ceftriaxone, cefepime, gentamicin, and piperacillin-tazobactam. These results are similar to those of the SENTRY Antimicrobial Surveillance Program, which also found high rates of resistance among gram-negative bacilli in Latin America, including Mexico [61]. This included MDR phenotypes in 24.7% of E. coli and 52.7% of Klebsiella spp. Gram-negative bacilli also accounted for a significantly higher proportion of infections in Latin American than in similar studies in the United States and Canada, and the authors raised the concern that infections in these regions may best be treated by combination empiric antimicrobial therapy rather than single agents.

Conversely, rates of S. aureus resistance often are higher on the U.S. side of the border. Rivera et al. compared rates of MRSA in El Paso, Texas, and Ciudad Juarez, Mexico, finding significantly higher rates in the United States (44.3% vs. 7.8% in Mexico)[62]. The S. aureus isolates from the United States also showed significantly higher resistance to an additional six antibiotics; no specific resistance pattern was more common in the Mexican patients. In investigating the potential etiology of these strains, Rivera et al. concluded that 35% of the resistance patterns seen in the U.S. patients were consistent with community-acquired MRSA, whereas no community-acquired strains were detected in Mexico. It is possible that this represents a difference in patients tested, particularly as other studies in Latin America have shown much higher rates of MRSA [60,63], or this may reflect differing community antibiotic use. Differences in MRSA rates also have been identified in the Dutch–German–Belgian border region in Europe [64,65].

Future Directions

The source of antimicrobial resistance and how it spreads throughout a population are continuing research questions that may be partially answered in the future by whole-genome sequencing (WGS). This is a relatively new technique that can be used to analyze individual strains of resistant organisms and categorize them by clonal group, allowing investigators to track the source of infections and the spread of resistance genes. In the setting of infection control this analysis can be critical, as WGS can determine whether specific pathogens are being spread within a hospital or community or instead are separate strains coming in from an outside source. These differing sources of transmission require distinct infection control interventions for containment; thus, identification of organism source can be critical to limiting the impact of resistant organisms in patients. Thus far, use of WGS in LMICs has been limited primarily to the study of infections such as tuberculosis, malaria, cholera, and viral diseases [66 –69]. There is minimal literature thus far on more typical bacterial infections such as pneumonia, urinary tract infections, or bacteremia; the only surgery-specific study identified used WGS to analyze organism source but did not evaluate antimicrobial resistance [70].

The known discrepant rates of AMR between LMICs and high-income countries, and the ability of resistance factors to spread from one area to another, again raises the question of the scope of surveillance for AMR organisms. In 2010, France published guidelines for the screening of French citizens repatriated from foreign hospitals as well as travelers who had been hospitalized in a foreign country within the past year, focusing specifically on controlling the spread of carbapenemase-producing Enterobacteriaceae and vancomycin-resistant Enterococcus [71]. These extensive guidelines include screening patients for asymptomatic carriage of these organisms in the gastrointestinal tract and recommend contact isolation precautions until the results are obtained. Québec has implemented similar methods [72], while the Dutch have a longer-standing policy with surveillance for multiple organisms in ICU patients treated in a foreign hospital within the last two months who have open wounds or are undergoing invasive procedures [73]. Each of these policies covers surveillance of potentially asymptomatic carriers; whether isolation of these patients is necessary to prevent organism spread is unclear. Additional unanswered questions include which organisms to screen for and what patient risk factors should trigger screening—length of time since foreign hospital contact, whether invasive procedures were performed, patient co-morbidities, etc. are all potential risk factors. Wide-spread screening may be nearly impossible in border regions with high volumes of back and forth patient traffic [60]. Kaspar et al. evaluated a MDR organism surveillance program in Switzerland and concluded that >80% of patients transferred to Swiss hospitals from high-risk areas were screened unnecessarily; they instead recommend more limited screening based on identifiable risk factors [28]. Ultimately, the appropriate level of surveillance for each facility likely will differ on the basis of the number of patients coming in from areas of concern as well as what infections are prevalent in both regions; thus, targets also will vary over time. This can be addressed only with active and responsive infection control programs within each facility or region.

Conclusions

The threat of antimicrobial resistance continues to grow worldwide, exacerbated by poor antibiotic stewardship practices, limited development of new antimicrobial agents, and increasing globalization. Human movement, including travel, medical tourism, military service, and migration contribute to the worldwide spread of resistant organisms between high-income countries and LMICs. Increased surveillance, WGS, and focused infection control and stewardship practices are needed to maintain the efficacy of antibiotics.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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