Risk of Highly Resistant Bacteria Importation from Repatriates and Travelers Hospitalized in Foreign Countries: About the French Recommendations to Limit Their Spread

The rapid development of transport and communication, environmental exchanges, and migration of populations creates opportunities for the spread of infectious diseases. The emergence and spread of pathogenic and epidemic pathogens is a major emerging phenomenon of the past 30 years. Some species of bacteria have become resistant to multiple antibiotics and, sometimes, to all antibiotics available: multidrug‐resistant bacteria (MDR), extensively drug‐resistant bacteria (XDR), or pan drug‐resistant bacteria (PDR). 1–3 These terminologies have drawn attention to the evolution of multidrug resistance and the potential difficulties in treating bacterial infections now and in the future. 4 The very high levels of resistance that are currently observed result from massive exposure to antibiotics, to which humans and animals have been subjected over the past 50 years. 5 Resistance to antibiotics concerns not only pathogens but also, and probably even more importantly, the commensally bacteria colonizing individuals (humans and animals). These are less easily detected because the carriage is asymptomatic. More than 80 million foreign visitors travel in France each year. In the same period, 19.4 million French peoples travel to foreign countries, more often in Europe. 6 In addition, 1.4 million French peoples live in foreign countries (i.e., 48% Europe, 20% America, 15% Africa, 8.5% in Asia‐Oceania, and 6.6% in the Near and Middle East). 7 The repatriation of French patients from foreign hospitals, but also health care provided to foreigners traveling in France, whatever their nationality, then expose the French population to highly resistant bacteria acquired in high resistance prevalent areas. The risk of the emergence and spread of highly resistant bacteria from migration has been recently evaluated in France because sporadic or limited epidemic situations have occurred in the recent past with pathogens such as Clostridium difficile ribotype 027, 8,9 carbapenemase‐producing Enterobacteriaceae (CPE), 10–12 vancomycin‐resistant Enterococcus (VRE), 13,14 or multidrug‐resistant Acinetobacter baumannii.15 French guidelines to control the hospital spread of CPE and VRE from patients repatriated and travelers hospitalized in French hospitals were published in August 2010. 16 They are so far available in French only but an official translation into English is under consideration. This article reviews the highly resistant bacteria at risk of importation from high prevalence foreign countries, having only spread to France on sporadic or limited epidemic situations, and describes the recent French guidelines to control their spread. The emergence of CPE since the early 1990s is alarming, and carries the risk for therapeutic failures. 17 The carbapenems are now often used for the treatment of severe infections caused by Enterobacteriaceae producing extended‐spectrum β‐lactamases (ESBL). The large increase of ESBL prevalence and the exposure of hospitalized population to carbapenems appear to be a major factor favoring the emergence of carbapenem‐resistant bacteria via selective pressure, particularly in Klebsiella pneumoniae species, also in other species such as Escherichia coli. 18 Resistance is due to carbapenemases, of which there are three types: K pneumoniae carbapenemases (KPC), metallo‐β‐lactamases, and oxacillinases. 19 The production of metallo‐β‐lactamases has mostly been associated with Pseudomonas aeruginosa and Acinetobacter spp. and is rare in Enterobacteriaceae, except in isolates from Mediterranean Europe. 20 New Delhi metallo‐β‐lactamase (NDM) 1 was identified in K pneumoniae and E coli recovered from a Swedish patient who was admitted in a hospital in New Delhi, India. 21 The first CPE strain described was a Klebsiella isolate recovered in North Carolina, United States in 1996, and the enzyme was called KPC‐1. 22 Subsequently, other KPC‐type enzymes have been described throughout the United States (KPC‐2 to KPC‐7) by sporadic or epidemic spread. 23 The first outbreak of KPC outside the United States was reported in Israel, from passengers and/or patients having traveled between the two countries. 24 Since then, many continents, such as South America and Asia, have reported the emergence of CPE. In Europe, the phenomenon appears to be rare, but CPE strains were isolated sporadically in Sweden, Ireland, UK, 25 and Greece, which currently represents a high prevalence area. 2,26 Most of the CPE episodes observed in France were related to cross‐border transfer, mainly after hospitalization in countries abroad where CPE are endemic. Moreover, the origin of index cases was highly consistent with population migration routes and countries most frequently visited by French tourists. 11,12,27,28 Because OXA‐48 remains difficult to detect, especially when it is not associated with an ESBL, enhanced surveillance and rapid identification are essential to prevent cross‐transmission. 29 The European Antimicrobial Resistance Surveillance System (EARSS) began collecting antimicrobial susceptibility data for invasive K pneumoniae in 2005. 30 In 2008, 12,227 isolates were reported from 31 countries, and for the first time, the EARSS network was able to provide trends in time, as results are available now from the last 4 years. Carbapenem resistance is still absent in most countries (Figure 1). 30 Seven countries reported from 1 to 5% resistance: Bosnia and Herzegovina (3%), Italy (2%), Latvia (3%), Norway (1%,), Portugal (1%), Turkey (3%), and the UK (1%). In three countries, carbapenem resistance is considerably higher: Cyprus (10%), Greece (37%), and Israel (19%). Proportion of carbapenems resistant Klebsiella pneumoniae isolates in participating countries in 2009. 30 In the August 2010 issue of The Lancet Infectious Diseases, Kumarasamy and colleagues provided evidence that NDM‐producing Enterobacteriaceae (mostly K pneumoniae and E coli) are widespread in India and Pakistan. 31 They also identified patients in the UK infected with NDM‐producing bacteria who had recently traveled to India for various types of medical procedures. Since 2008, there has been repeated import of NDM‐1‐positive bacteria from the Indian subcontinent to Europe, the United States, Canada, Asia, and Australasia, which was often mediated via transfers of patients, as well as some direct transmission in Europe and some unaccounted clusters linked to the Balkans. 32,33 Enterococci belong to the resident flora of the gastrointestinal tract of humans. Under normal circumstances, they are harmless commensals and are even believed to have positive effects on a number of gastrointestinal and systemic conditions. Resistance to glycopeptides has emerged first in the United States, and more recently, in Europe. 34 The emergence of VRE in Europe is alarming because of the pan drug‐associated resistance involving difficulties to treat infected patients. Moreover, glycopeptides are one of the last lines of treatment for methicillin‐resistant Staphyloccocus aureus (MRSA) infections and the resistance gene can spread from VRE to MRSA strains. The transmission of this glycopeptides resistance to other bacteria such as MRSA, which is highly pathogenic and widespread, is quite rightly feared. Seven cases of VRSA have already been described in the United States. 35 VRE currently represents over 30% cases of enterococcal infections in the United States 36 despite the publication of guidelines for control of VRE. 37 In Europe, the situation is heterogeneous, as shown by the EARSS network data (Figure 2). 30 Three countries reported resistance rates above 25% (Ireland, Luxembourg, and Greece) and five countries reported resistant rates between 10 and 25%, whereas the majority of countries (18 of 26) reported resistant rates below 10%; rates below 1% were reported from seven countries (Bulgaria, Estonia, Finland, France, Norway, Romania, and Sweden). From 2005 to 2009, a significant decrease in vancomycin resistance was observed in France (from 2 to 0.8%), 38 Greece (from 37 to 27%), and Italy (from 19 to 4%). Greece, in particular, has managed to downsize the very high levels of vancomycin resistance, but still has higher resistance levels than most of the other countries under surveillance. Proportion of vancomycin‐resistant Enterococcus faecium in participating countries in 2009. 30 The prohibition of glycopeptides' derivatives use as growth promoters in animals in Europe since 1997 and the moderate use of vancomycin (particularly as oral formulation) in human medicine in Europe have protected France from VRE high endemic emergence, as only few cases of colonization were reported. However, since 2004, several outbreaks have been reported in French healthcare facilities. 13,14 This emergence seems unpredictable and all institutions may be affected. The rapid implementation of infection control measures, such as outlined in the French guideline published in 2010, remains a key factor to controlling a sporadic case, before a major outbreak occurs. 39,40 The VRE prevalence is actually changing in some European countries, and the risk to move from a sporadic to an endemic situation is real in France from repatriated French people or foreign travelers requiring hospital care. The worldwide spread of multidrug‐resistant A baumannii seems different from other pathogens. It is a saprophytic bacteria that lives mainly in the environment and its epidemiology varies from one country to another and from one institution to another. 41 The species A baumannii is naturally resistant to many antibiotics. Moreover, strains have acquired additional resistance mechanisms using hospital antibiotic selective pressure. Some strains are pan‐resistant to all available antibiotics, exposing patients to therapeutic failures, particularly when resistance to imipenem is present. Acinetobacter baumannii often affects patients in intensive‐care unit and spreads mostly by cross‐transmission, with environmental reservoirs often playing a major role. A multidrug‐resistant A baumannii epidemic spread in non‐ICU area is possible, as it has been observed in several hospitals in Northern France in 2005. 15 Thus, Acinetobacter is an old friend but a new enemy. 42 A large number of European countries have reported outbreaks of imipenem‐resistant A baumannii. 2 Several episodes of imported multidrug‐resistant A baumannii have already been reported in specific situations, such as natural disasters 43 or situations of war, particularly among American and Canadian soldiers repatriated from Afghanistan or Iraq. 44–47 The risk of importation of multidrug‐resistant A baumannii seems difficult to assess because clones carrying genes for resistance are already circulating in France. The French Health Authorities published in 2010 guidelines to limit the spread of highly resistant bacteria. These French guidelines were developed by the members of a national working group, from their experiences and following the international literature. 16 The guidelines target two main commensally MDR, CPE and VRE, that have only been observed in France sporadically, but may spread on a sporadic or epidemic way when introduced in the hospital by carriers needing medical or surgical cares in French hospitals The aims of these guidelines are to control and limit the hospital spread of these two pathogens among (1) repatriated patient hospitalized more than 24 h in foreign hospitals, whatever the medical or surgical wards in high‐level resistance prevalence areas; or (2) among travelers hospitalized in foreign countries within the last year. The CPE culture media recommended in these guidelines are also able to detect other Gram‐negative MDR such as A baumannii and P aeruginosa. However, these media perform rather poorly to detect some bacteria that produce enzymes, which confer only low levels of carbapenem resistance (e.g., OXA‐48). This flaw underlines, however, the urgent needs to make available new generation of tests, most probably molecular that will allow detection of such resistance mechanisms. Even if some countries are well known to present high‐level rates of multidrug resistance, as outlined above, the French guidelines do not provide a list of “suspected” countries, as the epidemiological situation is changing continuously and few countries have no risk of multidrug resistance. These guidelines include six recommendations (1–6) to be taken upon patients' hospital admission and four recommendations (7–10) when the patient is detected positive for CPE or VRE carriage after systematic rectal screening (Table 1). Upon hospital admission of patients at risk of CPE and VRE carriage, the French guidelines recommend to inform the Infection Control Team and the patient about the situation. The best way to detect repatriated patients is through an automatic alert system. During the first 48 h after admission and before the microbiological results of the screening (rectal swab or stool sample) are obtained, it is recommended to put the patient in contact isolation precautions. 48 When CPE or VRE is detected on screening sample, it is recommended (1) to maintain the contact precautions; (2) to identify the mechanism of resistance (e.g., resistance to imipenem: VIM, KPC, OXA‐48); and (3) to alert the French Public Health Authorities for the national Healthcare‐Associated Infections Early Warning and Response System. 12 If control measures have not been implemented upon admission, a systematic screening for CPE or VRE of patients hospitalized in the same ward and cared for by the same personnel is recommended to identify the reservoir and secondary cases that might have developed via cross‐transmission during the time elapsed when the patient was not in contact isolation precautions. If at least one secondary case is detected, all carriers must then be cohorted in a dedicated area and cared for by a dedicated staff. If transferred to another ward or hospital, contact patients must be maintained under control measures in other wards or hospitals and must be screened every week. If remaining in the hospital, control measures must be maintained until three negative rectal swabs for CPE and VRE are obtained. The French Ministry of Health has endorsed and enforced these recommendations through a directive for all hospitals. 49 French guidelines to control the emergence and spread of carbapenemase producing Enterobacteriaceae (CPE) producing carbapenemase and vancomycin‐resistant Enterococcus (VRE) among repatriated patients or travelers hospitalized in foreign countries 16 French guidelines to control the emergence and spread of carbapenemase producing Enterobacteriaceae (CPE) producing carbapenemase and vancomycin‐resistant Enterococcus (VRE) among repatriated patients or travelers hospitalized in foreign countries 16 Over the last 10 years, international health authorities observed the emergence and rapid spread throughout the world of new strains of the influenza virus, C difficile or multidrug‐resistant tuberculosis. 50 The modern transport and increased tourism, business travel, and migration population have contributed to the spread of these pathogens with high epidemic impacts. 51–55 Data on systematic screening of repatriated patients hospitalized in foreign hospitals are scarce and relatively old. 56,57 Fifteen percent 58 to sixty‐four percent 59 of travelers report health complaints during travel, and 5 of 1000 are admitted in foreign hospital during their travels. 58 The global spread of resistance has not escaped this phenomenon. CPE and VRE have increasingly been isolated worldwide. The spread of these highly resistant bacteria is alarming, from a public health point of view, because this species is prone to be the source of many hospital‐acquired infections in severely ill patients, and is well known for its ability to accumulate and transfer resistance determinants as illustrated with ESBLs. Current reports indicate that CPE (mainly KPC‐producing bacteria) 60,61 and VRE 34,36 are widespread in many continents or countries such as Asia, Israel, Greece, South America, Canada, and the United States. Fortunately, in western and northern Europe, CPE and VRE are still rare. So, why worry? Highly resistant and even pan drug‐resistant (i.e., resistant to all available classes) CPE may be the source of therapeutic dead‐ends, because novel anti‐Gram‐negative molecules are not expected in the near future. 62 Careful and conservative use of antibiotics, combined with good infection control practices, is therefore mandatory. 63 Little is known about the repatriates‐ or travelers‐related risk factors other than hospitalization in foreign hospitals, but the description of outbreaks indicates that producer strains seem to benefit from selective advantages in hospitals where antimicrobial use is much higher and opportunities for transmission are more frequent than in the community. 64 In this complex and evolving epidemiological situation, and because France is so far less affected by this phenomena than other countries, the French Health Authorities published guidelines to limit the spread of CPE and VRE in 2010. Choices were made to select the types of patients that should be screened and the types of bacteria that must be sought. The choices are, as always, the result of a compromise between what appeared absolutely necessary and, at the same time, possible. The strategy of the French recommendations is based on the rapid detection and isolation upon admission, in any medical or surgical wards, of repatriates and travelers hospitalized for more than 24 h in foreign countries within the last year. The rapid detection of CPE and VRE digestive carriage will also help to prescribe antibiotic treatment if the patients are infected, even if difficulties are also encountered by laboratories when trying to detect carbapenemase production during routine diagnostic procedures due to an often heterogeneous expression of resistance. To ensure the application of these recommendations by French hospitals, a directive was published recently by the French Ministry of Health. 49 This directive reiterates the control measures to limit or delay the spread of CPE and the need to limit the use of carbapenems. In case of an epidemic spread, control measures adopted in a national program initially designed to contain the spread of VRE 40 must be applied to each outbreak caused by CPE or VRE. This consists in the rapid implementation of a step‐by‐step containment plan within the affected hospital; constant support by local infection control teams, regional experts and health authorities; and feedback to the medical community at the national level. The hospital containment strategy has the following components: (1) stopping transfer of cases and contacts within and between hospitals; (2) cohorting separately case and contact patients with dedicated healthcare workers; (3) screening all contact patients; and (4) continuous vigilance through surveillance. Other countries also recommend strict infection control measures to prevent the further spread of CPE, based on Israeli or US experiences. For example, the Nosocomial Infections Committee of Quebec recently published guidelines to prevent and control the spread of KPC‐producing bacteria in acute healthcare facilities, although no strain of NDM‐1 producing Enterobacteriaceae has been identified in Quebec, and only 14 KPC‐producing isolates have been identified in the past. These recommendations are to the French guidelines and recommend to all patients admitted from a healthcare outside of in last during 24 h or more or from a Canadian hospital with an outbreak situation. 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