Travel to Asia is a strong predictor for carriage of cephalosporin resistant E. coli and Klebsiella spp. but does not explain everything; prevalence study at a Norwegian hospital 2014–2016

Escherichia coli and other Enterobacteriaceae frequently cause nosocomial and community acquired infections [1] and the burden due to infection with Enterobacteriaceae resistant to extended-spectrum cephalosporins (ESC) is increasing worldwide [2]. Infections are often preceded by colonisation of the gut with these bacteria. Among Enterobacteriaceae, resistance to ESC is often caused by production of extended-spectrum beta-lactamases (ESBLs) or plasmid mediated AmpC (pAmpC) [2]. In a hospital setting, carriage of Enterobacteriaceae resistant to ESC (ESCr-E) is not only a concern for the individual patient, but also for the surrounding patients as these bacteria can spread via the faecal-oral route between patients within the hospital [3]. In addition, plasmids conferring ESC resistance can be transferred between different bacterial strains and species. Outbreaks of ESBL-producing E. coli and Klebsiella spp. have been reported in healthcare institutions in Norway [4–6]. Yet another concern is that ESC-resistance often occurs along with co-resistance to important non-beta-lactam antibiotic classes [7], significantly limiting treatment options for these patients.

Enterobacteriaceae are part of the normal gut flora and pose a complex challenge as eradication is problematic [8]. If introduced within a hospital, infection prevention and control rely on strict compliance to standard precautions [3, 9]. The Norwegian Institute of Public Health (NIPH) recommends isolation of patients in general hospital wards if they carry carbapenemase producing Enterobacteriaceae or vancomycin resistant enterococci. Patients who carry ESC resistant Enterobacteriaceae should be isolated if admitted to departments with particularly vulnerable patients (neonatal, cancer or intensive care units) [10]. Even though the Nordic countries have a low prevalence of antimicrobial resistance among Enterobacteriaceae, resistance to ESC in E. coli and Klebsiella ssp in urine and blood specimens is increasing [11]. In order to better target interventions to prevent spread between patients and to guide empirical antibiotic treatment we aimed to estimate the prevalence of faecal carriage of ESC resistant E. coli and K. pneumoniae (ESCr-EK) and vancomycin resistant enterococci (VRE) in patients upon hospital admission, and to identify factors associated with carriage. Additionally we aimed to explore the diversity of ESCr-EK and determine the genetic background for resistance to ESC.

In this study, including 747 patients from two emergency departments and three surgical units, we found no E.coli or Klebsiella spp. resistant to carbapenems, and no vancomycin resistant enterococci. The prevalence of colonisation of ESCr-EK upon admission was 6.0%. A major predictor for colonisation was travel to Asia. However, the majority of colonised patients had not been to Asia 12 months prior to admission.

The observed prevalence of ESCr-EK (6.0%) and ESBL-EK colonisation (5.6%) at admission was in the same range but lower than reported in similar studies from Germany (7.5–9.5%) [15], the Netherlands (8.2%) [16], and Israel (10.8%) [17] and slightly higher than previously reported in healthy individuals in Sweden (4.7%) [18] and Norway (4.9%) [19]. Varying methods and definitions challenge direct comparison between studies and this may, at least in part, explain these differences between countries. Other explanations may be differences in age, ethnicity, co-morbidity, previous hospital admissions or a true lower prevalence upon admission in the Norwegian population compared to the prevalence in the Netherlands, Germany or Israel. To our knowledge, there has been no previous Norwegian studies of ESBL prevalence in patients at admittance to hospital.

Self-reported use of antibiotics has been found to be a risk factor for ESC-E colonisation at admission in Germany [15]. We could not confirm this finding, nor could studies from the Netherlands [16] and Sweden [18]. Differing antibiotic-prescription policies may be one explanation for this. It was not possible to perform stratified analyses on antibiotics class as one third of participants who had used antibiotics 12 months prior to the admission did not indicate which class.

Consistent with other studies, visiting Asia within 12 months prior to faecal sampling, was associated with ESCr-EK colonisation (PR 6.8, p < 0.001). Prevalence ranging from 13 to 45% has been found in Swedish [18, 20] and Danish [21] travellers to Asia. In accordance with our study, none of these studies found carbapenem-resistant Enterobacteriaceae. However, the methods we used were not optimised to detect carbapenemases like OXA-48, which do not also confer resistance to cefotaxime or ceftazidime. The higher prevalence in patients who had travelled to Asia is also consistent with results from prevalence studies from Asia (Pakistan [22], Thailand [23–25], Turkey [26]) on different populations and types of specimens, where a prevalence of up to 40–77% has been reported even in healthy adults and food products.

This study covers a convenience sample of a population utilizing the hospital. We recruited patients from two emergency departments and three elective surgery units, and a wide range of ages from infancy to elderly patients. It was not practically feasible to recruit critically ill patients admitted to intensive care units in the hospital. Hence, we do not describe the prevalence of ESCr-EK in units with patients at the higher risk for a severe outcome if colonised with resistant bacteria. The prevalence tended to be higher amongst patients who reported having received health care outside of the Nordic countries. However, there were not enough patients in this category to give sufficient power to quantify a difference. The data collected was not detailed to a level allowing for stratification on type of health care (hospital admission, dental care, primary health care, etc.).

The genetic mechanisms behind ESC resistance was mainly ESBL production due to bla_CTX-M. Only two ESCr-EK could not be explained by ESBL or pAmpC production. We found a large diversity of MLSTs in the 45 patients carrying ESCr-EK, making comparison with previous findings challenging. Sixteen different MLSTs were found in patients who had travelled to Asia, nine of these were found in travellers who had only been in Asia. However, many of these MLSTs represent well-known clones that have been found in various sources in several countries, including in Norway [7]. The dominant ESBL allele was bla_CTX-M-15 which has emerged and disseminated worldwide [27] and has previously been found in travellers returning from all over the world [20], and in environmental samples from our area [7]. The ESBL allele bla_CTX-M-55 has been found to be one of the most commonly encountered ESBL-encoding genes in Enterobacteriaceae from food animals in China and has also been found in food animals in Europe together with other CTX-M types [28, 29] suggesting the potential importance of animal-to-human spread via contaminated food [20].

In our study, travel to Asia was primarily to Thailand and Pakistan. We expect that travel to other high endemic areas in Asia like India, or to Africa as found in other studies [18, 20], might also be a risk factor for colonisation as also indicated in our study. All the ESCr-EK isolates from patients who had travelled to Asia were multidrug resistant.

Urinary tract infections and bacteraemia are often preceded by colonisation of the gut [17, 30]. As more than one third of patients who had travelled to Asia within the last 12 months carried ESCr-EK, we would recommend that these patients receive empiric antimicrobial treatment effective against ESCr-EK if they present with signs of serious infections of possible Gram-negative origin. According to findings in several studies, and repeated here, ESCr-EK are often multidrug resistant, and carbapenems is probably the safest choice for empirical treatment [31]. Treatment should always be adjusted and, if possible, de-escalated as soon as culture results are available [32, 33].

Certain ESCr-EK phylogroups or subclones have been linked to increased potential to cause severe infections because of higher virulence [18]. More knowledge of the more virulent phylogroups or subclones and risk factors for colonisation would allow targeted screening/treatment guidelines. As of today, the national guidelines for ESCr-EK infection control and prevention do not differentiate between MLSTs.

The prevalence of colonisation of ESCr-EK upon admission was 6.0%, none of the isolates identified from the patients produced carbapenemases and we did not identify any VRE, supporting other surveillance studies which indicate that carbapenemase-producing E. coli and Klebsiella and VRE are still very uncommon in the Norwegian population [11, 19]. Travel to Asia was a strong predictor for colonisation of ESCr-EK to be considered when administering empiric antimicrobial treatment. Less than one third of the colonised patients had travelled to Asia, and no other factors investigated were found to be strongly associated with carriage. For infection prevention and control, these findings underscore that health care personnel cannot rely solely on risk assessment and screening results but must apply standard infection control precautions for all patients.