Prevalence of multidrug-resistant organisms in refugee patients, medical tourists and domestic patients admitted to a German university hospital

Background Patients with contact to healthcare-system in high-prevalence countries (HPC) and refugee patients in hospital settings (REF) have previously been identified to be at risk of carrying multidrug-resistant organisms (MDRO). Comparative studies addressing the epidemiology of MDRO in patients transferred from hospitals abroad (ABROAD) and REF are lacking but are necessary to introduce refined infection control measures. Methods From December 2015 to June 2016, 117 REF, 84 ABROAD and 495 patients admitted to intensive care unit, with no refugee history or pre-treatment abroad (ICU), at University Hospital Frankfurt, Germany (UHF) were screened for MDRO on day of admittance. Data within these groups were compared and set in an epidemiological context. Results 52.1% (95% confidence interval = 42.7-61.5) of REF and 41.6% (31.0-52.9) of ABROAD, were positive for at least one MDRGN, respectively. In contrast, 7.9% (5.6-10.6) of ICU were positive for MDRGN. Thereof, 0.9% (0.0-4.7) of REF, 15.5% (8.5-25.0) of ABROAD and 0% (0.0-0.7) of ICU were positive for at least one MDRGN with carbapenem resistance (CR). In total, 19 MDRGN with CR were detected in ABROAD, with the most frequent species with CR being A. baumannii with 42.1% (20.3-66.5). Regarding MRSA, 10.3% (5.4-17.2) of REF, 5.9% (1.9-13.3) of ABROAD and a significantly lower proportion 1.4% (0.6-2.9) of ICU, respectively, were tested positive. Conclusions Both REF and ABROAD pose a relevant hospital hygiene risk. High prevalence of MDRGN with CR in ABROAD was observed. Concise screening and infection control guidelines are needed in patient cohorts with increased risk for MDRO carriage.


Background
Traveling to high-prevalence countries (HPC) for multidrug-resistant organisms (MDRO), such as multidrugresistant Enterobacteriaceae and Acinetobacter baumannii (MDRGN) and methicillin-resistant Staphylococcus aureus (MRSA), as well as contact with the local healthcare-system in HPC have previously been identified as risk factors to for acquiring MDRO [1][2][3][4][5][6][7][8][9]. UHF is located in the direct vicinity of the Frankfurt international airport which processes almost 60 million passengers per year [10]. German residents returning after pre-treatment in healthcare-system in HPC, medical travelers seeking healthcare in Germany as well as travelers who experience medical problems during transit represent a relevant number of patients admitted to UHF.
Refugee patients' countries of origin (COO) have previously been described as HPCs [11][12][13]. Since 2015, refugee influx to Germany has been high [12]. Concise hygiene management strategies therefore are required not only for refugees (REF) [11], but also for patients admitted from health-care systems abroad (ABROAD). Since the first study addressing the prevalence of multidrug-resistant organisms (MDRO) in refugee patients in hospital settings has been published in January 2016 [11], wide-ranging experiences in management of REF in European hospitals have been achieved. However, apart from a recent Dutch investigation [13], further data on MDRO in REF are available only to limited degree. This study therefore addresses the epidemiology of MDRO in refugee patients compared to patients after pre-treatment in hospitals abroad admitted to UHF between December 2015 and June 2016. Furthermore, these data were compared to the epidemiology of MDRO of residents, without any history of fleeing or pretreatment abroad, within the same period. These data are needed to highlight challenges in terms of hospital hygiene and the need for specific demands on infection control and hospital hygiene.

Patients and specimens
We retrospectively evaluated data of 117 patients admitted from refugee accommodations (REF) to UHF between December 2015 and June 2016. All REF were systematically screened via rectal and nasal swabs for MDRO, i.e. MRSA and MDRGN. MDRGN are defined as Enterobacteriaceae with extended spectrum beta-lactamase (ESBL)phenotype as well as Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii resistant against Piperacillin, any 3 rd /4 th generation cephalosporin, and fluoroquinolones. MDRGN with additional resistance to carbapenems (CR) are assigned to "MDRGN with CR". This approach is according to the hygiene plan of the University Hospital Frankfurt (UHF) and has previously been described [11]. In addition, 84 patients admitted from abroad (ABROAD), e.g. foreigners admitted to UHF for reasons of medical tourism or resident patients admitted to UHF for further treatment after initial treatment in foreign hospitals were screened for MDRO during the observational period. However, due to language difficulties in patient anamnesis, data concerning details (length of stay in hospitals abroad etc.) could not systematically be explored. We furthermore evaluated the MDRO prevalence among 495 German resident patients without refugee history or documented pre-treatment abroad, admitted to a intensive care unit (ICU) at UHF. Patients admitted for follow-up treatment from abroad or with refugee history were excluded from this ICU cohort.
We furthermore assume that vascular and thoracic surgery patients are more likely patients with long-term hospital history compared to traumatology patients (injured by e.g. road accidents). We therefore additionally investigated the MDRGN prevalence in surgical subgroup.

Group ascertainment for REF and ABROAD
Subjects were fully assessed and assigned to groups according to several aspects. Distinguishability was covered by several aspects: first, we examined the patient data files for records of hospital stays abroad, residential status in a refugee accommodation, or records indicating a history of refugee status. We then investigated differences in funding of healthcare services also helped to distinguish patients into ABROAD and REF groups; German patients admitted from abroad are more likely to have health insurance whereas non-German patients from abroad (without refugee status) more commonly pay directly for services.

Infection control measurements
According to German infection protection law ("Infektionsschutzgesetz") it is mandatory for hospitals to execute a documented infection control strategy intended to prevent the transmission of infective agents and their potential harmful consequences on patients' health. At UHF, all patients admitted from hospitals in HPC or arriving from refugee accommodations are pre-emptively isolated and screened for MDRO on day of admission. Screening procedure also applies to patients without history of pretreatment abroad or refugee status admitted to an intensive care unit (ICU). Immediately after negative results for MDRGN and MRSA are available, patients are released from isolation. In case of a positive MDRGN and/or MRSA result, patients will remain in isolation during their entire stay at UHF to prevent MDRO transmission, as previously described [11].

Detection of MRSA and determination of spa type
For the detection of MRSA, nasal swabs were inoculated on Brilliance MRSA Agar (Oxoid, Wesel, Germany). Identification of MRSA was done by MALDI-TOF and antibiotic susceptibility testing according to CLSI guidelines using VITEK 2. Clonal identity of MRSA isolates was analyzed by staphylococcal protein A (spa) typing using the Ridom StaphType software (Ridom GmbH, Würzburg, Germany) [17].

Statistical analysis
Chi squared test was performed for statistical analysis. 95% confidence intervals (95% CI) for frequencies were calculated based on binomial distribution and used to confirm statistical significance. P-value calculations were not used to evaluate statistical significance as it has been criticized for low reliability [18].

Results
Between  Table 2.
Furthermore, we found a low prevalence of MDRGN in the REF, ABROAD and ICU surgical group (Table 2). In particular, in the traumatology ICU group, the prevalence of MDRGN was lowest with 4.3% (0.9-12.2).

Discussion
The rapid global spread of MDRO is a serious global health risk and must direct attention to the development of effective strategies to prevent the spread of antibiotic    spa types (n) t304 (2) t4892 (2) t044 (1) t131 (1) t311 (1) t003 (1) t217 (1) t325 (1) t020 (2) t003 (1) t223 (1) resistances and life-threatening infections caused by MDRO. Diligent prevention strategies of MDRO transmission in hospital settings should therefore be the focus of preventive efforts. Traveling to HPC, medical tourism, contact to local health care systems as well as history of refugee status have previously been identified as risk factors for carrying MDRO [1-11, 19, 20]. The objective of our study was to give a firm insight into the epidemiology of MDRO in refugee patients (REF), patients admitted from abroad (ABROAD) and German resident patients admitted to a intensive care unit at UHF (ICU). The major strength of our investigation is the direct comparison of these three groups as this issue for our knowledge has not been addressed in scientific literature so far.
No significant difference in the overall prevalence of MDRGN between REF and ABROAD was found, the prevalence of MDRGN with CR in ABROAD (15.5%), however, significantly exceeded the prevalence in REF (0.9%) by 17-fold (Table 2). This phenomenon might reflect an inherent risk to acquire highly resistant MDRGN in hospitals in HPC, from which the majority of ABROAD are admitted from to UHF, such as e.g. Turkey, Egypt, Ethiopia or Somalia (Table 1). For repatriates, this aspect has previously also been mentioned by Josseaume et al. [8]. Considering that conditions under which refugees make their way to Germany might have been poor, we hypothesize that refugees in good health condition are more likely to make the journey than refugees suffering from severe disease or disability and with a strong history of hospital treatment in their country of origin. We however cannot quantify the level of contact REF have had with their local health care system, which therefore might be a source of bias in our setting. In a future setting, it therefore might be interesting to evaluate the MDRO prevalence in refugees without any contact to their local health care system compared to refugees without.
Our data thus indicate, that ABROAD are more likely to represent the prevalence of highly resistant bacteria in hospitals abroad, whereas REF are more likely to portray the general prevalence of highly resistant bacteria in their COO. Furthermore, this finding is additionally underlined by previous findings showing a high prevalence of A. baumannii with CR in hospitals in Syria and Iran [21][22][23][24].
However, due to language barriers, data regarding e.g. exact previous medical treatment or length of stay in the hospitals abroad was available only in a minority of REF patients as well as a low number of ABROAD patients. This aspect could be interesting to evaluate the timeframe that MDRO might be acquired within in hospitals abroad. Moreover, exact phylogeny analysis of isolated resistant strains (e.g., via NGS techniques) was not performed which might have demonstrated a potential clonal spread of resistant pathogens in some particular countries of patients from ABROAD.
In the traumatology ICU group we found a MDRGN prevalence of 4.3% (0.9-12.2), which is in the range of general German population's MDRGN prevalence [25].

Conclusions
In summary, our findings demonstrate a significant and inherent risk for REF and ABROAD to carry MDRGN and MRSA. While it is hardly possible to predict whether these MDRGN and MRSA strains will have evolutionary advantage in German population or in German hospitals, this investigation revealed the indispensability of screening programs and appropriate hygiene measurements in refugee patients as well as in patients pretreated in hospitals abroad. In particular, the overwhelming high proportion of MDRGN with CR in patients after pre-treatment in hospitals abroad should be considered by domestic healthcare systems. Therefore, this risk must be covered by adequate hospital infection control measurements. Based on our findings, we feel a strong need to implement a concise screening procedure for patients arriving from abroad as well as refugee patients. This should also include German residents after pre-treatment in hospitals abroad. We therefore suggest screening for MDRO on day of admittance as well as pre-emptive isolation for both groups.