Antibiotic-resistant pathogens in different patient settings and identification of surveillance gaps in Switzerland – a systematic review

The prevalence of antimicrobial resistance (AMR) varies significantly among different patient populations. We aimed to summarise AMR prevalence data from screening studies in different patient settings in Switzerland and to identify surveillance gaps. We performed a systematic review, searching Pubmed, MEDLINE, Embase (01/2000–05/2017) and conference proceedings for Swiss studies reporting on carbapenemase-producing Enterobacteriaceae (CPE), extended-spectrum beta-lactamases (ESBL), mobilised colistin-resistance, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) within different patient settings. We identified 2345 references and included 46 studies. For acute care patients, most screening data come from admission screenings, whereas AMR prevalence among hospitalised patients is largely unknown. Universal admission screenings showed ESBL-prevalences of 5–8% and MRSA-prevalences of 2–5%. For targeted screening, ESBL-prevalence ranged from 14–21%; MRSA-prevalence from 1–4%. For refugees, high ESBL (9–24%) and MRSA (16–24%) carriage rates were reported; returning travellers were frequently (68–80%) colonised with ESBL. Screening data for other pathogens, long-term care facility (LTCF) residents and pediatric populations were scarce. This review confirms high ESBL- and MRSA-carriage rates for risk populations in Switzerland. Emerging pathogens (CPE and VRE) and certain populations (inpatients, LTCF residents and children) are understudied. We encourage epidemiologists and public health authorities to consider these findings in the planning of future surveillance studies.


Introduction
According to the World Health Organisation antimicrobial resistance (AMR) is one of the most concerning threats to modern medicine [1]. Surveillance has been formulated by the Centers for Disease Control and Prevention (CDC) as one of the four core actions among public health strategies against AMR [2]. Both national and international AMR surveillance programs are mainly based on phenotypic resistance data of bacterial isolates from clinical routine, without detailed information on patient characteristics or patient setting [3,4]. However, AMR prevalence varies considerably between different patient populations, a fact which is not adequately represented in current surveillance systems. Examples for high-risk populations include patients transferred from abroad or residents of long-term care facilities (LTCF) [5,6]. These high-risk groups could potentially act as reservoir for the distribution and spread of AMR within healthcare networks [7].
Knowing the prevalence of AMR among these populations might not only aid clinicians in their choice of empirical antibiotic treatment, but also support infection control specialists in prioritising prevention measures or guide public health authorities in planning future screening studies. In this systematic review, we aimed to summarise patient screening data for the most important antibiotic resistant pathogens within different patient settings in Switzerland, to identify screening gaps and to interpret these findings in the context of resistance data from neighbouring countries.

Aims
The primary study aims were (i) to summarise prevalence data on antibiotic resistance from studies performed in different patient settings in Switzerland between the year 2000 and 2017 and (ii) to identify gaps in surveillance for important patient populations. We focussed on studies reporting on carbapenemaseproducing Enterobacteriaceae (CPE), extended-spectrum β-lactamase (ESBL)-producing or extended-spectrum cephalosporin resistant (ESC-R) Enterobacteriaceae, pathogens harbouring the mobilised colistin resistance (MCR)-gene, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). These five resistant pathogen groups (subsequently simply called pathogens)accounting for almost two thirds of deaths caused by AMR in the USwere chosen based on their presumed importance for Switzerland [2].
The following settings are defined: acute/intensive care (i.e. universal and targeted admission screenings, other screenings), outpatients, LTCF and specific risk groups (i.e. refugees, travellers, people in contact with livestock, intravenous drug users [IVDU] and others). Studies in the paediatric population were analysed separately. This study is being reported according to the PRISMA guidelines [8].

Design and study criteria
We performed a systematic literature search for studies meeting all of the following inclusion criteria: (i) studies (i.e. pointprevalence, cross-sectional and interventional studies, admission screenings, cohort and case-control studies) reporting prevalence data among specific patient populations; (ii) studies performed in Switzerland and (iii) majority of data collected after 1999. Studies on patients of all ages colonised with any of the five pathogen groups of interest at any body site (i.e. any screening method) were included.
The following exclusion criteria were applied: studies not including prevalence data (e.g. comments, reviews or editorials, case reports or outbreak reports without additional screenings); studies reporting AMR prevalence among clinical isolates but not among patients; studies focussing on animal or environmental samples; studies reporting only data on molecular epidemiology and studies including data from other countries, where the Swiss data were not presented separately.
The following microbiologic definitions had to be met:

Results
We identified a total of 791 unique references and 1554 conference abstracts. One-hundred and eighteen records underwent full-text review and 46 records, thereof eight conference abstracts, were included in our review (Fig. 1). A descriptive summary of the available literature by patient setting is given below. Details of included studies, separated by Gram-negative and Gram-positive pathogens, are presented in Tables 1 and 2. For identification of surveillance gaps, studies are plotted in Figure 2, stratified by pathogen, patient setting and time period.
Other screening studies One study from 2005/2006 screened patients before colorectal surgery, whereof 9% were MRSA positive [21]. Another study found a MRSA prevalence of 7% among all discharged patients 2 R. Fulchini et al.   [25]. Screening of nursing home residents in 2010/11 showed a similar prevalence of 9%, with a decreasing trend over time (5% in a follow-up study from 2015) [26,27]. All these studies were performed in the French speaking part of Switzerland.

Outpatients
No CPE carriers were detected in two cross-sectional studies among primary care (2012) and HIV-infected patients (2016) [28,29]. The same studies also assessed ESBL carriage, showing a prevalence of 5% and 7% [28,29]. Two cross-sectional studies looked at MCR prevalence among outpatients. Whereas the one study among HIV patients found 1% to be colonised with an MCR-1 producing E. coli [29], the other study did not identify any cases [30]. Other screening studies among outpatients have shown MRSA prevalence rates of 0% (pregnant women from former Yugoslavia), 1% (dental care patients) and 2% (patients with skin infections) [31][32][33].
Other specific risk groups
People in contact with livestock A dedicated group of Swiss investigators has studied the presence of resistant pathogens among workers of a meat processing factory. In one study, one out of more than 1000 (0.1%) workers was colonised with an OXA-48-producing E. coli (2014), whereas no CPE were detected in a similar study 2 years earlier [38,39]. For ESBL, prevalence was 6% in the same population (2010) [40]; a study from 2016 regarding colonisation with MCR-producers revealed no positive sample [30]. Among pig farmers, no CPE were detected in 2015 whereas ESBL-prevalence was relatively high at 12% [41]. MRSA prevalence among pig farmers was 6.6% in 2008 [42], 0% in 2009 [43] and 12% in 2015 [41]. No MRSA was detected among slaughterhouse workers (2009), whereas 3% and 4% of screened veterinarians were MRSA-positive (2009 and 2012) [42][43][44].

Refugees
Two studies have assessed carriage of resistant pathogens among refugees. One study which screened asylum seekers presenting at a tertiary care hospital (2014/2015) showed an MRSA-prevalence of 21%, whereas ESBL-and CPE-prevalence was 9% and 0%, respectively [16]. Another cross-sectional study (2015)  Result from contact screening, in addition three neonates were involved in the actual outbreak.  [47,48].

Pediatric population
During an outbreak of ESBL-producing Klebsiella pneumoniae in a neonatal intensive care unit 108 patients were screened, whereof six were positive. Unexpectedly, 2% were also positive for OXA-48 producing K. pneumoniae [51]. For MRSA, admission screening of high-risk patients found prevalence rates of 0.1% (2006) and 0% (2014/2015) [52,53]. Another study from 2009 screening hospitalised contacts of pediatric MRSA patients confirmed this very low prevalence [24].

Discussion
We comprehensively summarised the available literature on AMR screening data with regard to different patient settings in Switzerland. Data in this review confirm the high prevalence of ESBL among patients transferred from abroad and returning travellers; refugees are at high risk for both ESBL-and MRSA-carriage. In general, little information is available from LTCFs and the pediatric population; prevalence data on emerging pathogens such as CPE and VRE are scarce. AMR is primarily a concern in acute and intensive care patients due to severe underlying illnesses, antibiotic pre-treatment and medical interventions predisposing for hospital-acquired infections [54][55][56][57]. According to a nation-wide survey in Swiss healthcare facilities, 83% of institutions are currently performing targeted admission screenings for multidrug-resistant pathogens. Considerable heterogeneity exists regarding target populations and screening methods [58]. Data from targeted admission screenings in Switzerland are comparable to numbers in Germany, where similar carriage rates among patients transferred from abroad for resistant Gram-negatives (13% vs. 14-17% in our review) and for MRSA (4% vs. 1-4% in our review) were found [6]. ESBL-prevalence from universal admission screening was 8% in a study included in our review, which is comparable to the 10% prevalence found in a German study [9,59]. One of the most urgent antibiotic resistant threats, coming along with increased morbidity and mortality in infected patients, are CPE [60]. Looking at neighbouring countries, CPE prevalence in acute care settings varies considerably. Prevalence was reported to be as low as 0.1% upon hospital admission in Germany [61] and 0.4% among hospitalised acute care patients in southern France in 2012 [62]. In Italy, 8% of clinical Enterobacteriaceae isolates from inpatients were carbapenem-resistant in 2013 [63]. In Switzerland, according to national laboratory-based surveillance data, absolute numbers of CPE have been increasing in recent years, with OXA-48 being the most commonly reported carbapenemase followed by K. pneumoniae carbapenemase [64]. The fact that only 64% of Swiss healthcare institutions are actually performing targeted CPE admission screenings is worrisome [58]. Except from admission screenings, no prevalence data exist from Swiss acute care hospitals for these primarily nosocomial pathogens. However, modelling studies for the English hospital networks have shown that, because of the high number of patient transfers within the own healthcare network, the absolute risk of CPE introduction is higher for patients transferred within than those transferred from outside these networks, even if the local CPE prevalence is low [65]. In accordance with the conclusions drawn by the authors of this study, we think that further studies are needed to evaluate if CPE emergence in Switzerland is merely due to an increase of imported cases or if patients are increasingly acquiring CPE in Swiss hospitals. Regarding VRE, no screening studies have been published until date of this literature search. Of note, VRE have lately become a pressing issue in Switzerland, with multiple outbreaks having been reported within and between healthcare facilities [66,67]. It remains to be seen if VRE will become endemic in this patient setting as it has for certain regions in Germany [68]. An important finding of our review is the scarcity of resistance data from Swiss LTCFs. This is concerning, because (i) LTCFs have been recognised as highly endemic settings for resistant pathogens already more than two decades ago [5,69] and (ii) a recent laboratory-based study from Swiss LTCFs showed a clear increase in E. coli isolates resistant to extended-spectrum cephalosporins over the last decade [70]. Looking at neighbouring countries, data from LTCFs in Italy show that the prevalence of ESBL-producers and CPE is as high as 64% and 6%, respectively [71,72]. A point prevalence study from 2015 performed in an Austrian LTCF reported a prevalence of 13% for ESBL, whereas no CPE were found [73]. In Germany, data from 2012 among nursing home residents showed a prevalence of 27% for ESBL, 9% for MRSA and 3% for VRE [74]. Only a minority of hospitals in Switzerland are routinely screening patients residing in LTCFs upon hospital admission [58]. Whether this strategy misses a relevant number of patients carrying resistant pathogens is currently unknown.
Similar to our data, a recently published review on AMR among European migrants found a high prevalence of MRSA (8%) and resistant Gram-negative bacteria (27%), concluding that living conditions, access to healthcare and AMR detection should be improved in this high-risk population [75]. In line with our findings, data from Germany suggest that ESBL-colonisation seems to be common among refugees, whereas CPE are rarely detected [76]. Data from other countries as well as a recent review confirm the high prevalence of particularly resistant Gram-negative pathogens among returning travellers [77][78][79][80]. None of the studies in our review performed MRSA screening among returning travellers. However, a multicentre study from different European citiesincluding a Swiss study centrereported an MRSA prevalence of 14% (2019) among returning travellers with skin and soft tissue infections, with Latin America as travel destination being a risk factor for MRSA carriage. A large proportion of these isolates were PVL-producing CA-MRSA [81]. Interestingly, although MRSA rates are generally decreasing in Switzerland [82], the prevalence among pig farmerswho are likely to be colonised with livestock-associated MRSAhas increased between 2009 and 2015. This finding is in line with reports from Germany, showing increasing trends for LA-MRSA while overall MRSA rates are declining [83,84]. Until now, CPE and MCR are not commonly detected in these settings in Switzerland. Again, no data exist for VRE. Studies on AMR screening from the pediatric population are rare in Switzerland. National laboratory-based surveillance data suggest that the prevalence of ESBL and MRSA among clinical isolates is similar to that of the adult population [82,85,86]. Of note, the unexpected finding of two neonates carrying OXA-48-producing K. pneumoniae in Switzerland is worrying and warrants further study [51]. Similar to adult refugees, pediatric refugees are at particular risk of carrying resistant pathogens, as shown recently in two German studies [76,87].
Our study has some limitations. First, the heterogeneity among included studies (e.g. definitions of risk for targeted admission screenings, different screening sites) precluded us from calculating a pooled prevalence or from statistically assessing trends over time. In this context it is particularly important to note that clinical microbiology breakpoints have changed during the observed time period. Second, although we performed a thorough literature search we might have missed studies, especially those only presented as abstracts in conferences which were not on our screening list. Third, some of the most recent publications were only available in an abstract form. Nonetheless, we included these studies as we would have otherwise missed the most recent data in this rapidly changing field.
In conclusion, this review confirms data from other countries showing high prevalence of ESBL-carriage among patients transferred from abroad and returning travellers; refugees are at risk for both ESBL and MRSA. There is a scarcity of AMR prevalence data from Swiss LTCFs and the pediatric population. Also, screening data are generally scarce for emerging pathogens such as CPE or VRE, which often spread within and between acute care facilities. We encourage epidemiologists and public health authorities to consider these gaps in the planning of future surveillance studies.
Supplementary material. The supplementary material for this article can be found at https://doi.org/10.1017/S0950268819001523.