Antimicrobial consumption and impact of antimicrobial stewardship

Clinical Microbiology and Infection xxx (2018) 1e8

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Narrative review

Antimicrobial consumption and impact of antimicrobial stewardship programmes in long-term care facilities M. Falcone 1, *, M. Paul 2, D. Yahav 3, G. Orlando 4, G. Tiseo 5, V. Prendki 6, ndez 7, G. Gavazzi 8, N.T. Mutters 9, B. Cookson 10, y, M. Tinelli Marco 11, on R. Güerri-Ferna behalf of the Study Group for Infections in the Elderly (ESGIE) 1)

Division of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Pisa, Italy Infectious Diseases Institute, Rambam Health Care Campus, The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel 3) Infectious Diseases Unit, Rabin Medical Centre, Beilinson Hospital, Petah-Tikva, Israel 4) Clinic of Infectious Diseases, University Hospital, University of Modena and Reggio Emilia, Modena, Italy 5) Department of Internal Medicine and Medical Specialties, “Sapienza” University of Rome, Rome, Italy 6) Internal Medicine and Rehabilitation Unit, Department of Internal Medicine, Rehabilitation and Geriatrics, Geneva University Hospitals and University of Geneva, Geneva, Switzerland 7) noma de Barcelona, Barcelona, Spain Infectious Diseases, Hospital Del Mar Medical Research Institute, Departament de Medicina, Universitat Auto 8) University of Grenoble-Alpes and Clinic of Geriatrics, University Hospital of Grenoble-Alpes, Grenoble, France 9) Institute for Infection Prevention and Hospital Epidemiology, Medical Centre e University of Freiburg, Faculty of Medicine, Freiburg, Germany 10) Division of Infection and Immunity, University College London, Gower Street, London, WCl E 68T, UK 11) Long Term Care Facility “Pio Albergo Trivulzio”, Milan, Italy 2)

a r t i c l e i n f o

a b s t r a c t

Article history: Received 3 June 2018 Received in revised form 13 July 2018 Accepted 19 July 2018 Available online xxx

Background: Antimicrobials are among the most frequently prescribed drugs in long-term care facilities (LTCFs). Implementation of antimicrobial stewardship programmes (ASPs) is often challenging because of scarce data in this setting. Objectives: This narrative review aimed to provide data about antibiotic consumption in LTCFs and the need, implementation, and organization of ASPs in this setting. Source: PubMed was searched for studies assessing antimicrobial consumption and implementation of ASPs in LTCFs. The search was restricted to articles published in English in the last 10 years. Experts belonging to the ESCMID Study Group for Infections in the Elderly (ESGIE) reviewed the selected studies and evaluated the studies on ASPs according to the GRADE approach. Moreover, the quality of reporting has been assessed according to TREND and CONSORT checklists for quasi-experimental and cluster randomized clinical trials (cRCT), respectively. Content: Data on antibiotic consumption in LTCFs show great variability in LTCFs across and within countries. Reasons for this variability are difficult to analyse because of the differences in the types of LTCFs, their organization, and the population cared-for in the different LTCFs. However, studies show that the use of antibiotics among elderly patients in LTCFs, especially in cases of asymptomatic bacteriuria and influenza-like syndromes, is often inappropriate. High-quality cRCTs and low to moderate quality quasiexperimental studies show that educational interventions direct at nurse and physicians are effective in reducing unnecessary antibiotic prescriptions. Implications: There is an urgent need for ASPs tailored for LTCFs. Multifaceted organized educational interventions, involving both clinicians and nursing staff, should be advocated and require institutional intervention by health authorities. Future studies assessing the impact of well-defined ASPs in LTCFs should produce compelling evidence in this setting. M. Falcone, Clin Microbiol Infect 2018;▪:1 © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Editor: L. Leibovici Keywords: Antimicrobial stewardship Elderly Inappropriate antimicrobial therapy Long-term care facilities Multidrug resistance

* Corresponding author. M. Falcone, Division of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Pisa, Italy. E-mail address: [email protected] (M. Falcone). y Present address: External Consultant to the World Health Organization. https://doi.org/10.1016/j.cmi.2018.07.028 1198-743X/© 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Falcone M, et al., Antimicrobial consumption and impact of antimicrobial stewardship programmes in longterm care facilities, Clinical Microbiology and Infection (2018), https://doi.org/10.1016/j.cmi.2018.07.028

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M. Falcone et al. / Clinical Microbiology and Infection xxx (2018) 1e8

Introduction Owing to immunosenescence, comorbidities, and malnutrition, elderly patients are particularly susceptible to infections [1,2]. The increase in the aged population and the need for cost optimization of healthcare systems have led to a rapid rise in the demand for elderly healthcare services [3]. Different types of services that deliver long-term care are widespread in EU countries. These include, home care, assisted living facilities, residential care facilities, nursing homes (NHs), and long-term care facilities (LTCFs), each of which can be organized differently. Differences in languages, healthcare systems (including organizational structures, financing, available resources, and types of services provided), demographic profiles, and cultural practices have created a great variation (the so-called EU ‘puzzle’) in long-term care in Europe [4]. The EU Centre for Disease Prevention and Control (ECDC) estimated the number of residents in LTCFs in the EU to be approximately 3.7 million in 2010; this number will certainly increase in the coming decades [1]. Patients residing in LTCF are often elderly (more than 85% are aged 65 years and older [5,6]) and, in most of cases frail subjects with increasing vulnerability to infectious disease. This increasingly aged LTCF population contributes more and more to the burden of healthcare-associated infections. The most commonly reported infections are urinary tract infections (UTIs), lower respiratory tract infections, including pneumonia, skin and soft tissue infections, and gastroenteritis [7,8]. Infections are among the most frequent causes of transfer to acute care hospitals, and 30day hospital readmissions from LTCF are associated with increased mortality in this population [9]. The burden of multidrug-resistant organisms (MDROs) has also been identified as a key issue in this population, often a consequence of the overuse of antibiotics [10] and poor infection prevention and control practices. It has been observed that LTCF is the major risk factor for multidrug-resistant aetiology in patients with bloodstream infections caused by Gram-negative bacilli [11]. Antimicrobials are among the most frequently prescribed medications in LTCFs and have the second highest rate of adverse drug events following antipsychotic medications [12]. In elderly people, diagnosis of infection is often difficult because of more non-specific clinical manifestations and the inability of people with dementia to describe complaints well. It has been described that up to half of antimicrobial use is either unnecessary or inappropriate in LTCFs, a fact that increases the risk of MDRO and the development of Clostridium difficile infection (CDI) [13e18]. Antimicrobial stewardship programmes (ASPs) are thus urgently needed, but implementation of these and other requirements such as effective infection surveillance prevention and control programmes in LTCFs are often challenging as a result of scarce resources and poor coordination of medical care [19]. Their implementation is made all the more problematic by the lack of evidence-based guidelines regarding appropriate antibiotic use and optimal organization of ASP in LTCF. The aim of this paper is to review the data on antibiotic consumption and existing ASPs in LTCFs and discuss the need, implementation, and organization of ASPs in LCTFs. Methods This narrative review was conducted by a team of experts belonging to the ESCMID Study Group for Infections in the Elderly (ESGIE). The objectives of the review were (1) to provide an updated description of the antimicrobial consumption in LTCFs for the aged; (2) to review the studies that evaluated ASPs in these LTCFs in the last 10 years; (3) to critically judge the level of evidence provided by these studies; (4) to explore the accuracy of adherence

to the reporting guidelines of the studies on ASP. Several types of LTCFs have been described in EU countries (general NHs, specialized LTCFs, residential homes, mixed LTCFs) [6]. The review targeted residential structures dedicated to long-term care, which mainly host elderly patients. The term LTCF and NHs will be used to indicate these types of facilities. A computerized literature search using MEDLINE (National Library of Medicine, Bethesda, MD, USA) was conducted. Index search terms included ‘antimicrobial use’, ‘antimicrobial consumption’, ‘long-term care facilities’, ‘nursing homes’, ‘antimicrobial stewardship’. The search was restricted to full-text articles published in English in the last 10 years. Studies assessing the effects of ASP in LTCF underwent an evaluation of the evidence quality by two independent members. The quality of the studies was classified as high, moderate, low, or very low, according to the GRADE methodology (http://www. gradeworkinggroup.org). In case of disagreement among members, the quality of the paper was judged by a third member of the ESGIE. In addition, for this set of studies, we evaluated adherence to reporting guidelines. Quasi-experimental studies and cluster randomized clinical trials were reviewed according to the TREND and CONSORT checklists, respectively [20,21]. Entries for each item of the TREND and CONSORT statement were categorized as ‘Yes’, if they were completely in agreement with the guidelines statement explanation and elaboration documentation, ‘No’, if this was not satisfied, and ‘Partly’, if evident only in part of the text. Absolute and relative frequencies were used to describe the results of these judgements about the quality of reporting according to the abovementioned statements. Results Antimicrobial consumption in elderly people residing in LTCFs Table 1 summarizes the main findings of the most important studies reporting antibiotic use in LTCFs [21,35]. Two point prevalence surveys (PPSs) have simultaneously compared prevalence of antibiotic prescribing across EU LTCFs: the ESAC-NH [22] and the HALT-2 project [23]. The picture emerging from these surveys is that of extreme variability of antimicrobial prescription across and within countries. Considering, for example, the 2009 ESAC-NH survey, the prevalence of antimicrobial prescriptions ranged from 1.2% in Latvia to 19.4% in Northern Ireland [22] (see Fig. 1). Studies based on PPS showed a median prevalence of antibiotic prescription ranging from 3% (11) to 11% (9), while in retrospective studies the proportion of LTCF residents receiving at least one antibiotic treatment course varied from 44.9% to 77.8% [31,35e37]. A point prevalence survey conducted in 323 NHs across 21 EU countries highlighted that antimicrobials were most frequently prescribed for the prevention or treatment of urinary (49.5%) and respiratory (31.8%) tract infections and a very high proportion of uroprophylaxis (25.6% of all prescribed antimicrobials) was reported [14] In the above-mentioned ESAC survey [22] b-lactams accounted for 45.0% and 42.9% of all defined daily doses (DDDs) per 1000 residents-day prescribed, respectively, while in other studies the most commonly prescribed antibiotics were agents typically used in UTI treatment or prevention such as trimethoprim, nitrofurantoin, and methenamine [24,28,30]. A further study revealed that cephalosporins (30%) and fluoroquinolones (28%) were the most frequently prescribed antibiotic classes in LTCF patients [38]. This large disparity in antibiotic use may be explained by several factors; first, three types of LTCFs can be identified: Type 1 facilities provides medical and nursing care; Type 2 facilities provide nursing assistance but rely on external medical advice (general practitioner or physician are available for consultation but are not present at the



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Table 1 Results of the main study analysing antibiotic prescriptions in LTCFs First author

Country

Design

Setting

Type of LTCFa Study period Variable

Results

Blix HS, 2007 [28] Blix HS, 2010 [29]

Norway Norway

PPS PPS

133 LTCFs 44 LTCFs

Type A Type A

2003 2006

14.8 DDDs/100 bed-day 3%

Rummukainen ML, 2013 [30] Roche FM, 2016 [26]

Finland

ESAC PPS

9 LTCFs

Type A

2009e2010

Ireland

PPS

24 LTCFs

Type B

2013

McClean P, 2012 [24]

Ireland

PPS

30 LTCFs

Type C

2010e2011

Stuart RL, 2012 [38]

Australia

PPS

5 LTCFs

Type C

2011

van Buul LW, 2015 [13] Netherlands Prospective study.

10 LTCFs

Type D

2012

Andersen BA, 2000 [27] Norway

PPS

65e70 LTCFs

Types A, C

1997e1999

Sundvall PD, 2015 [31]

UK

Gillespie D, 2015 [32]

UK

Retrospective Number not specified Types A, C longitudinal cohort study Prospective 10 LTCFs Types A, C, D cohort study

Mean use of antibiotics Median prevalence of antibiotic prescription Prevalence of antimicrobial prescription Median prevalence of antibiotic prescription Median prevalence of antibiotic prescription Prevalence of antibiotic prescription Prevalence of antibiotic prescription in Registered Infection Consultations Median prevalence of antibiotic prescription Percentage of individuals prescribed antibiotics

2010e2012

Incidence of antibiotic prescription

Burns K, 2015 [25]

Ireland

Median prevalence of antibiotic prescription Mean total use of systemic antimicrobials Prevalence of antibiotic use Prevalence of incident antibiotic treatment course Median prevalence of antibiotic prescription

2.16 prescriptions per resident year (95% CI 1.90e2.46) 11.0%/9.7%

Roukens M, 2017 [33] Daneman N, 2011 [34] Daneman N, 2013 [35] Daneman N, 2017 [36]

HALT-1/ HALT-2-PPS Netherlands Retrospective study Canada PPS Canada Retrospective study Canada Retrospective cohort study

2011

69/190 LTCFs

Types A, C, D

2010/2013

96 LTCFs

All types

2012e2014

363 LTCFs 630 LTCFs

All types All types

2009 2010

600 LTCFs

All types

2014

5e30% 7.5% 9.2% 9% 88%

7% 49% (82% with urinary catheter)

73 DDDs/1000 residents-day 5.9% 77.8% 44.9%

DDD, defined daily dose; ESAC, European Surveillance of Antimicrobial Consumption; LTCFs, long-term care facilities; PPS, point-prevalence survey. a LTCFs were classified according to the EU/EEA reports [6]: Type A: general nursing home (a general nursing home is an institution where elderly stay temporarily e long or short e or permanently; the residents in these NHs need medical and/or skilled nursing care and supervision 24 h a day; these LTCFs provide principally care to elderly with severe illnesses or injuries); Type B: specialized LTCFs (specialized in one specific type of care, for example physical impairment, chronic diseases such as multiple sclerosis, dementia, psychiatric illnesses, rehabilitation care, palliative care, intensive care, etc.). Type C: residential homes (residents are unable to live independently; they require supervision and assistance for the activities of daily living; these LTCFs usually include personal care, housekeeping and three meals a day). Type D: mixed LTCFs (these LTCFs provide different types of care in the same LTCFs e a mix of type A, B and C). Type E: other LTCFs (other facilities, not classifiable among the above-mentioned types of LTCFs).

Fig. 1. Variation in prescribing of antimicrobials in nursing homes between and within European countries in April (left) and November (right) 2009 (short horizontal lines correspond to mean values) as described in the ESAC study [22].


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site of care), and Type 3 LTCFs where both medical and nursing care are commissioned. These facilities include people with different levels of functional disability. For example, data from the literature reveals that the percentage of patients with dementia ranges from 13.4% in Hungary to 70e80% in Sweden [39]. Moreover, proportion of deaths among older people in LTCFs varied from no deaths in Albania to 61.1% of deaths in Finland, with the highest proportion of deaths in the higher dependency settings [39]. According to these data, it is very difficult to generalize findings from different countries and institutions. Second, different patterns of organization are present in terms of funding structures, with public, not-for-profit and private institutions varying in prevalence across the countries. The public sector prevails in countries with a strong social model (e.g., Italy, Norway, Sweden, Denmark), while private-forprofit LTCFs are the most common in countries such as United Kingdom, Ireland, and Spain [39]. The use of antibiotics in LTCFs is also influenced by the availability of diagnostic techniques [40]. Qualitative interviews conducted in LTCFs demonstrated that the extent to which physicians' access to diagnostic resources is limited in this setting [41]. The lack of on-site diagnostic resources (e.g., C-reactive protein, X-ray, urine culture), difficulties in consulting the laboratory outside regular work days, and the length of time needed to obtain laboratory culture results contribute to lower accuracy of diagnosis in LTCFs and promote the administration of empiric, instead of targeted, antibiotic therapies [41]. The most common reasons for unnecessary antibiotics in LTCFs are the administration of antimicrobials for asymptomatic bacteriuria or pyuria and treatment of other non-infectious or nonbacterial syndromes [16]. UTIs account for 20e60% of systemic antimicrobials prescribed in LTCFs [42,43]. Achieving optimal management of UTI in this population is problematic because of the high prevalence of asymptomatic bacteriuria and the difficulty in distinguishing UTI from asymptomatic bacteriuria from the healthcare personnel. In a recent 4-year (2010e2014) study patients living in the community were compared with LTCF residents. The latter had a significantly higher rate of developing UTIs caused by E. coli and Klebsiella spp. resistant to trimethoprim (RR ¼ 4.41, 95% CI ¼ 4.25e4.57), nitrofurantoin (RR ¼ 4.38, 95% CI ¼ 3.98e4.83), ciprofloxacin (RR ¼ 5.18, 95% CI ¼ 4.82e5.57), or third-generation cephalosporins (RR ¼ 4.49, 95% CI ¼ 4.08e4.94) [43], probably reflecting the higher exposure to these antibiotics before infection. Another important aspect is the seasonality in antibiotic prescriptions, reflecting the seasonal variation of respiratory infections [44]. In a French survey, respiratory infections including upper and lower respiratory tract infections, bronchitis or tracheobronchitis, and influenza-like syndromes were the most frequent infections observed in elderly patients residing in LTCFs during winter [45]. However, infections in LTCF residents are frequently viral rather than bacterial, and the use of antimicrobials should be discouraged [46,47]. The close relationship between respiratory infections and antibiotic prescriptions in the cold season suggests that reducing the incidence of influenza through vaccination efforts in elderly people could help to decrease overprescription of some antibiotic classes and to reduce the annual increase in antibiotic-resistant infections. Antimicrobial stewardship programmes in LTCFs Fourteen studies (10 quasi-experimental studies and 4 cluster randomized clinical trials (cRCTs)) evaluating the role of an ASP in elderly patients residing in LTFC were analysed. Table S1 and Table 2 summarize details of quasi-experimental studies and cRCTs, respectively [48e60].

The adherence to reporting guidelines (TREND or CONSORT) is shown in Table S2 and Table S3, respectively. The quality of reporting was slightly higher for cluster RCTs than that for quasiexperimental studies. In quasi-experimental studies (Table S2), some items were satisfied in >75% of the studies, but almost half of the 22 domains included in the TREND checklist were not satisfied. In particular, the participant flow, data on eligibility criteria, and methods of recruitment were the most common unsatisfied items. This inaccuracy increased the difficulty in standardizing the ASP models in the different type of LTCFs in Europe and did not enable us to define with accuracy the setting of the ASP. In cRCTs (Table S3), five items (sequence generation, implementation, participant flow, generalizability, and link to protocol) were satisfactory in less than 25% of the studies. All the studies proposed educational interventions, while restrictive measures were not implemented. No studies compared educational vs. a restrictive model of ASP in LCTFs. There were three studies with a high GRADE scoring as follows. Firstly, a cRCT conducted in eight LTCFs evaluated the efficacy of an educational intervention that consisted of mailing an antibiotic guide to physicians [48]. By the end of the study, non-adherent antibiotic prescriptions decreased by 20.5% in the experimental group, compared with 5.1% in the control group. The strength of the tested intervention is that it appears to be less time-consuming, less costly, and more easily implemented than the other multifaceted interventions conducted in LTCFs [48]. However, the study intervention involved only physicians, the sample size was low, and the trend of the non-adherent antibiotic prescriptions between study groups was not confirmed in a subsequent period of 3 months of follow-up. Secondly, another cRCT tested a multifaceted educational intervention involving both nurses and physicians of 58 NHs [51]. The intervention consisted of small group meetings (2e13 participants) with discussions among physicians, nurses, and nursing assistants. During the educational sessions, two to three external facilitators (one pharmacist, one physician, and when possible a hygiene nurse) presented the guidelines and stimulated interactions between participants. Feedback on performance was individually evaluated through verbal summary at the end of the sessions. The use of quinolones for lower UTIs in women (primary outcome) decreased significantly in both the intervention and control group, by e0.196 and e0.224, respectively (95% CI e0.338 to e0.054 and e0.394 to e0.054), but the difference between the two groups was not significant, with an absolute risk reduction of 0.028 (95% CI e0.193 to 0.249). Among secondary outcomes, a significant decrease in the proportion of infections treated with an antibiotic (decrease of e0.124, 95% CI e0.228 to e0.019) was observed in the intervention group, as well as an increase in the proportion of infections handled by physicians as ‘wait and see’ (increase of 0.143, 95% CI 0.047e0.240) [51]. Thirdly, a study including 30 NHs from UK evaluated a specific intervention, named the ‘Resident Antimicrobial Management Plan (RAMP)’ [54]. The RAMP represented a novel self-monitoring antimicrobial stewardship educational tool. Nurses were requested to complete an antimicrobial management plan for all residents with antimicrobials prescription. No resident doctors were present in the LTCFs, but medical care was provided by general practitioners. Nurses had to monitor antibiotic prescriptions up to 48e72 h after starting treatment. The introduction of the RAMP was associated with a statistically significant decrease in total antibiotic consumption [54]. Among the remaining studies, UTIs were a major target of intervention in studies evaluating the impact of ASPs in LTCFs, especially among patients with asymptomatic bacteriuria [50,56,58,59]. The appropriateness of urine culture collection and


Study

Objective

Setting

Participants Type of intervention

Description of intervention

Targeted infections

Study periods

Results

GRADE Reporting quality evaluation (guidelines adherence)

Monette, 2007 [48]

To assess the effect of an educational intervention on antibiotic prescribing

8 LTCFs (Canada)

Physicians

An antibiotic guide with specific recommendations about the selection, dosages, frequencies and duration of the empirical antibiotic therapy was mailed to participants of intervention group

UTI LRTI SSTI Septicaemia of unknown origin

Non-adherent antibiotic prescriptions decreased by 20.5% in the experimental group, compared with 5.1% in the control group. During follow-up, nonadherent antibiotic prescriptions remained lower in the experimental group (but there was no statistical significance)

High

CONSORT checklist adherence: 15/25 items

Pettersson, 2011 [51]

To assess the impact of a multifaceted educational intervention concerning treatment of infections

Multifaceted 46 NHs Physicians (Sweden) and nursing educational intervention staff

Pre-intervention period: Dec 2001eFebruary 2002 Intervention I delivery: MarcheApril 2002 Post-intervention I period: MayeJuly 2002 Intervention II delivery: August 2002 Post-intervention II period: SepeNov 2002 Follow-up: Nov 2002eFeb 2003 Pre-intervention period: SepeDec 2003 Intervention delivery: Oct 2004eJan 2005 Post-intervention period: FebeMay 2005 Follow-up: no

High The educational intervention had no effect on the primary outcome (quinolones prescribing). However, the proportion of infections treated with antibiotics decreased and that of infections handled by physicians as ‘wait and see’ significantly increased in the intervention group High There was a significant decrease of 4.9% of antimicrobial consumption in the intervention group compared with a significant increase of 5.1% in the control group

CONSORT checklist adherence: 23/25 items

30 NHs Fleet 2014 [54] To evaluate (UK) the impact of ‘a novel antimicrobial stewardship tool on antibiotic use

Nurses

Educational intervention

Introduction of the ‘Resident Antimicrobial Management Plan” (RAMP) antimicrobial stewardship tool

UTI Small educational group sessions with nurses and physicians, feedback on prescribing, presentation of guidelines and written materials

RAMPs were completed by nursing staff for all residents newly prescribed antimicrobial treatment.

UTI LRTI SSTI

Pre-intervention period: JaneMay 2010 Intervention delivery: June eDec 2010 Post-intervention period: JaneMay 2011 Follow-up: no

CONSORT checklist adherence 21/25 items



Table 2 Cluster randomized clinical trials focusing on antimicrobial stewardship in LTCFs

LTCF, long-term care facility; LRTI, low tract respiratory tract infection; NH, nursing home; NHAP, nursing home acquired pneumonia; SSTI, skin and soft tissue infections; UTI, urinary tract infections.

5

6


antibiotic treatment based on published guidelines has been evaluated in a beforeeafter study [50]. The intervention consisted of educating nursing staff and primary care practitioners on the management of uncomplicated UTIs according to criteria described in Table 3. Before the intervention, nursing staff frequently requested urine cultures for reasons that were not in accordance with current guidelines (presence of cloudy or foul-smelling urine or non-specific symptoms such as malaise or poor appetite, or at the time of patient admission or urethral catheter change). Moreover, physicians often prescribed treatment for UTIs without seeing the patients and depended on the nursing staff to provide information regarding symptoms and signs of UTI. Overall, in the 6 months after intervention, the rate of inappropriate submission of urine cultures, the number of treatments for asymptomatic bacteriuria, and the total antimicrobial days significantly decreased [50]. In this study, the post-intervention period was divided into an initial period (the first 6 months after the beginning the intervention) and a continuation period (from 7 to 30 months after beginning the initiative), which involved less effort to maintain the programme [50]. Importantly, in the continuation period, the rates of inappropriate submission of urine cultures for asymptomatic bacteriuria and of treatment of asymptomatic bacteriuria continued to decrease [50]. Another quasi-experimental study evaluated the feasibility and efficacy of implementing an ASP targeting UTIs [58]. During the intervention phase, an infectious disease pharmacist and an infectious disease physician performed weekly audits of residents who received antibiotic therapy for UTIs. Loeb clinical consensus criteria were used to assess the appropriateness of these prescriptions. Then, the two experts formulated recommendations and sent them to the primary care provider [58]. During the study period, only 8% of residents who received antibiotics for UTI met the Loeb criteria for antibiotic initiation [61], highlighting the great proportion of unnecessary antibiotic prescriptions in LTCFs [58]. The implementation of the above-described ASP caused an immediate 26% decrease in antibiotic prescriptions for UTI and a subsequent 6% reduction per month continuing through the whole intervention period [58]. Similarly, a beforeeafter study [59] evaluated the effectiveness of an intervention consisting of the evaluation of UTI symptoms and the application of clinical practice guidelines from the Infectious Disease Society of America [62,63]; a marked decrease of written prescriptions for asymptomatic bacteriuria was observed [59]. However, it should be considered that infections in older adults may present in unusual ways [64] and it is often difficult to determine whether bacteriuria is accompanied by symptoms of a UTI in elderly patients, who often are incontinent and cognitively impaired [64]. Moreover,

Table 3 Proposed criteria for sending urine culture by nurse staff in LTCF [49] Proposed criteria for sending a urine culture in LTCF SEND a urine specimen if Fever or rigors Urinary urgency or frequency Dysuria Haematuria New onset of urinary incontinence Acute urinary retention Flank pain Significant change in mental status, with no other explanation Do NOT send a urine specimen routinely for Foul-smelling or cloudy urine After every urethral catheter change Upon admission After treatment to document cure

uncontaminated urine specimens are difficult to obtain in the LTCF setting. Thus, a careful clinical evaluation, the application of standard procedures for obtaining clean-catch urine specimens, and the help of an expert laboratory are useful to identify patients who need antimicrobial therapy. LTCF-acquired pneumonia (NHAP) represents another important scenario for ASP, but data are limited. A multifaceted and multidisciplinary intervention conducted in 16 US NHs comprised a multidisciplinary team including physicians, pharmacists, and nurses, and a care pathway starting with observation of symptoms by nurses was elaborated and strictly followed [52]. The intervention was associated with an increase in adherence to national evidence-based guidelines for NHAP [52]. Finally, an important issue in the setting of LTCFs is the appropriate use of biomarkers, such as C-reactive protein (CRP), to guide antibiotic therapy [64]. While the role of CRP in optimizing the antibiotic therapy in adult patients with infections has been studied in the acute-care setting, too few data regarding CRP helping in diagnosis are available for elderly patients in LTCFs [64]. Moreover, the systematic use of this low specific marker in a complex population such as LTCF residents may promote a paradoxical overuse of antibiotics. Thus, awareness of its interpretation in older age groups is necessary [64]. Conclusions and implications Antibiotics are among the most prescribed drugs among elderly patients residing in LTCFs. Data on antibiotic consumption in LTCFs show great variability in LTCFs across and within countries. Reasons for this variability are difficult to analyse, because of the differences in the types of LTCFs, their organization and the population cared for in the different LTCFs. Studies show that the use of antibiotics among elderly patients in LTCFs is often inappropriate; in particular, use of antibiotics for asymptomatic bacteriuria and for influenza-like syndromes. High-quality cluster RCTs and low to moderate quality quasi-experimental studies show that educational interventions directed at nurses and physicians are effective in reducing unnecessary antibiotic prescriptions, especially for asymptomatic bacteriuria. The long-term effectiveness of these interventions remains unclear. Clearly, there is an urgent need for antibiotic stewardship programs tailored to the needs of LTCFs. Starting from this need and following the literature review, an expert panel belonging to the ESGIE group was convened to discuss potential interventions to improve antibiotic use in LTCFs. The group reached consensus on the following interventions: 1. considering the great variability in the antimicrobials prescription in LTCFs, antimicrobial use and indications for antimicrobial prescribing should monitored in a standardized manner. These data will allow comparisons between similar LTCFs, monitoring trends in time and assessing the effects of interventions to improve antibiotic use; 2. standardizing access to diagnostic tests with results available in real time. Diagnostic algorithms should accompany the introduction of a test to avoid unnecessary testing and direct interpretation of the test; 3. better collaboration is required between nursing staff and physicians to rationalize the indications for the use of antimicrobial agents; 4. there is a great need for a multifaceted organized educational interventions, directed both at physicians and nursing staff, organized in small groups and periodically repeated; 5. greater efforts are required to agree on common indicators to improve the efficacy of LTCF antimicrobial use.



6. implementation of ASPs targeting infections other than UTIs (e.g., NHAP) and new high quality studies assessing these interventions are needed. Recently, a manageable number of ASP indicators that are relevant and feasible for comparison of ASPs among EU and US hospitals has been identified [65]. A set of 33 indicators was developed to characterize the infrastructure and activities of hospital ASP and among them 17 indicators were considered essential to characterize an ASP [65]. A similar effort has been conducted in the specific setting of LTCFs [66]. Forty-two agreed component indicators were grouped into six national performance indicators categories: ‘national programme’, ‘guidelines’, ‘expert advice’, ‘infection control structure’, ‘surveillance’, and ‘composite’. The mean score for compliance with 11 indicators in 32 countries ranged from 1.9 to 2.8 of a maximal score of 5. Thus, prospective monitoring with the proposed national performance indicators should be advocated in EU LTCFs, allowing countries to monitor their own progress and benchmarking themselves against others. Transparency declaration The authors declare no conflict of interest. Acknowledgements All the authors are active members of the European Society of Clinical Microbiology and Infectious DiseasesdStudy Group for Infections in the Elderly (ESGIE) and would like to thank the ESGIE members for their stimulating support to write this Review. Funding None. Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.cmi.2018.07.028. References [1] Gavazzi G, Herrmann F, Krause KH. Aging and infectious diseases in the developing world. Clin Infect Dis 2004;39:83e91. [2] Hepper HJ, Sieber C, Walger P, Bahrmann P, Singler K. Infections in the elderly. Crit Care Clin 2013;29:757e74. [3] Suetens C. Healthcare-associated infections in European long-term care facilities: how big is the challenge? Euro Surveill 2012;17. pii 20259. [4] Moro ML, Jans B, Cookson B, Fabry J. The burden of healthcare-associated infections in European long-term care facilities. Infect Control Hosp Epidemiol 2010;31:S59e62. [5] Jones AL, Dwyer LL, Bercovitz AR, Strahan GW. The national nursing home survey: 2004 overview. Vital Health Stat 13 2009;167:1e155. [6] https://ecdc.europa.eu/en/healthcare-associated-infections-long-term-carefacilities/facts. Retrieved 14 March 2018. [7] Rhee SM, Stone ND. Antimicrobial stewardship in long-term care facilities. Infect Dis Clin North Am 2014;28:237e46. [8] Falcone M, Russo A, Gentiloni Silverj F, Marzorati D, Bagarolo R, Monti M, et al. Predictors of mortality in nursing-home residents with pneumonia: a multicentre study. Clin Microbiol Infect 2018;24:72e7. [9] Boockvar KS, Gruber-Baldini AL, Burton L, Zimmerman S, May C, Magaziner J. Outcomes of infection in nursing home residents with and without early hospital transfer. J Am Geriatr Soc 2005;53:590e6. [10] Loeb MB1, Craven S, McGeer AJ, Simor AE, Bradley SF, Low DE. Risk factors for resistance to antimicrobial agents among nursing home residents. Am J Epidemiol 2003;157:40e7. [11] Falcone M, Tiseo G, Dentali F, La Regina M, Foglia E, Gambacorta M, et al. Predicting resistant etiology in hospitalized patients with blood cultures positive for Gram-negative bacilli. Eur J Intern Med 2018. pii: S0953-6205(18) 30045-1.

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[12] Nicolle LE, Bentley DW, Garibaldi R, Neuhaus EG, Smith PW. Antimicrobial use in long-term-care facilities. SHEA Long-Term-Care Committee. Infect Control Hosp Epidemiol 2000;21:537e45. [13] van Buul LW, Veenhuizen RB, Achterberg WP, Schellevis FG, Essink RT, de Greeff SC, et al. Antibiotic prescribing in Dutch nursing homes: how appropriate is it? J Am Med Dir Assoc 2015;16:229e237. [14] Stuart RL, Wilson J, Bellaard-Smith E, Brown R, Wright L, Vandergraaf S, et al. Antibiotic use and misuse in residential aged care facilities. Intern Med J 2012;42:1145e9. [15] Rotjanapan P, Dosa D, Thomas KS. Potentially inappropriate treatment of urinary tract infections in two Rhode Island nursing homes. Arch Intern Med 2011;171:438e43. [16] Peron EP, Hirsch AA, Jury LA, Jump RL, Donskey CJ. Another setting for stewardship: high rate of unnecessary antimicrobial use in a Veterans Affairs long-term care facility. J Am Geriatr Soc 2013;61:289e90. [17] Campbell RJ, Giljahn L, Machesky K, Cibulskas-White K, Lane LM, Porter K, et al. Clostridium difficile infection in Ohio hospitals and nursing homes during 2006. Infect Control Hosp Epidemiol 2009;30:526e33. [18] Falcone M, Iraci F, Raponi G, Goldoni P, Belvisi V, Delle Rose D, et al. Nursing home residence is associated with spread of Clostridium difficile ribotype 027 in central Italy. J Hosp Infect 2016;94:201e3. [19] Moro ML, Gagliotti C. Antimicrobial resistance and stewardship in long-term care settings. Future Microbiol 2013;8:1011e25. [20] Des Jarlais DC, Lyles C, Crepaz N, TREND Group. Improving the reporting quality of nonrandomized evaluations of behavioral and public health interventions: the TREND statement. Am J Publ Health 2004;94:361e6. [21] Campbell MK, Piaggio G, Elbourne DR, Altman DG, CONSORT Group. Consort 2010 statement: extension to cluster randomised trials. BMJ 2012;345: e5661. [22] McClean P, Hughes C, Tunney M, Goossens H, Jans B, the European surveillance of antimicrobial Consumption (ESAC) Nursing Home Project Group, Antimicrobial prescribing in European nursing homes. Antimicrobial prescribing in European nursing homes. J Antimicrob Chemother 2011;66: 1609e16. [23] European Centre for Disease Prevention and Control. Point prevalence survey of healthcare- associated infections and antimicrobial use in European longterm care facilities. AprileMay 2013. Stockholm: ECDC; 2014. https://ecdc. europa.eu/sites/portal/files/media/en/publications/Publications/healthcareassociated-infections-point-prevalence-survey-long-term-care-facilities2013.pdf. [24] McClean P, Tunney M, Gilpin D, Parsons C, Hughes C. Antimicrobial prescribing in residential homes. J Antimicrob Chemother 2012;67:1781e90. [25] Burns K, Roche F, Donlon S. Healthcare-associated infections and antimicrobial use in long-term care facilities: the Irish experience with the HALT surveys. J Hosp Infect 2015;89:276e80. [26] Roche FM, Donlon S, Burns K. Point prevalence survey of healthcareassociated infections and use of antimicrobials in Irish intellectual disability long-term care facilities: 2013. J Hosp Infect 2016;93:410e7. [27] Andersen BA, Rasch M. Hospital-acquired infections in Norwegian long-termcare institutions. A three-year survey of hospital-acquired infections and antibiotic treatment in nursing/residential homes, including 4500 residents in Oslo. J Hosp Infect 2000;46:288e96. [28] Blix HS, Røed J, Sti MO. Large variation in antibacterial use among Norwegian nursing homes. Scand J Infect Dis 2007;39:536e41. [29] Blix HS, Bergman J, Schjøtt JJ. How are antibacterials used in nursing homes? Results from a point-prevalence prescription study in 44 Norwegian nursing homes. Pharmacoepidemiol Drug Saf 2010;19:1025e30. €rki T, Kanerva M, Haapasaari M, Ollgren J, Lyytika €inen O. [30] Rummukainen ML, Ka Antimicrobial prescribing in nursing homes in Finland: results of three point prevalence surveys. Infection 2013;41:355e60. [31] Sundvall PD, Stuart B, Davis M, Roderick P, Moore M. Antibiotic use in the care home setting: a retrospective cohort study analysing routine data. BMC Geriatr 2015;15:71. [32] Gillespie D, Hood K, Bayer A, Carter B, Duncan D, Espinasse A, et al. Antibiotic prescribing and associated diarrhoea: a prospective cohort study of care home residents. Age Ageing 2015;44:853e60. [33] Roukens M, Verhoef L, Stobberingh E, Natsch S. Surveillance of antimicrobial use in Dutch long-term care facilities. J Antimicrob Chemother 2017;72: 1516e20. [34] Daneman N, Gruneir A, Newman A, Fischer HD, Bronskill SE, Rochon PA, et al. Antibiotic use in long-term care facilities. J Antimicrob Chemother 2011;66: 2856e63. [35] Daneman N, Gruneir A, Bronskill SE, Newman A, Fischer HD, Rochon PA, et al. Prolonged Antibiotic treatment in long-term care. Role of the prescriber. JAMA Intern Med 2013;173:673e82. [36] Daneman N, Campitelli MA, Giannakeas V, Morris AM, Bell AC, Maxwell CJ, et al. Influences on the start, selection and duration of treatment with antibiotics in long-term care facilities. CMAJ 2017;189:E851e60. [37] Nicolle LE, SHEA Long-Term-Care-Committee. Urinary tract infections in longterm-care facilities. Infect Control Hosp Epidemiol 2001;22:167e75. [38] Wu LD, Walker SA, Elligsen M, Palmay L, Simor A, Daneman N. Antibiotic use and need for antimicrobial stewardship in long-term care. Can J Hosp Pharm 2015;68:445e9.


8


[39] Palliative care systems and current practices in long term care facilities in Europe. Report of the European association of palliative care taskforce on mapping palliative care systems in long term care facilities in Europe January 2017 (amended March 2017) http://www.eapcnet.eu/Portals/0/Policy/EU% 20sup_proj_/PACE/EAPC_PACE_WP1_Deliverable_v.1.1_March_2017.pdf. [40] Fleming A, Bradley C, Cullinan S, Byrne S. Antibiotic prescribing in long-term care facilities: a meta-synthesis of qualitative research. Drugs Aging 2015;32: 295e303. [41] van Buul LW, van der Steen JT, Doncker SM, Achterberg WP, Schellevis FG, Veenhuizen RB, et al. Factors influencing antibiotic prescribing in long-term care facilities: a qualitative in-depth study. BMC Geriatr 2014;14:136. [42] Latour K, Catry B, Broex E, Vankerckhoven V, Muller A, Stroobants R, et al. Indications for antimicrobial prescribing in European nursing homes: results from a point prevalence survey. Pharmacoepidemiol Drug Saf 2012;21: 937e44. [43] Rosello A, Hayward AC, Hopkins S, Horner C, Ironmonger D, Hawkey PM, et al. Impact of long-term care facility residence on the antibiotic resistance of urinary tract Escherichia coli and Klebsiella. J Antimicrob Chemother 2017;72: 1184e92. [44] Mylotte JM. Antimicrobial prescribing in long-term care facilities: Prospective evaluation of potential antimicrobial use and cost indicators. Am J Infect Control 1999;27:10e9. res B, Lejeune B, Piette F, et al. Burden [45] Chami K, Gavazzi G, Carrat F, de Wazie of infections among 44,869 elderly in nursing homes: a cross-sectional cluster nationwide survey. J Hosp Infect 2011;79:254e9. [46] Kodama F, Nace DA, Jump RLP. Respiratory syncytial virus and other noninfluenza respiratory viruses in older adults. Infect Dis Clin North Am 2017;31:767e90. [47] Lansbury LE, Brown CS, Nguyen-Van-Tam JS. Influenza in long-term care facilities. Influenza Other Respir Virus. 2017;11:356e66. [48] Monette J, Miller MA, Monette M, Laurier C, Boivin JF, Sourial N, et al. Effect of an educational intervention on optimizing antibiotic prescribing in long-term care facilities. J Am Geriatr Soc 2007;55:1231e5. [49] Schwartz DN, Abiad H, DeMarais PL, Armeanu E, Trick WE, Wang Y, et al. An educational intervention to improve antimicrobial use in a hospital-based long-term care facility. J Am Geriatr Soc 2007;55:1236e42. [50] Zabarsky TF, Sethi AK, Donskey CJ. Sustained reduction in inappropriate treatment of asymptomatic bacteriuria in a long-term care facility through an educational intervention. Am J Infect Control 2008;36:476e80. €lstad S, Lundborg CS. Can a multifaceted educa[51] Pettersson E, Vernby A, Mo tional intervention targeting both nurses and physicians change the prescribing of antibiotics to nursing home residents? A cluster randomized controlled trial. J Antimicrob Chemother 2011;66:2659e66. [52] Linnebur SA, Fish DN, Ruscin JM, Radcliff TA, Oman KS, Fink R, et al. Impact of a multidisciplinary intervention on antibiotic use for nursing home-acquired pneumonia. Am J Geriatr Pharmacother 2011;9:442e450.e1. [53] Jump RL, Olds DM, Seifi N, Kypriotakis G, Jury LA, Peron EP, et al. Effective antimicrobial stewardship in a long-term care facility through an infectious disease consultation service: keeping a LID on antibiotic use. Infect Control Hosp Epidemiol 2012;33:1185e92.

[54] Fleet E, Rao GG, Patel B, Cookson B, Charlett A, Bowman C, et al. Impact of implementation of a novel antimicrobial stewardship tool on antibiotic use in nursing homes: a prospective cluster randomized control pilot study. J Antimicrob Chemother 2014;69:2265e73. [55] Zimmerman S, Sloane PD, Bertrand R, Olsho LE, Beeber A, Kistler C, et al. Successfully reducing antibiotic prescribing in nursing homes. J Am Geriatr Soc 2014;62:907e12. [56] Trautner BW, Grigoryan L, Petersen NJ, Hysong S, Cadena J, Patterson JE, et al. Effectiveness of an antimicrobial stewardship approach for urinary catheterassociated asymptomatic bacteriuria. JAMA Intern Med 2015;175:1120e7. [57] van Buul LW, van der Steen JT, Achterberg WP, Schellevis FG, Essink RT, de Greeff SC, et al. Effect of tailored antibiotic stewardship programmes on the appropriateness of antibiotic prescribing in nursing homes. J Antimicrob Chemother 2015;70:2153e62. [58] Doernberg SB, Dudas V, Trivedi KK. Implementation of an antimicrobial stewardship program targeting residents with urinary tract infections in three community long-term care facilities: a quasi-experimental study using timeseries analysis. Antimicrob Resist Infect Control 2015;4:54. [59] McMaughan DK, Nwaiwu O, Zhao H, Frentzel E, Mehr D, Imanpour S, et al. Impact of a decision-making aid for suspected urinary tract infections on antibiotic overuse in nursing homes. BMC Geriatr 2016;16:81. [60] Tedeschi S, Trapani F, Giannella M, Cristini F, Tumietto F, Bartoletti M, et al. An antimicrobial stewardship program based on systematic infectious disease consultation in a rehabilitation facility. Infect Control Hosp Epidemiol 2017;38:76e82. [61] Loeb M, Bentley DW, Bradley S, Crossley K, Garibaldi R, Gantz N, et al. Development of minimum criteria for the initiation of antibiotics in residents of long-term-care facilities: results of a consensus conference. Infect Control Hosp Epidemiol 2001;22:120e4. [62] High KP, Bradley SF, Gravenstein S, Mehr DR, Quagliarello VJ, Richards C, et al. Clinical practice guideline for the evaluation of fever and infection in older adult residents of long-term care facilities: 2008 update by the Infectious Diseases Society of America. J Am Geriatr Soc 2009;57:375e94. [63] Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM, et al., Infectious Diseases Society of America, American Society of Nephrology, American Geriatric Society. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005;40:643e54. [64] van Duin D. Diagnostic challenges and opportunities in older adults with infectious diseases. Clin Infect Dis 2012;54:973e8. [65] Pollack LA, Plachouras D, Sinkowitz-Cochran R, Gruhler H, Monnet DL, Weber JT, et al. A concise set of structure and process indicators to assess and compare antimicrobial stewardship programs among EU and US hospitals: results from a multinational expert panel. Infect Control Hosp Epidemiol 2016;37:1201e11. [66] Cookson B, Mackenzie D, Kafatos G, Jans B, Latour K, Moro ML, et al. Development and assessment of national performance indicators for infection prevention and control and antimicrobial stewardship in European long-term care facilities. J Hosp Infect 2013;85:45e53.
