ISSN: 0214-3429 / ©The Author 2021. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/). Systematic review Revista Española de Quimioterapia doi:10.37201/req/028.2021 Jesus Ruiz-Ramos1 Emili Vallvé Alcón2 Antimicrobial stewardship programs in emergency Francisco Moreno Ramos3 Rosario Santolaya-Perrín4 departments: how do we measure antimicrobial Jose María Guardiola Tey5 use? A systematic review 1 Pharmacy Department, Hospital Santa Creu i Sant Pau, Barcelona, Spain. 2 Pharmacy Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain 3 Pharmacy Department, Hospital Universitario La Paz, Madrid, Spain 4 Pharmacy Department, Hospital Universitario Príncipe de Asturias. Alcalá de Henares, Spain. 5 Emergency Department, Hospital Santa Creu i Sant Pau, Barcelona, Spain. Article history Received: 4 February 2021; Revision Requested: 25 March 2021; Revision Received: 10 May 2021; Accepted: 26 July 2021; Published: 15 September 2021 ABSTRACT which makes it difficult to compare results. Therefore, antimi- crobial use indicators for ASPs must be standardised between Objectives. The implementation of antimicrobial steward- hospital units. ship programs (ASPs) has become a usual practice in hospital Key words: Antimicrobial stewardship; antibiotic, emergency care, infec- settings. However, the method for monitoring antimicrobial tion use in accident and emergency departments (ED) is not yet adequately defined. Thus, the objective of this review is to de- Programas de optimización de uso de scribe antimicrobial use indicators used by ASPs implemented antimicrobianos en los servicios de urgencias: in ED. ¿cómo medimos el uso de antimicrobianos? Material and methods. A systematic review was per- Una revisión sistemática formed based on studies found in the following academic research databases: MEDLINE, EMBASE, Web of Science, and RESUMEN Scopus (Period: January 2000 to December 2019). Controlled clinical trials, before-and-after studies, interrupted time series, Objetivos. La implantación de programas de optimización and repeated measures studies assessing the impact of ASPs de antimicrobianos (PROA) se ha convertido en una práctica on antimicrobial use in ED were included; studies published in asistencial habitual en el medio hospitalario. No obstante, la languages other than English or Spanish were excluded from metodología para monitorizar el uso de antimicrobianos en los this review. servicios de urgencias no están aún adecuadamente definidas. Results. Twenty-six studies met the inclusion criteria and El objetivo de esta revisión es describir los indicadores de uso were included in this systematic review. In total, 15 (62.5%) de antimicrobianos utilizados por los programas PROA implan- studies described the ASP team members who collaborated tados en los servicios de Urgencias. with the ED staff. Most (21; 80.8%) studies used the percent- Material y métodos. Se realizó una revisión sistemáti- age of patients with an antibiotic prescription as an indica- ca en base a los resultados obtenidos en las siguientes bases tor. Four (15.4%) studies included defined daily dose data. The bibliográficas: MEDLINE, EMBASE, Web of Science y Scopus. El antibiotic treatment duration was reported in four (15.4%) periodo de búsqueda abarcó desde Enero de 2000 a Diciembre studies. Only two studies assessed the impact of the ASP using de 2019. Se incluyeron ensayos clínicos controlados, estudios microbiological indicators, both of which used the incidence of antes-después, estudios de series de tiempo interrumpido y infection with Clostridioides difficile as the indicator. los estudios de medidas repetidas que evaluaron las interven- Conclusions. The reports of experiences in implementing ciones de los programas PROA en los servicios de urgencias so- ASPs in ED show heterogeneous antimicrobial use indicators, bre el impacto del consumo de antimicrobianos. Se excluyeron los estudios publicados en otros idiomas además del inglés o Correspondence: español. Jesus Ruiz Pharmacy Department, Hospital Santa Creu i Sant Pau. C/San Quintín 89, 08041 Barcelona, Resultados. 26 estudios cumplieron los criterios y se in- Spain.. Phone: +34-932919000 (Ext: 1887) cluyeron en la revisión sistemática. En 15 (62,5%) de los estu- E-mail: Jruizr@santpau.cat j dios incluyeron en su descripción los componentes del equipo PROA que colaboraron junto con el del equipo de urgencias. Rev Esp Quimioter 2021;34(6): 610-617 610 J. Ruiz-Ramos, et al. Antimicrobial stewardship programs in emergency departments: how do we measure antimicrobial use? A systematic review La mayor parte de los estudios utilizaron el porcentaje de scribe the methods, healthcare professionals involved in these pacientes con prescripción de antibióticos como indicador, programs, and clinical and microbiological indicators that are estando presente en 21 (80,8%) de los estudios publicados. Cu- used with consumption indicators in these hospital units. atro (15,4%) de los estudios incluyeron datos en Dosis Diarias Definidas (DDD). La duración del tratamiento antibiótico fue MATERIAL AND METHODS recogida en cuatro (15,4%) de los estudios. Únicamente dos estudios evaluaron el impacto del programa con indicadores A systematic review was conducted based on published microbiológicos, siendo en ambos casos la incidencia de infec- articles. Due to the variability in the methods, design, and re- ción por Clostridioides difficile el indicador utilizado. sults of the studies found in the literature, the indicators of Conclusiones. Las experiencias descritas de implantación both antimicrobial consumption and clinical and microbiologi- de programas PROA en los servicios de urgencia presenta in- cal results, as well as the methods used in these studies, are dicadores de uso de antimicrobianos heterogéneos, que difi- summarised descriptively. cultan la comparación de resultados. Es necesario estandarizar Data source and search strategy. Searches were per- los indicadores de optimización de uso de antimicrobianos en formed in the following databases from January 2000 to De- estas unidades. cember 2019 MEDLINE, Web of Science, Scopus and EMBASE. Palabras clave: optimización de uso de antimicrobianos, Antibióticos, ur- The following search terms were used in those databases: an- gencias, infección tibiotic AND (stewardship OR audit OR restriction OR decision support OR education OR guideline OR policy OR control OR INTRODUCTION de-escalation) AND (emergency department OR emergency service). Full-text, brief communications, and letters to the ed- The increase in antibiotic resistance observed in recent itor on randomised and non-randomised and controlled clin- decades has had a significant effect on healthcare systems ical trials, non-controlled before-and-after studies, interrupt- worldwide [1]. Infections caused by multiresistant microorgan- ed time series, and repeated measures studies were included isms are associated with higher mortality and longer hospital in this review. The exclusion criteria were studies outside the stay, as well as with a significant increase in healthcare costs scope of the ED and studies without antimicrobial use meas- [2]. Excessive or inappropriate antimicrobial use is known to ures. Studies published in languages other than English or have helped generate and perpetuate these multi-resistant Spanish were also excluded from this review. strains [3]. Therefore, in recent decades, antimicrobial steward- The following variables were collected from each manu- ship programs (ASPs) have become a priority for health au- script: country and year of publication; study design; group of thorities to minimise the expansion and number of infections patients or antimicrobials targeted by the ASP team; and clini- caused by multi-resistant bacteria [4,5]. cal, microbiological, and antimicrobial consumption indicators. The application of ASPs in hospital settings has reduced When requiring additional information regarding the manu- antimicrobial consumption and improved the clinical out- scripts, the original authors of the corresponding articles were comes of patients [6], albeit with a still unknown impact on contacted to gather necessary data. resistance reduction [7,8] and the implementation of these All indicators that reflected the variation in antimicro- programs is strongly recommended by various scientific soci- bial consumption before and after intervention were con- eties [9-13]. sidered antimicrobial use indicators. The rates of infection Most experiences of such programs described in the liter- with Clostridioides difficile, as well as variations in the rates ature thus far have focused on hospitalised patients, particu- of antimicrobial resistance and infection or colonisation with larly critically ill patients, and more recently on primary care multidrug-resistant bacteria, were considered microbiologi- settings [6]. Emergency departments (ED) are one of the most cal indicators. The following clinical outcomes were analysed: important services where these programs can be implemented mortality, mean length of stay (both in the ED and in hospital), revisits, and adverse events.; whether the studies assessed the as they are the site of prescription of the first doses of an- effect of ASPs on health costs was also recorded. tibiotics in hospitals and of a large number of antibiotics for patients discharged directly to their homes or other healthcare Similarly, the work method was analysed, including pro- centres. Although the guidelines for the implementation of spective audit and feedback systems, formulary restrictions, ASPs recognise that ED are the preferred sites for these pro- application and compliance with internal clinical guidelines, grams, the participation of multidisciplinary teams in these treatment-shortening regimens, interventions in specific in- hospital units is still low [14]. In turn, the indicators used to fections, dose-optimisation programmes, switch therapy from monitor antibiotic use lack uniformity. On the other hand, intravenous to oral route, computer support systems, review of clinical outcomes related to an appropriate antibiotic use, such microbiological records on discharge, pharmacokinetic moni- as mortality or length of hospital stay, are difficult to relate di- toring, rapid diagnostic tests, training programmes, and specif- rectly to the actions carried out in these units. The primary ob- ic interventions for allergies [9,11,15,16]. jective of this review is to identify antimicrobial use indicators Study selection and data extraction. Two clinical phar- used by ASPs in ED, and the secondary objectives are to de- macists with training and experience in the implementation Rev Esp Quimioter 2021;34(6): 610-617 611 J. Ruiz-Ramos, et al. Antimicrobial stewardship programs in emergency departments: how do we measure antimicrobial use? A systematic review of ASPs and ED care independently examined all titles and measure described in three (11.5%) studies. The implementa- abstracts retrieved during the literature search. In texts over tion of local and national guidelines/protocols was reported which the two specialists disagreed, a third specialist was in- in 16 (61.5%) studies. In 10 (38.4%) studies, prospective au- cluded to reach a consensus decision after discussion the study dit and feedback systems were established for the prescribers. with the other researchers. Other measures included the establishment of a consulting system (2; 7,7%), implementation of a computer support sys- RESULTS tem (3; 11.5%), review of microbiological records on discharge (1; 3.8%), and formulary restrictions (1; 3.8%). A total of 8,451 references were found in the initial search. Respiratory tract infections were the main target of After applying the inclusion and exclusion criteria, 26 articles ASP teams, being their objective in 13 (50.0%) studies, of were included in the systematic review (Figure 1). Among the which six (23.1%) exclusively included a paediatric pop- selected studies, four (15.4%) were controlled clinical trials, ulation. Urinary tract infections were the second most with 10 (38.5%) time series and 12 (45.1%) before-and-af- common infection targeted by ASPs, being present in five ter studies. The median intervention period was 12 months (19.2%) studies. Five (19.2%) studies targeted all patients (Range: 3 months–5 years). Table 1 outlines the characteristics on antibiotic treatment. of the studies selected for analysis, which are detailed in Table Consumption indicators. The different indicators used in 1S-Supplementary material. the studies are outlined in Table 2. The percentage of patients Team members. In total, 15 (62.5%) studies described the with an antibiotic prescription was the most widely used indi- ASP team members who collaborated with the ED staff. The cator, being used in 21 (80.8%) of the published studies. Four ASP team included an infectologist in eight (30.8%), a phar- (15.4%) studies included defined daily dose (DDD) data, adjust- macist in 11 (42.5%), the microbiology department in four ed for the number of stays in three (11.5%) studies and for the (15.4%), the informatic deparment team in two (7.7%), and number of admissions in one. The duration of the antibiotic other staff in two (7.7%) studies. Nursing staff participation treatment was recorded in four (15.4%) studies, being adjusted was described in five (19.2%) studies. for the number of stays in two (7.7%) and expressed as days Method and performance targets. Most studies (21; of treatment (DOT) in one of the studies. Four (15.4%) studies 80.8%) reported training sessions as one of the strategies of evaluated antimicrobial spending after the implementation of the programmes, and these training sessions were the only the programmes. Records identified through database searching January 2000- December 2019) n=8,451 Duplicates n=2,958 Records screened (January 2000-December 2019) n=5,493 Records excluded n=5,381 Records evaluated n=112 No antibiotic use indicators (n=68) Main intervention outside emergency service (n=8) Records included in the systematic review n=26 Language (n=3) Others (n=5) Figure 1 Study selection flow-chart Rev Esp Quimioter 2021;34(6): 610-617 612 J. Ruiz-Ramos, et al. Antimicrobial stewardship programs in emergency departments: how do we measure antimicrobial use? A systematic review that multidisciplinary training in these units and prospective Table 1 Characteristics of the studies included in audit and feedback systems remain limited. the analysis. Although ED are an essential contributor to antimicrobi- al use as the starting point for many antibiotic prescriptions Design [17], our study has shown that few experiences described in Randomized trial with control group 4 (15.4%) the literature analyse the antibiotic use in these departments. Time series study 10 (38.5%) A review on the clinical effect of implementing ASPs in ED has concluded that applying this type of programme has fa- Retrospective before-after study 12 (46.1%) vourable clinical outcomes in most studies [14]. Our review is Studies in paediatric patients 8 (30.7%) focused on the indicators used in these types of programmes Target of intervention and on the structure of the ASP team, beyond clinical out- comes. For this reason, a large number of studies on ASP-like All patients with antibiotics 5 (19.2%) interventions in theses departments were excluded from this Respiratory infections 13 (50.0%) review because these interventions failed to include antimicro- Urinary-tract infections 4 (15.4%) bial use monitoring in their activities. This element is essential Otitis 1 (3.8%) to monitor the activity of such programmes, since the reduc- tion in antimicrobial use is a primary objective of them and Quinolones 1 (3.8%) one of the tools that can predict the development of resist- Vancomycin 1 (3.8%) ance [9,18-22]. Sepsis 1 (3.8%) According to our review, the percentage of patients pre- Participants scribed antibiotics is the most frequently used indicator in Without description 11 (42.3%) these units. However, indicators based on daily doses of antibi- otics have gradually been used in the last decade [23,24]. DDD, Infectologists 8 (30.7%) the main indicator used by ASP in hospitalized adults [25], is Pharmacists 11 (42.3%) disadvantageous because it is not applicable to the paediat- Microbiologist 4 (15.4%) ric population or to patients with impaired renal function. On Informatic 2 (7.7%) the other hand, first dose of antibiotic administered in EDs in patients with serious infections may be higher than the main- Nursing 5 (19.2%) tenance dose, which makes it difficult to compare it with other Others 3 (11.5%) services at the same center. DOT is widely accepted and ap- plicable to the paediatric population. However, it requires an electronic administration record system for its calculation, in Clinical outcome indicators. Among the clinical out- contrast to the DDD, and focuses on the duration of the anti- come results that accompanied the results of antimicrobial biotic treatment, which is general poorly controlled in ED [26]. consumption, the number of readmissions or re-visits to the Other indicators, such as prescribed daily dose, which makes it ED was the most frequently used, occurring in nine (37.5%) of possible to adapt to the specific dosages of each unit, can be the studies. The effect of the ASPs on mortality was evaluated a suitable alternative, although it was not described in any of in four (57.4%) studies, on mean stay in the ED in two (7.7%) the studies included in this review,. Another important point studies, and on total hospital stay in five (19.2%) studies. Only to note is the importance of monitoring hospital consumption two (7.7%) studies assessed the effect of ASPs using microbio- of all groups of antimicrobials in ED, since reductions in the consumption of certain antibiotics are usually accompanied logical indicators; in both cases, the incidence of infection with by increased consumption of others, which may even have a C. difficile was the indicator used. One study (3.5%) collect- greater ecological impact or lead to changes. Regarding the ed the incidence of adverse events associated with antibiotic denominator, the short stay of patients in these units makes it treatment. Evaluation of cost of antibiotic use was evaluated difficult to apply weighting based on the number of stays. For in two (7.7%) studies, observing a reduction in antimicrobials this reason, several authors have used the number of visits to cost after the implementation of ASP in both cases. the ED as an indicator, which is a more accepted denominator. The selection of indicators that include groups of antibiotics DISCUSSION at a higher risk of generating resistance, such as quinolones or carbapenems, should also be part of the indicators used According to the results from the present review, ASPs in ASPs in these units but were described in only two of the are applied in ED using different indicators to monitor anti- studies analysed [27,28]. Other mixed indicators have been microbial consumption, and the percentage of patients with proposed for other units even though their use in ED remains antibiotic prescription is the most widely used indicator. Most undescribed [29]. programmes described in the studies lack microbiological in- It should be noted that the difficulties inherent to these dicators. The experiences published in these studies highlight units derived from the short stay and the empirical manage- Rev Esp Quimioter 2021;34(6): 610-617 613 J. Ruiz-Ramos, et al. Antimicrobial stewardship programs in emergency departments: how do we measure antimicrobial use? A systematic review Table 2 Indicators used in the studies included (n = 26) Indicator Adult patients (n=19) Peadiatric patients (n=7) Antibiotic use indicators % Patients with antibiotic prescription 15 (78.9%) 7 (100%) DDD / 100 stays 3 (15.7%) 0 (0%) RDD / 100 stays 1 (5.3%) 0 (0%) DDD / 100 income 1 (5.3%) 0 (0%) DOT / 100 admissions 1 (5.3%) 1 (14.8%) Treatment duration 1 (5.3%) 0 (0%) Intravenous treatment duration 1 (5.3%) 0 (0%) Adjusted prescription ratio 1 (5.3%) 0 (0%) Antimicrobial costs 0 (0.0%) 2 (28.5%) Outcome indicators Length of stay in the emergency room 1 (5.3%) 1 (14.8%) Length of hospital stay 4 (21.0%) 1 (14.8%) Readmissions / Revisits 7 (37.5%) 2 (28.5%) Mortality 4 (21.0%) 0 (0%) Treatment failure 1 (5.3%) 0 (0%) Microbiological indicators No. C difficile infections / 100 patients 1 (5.3%) 0 (0%) No. C difficile infections / 10,000 stays 1 (5.3%) 0 (0%) DDD: Defined daily dose; RDD: Doses adjusted to guidelines; DOT: Days of treatment ment of infectious pathology make it necessary to complement that are not directly associated with the adequate use of anti- these consumption indicators with other indicators related to biotics, such as cross-contamination. clinical processes and results related to the optimization of the The methods used in this type of unit are highly heter- activity carried out by these programs, such as the percentage ogeneous. All these interventions have been designed with of prescriptions that meet the accepted guidelines or used as strategies for optimising antimicrobial use in these units [16] references in the centre. However, these indicators have some and have demonstrated, in all cases, benefits by reducing an- limitations because they require a high workload to assess tibiotic prescription in these units [32]. The optimal strategy them and are partly affected by the subjectivity of the evalua- for ASPs in ED has not yet been established because no study tor [30]. Using clinical outcome variables, such as mortality or has compared the different interventions proposed for such number of re-visits, as indicators is also highly recommended purposes. Regarding the ASP team members, the participation [29], although these variables were poorly represented in the of an infectologist and pharmacist, together with the head of studies included in our review. the ED and with the support of microbiology services, is the Another finding of our review is the limited evaluation basis for implementing such programmes [33-35]. The success of the ecological impact of these programmes. C. difficile in- of these programmes requires adjusting the interventions to fection rate was used in two studies [26,31], being its value the local needs and to the available resources [9]. However, our of doubtful applicability for ED intervention, as most of pa- review shows that most experiences described in the literature tients are already affected before ED admission. The selection do not include this type of the ASP team composition, with in- of microbiologic indicators for these units remains a challenge fectologists being represented in only 30.7% and pharmacists because interventions such as antibiotic treatment shortening in 42.3% of ASP teams. or antibiotic de-escalation, associated with reductions in the In this review we have included studies of ASPs in adult number of nosocomial infections due to multiresistant strains and paediatric population. Although the objectives and indi- mostly match other levels of care. In turn, although these in- cators proposed for ASP in hospitalized patients and primary dicators are necessary, they are often difficult to interpret be- care are different from each other’s, the high care burden, the cause their number depend, to a large extent, on other factors lack of diagnostic results for the initiation of antibiotic therapy Rev Esp Quimioter 2021;34(6): 610-617 614 J. Ruiz-Ramos, et al. 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