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Linking infection control to clinical management of infections to overcome antimicrobial resistance

  • E. Tacconelli
    Correspondence
    Address: Malattie Infettive, Dipartimento Diagnostica e Sanità pubblica, Ospedale Borgo Roma, Piazzale L.A. Scuro, 10 - 37134, Verona, Italy.
    Affiliations
    Infectious Disease Division, Department of Diagnostics and Public Health, University Hospital Verona, Verona, Italy

    Infectious Disease Division, Department of Internal Medicine I, Tuebingen University, Tuebingen, Germany
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      Keywords

      Introduction

      The ‘Healthcare Standards in Europe’ document (2013) makes it clear that ‘access to healthcare is an essential element of human dignity and human rights, and guaranteed by the European Union's Charter of Fundamental rights'. Thus, everyone has the right to access preventive healthcare and the right to benefit from medical treatment [

      EU Charter of Fundamental Rights. Available at: https://fra.europa.eu/en/eu-charter/article/35-health-care [last accessed April 2021].

      ]. While this premise can be satisfied only if the standard of healthcare is the same in all of Europe, at present healthcare status indicators such as life expectancy and morbidity and mortality of many communicable diseases are heterogeneous [

      European Commission. European Core Health Indicators (ECHI). Available at: https://ec.europa.eu/health/indicators_data/indicators_en [last accessed April 2021].

      ]. Within this scenario, antimicrobial resistance (AMR) continues to represent growing threat to public health in Europe and worldwide. The global spread of AMR and differences in resistance rates among European countries must therefore be considered a threat for public health and the rights for equivalent healthcare standards.
      There are multiple causes for the differences in resistance rates, with dissimilarities in annual investment in healthcare, case-mix hospital populations, organization of healthcare in the community, personnel:patient ratio, number of long-term care facilities and rehabilitation centres, climatic factors, travel, medical tourism, usage of antibiotics in animals and the environment, and smoking and drinking habits, among others [
      • Chatterjee A.
      • Modarai M.
      • Naylor N.R.
      • Boyd S.E.
      • Atun R.
      • Barlow J.
      • et al.
      Quantifying drivers of antibiotic resistance in humans: a systematic review.
      ]. As expected, the prevalence of invasive infections caused by antibiotic-resistant bacteria seems inversely associated with gross national income (GNI) per capita at a global level [
      • Savoldi A.
      • Carrara E.
      • Gladstone B.P.
      • Azzini A.M.
      • Gopel S.
      • Tacconelli E.
      Gross national income and antibiotic resistance in invasive isolates: analysis of the top-ranked antibiotic-resistant bacteria on the 2017 WHO priority list.
      ]. Analysis of surveillance data from 67 countries (57% high income, 24% upper-middle income, and 9% low-middle income) and GNI per capita showed a significant inverse association between prevalence of third-generation cephalosporin-resistant Klebsiella spp., carbapenem-resistant Acinetobacter spp. and third-generation cephalosporin Escherichia coli invasive infections and GNI per capita (Figure 1). This highlights that development of public health interventions, designed to limit the burden of AMR, is extremely complex and suggests the need to consider not only healthcare-associated drivers, but also the causes of poverty, especially in countries with lower-middle and low incomes.
      Figure 1
      Figure 1Linear regression analysis displaying gross national income per capita in US dollars and prevalence of third-generation cephalosporin-resistant (3GCR) Klebsiella spp. resistance rates (log10 scale) [
      • Savoldi A.
      • Carrara E.
      • Gladstone B.P.
      • Azzini A.M.
      • Gopel S.
      • Tacconelli E.
      Gross national income and antibiotic resistance in invasive isolates: analysis of the top-ranked antibiotic-resistant bacteria on the 2017 WHO priority list.
      ]. The solid line represents the estimated increase in resistance; the dashed lines represent the 95% CI. The countries are grouped by income in three categories, according to the 2019 World Bank Classification thresholds: high income, upper-middle income, lower-middle income.
      The magnitude of healthcare-associated infections (HCAIs) and AMR in Europe is established mainly by point-prevalence surveys carried out by the European Centre for Disease Prevention and Control (ECDC), the European Antimicrobial Resistance Surveillance Network (EARS-Net), and national institutions or networks. The most recent point-prevalence survey in acute care hospitals reported that 5.7% of patients developed HCAIs, totalling 3.2 million cases annually with a contributory impact of approximately 150,000 deaths and 16 million additional hospital-days each year in Europe [
      European Centre for Disease Control and Prevention
      Point prevalence survey of healthcare-associated infections and antimicrobial use in European acute care hospitals 2011–2012.
      ]. In addition, a point-prevalence survey estimated that there were an additional 4.2 million HCAIs annually in long-term care facilities [].
      AMR adds significantly to the burden of HCAIs. In the 2011–2012 hospital point-prevalence survey, resistance to meticillin was found in 41% of invasive Staphylococcus aureus isolates, vancomycin resistance in 10% of enterococci, third-generation cephalosporin resistance in 33% of Enterobacteralesand carbapenem resistance in 8% of Enterobacterales, 32% of Pseudomonas aeruginosa and 81% of A. baumannii isolates [
      European Centre for Disease Control and Prevention
      Point prevalence survey of healthcare-associated infections and antimicrobial use in European acute care hospitals 2011–2012.
      ]. In community-acquired infections as well as in the animal and food compartment and environment, AMR is also increasingly detected even if there is evident variation between countries [
      • Armand-Lefevre L.
      • Andremont A.
      • Ruppe E.
      Travel and acquisition of multidrug-resistant Enterobacteriaceae.
      ,
      • Bombaywala S.
      • Mandpe A.
      • Paliya S.
      • Kumar S.
      Antibiotic resistance in the environment: a critical insight on its occurrence, fate, and eco-toxicity.
      ,
      • Chong Y.
      • Shimoda S.
      • Shimono N.
      Current epidemiology, genetic evolution and clinical impact of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
      ,
      • McNeil J.C.
      • Fritz S.A.
      Prevention strategies for recurrent community-associated Staphylococcus aureus skin and soft tissue infections.
      ].

      The burden of AMR

      The burden of increasing rates of AMR has a broad impact on healthcare. AMR threatens the safety and efficacy of surgical procedures and immunosuppressing therapies as it increases the risk of infections by isolates that are resistant to front-line antibiotics. In the USA, for example, it has been estimated that the reduced efficacy of prophylaxis from AMR in post-surgical infections leads to 120,000 more infections annually with more than 6000 related deaths [
      • Teillant A.
      • Gandra S.
      • Barter D.
      • Morgan D.J.
      • Laxminarayan R.
      Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a literature review and modelling study.
      ]. Highly increased risk for infection after routine procedures such as Caesarean section (>21,000 additional wound infections) and transurethral prostate biopsy (>17,000 additional urinary tract infections) was also estimated [
      • Teillant A.
      • Gandra S.
      • Barter D.
      • Morgan D.J.
      • Laxminarayan R.
      Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a literature review and modelling study.
      ].
      The burden of AMR seems to encompass the most common bacteria responsible for HCAIs and community-acquired infections. In this regard, Helicobacter pylori isolates are increasingly reported as being resistant to first-line antibiotics. In a meta-analysis of 178 studies that included 66,142 isolates from 65 countries, the overall prevalence of primary and secondary resistance of H. pylori to clarithromycin, metronidazole and levofloxacin was >15%, which is the standard threshold for preferring unconventional empirical regimens according to international guidance [
      • Savoldi A.
      • Carrara E.
      • Graham D.Y.
      • Conti M.
      • Tacconelli E.
      Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in World Health Organization regions.
      ]. Moreover, the increased resistance to clarithromycin causes additional burden of H. pylori infection since it is significantly associated with failure of antibiotic regimens containing clarithromycin [
      • Savoldi A.
      • Carrara E.
      • Graham D.Y.
      • Conti M.
      • Tacconelli E.
      Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in World Health Organization regions.
      ]. The increase in AMR in H. pylori may also lead to an increase in the incidence of gastric cancer. Based on estimates from GLOBOCAN, gastric cancer has the highest incidence in Western Asia (China, Japan and Korea), where rates of AMR are very high [
      • Torre L.A.
      • Bray F.
      • Siegel R.L.
      • Ferlay J.
      • Lortet-Tieulent J.
      • Jemal A.
      Global cancer statistics, 2012.
      ]. By contrast, in regions with lower levels of AMR such as the Americas, a lower incidence of gastric cancer is observed [
      • Torre L.A.
      • Bray F.
      • Siegel R.L.
      • Ferlay J.
      • Lortet-Tieulent J.
      • Jemal A.
      Global cancer statistics, 2012.
      ]. Notwithstanding, a causal relationship is difficult to demonstrate since the lack of surveillance systems for antibiotic-resistant H. pylori does not allow for precise quantification of the actual incidence of infections that are resistant to antibiotics. In countries where H. pylori is endemic, the role of eradication in reducing the incidence of gastric cancer has been widely recognized [
      • Lee Y.C.
      • Chiang T.H.
      • Chou C.K.
      • Tu Y.K.
      • Liao W.C.
      • Wu M.S.
      • et al.
      Association between Helicobacter pylori eradication and gastric cancer incidence: a systematic review and meta-analysis.
      ,
      • Rokkas T.
      • Rokka A.
      • Portincasa P.
      A systematic review and meta-analysis of the role of Helicobacter pylori eradication in preventing gastric cancer.
      ]. Based on current levels of AMR, it can be hypothesized that the trend in reduction will soon invert, since current treatments no longer guarantee satisfactory eradication of H. pylori [
      • Savoldi A.
      • Carrara E.
      • Graham D.Y.
      • Conti M.
      • Tacconelli E.
      Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in World Health Organization regions.
      ].
      Accurate assessment of the impact of AMR is fundamental for public health, since it evaluates the relevance of specific interventions as well as decisions on policy and investment. However, the burden of AMR at national and global levels is substantially underestimated and is mainly derived from surveillance systems data [
      UK Department of HealthWellcome Trust
      Tackling drug-resistant infections globally: final report and recommendations. The review on antimicrobial resistance.
      ,
      US Centers for Disease Control and Prevention
      Biggest threats and data.
      ,
      European Centre for Disease Prevention and Control
      Annual surveillance reports on antimicrobial resistance.
      ,
      • Cassini A.
      • Högberg L.D.
      • Plachouras D.
      • Quattrocchi A.
      • Hoxha A.
      • Simonsen G.S.
      • et al.
      Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis.
      ]. In a recent meta-analysis examining the effects of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales in 22,030 patients and 149 outcome measures, ESBL production in patients with bloodstream infections increased the risk ratio for all-cause mortality by 1.70 and attributable mortality by 1.75, while increasing stay in the intensive care unit and hospital by 3.07 days and 4.41 days, respectively [
      • Shamsrizi P.
      • Gladstone B.P.
      • Carrara E.
      • Luise D.
      • Cona A.
      • Bovo C.
      • et al.
      Variation of effect estimates in the analysis of mortality and length of hospital stay in patients with infections caused by bacteria-producing extended-spectrum beta-lactamases: a systematic review and meta-analysis.
      ].
      The Global Burden of Disease (GBD) study is the most comprehensive assessment of the burden of disease on global health, stratified by age, sex, and region [
      • Murray C.J.
      • Lopez A.D.
      Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study.
      ]. However, AMR was never included in the GBD study, the only exception being multidrug-resistant tuberculosis [
      GBD 2015 DALYsHALE Collaborators
      Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015.
      ,
      GBD 2016 DALYsHALE Collaborators
      Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.
      ]. This highlights the difficulties of comparing AMR with other health problems in order to correctly prioritize public health measures and interventions.

      Identifying priority antibiotic-resistant bacteria

      Despite the fact that the spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide, the clear clinical need for new antibiotics has not been met [

      World Health Organization. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Available at: https://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf?ua=1 [last accessed April 2021].

      ,
      • Tacconelli E.
      • Carrara E.
      • Savoldi A.
      • Harbarth S.
      • Mendelson M.
      • Monnet D.L.
      • et al.
      Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis.
      ,
      • Theuretzbacher U.
      • Bush K.
      • Harbarth S.
      • Paul M.
      • Rex J.H.
      • Tacconelli E.
      • et al.
      Critical analysis of antibacterial agents in clinical development.
      ]. To prioritize funding and facilitate global coordination of research and development strategies for the discovery of new antimicrobial agents, the World Health Organization (WHO) was requested by Member States to develop a priority list for antibiotic-resistant bacteria as a guide to pharmaceutical companies, universities, public research institutions and public–private partnerships in the research and development of new antibiotics [

      World Health Organization. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Available at: https://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf?ua=1 [last accessed April 2021].

      ]. The WHO priority list, an innovative example of an international effort to prioritize research and development of new antibiotics, combines evidence and expert opinion via a multi-criteria decision analysis (MCDA) method including availability and effectiveness of infection prevention and control (IPC) and antibiotics [
      • Kaksalan M.Z.S.
      • Wallenius J.
      Multiple criteria decision making from early history to the 21st century.
      ]. The methodology applied, MCDA, is actually a family of methods used to identify priorities by comparing alternatives on the basis of multiple criteria and has been increasingly used in many decision-making processes in several environmental and healthcare-related processes to allocate resources, prioritize research, and manage risk [
      • Frazao T.D.C.
      • Camilo D.G.G.
      • Cabral E.L.S.
      • Souza R.P.
      Multicriteria decision analysis (MCDA) in health care: a systematic review of the main characteristics and methodological steps.
      ,
      • Guarga L.
      • Badia X.
      • Obach M.
      • Fontanet M.
      • Prat A.
      • Vallano A.
      • et al.
      Implementing reflective multicriteria decision analysis (MCDA) to assess orphan drugs value in the Catalan Health Service (CatSalut).
      ,
      • Howard S.
      • Scott I.A.
      • Ju H.
      • McQueen L.
      • Scuffham P.A.
      Multicriteria decision analysis (MCDA) for health technology assessment: the Queensland Health experience.
      ,
      • Lasalvia P.
      • Prieto-Pinto L.
      • Moreno M.
      • Castrillón J.
      • Romano G.
      • Garzón-Orjuela N.
      • et al.
      International experiences in multicriteria decision analysis (MCDA) for evaluating orphan drugs: a scoping review.
      ,
      • Hansen P.
      • Ombler F.
      A new method for scoring additive multi-attribute value models using pairwise rankings of alternatives.
      ].
      Of interest, two large prioritization exercises were developed before the WHO list: the 2013 list from the US Centers for Disease Control and Prevention (CDC) and the 2015 list from the Public Health Agency of Canada [
      Centers for Disease Control and Prevention
      Antibiotic resistance threats in the United States 2013.
      ,
      • Garner M.J.
      • Carson C.
      • Lingohr E.J.
      • Fazil A.
      • Edge V.L.
      • Trumble Waddell J.
      An assessment of antimicrobial resistant disease threats in Canada.
      ]. It is important to note that the WHO list focuses on research and development, and does not have the intent to give priority to public health interventions. It is important to note this difference since prioritization for public health must consider other aspects such as investments in vaccination, sanitation, and health management. These factors can reduce the burden of disease much more quickly than development of new antibiotics, which is time-consuming and resource intense [
      • Tacconelli E.
      • Carrara E.
      • Savoldi A.
      • Harbarth S.
      • Mendelson M.
      • Monnet D.L.
      • et al.
      Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis.
      ].
      The final ranking of antibiotic-resistant bacteria comprised 20 bacteria that showed 25 patterns of antibiotic resistance. Bacteria were grouped into three priority tiers (critical, high, and medium) based on the 33rd percentile of the total scores as a cut-off. Carbapenem-resistant A. baumannii and P. aeruginosa, and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacterales, were ranked as having critical priority, while the high priority bacteria were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus (MRSA). Clarithromycin-resistant H. pylori, fluoroquinolone-resistant Campylobacter spp., Neisseria gonorrhoeae, and Salmonella typhi, typically responsible for community infections, were also included in the high priority tier.

      Effectiveness of infection control measures and antibiotic stewardship interventions in reducing AMR

      A systematic review using a One Health approach to quantify the key risk factors for AMR in humans assessed 565 studies, reporting that among the 88 risk factors retrieved, previous antibiotic exposure, underlying disease, and invasive procedures had the most supporting evidence [
      • Chatterjee A.
      • Modarai M.
      • Naylor N.R.
      • Boyd S.E.
      • Atun R.
      • Barlow J.
      • et al.
      Quantifying drivers of antibiotic resistance in humans: a systematic review.
      ]. It is clear that minimizing the spread of AMR in healthcare settings requires an all-inclusive approach that targets infection control as well as diagnostic and antibiotic stewardship (Figure 2). Any intervention must also target several components that influence endemicity. Some of the main targets include minimizing the constant influx of resistant bacteria into the healthcare environment from newly admitted patients, avoiding cross-transmission between hospitalized patients and healthcare staff, and circumventing community transmission of resistant bacteria from the healthcare environment following discharge of patients. For example, with ESBL-producing Enterobacterales, it has been recently demonstrated that cases discharged from hospital are a relevant source of community infections, with the majority of transmission events related to care activities in the home [
      • Riccio M.E.
      • Verschuuren T.
      • Conzelmann N.
      • Martak D.
      • Meunier A.
      • Salamanca E.
      • et al.
      Household acquisition and transmission of extended-spectrum beta-lactamase (ESBL)-producing Entero-bacteriaceae after hospital discharge of ESBL-positive index patients.
      ]. Thus, developing effective prevention strategies and hygiene measures mandates full comprehension of all these processes.
      Figure 2
      Figure 2Priority areas to be considered when implementing an antibiotic stewardship programme.
      International recommendations and guidance documents strongly encourage implementing a multi-component approach in which unnecessary antibiotic use is restricted and adequate infection control measures are adopted [
      • Tacconelli E.
      • Cataldo M.A.
      • Dancer S.J.
      • De Angelis G.
      • Falcone M.
      • Frank U.
      • et al.
      ESCMID guidelines for the management of the infection control measures to reduce transmission of multidrug-resistant Gram-negative bacteria in hospitalized patients.
      ,

      World Health Organization. Infection control standard precautions in health care. Available at: https://www.who.int/csr/resources/publications/4EPR_AM2.pdf [last accessed April 2021].

      ,

      European Centre for Disease Prevention and Control. Infection prevention and control and preparedness for COVID-19 in healthcare settings – sixth update. Available at: https://www.ecdc.europa.eu/en/publications-data/infection-prevention-and-control-and-preparedness-covid-19-healthcare-settings [last accessed April 2021].

      ]. The effectiveness of infection control programmes on prevention of cross-transmission and association of antibiotic use with AMR is well documented. A meta-analysis of 145 studies reported that guideline-adherent empirical therapy, therapeutic de-escalation, switching from intravenous to oral therapy, therapeutic drug monitoring, compiling a list of antibiotics whose use should be restricted, and bedside consultation all had significant benefit on at least one of four outcomes (clinical outcomes, adverse events, costs, and bacterial resistance rates). Importantly, empirical therapy that adhered to guidelines was associated with a reduced risk for mortality of 35%, and de-escalation of therapy of 66%. This provides strong evidence that restrictive and guideline-adherent strategies undoubtedly improve appropriate antimicrobial use and should be used to guide patient care and stewardship teams.
      Interestingly, infection control and stewardship interventions appear to be running ‘in real life’ on two separate paths with limited crosstalk. This perceived separation is remarkable because several international guidance documents stress the importance of linking IPC and antimicrobial stewardship (AMS) strategies [
      • Shlaes D.M.
      Research and development of antibiotics: the next battleground.
      ].
      One of the first examples on how common efforts can be successfully implemented in combination was documented in studies on control of MRSA. In 2015, Lawes et al. reported on the results of a non-linear time-series analysis that explored the ecological determinants of MRSA epidemiology among 1,289,929 hospital admissions and 455,508 adults in primary care in Scotland [
      • Lawes T.
      • Lopez-Lozano J.M.
      • Nebot C.A.
      • Macartney G.
      • Subbarao-Sharma R.
      • Rj Dare C.
      • et al.
      Effects of national antibiotic stewardship and infection control strategies on hospital-associated and community-associated meticillin-resistant Staphylococcus aureus infections across a region of Scotland: a non-linear time-series study.
      ]. Interventions included restricting the use of both 4C (cephalosporins, co-amoxiclav, clindamycin, and fluoroquinolones) and macrolide antibiotics, in addition to a hand hygiene campaign, inspections in hospital, and screening for MRSA upon admission. AMS interventions significantly decreased the use of 4C and macrolide antibiotics by almost 50% in hospitals and by around 25% in the community. Moreover, the prevalence of MRSA in hospitals was inversely correlated with increased use of IPC, but positively correlated with MRSA rates in neighbouring hospitals, bed occupancy, and use of 4C antibiotics that surpassed specific thresholds. The highest impact was achieved by combined AMS and IPC measures, which reduced the prevalence density of MRSA by 50% in hospitals and by 47% in the community. Similar experiences have been reported in different countries. As one example, efforts in South Korea to use a strategy of AMS and hand hygiene for 3 years reduced the incidence of MRSA bloodstream infections from 0.171 per 1000 patient-days to 0.116 per 1000 patient-days where the rate of MRSA was about 65% in hospital [
      • Kim Y.C.
      • Kim M.H.
      • Song J.E.
      • Ahn J.Y.
      • Oh D.H.
      • Kweon O.M.
      • et al.
      Trend of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in an institution with a high rate of MRSA after the reinforcement of antibiotic stewardship and hand hygiene.
      ].
      The combination of stewardship and infection control has also been successfully reported even in countries with high endemicity for carbapenem-resistant Gram-negative bacteria. In a study of a multi-faceted control programme to reduce infections with carbapenem-resistant Enterobacterales, the interventions implemented included screening in all patients admitted to any high-risk unit, cohorting of carriers, intensification of education, cleaning, and hand-washing programmes and endorsing an AMS carbapenem-sparing regimen [
      • Viale P.
      • Tumietto F.
      • Giannella M.
      • Bartoletti M.
      • Tedeschi S.
      • Ambretti S.
      • et al.
      Impact of a hospital-wide multifaceted programme for reducing carbapenem-resistant Enterobacteriaceae infections in a large teaching hospital in northern Italy.
      ]. Following these interventions, the incidences of both bloodstream infections and colonization with carbapenem-resistant Enterobacterales decreased significantly over a 30-month period. Additionally, the mean monthly rate of compliance with carbapenem-resistant Enterobacterales screening procedures was independently associated with a decreased monthly incidence of colonization with these bacteria.
      The positive link is frequently documented in epidemic settings. A successful combination of measures was reported in a secondary/tertiary care hospital in Quebec to control an epidemic of a virulent strain causing nosocomial Clostridioides difficile-associated disease (n-CDAD) [
      • Valiquette L.
      • Cossette B.
      • Garant M.P.
      • Diab H.
      • Pepin J.
      Impact of a reduction in the use of high-risk antibiotics on the course of an epidemic of Clostridium difficile-associated disease caused by the hypervirulent NAP1/027 strain.
      ]. In addition to infection control measures, a non-restrictive AMS programme was developed. Of the two time-periods evaluated, namely 2003–2004 to 2005–2006, total and targeted antibiotic consumption decreased by 23% and 54%, respectively, with a concomitant decrease in the incidence of n-CDAD by 60%. The authors highlighted that non-restrictive measures to optimize use of antibiotics can lead to good results only if healthcare professionals are adequately motivated and that the measures adopted should be a compulsory part of control measures for n-CDAD. Whereas no change was seen in the incidence of n-CDAD following implementation infection control measures, it was hypothesized that this might be explained by the fact that the measures were implemented late in the epidemic, and thus the hospital was likely heavily contaminated with spores.
      A meta-analysis of 16 studies evaluating effect of AMS on the risk of C. difficile infection in hospitalized adult patients reported a significant protective effect of AMS and the incidence of C. difficile infection (relative risk: 0.48; 95% confidence interval (CI): 0.38–0.62) [
      • Feazel L.M.
      • Malhotra A.
      • Perencevich E.N.
      • Kaboli P.
      • Diekema D.J.
      • Schweizer M.L.
      Effect of antibiotic stewardship programmes on Clostridium difficile incidence: a systematic review and meta-analysis.
      ]. Moreover, when stratified by type of intervention, a significant benefit was seen for restrictive AMS (i.e. complete removal of drug or requirement for approval for use). AMS was found to be particularly beneficial in geriatric settings in hospital.
      The combination of infection control and AMS also seems to increase the effectiveness of results in the emergency department (ED) and may represent a crucial setting for implementing AMS programmes. In a study by Savoldi et al., a non-restrictive, multi-faceted AMS programme lasting 4 years was implemented in a general ED in order to evaluate the impact on antibiotic use and costs. The intervention included enhanced training in infection control and active AMS recommendations tailored by local microbiological data. The intervention was associated with a reduction in both antibiotic use and costs. A decrease in hospital length of stay was also seen across all medical wards together with a significant decrease in C. difficile infections [
      • Savoldi A.
      • Foschi F.
      • Kreth F.
      • Gladstone B.P.
      • Carrara E.
      • Eisenbeis S.
      • et al.
      Impact of implementing a non-restrictive antibiotic stewardship program in an emergency department: a four-year quasi-experimental prospective study.
      ].
      The importance of AMS in reducing the burden of AMR was demonstrated in a systematic review and meta-analysis of 32 studies including 9,056,241 patient days and 159 estimates of incidence ratios [
      • Baur D.
      • Gladstone B.P.
      • Burkert F.
      • Carrara E.
      • Foschi F.
      • Döbele S.
      • et al.
      Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis.
      ]. AMS programmes were found to significantly decrease the incidence of both infections and colonization with multidrug-resistant Gram-negative bacteria by 51%, extended-spectrum β-lactamase-producing Gram-negative bacteria by 48%, MRSA by 37%, and C. difficile infections by 32% (Figure 3). AMS programmes were also significantly more effective when implemented with infection control measures, and especially hand hygiene compared to AMS by itself. However, AMS had no effect on the incidence ratios of vancomycin-resistant enterococci and quinolone-resistant and aminoglycoside-resistant Gram-negative bacteria.
      Figure 3
      Figure 3Forest plots of the incidence ratios for studies investigating the effect of antimicrobial stewardship on incidence of antibiotic resistant infections in hospitalized patients (modified from [
      • Baur D.
      • Gladstone B.P.
      • Burkert F.
      • Carrara E.
      • Foschi F.
      • Döbele S.
      • et al.
      Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis.
      ]). ICU, intensive care unit; ICM, infection control measure; ASP, antibiotic stewardship programme.
      Thus, the effectiveness of AMS and IPC in reducing the diffusion of AMR is supported by abundant evidence, strongly suggesting that these tools should be implemented together into daily practice.

      Linking surveillance and stewardship intervention

      Among ICP, major international public health institutions have made recommendations that consider surveillance as essential pillars to combat AMR [
      • Pollack L.A.
      • Srinivasan A.
      Core elements of hospital antibiotic stewardship programs from the Centers for Disease Control and Prevention.
      ,
      • Schuts E.C.
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      Current evidence on hospital antimicrobial stewardship objectives: a systematic review and meta-analysis.
      ,

      World Health Organization. Global action plan on antimicrobial resistance. Available at: https://apps.who.int/iris/bitstream/handle/10665/193736/9789241509763_eng.pdf?sequence=1 [last accessed April 2021].

      ]. Given the different structures of healthcare systems worldwide together with disparities in the availability of surveillance data and resources, these activities are difficult to standardize, and therefore practical guidance is lacking for many aspects. In addition, the available data are not homogeneous, and broad efforts are required to achieve greater harmonization, representativeness, and overall quality of reporting [
      • Pezzani M.D.
      • Tornimbene B.
      • Pessoa-Silva C.
      • de Kraker M.
      • Rizzardo S.
      • Duccio Salerno N.
      • et al.
      Methodological quality of studies evaluating the burden of drug-resistant infections in humans due to the WHO Global Antimicrobial Resistance Surveillance System target bacteria.
      ]. Whereas guidelines for implementation of AMS policies in acute care settings recommend tailoring AMS interventions to local epidemiology, they seldom provide details on how surveillance data should be integrated with AMS [
      British Society for Antimicrobial Chemotherapy
      Antimicrobial stewardship from principles to practice, UK.
      ,
      • Barlam T.F.
      • Cosgrove S.E.
      • Abbo L.M.
      • MacDougall C.
      • Schuetz A.N.
      • Septimus E.J.
      • et al.
      Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.
      ,
      • Dellit T.H.
      • Owens R.C.
      • McGowan Jr., J.E.
      • Gerding D.N.
      • Weinstein R.A.
      • Burke J.P.
      • et al.
      Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship.
      ]. In fact, only limited information is available regarding how and when data should be reported, how data should be aggregated, and, crucially, how this data should be used to implement AMS strategies [
      • Barlam T.F.
      • Cosgrove S.E.
      • Abbo L.M.
      • MacDougall C.
      • Schuetz A.N.
      • Septimus E.J.
      • et al.
      Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.
      ,

      European Centre for Disease Prevention and Control. EU guidelines for the prudent use of antimicrobials in human health. Available at: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A52017XC0701%2801%29 [last accessed April 2021].

      ,
      • Davey P.
      • Marwick C.A.
      • Scott C.L.
      • Charani E.
      • McNeil K.
      • Brown E.
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      Interventions to improve antibiotic prescribing practices for hospital inpatients.
      ,
      • de With K.
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      • Brodt H.-R.
      • Eckmanns T.
      • et al.
      Strategies to enhance rational use of antibiotics in hospital: a guideline by the German Society for Infectious Diseases.
      ].
      An example of the difficulty in linking the two components was reported in US Veterans Affairs (VA) Medical Centers, which registered an increase in vancomycin use after the implementation of an active surveillance programme for MRSA [
      • Jones M.
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      • Damal K.
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      • et al.
      Does universal active MRSA surveillance influence anti-MRSA antibiotic use? A retrospective analysis of the treatment of patients admitted with suspicion of infection at Veterans Affairs Medical Centers between 2005 and 2010.
      ]. In that study, the availability of nasal surveillance tests for MRSA did not appear to provide any benefit in the ability to predict the need for initial therapy for MRSA, despite the high negative predictive value of surveillance tests. Positive MRSA surveillance tests were found to be strong predictors of positive MRSA cultures on admission (odds ratio: 8.5; 95% CI: 8.2–8.8). Moreover, for patients without surveillance tests the diagnostic odds ratio was 3.2 for initial anti-MRSA antibiotic use and a positive MRSA culture on admission, which was not different for patients admitted with surveillance tests.
      Even when data are available, it seems that the prescribers do not trust it. For example, an epidemiological study correlated resistance rates of Gram-positive bacteria and glycopeptide antibiotic use in 31 countries over a period of 19 years [
      • Gladstone B.P.
      • Cona A.
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      • Vilken T.
      • Kern W.V.
      • Malek N.
      • et al.
      Antimicrobial resistance rates in Gram-positive bacteria do not drive glycopeptides use.
      ]. In the majority of countries, use of glycopeptides increased and the rates of MRSA bloodstream infections decreased, while bloodstream infections with meticillin-resistant coagulase negative staphylococci and vancomycin-resistant enterococci were unchanged. Moreover, changes in the defined daily dose of glycopeptides were not associated with changes in bloodstream infections due to MRSA or vancomycin-resistant enterococci. Among 21 countries, about half had a concordant or discordant trend in annual defined daily dose of glycopeptides and rates of bloodstream infections due to MRSA, while in eight countries no correlation was seen between resistance rates and defined daily dose. In order to promote the use of epidemiological data to bridge the gap between surveillance data and AMS, the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR)-funded ARCH Network (Bridging the gap between humAn and animal suRveillance data, antibiotic poliCy, and stewardsHip (ARCH)) was established, bringing together multi-sector specialists and networks in both animal and human surveillance. ARCH Net has several broad goals. These comprise: (i) provide new tools to favour cooperation between surveillance and AMS teams; (ii) enable AMS teams to carry out appropriate assessment of AMR rates depending on the case-mix of patients and settings to provide policy recommendations; (iii) minimize heterogeneity of microbiological and sensitivity data in surveillance systems; (iv) harmonize reporting in animal surveillance and stewardship and to relate this with human recommendations.
      To achieve these goals, the ARCH, in collaboration with the Innovative Medicines Initiative (IMI)-funded Combatting Bacterial Resistance in Europe – Molecules Against Gram Negative Infections (COMBACTE-MAGNET) Epidemiology Network (EPI-Net), designed a structure that defines actions to facilitate interventions on antibiotic policy and to link surveillance data on AMR, antibiotic consumption, and implementation of AMS [

      Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). ARCH NET. Available at: https://archnet-surveillance.eu/ [last accessed April 2021].

      ,

      Combatting Bacterial Resistance in Europe – Molecules Against Gram Negative Infections (COMBACTE-MAGNET). EPI-Net. Available at: https://epi-net.eu/ [last accessed April 2021].

      ]. This network of experts published a series of four White Papers – ‘Bridge the Gap: Survey to Treat’ – each of which focused on four settings: hospital, outpatient, long-term care facilities, and veterinary [
      • Arieti F.
      • Gopel S.
      • Sibani M.
      • Carrara E.
      • Pezzani M.D.
      • Murri R.
      • et al.
      White Paper: Bridging the gap between surveillance data and antimicrobial stewardship in the outpatient sector – practical guidance from the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks.
      ,
      • Compri M.
      • Mader R.
      • Mazzolini E.
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      • Mutters N.T.
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      • et al.
      White Paper: Bridging the gap between surveillance data and antimicrobial stewardship in the animal sector – practical guidance from the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks.
      ,
      • Pezzani M.D.
      • Carrara E.
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      • Gastmeier P.
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      • et al.
      White Paper: Bridging the gap between human and animal surveillance data, antibiotic policy and stewardship in the hospital sector – practical guidance from the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks.
      ,
      • Sibani M.
      • Mazzaferri F.
      • Carrara E.
      • Pezzani M.D.
      • Arieti F.
      • Göpel S.
      • et al.
      White Paper: Bridging the gap between surveillance data and antimicrobial stewardship in long-term care facilities-practical guidance from the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks.
      ]. Each provided practical checklists and summarized the available epidemiological, microbiological and antimicrobial data needed for decisions on antibiotic prescribing and policy. These publications were all based on the One Health approach and focused on the practicability of the actions recommended and their relevance in diverse economic settings and in contexts with limited proficiency in surveillance and AMS. Easy-to-use checklists can also be downloaded to facilitate their use.

      Learning from COVID-19

      The COVID-19 pandemic has ushered in a new era, highlighting a paradigm shift in infection management. The population at risk of severe COVID-19 largely overlaps with the population at risk of HCAIs [
      • Rodríguez-Baño J.
      • Rossolini G.M.
      • Schultsz C.
      • Tacconelli E.
      • Murthy S.
      • Ohmagari N.
      • et al.
      Key considerations on the potential impacts of the COVID-19 pandemic on antimicrobial resistance research and surveillance.
      ]. The question then arises as to whether high income societies will continue to accept substantial numbers of avoidable deaths caused by HCAIs and antibiotic-resistant infections while risking an unprecedented economic and societal burden to protect the same risk group from COVID-19. The necessary efforts against HCAIs and AMR are now marginal compared with current efforts against COVID-19. However, the pandemic has changed our ways of thinking and has paved the way for more efficient measures against other types of infection [
      • Vehreschild M.
      • Tacconelli E.
      • Giske C.G.
      • Peschel A.
      Beyond COVID-19 – a paradigm shift in infection management?.
      ]. The pandemic has established new forms of networking and collaboration processes: we learned how to rapidly disseminate new data on preprint servers and social Internet platforms; how to analyse viral genomes instantaneously on GISAID by different evolutionary biologists; and how to link clinical and epidemiological cohorts [
      • Rodriguez-Bano J.
      • Rossolini G.M.
      • Schultsz C.
      • Tacconelli E.
      • Murthy S.
      • Ohmagari N.
      • et al.
      Antimicrobial resistance research in a post-pandemic world: insights on antimicrobial resistance research in the COVID-19 pandemic.
      ].

      Concluding remarks

      The rate of infections caused by antimicrobial resistant micro-organisms is seen increasingly by the public and healthcare inspection organizations as an indicator of quality of healthcare and patient safety. Reducing the burden of AMR can be achieved only with coordinated efforts of both preventive and therapeutic approaches. To help achieve this, evidence-based, integrated modular strategies need to be developed to carry out interventional programmes integrating IPC and AMS. New educational tools are also needed that link infection control and therapeutic perspectives using a meta-competence approach, while the integration of ICP and clinical management also needs to be disseminated through common guidance documents. It is extremely urgent improve and connect surveillance systems all over Europe to guarantee rapid acquisition of constantly updated resistance rates to drive therapeutic recommendations and IPC measures. Finally, the COVID-19 experience should not be lost; sustainability plans must be developed to ensure that the new coordinated networks for COVID-19 can be ‘reused’ for AMR. Creating perpetual cohorts to prevent and treat infectious diseases seems the right investment to increase preparedness and avoid waste of research funding and manpower. This lesson seems even more important considering that antimicrobial-resistant infections are not disappeared and are adding to the burden of the ongoing pandemic.

      Conflict of interest statement

      None declared.

      Funding sources

      None.

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