In Europe in 2008, 16 countries had developed a national strategy to contain antimicrobial resistance, and 9 countries had an action plan (11). If we are to preserve antibiotics as a valuable and precious resource and extend their useful life, a core component of most of these strategies is antimicrobial stewardship (ABS), which has been defined as a set of measures or interventions delivered by a multidisciplinary team working in healthcare institutions to optimize antimicrobial use among patients in order to improve patient outcomes, ensure cost-effective therapy, and reduce adverse sequelae of antimicrobial use including ecological effects such as resistance and Clostridium difficile infections (CDI) (12, 13 and 14). There are also formidable hospital and society costs associated with antimicrobial-resistant infections (ARI). In a recent study of 1391 hospitalised patients 188 (13.5%) had a antimicrobial resistant infection (ARI). The medical costs attributable to the ARI ranged from $18,588 to $29,069 and excess duration of hospital stay and attributable mortality of 6.4 to 12.7 days and 6.5% respectively. The total costs to this patient cohort were $13.35 million in 2008. This study eloquently identifies the potential beneficial fiscal impact of good ABS programs and their cost-effectiveness (15).

At the heart of any stewardship program is an antimicrobial management (AMT) or stewardship (AST) team— terms commonly used for the multidisciplinary team. In this program, each member is given specific roles, which collectively take responsibility for the implementation of local policies. The critical value and role of the pharmacist as part of this team has recently been reviewed (16).
To be effective, the team must have full support from hospital leadership, work closely with infection control teams, and provide regular feedback to individual clinicians and clinical teams about their compliance with policies.

Stewardship programs are composed of organizational structures and action plans for implementing ABS. While many such programs have a hospital focus, they are also of relevance and importance to primary care (17). Targets for ABS include appropriate antibiotic selection, dosing, route, and duration of therapy. ABS needs to be combined with infection prevention measures and environmental decontamination to limit the emergence and transmission of antimicrobial resistance; this trio of measures will address the so-called holy trinity of resistance development and spread (18). This trinity recognizes that to minimize the development of resistance there must be a collaboration between ABS, infection control programs, and environmental service departments.

The focus of this review is primarily hospital stewardship programs. However, one should not underestimate the need for similar programs in the community, particularly longterm care facilities and the veterinary sector. They need to be developed and implemented strategically in conjunction and collaboration with hospital programs. There are many emerging examples of successful stewardship programs addressing primary care. Programs from Belgium (19), France (20), and Sweden (21,22) among others, are worthy of note. In France, a sustained national reduction in antibiotic use has been associated with a reduction in the proportion of penicillin-nonsusceptible Streptococcus pneumoniae in France (23). More recently, in Israel a national restriction of ciprofloxacin use was associated with an immediate, marked reduction in ciprofloxacin resistance in gram-negative bacteria isolated from urine by 1.16% for each decrease of 1,000 DDDs (defined daily doses) in ciprofloxacin use (24). Of these successful national initiatives, very few have been linked with improved patient clinical outcomes, which is a long-term ambition of these interventions.

One example of a more cohesive national stewardship program that integrates community and hospital stewardship and has a focus on CDI, an important adverse ecological outcome, is emerging from Scotland. Hospital-based studies have shown that the introduction of conservative antibiotic policies in hospitals aligned with strict infection control was associated with a reduction in CDI (25,26). In Scotland, this was one of the key factors that stimulated a national stewardship program with one aim: to reduce C. difficile-associated diarrhea (CDAD). In 2009, the Scottish government announced a new health efficiency and access to treatment target for C. difficile-associated disease by the National Health Service (NHS) Scotland. This was defined as being “to reduce the rate of CDAD among patients aged 65 and over by at least 30% by 31 March 2011.” The target will measure the rate of CDAD reported from acute hospitals, nonacute hospitals, and community settings per 1,000 occupied bed days in Scotland (27). Recognizing the key relationship between poor-quality antibiotic prescription, particularly cephalosporins and quinolones, and CDAD, the Scottish government and Scottish Antimicrobial Prescribing Group (SAPG) have agreed upon and set three supporting antimicrobial prescribing targets, in addition to infection control measures, that support and encourage hospitals and communities to achieve this CDAD target. The target related to community prescribing is seasonal variation in quinolone use (summer months vs. winter months). This indicator is now a set target of <5% variation for all health regions (NHS Health Boards) within Scotland (28). This is 1 of 12 quality indicators to evaluate the impact of primary care ABS interventions that have been developed by the European Surveillance of Antimicrobial Consumption Group (29). The indicators are either measurable from routinely available data or can be measured sustainably by clinical teams. Other targets related to hospital prescribing have also been set and are summarized in Box 87-1. In Scotland, national data on the primary care quinolones indicator is currently being analyzed, but data from the author’s region, NHS Tayside, one of the health regions in Scotland, show that consumption has fallen by 2 prescriptions per 1,000 residents per month in the past year (D. Nathwani, personal communication). Assuming seven DDDs per prescription, this equates to a decrease of at least 3,000 DDDs per month in NHS Tayside’s population of 350,000 people, which should be enough to reduce ciprofloxacin resistance in E. coli by 1% (24). Analysis of trends in antibiotic resistance will follow the analysis of the national impact of the primary care quinolone prescribing indicator.

The models of the various stewardship programs employed in the community need to reflect not only the clear differences in community and hospital-care provision but also national and regional sociocultural and economic differences in healthcare provision (30).

In the United States and Europe, a variety of organizations have proposed a framework and governing principles for hospital antimicrobial stewardship (H-ABS)
(2,14,17). This will help to support the development, implementation, and evaluation of existing and new programs within North America and Europe. However, their value in other countries may be more limited due to resourcing and sociocultural differences. For example, in India and Sri Lanka, 66% of community prescriptions include an antimicrobial, and in Bangladesh and Egypt, antibiotic use accounts for 54% and 61%, respectively, of all hospital prescriptions (31). The potential value of ABS in such countries and its current role have recently been reviewed (32). Therefore, a more global perspective, including cost-effectiveness of stewardship in developing countries, is also urgently required in keeping with the World Health Organization’s aspirations (33).

In 2005 and 2008, MacDougall and Polk (12) and Owens (18) have comprehensively reviewed ABS programs in healthcare systems. It is not the intention of this review to detail the key studies identified in these and subsequent studies but rather to highlight systematic evaluations of recent literature and summarize their key findings.

The first systematic review of the literature was undertaken by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA). The published guidelines (14) for developing an institutional program to enhance antimicrfobial stewardship provide a range of recommendations and the supporting evidence for the effectiveness of a range of strategies. Whilst the guidance is primarily from a US healthcare and hospital perspective, many of the recommendations are broadly applicable to most countries and settings. These recommendations are supported by the evidence base for the range of tools or interventions used in stewardship programs and are tabled (Table 87-1). These guidelines use the IDSA-United States Public Health Service grading system for ranking clinical guidelines (34).

The Cochrane Effective Practice and Organization of Care (EPOC)Group acceptd three designs for the evaluation of interventions: clinical trials, controlled before-andafter studies, and interrupted time-series (ITS) analysis (35). Guidelines on the application of these designs to the evaluation of interventions to reduce infection have been published (36) together with guidance on statistical analysis (37,38). All of these sources agree that an uncontrolled before-and-after study is not a valid study design (35, 36, 37 and 38). Less than 50% of articles published in 2004 to 2006 about interventions to improve hospital antimicrobial prescribing (39) met these minimum standards set by the Cochrane EPOC Group, which is an issue that scientific journals need to address to improve the quality of their publications.