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Antibiotic use in US hospitals: quantification, quality measures and stewardship Expert Rev. Anti Infect. Ther. Early online, 1–12 (2015)

Sujan C Reddy*1,2, Jesse T Jacob1, Jay B Varkey1 and Robert P Gaynes1,2 1 Division of Infectious Diseases, Emory University School of Medicine, 49 Jesse Hill Jr Drive, Atlanta, GA 30303, USA 2 Division of Infectious Diseases, Atlanta Veterans’ Affairs Medical Center, Atlanta, GA, USA *Author for correspondence: Tel.: +1 678 632 0777 Fax: +1 404 880 9305 [email protected]

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A majority of patients hospitalized in the US hospitals receive an antibiotic during their hospitalization. Furthermore, up to half of antibiotics prescribed in hospitals are inappropriate. In the setting of continued emergence of antibiotic-resistant pathogens and a limited pipeline of new antimicrobials, attention to optimizing antibiotic use in healthcare settings is essential. We review the measures of antibiotic consumption in the USA, the evolving metrics for comparing antibiotic use (known as benchmarking), trends in antibiotic use, the structure and outcome measures of Antimicrobial Stewardship Programs and interventions to optimize antimicrobial use. KEYWORDS: antimicrobial stewardship . appropriate use . benchmarking

Antibiotics are one of the most commonly prescribed medications in hospitals in the USA, with 55% of inpatients receiving an antibiotic during their hospitalization with significant variation between hospitals and within hospital units [1]. Historically, up to 50% of all antibiotic use may be considered inappropriate [2]. In the current environment of rising healthcare costs, continued emergence of antibiotic-resistant pathogens and a limited pipeline of new antimicrobials, patient groups, clinicians, healthcare administrators and policy makers are calling for increased examination of antibiotic consumption in the US healthcare facilities. In 2014, President Barack Obama issued an executive order with a focus on antibiotic stewardship as a means to combat the threat of antibiotic-resistant bacteria [3]. In order to understand how to improve antibiotic use in the US healthcare facilities, we review the measures of antibiotic consumption in the USA, the evolving metrics for comparing antibiotic use within and between facilities (known as benchmarking), trends in antibiotic use, the structure of Antimicrobial Stewardship Programs (ASPs) and the patient and process outcomes utilized to measure their effectiveness and interventions to optimize antimicrobial use. We review recent articles focused on the US perspective, and for topics that have a paucity of US-specific data, we cite literature from other 10.1586/14787210.2015.1040766

areas of the world. It is important to note that antibiotic use is widely used in food-producing animals in the USA, in fact, more kilograms of antibiotics sold in the USA are used for foodproducing animals rather than for humans [4]. However for this review, we will only focus on antibiotic use in the US healthcare facilities. Measurement of antibiotic use

Accurate measurement of antibiotics is required before any improvement can take place. However, the method for measuring antibiotic use in the USA has not been standardized. The two most commonly utilized numerators are defined daily dose (DDD) and days of therapy (DOT). DDD is measured by the total number of grams of an antibiotic used divided by the number of grams in an average adult daily dose of the antibiotic [2]. The average maintenance dose of an adult is defined by the WHO’s Anatomical, Therapeutic and Chemical classification. This standardization makes DDDs relatively easy to calculate for most healthcare facilities. However, differences in patient populations can affect DDD that are not measures of actual prescribing practices. For example, patients with renal impairment may require lower doses of antibiotic to achieve appropriate drug levels, which, in turn, would affect DDD interpretation. DDD interpretation can also be affected if the


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amount of antibiotic is measured by how much was purchased, how much was ordered or how much was actually administered to a patient. The denominator for DDD is often days of hospitalization; commonly the denominator is 1000 patient-days. In contrast to DDD, DOT is calculated by the number of days that a patient receives an antibiotic. DOT does not take dose into account; thus DOT does not fluctuate with changes in case mix and, unlike DDD, can be used in pediatric settings. However, DOT is difficult to measure without electronic pharmacy records and may overestimate the amount of antibiotics administered [5]. Earlier efforts to measure antibiotic use in the USA utilized DDD per 1000 patient-days. Notably, the CDC’s National Nosocomial Surveillance System and Project Intensive Care Antimicrobial Resistance Epidemiology assessed the DDD per 1000 patient-days for antibiotics in intensive care units (ICUs) and non-ICU settings [6]. In 2007, Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America published guidelines for antimicrobial stewardship recommending the use of DDD as a measure of antibiotic use due to the ability to compare between multiple facilities [2]. However, more recent studies evaluating use in networks of community hospitals and academic centers utilized DOT per patient-days [5,7,8]. Importantly, the CDC’s National Healthcare Safety Network (NHSN) antibiotic use option utilizes DOT. CDC approached vendors of pharmacy software to facilitate transfer of hospitals’ pharmacy data to CDC, although healthcare facilities often have to pay additional costs to the vendors, which has limited the use of DOT throughout the US healthcare facilities. The CDC approach also uses ‘days present’ rather than ‘patient-days’ in the denominator. The CDC launched the most recent approach to measuring antibiotic use in the USA, with a three-pronged approach using: ongoing facility-specific measures, point prevalence estimates from nationally representative facilities and proprietary systems tracking purchase of antimicrobials for specialized studies [9]. The first approach uses NHSN’s antibiotic use option as described above. Some of the earliest data (2012–2013) from 19 NHSN hospitals showed that ICUs had consistently higher antibiotic use than wards (937 vs 549 DOT/1000 days present), although there was great variability in use. Among medical and surgical patients, overall, the most commonly used antimicrobials were the anti-pseudomonal penicillins (50–100 DOT/1000 days present) followed by third- and fourth-generation cephalosporins, parenteral vancomycin and fluoroquinolones [1]. The second arm of the current approach uses point prevalence on a population basis with CDC’s Emerging Infectious Program sites. This method allows a more in-depth, manual collection of data for a limited period, including clinical documentation of signs, symptoms and indication, which can be used for national estimates of appropriateness of antibiotic use to inform stewardship efforts. In one such point prevalence estimate in 183 hospitals in 2011, 76% of antibiotic use was doi: 10.1586/14787210.2015.1040766

used to treat an infection and 24% was used for surgical or medical prophylaxis or unclassified indication [10]. The majority of infections were community-onset; the most common indication was for lower respiratory tract infections. Parenteral vancomycin (14% of antibiotics used to treat infection), ceftriaxone (11%), piperacillin-tazobactam (10%) and levofloxacin (9%) were the most commonly prescribed antibiotics. The third approach for measuring antibiotic use in the USA utilizes representative national purchasing data. For example, the CDC utilized administrative data from 323 hospitals through a drug database to estimate that 55.7% of hospitalized patients received an antibiotic during their hospitalization; nearly 30% received at least one dose of a broad-spectrum antibiotic [1]. In conjunction with NHSN and point prevalence studies mentioned above, these approaches can provide insights into risk adjustment methods for interfacility comparisons [9]. Benchmarks in antibiotic use in hospitals

Since measuring and interpreting antibiotic use in a single hospital is complex, comparisons among hospitals, whether in a single healthcare system or nationally, poses even greater challenges. In Europe with mostly nationalized healthcare systems with centralized data sources, aggregate national data on antibiotic use may be more readily available than in the USA with its fragmented healthcare system. However, single healthcare facilities and healthcare network systems in the USA have described and compared their use with other similar facilities possibly more readily than European colleagues. Benchmarking can be used in two potentially complementary approaches. A hospital can assess its performance over time using historical data, known as internal benchmarking. Since there may be outside forces that change usage (such as outbreaks, formulary or clinical pathway changes), another type of comparison may be to other hospitals over the same period, or external benchmarking. Because of the variety of antibiotic classes with overlapping antibacterial coverage, differences in antibiotic use may occur due to prescribing differences, so-called, ‘prescribing etiquette’ [11] These differences can make it challenging to determine if antibiotic use of a specific agent(s) or class(es) is high without some external comparison. Such external benchmarking may help an institution focus on their resources when an antibiotic or class of antibiotic appears to be an outlier when compared with other facilities as these differences may elucidate inappropriate antimicrobial prescribing behaviors. Other uses for benchmarking include determining the acceptable rates of inappropriate empiric antibiotic therapy [12]. While external benchmarking is an attractive idea, this approach comes with a price. Institutions submitting data to be aggregated in multi-institutional databases must use the same data collection approaches. Some forms of risk adjustment may be required if patient populations differ markedly across institutions submitting data to an external benchmark. A 2009 study evaluated antibiotic use by antibiotic class and by clinical service line among 70 academic medical centers [8]. Expert Rev. Anti Infect. Ther.

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Antibiotic use in US hospitals

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The aggregate data showed a median Table 1. Characteristics of an ideal benchmarking system. DOT of 809 per 1000 patient-days Characteristic Relevance (range 594–1109). Although these data Replicable Data taken from one hospital could be processed and the result was showed outliers of antibiotic use within a same at another hospital cohort of similar healthcare facilities, the aggregate data alone does not inform posScalable Implementable in all hospital sizes from critical access to >1000 bed, and across different pharmacy information systems sible interventions for a facility and can be potentially misleading without some Validated Externally audited to ensure adherence to protocols. Challenging to method of risk adjustment. For example, implement in this study, one hospital was identified Risk adjusted Reflects hospital case-mix, teaching status, bed-size and other factors as a high outlier in its antibiotic use, that may systematically affect consumption which the hospital tried to rationalize Sufficient numbers and types of units and hospitals are sampled to due to its high volume bone marrow Representative provide an accurate assessment transplant (BMT) patient population [13]. After risk adjustment, this hospital Actionable Data are available in real time so that immediate intervention is possible remained high among those clinical services that also had BMT patients; this same hospital had high use among non-BMT service lines [8]. empiric antibiotic therapy, inappropriate, redundant microbial This study shows that benchmarking with risk adjustment has coverage and antibiotic de-escalation. the potential to help ASPs convince service lines that improveAppropriate and improved diagnostics ment in antibiotic use is necessary. External benchmarking is particularly challenging due to An initial step in prescribing an antibiotic is assessing the the differences in patient population, local epidemiology, patient’s likelihood for infection, which includes assessing signs formulary and clinical practice considerations in member and symptoms and obtaining appropriate diagnostic tests such facilities. Appropriate benchmarking requires risk adjustment, as cultures. Obtaining appropriate data to inform antibiotic use although finding an appropriate but simple adjustment has been evaluated in numerous studies involving symptomatic remains a challenge [14,15]. Ideally, all results should also be urinary tract infections (UTIs), asymptomatic bacteriuria and validated by external audit, but this has not yet been done for pneumonia. In a study evaluating 36 hospitals in 2011, 40% any national surveillance system due to concerns about feasi- of patients treated for UTI without an indwelling catheter did not have documentation of a true infection: 16% did not have bility and resource limitations (TABLE 1). a urine culture ordered, 21% had a positive culture but no Measures of appropriateness of antibiotic use in the US documented symptoms and 3% had a negative culture and no documented symptoms [1]. A significant number of these hospitals Quantification of antibiotic consumption alone does not neces- patients did not have had a UTI, so antibiotic use was inapprosarily help guide interventions to improve the use of these priate. Ordering appropriate cultures may have improved antiagents. Understanding how and why antibiotics are utilized is a biotic use. National and local guidelines are often cited in definitions of crucial step in evaluating consumption. In particular, identifyappropriate use. Importantly, these guidelines help inform ing modifiable factors related to consumption is key to improve use. This requires taking consumption data to the patient-level, empiric antibiotic use and set the standard for appropriate which adds different complexities. In this setting, increasing diagnostic tests and duration of therapy. In a study of patients attention has been paid to defining appropriate antibiotic use. treated with community acquired pneumonia, >90% of nonThe CDC developed the 12 Steps to Prevent Antimicrobial ICU cases were treated with guideline-recommended empiric Resistance Among Hospitalized Adults framework in order to therapy. However, 56% received greater than 10 DOT and help identify key intervention areas; notably, half of the steps blood cultures were not obtained in 19% of non-ICU cases which suggests missed opportunities for de-escalation and focus on appropriate antimicrobial prescribing [16]. A standardized method for evaluating appropriate use potentially narrowing microbial coverage [17]. Further studies remains challenging. In the 1960–1980s, several studies docu- have shown that having cultures collected at start of therapy mented that 30–50% of antibiotics in the US hospitals were increases the likelihood of narrowing or discontinuing utilized inappropriately [2]. The prescription of antibiotics is antibiotics [18]. Improving diagnostics also play an important role in guided by numerous variables, such as treatment indication (including relevant data to inform that indication), microbial improving antibiotic use. Molecular testing for viral pathocoverage of the agent and duration, dose and route of therapy. gens can help confirm alternative non-bacterial sources of In studies on appropriate antibiotic use, five areas of focus infection for which antibiotics can be stopped. Improved emerge in the evaluation of appropriate use: appropriate and bacterial diagnostics are being implemented in microbiology improved diagnostics, appropriate antibiotic class, appropriate labs, such as matrix-assisted laser desorption/ionization-TOF informahealthcare.com

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mass spectrometry, and can give clinicians identification and susceptibility information sooner than traditional methods. Combined with intervention activities, these diagnostics can help narrow antibacterial spectrum as well as ensure timely delivery of optimal treatment [19,20]. Avdic and Carroll have summarized recent studies assessing the role of rapid diagnostics on antimicrobial stewardship. All these studies included an intervention program in conjunction with the rapid diagnostic method [21]. Whether rapid diagnostics alone will significantly impact prescriber behavior is unclear. Similarly, point-of-care testing, for biomarkers and even pathogen detection, may inform and improve appropriate initiation of antimicrobial therapy [21]. Appropriateness by antibiotic class

Due to high consumption rates and risk for resistant pathogens, certain antibiotic classes such as fluoroquinolones and carbapenems, demand particular attention. In a prospective evaluation of fluoroquinolone use in a large academic US hospital, 39% (690 of 1773) days of fluoroquinolone therapy were deemed unnecessary. The most common reasons for unnecessary use were for non-infectious or non-bacterial syndromes and longer than necessary duration [22]. Other studies have evaluated the appropriateness of parenteral fluoroquinolones since their bioavailability with oral administration is very high. In a study of non-ICU wards in 128 Veteran Affairs hospitals, the authors conservatively estimated that 46% of parenteral fluoroquinolone use was inappropriate [23]. With the rise of carbapenem-resistant enterobacteriaceae, carbapenem use has also received attention. Weston et al. evaluated carbapenem usage in four academic hospitals and showed that of the empiric carbapenem use 7% was inappropriate and 20% were suboptimal; whereas the non-empiric carbapenem use was inappropriate in 8% of cases [24]. Appropriate empiric antibiotics

The definition of appropriateness does not always denote usage that is excessive. Several studies have shown that the empiric antibiotic selection frequently does not adequately treat the pathogen that is eventually recovered. In a study of nine community hospitals, Anderson et al. showed that in patients with bacteremia, the empiric selection of antibiotics did not cover the recovered pathogen in 38% of patients [25]. Importantly, this result varied greatly from one hospital to another (range 21–71%). Given the importance of time to appropriate antibiotic in patients with infections, particularly those who are critically ill, ensuring empiric antibiotics cover potential pathogens is crucial to patient outcome. As previously mentioned, the newer diagnostic tests, such as matrixassisted laser desorption/ionization-TOF, may help shorten the time to appropriate antibiotics by detecting drug-resistant pathogens sooner. The proliferation of guidelines from the IDSA attempts to aid in appropriate empiric antibiotic choice [26]. However, numerous challenges exist in implementing these guidelines, including delivering this information to doi: 10.1586/14787210.2015.1040766

prescribers at the time of antibiotic selection and adapting the guidance to local epidemiology [27]. Inappropriate, redundant microbial coverage

Another method for evaluating antimicrobial appropriateness is to evaluate patients who received multiple antibiotics and assess whether those antibiotics covered the same organisms, often seen in patients who receive multiple anti-anaerobic medications. In a study of all Veteran Affairs medical centers, Huttner et al. evaluated the use of metronidazole with another anti-anaerobic medication in patients without Clostridium difficile infection (CDI), cholecystitis or cholangitis [28]. They found that 23% of all metronidazole DOT were combined with another anti-anaerobic medication (interquartile range 15–29%). Piperacillin-tazobactam was the most commonly co-administered agent. Redundancy has a significant economic impact. Evaluating 505 non-federal US hospitals, Schultz et al. identified 32,507 cases without CDI or methicillin-resistant Staphylococcus aureus in which redundant therapy was administered, including dual anti-anaerobic agents, dual b-lactams and dual agents active against resistant, Gram-positive infections [29]. These cases totaled 148,589 days of redundant therapy, which represents over US$12 million in potentially avoidable healthcare costs. Antibiotic de-escalation

Evaluation of the consumption of an antibiotic class may be partially measured by the use of appropriate diagnostics, but duration of therapy plays a crucial role. In evaluating patients treated with parenteral vancomycin, Fridkin et al. found that 36% of the 185 patients did not meet diagnostic criteria for need of prolonged vancomycin use (no diagnostic culture was obtained, or diagnostic culture did not show Gram-positive bacterial growth, or culture grew oxacillin-susceptible S. aureus) [1]. In many infections, the duration of therapy remains an unknown, based only on expert opinion. Increasingly, studies suggest that for many infections such as pneumonia and pyelonephritis, a shorter duration of therapy is equivalent to a longer one [30]. Understanding the rationale for inappropriately prolonged use may help inform interventions to improve this practice. Standardized approaches to define appropriateness

The studies above show a variety of definitions for appropriate antibiotic use. Other studies have attempted standardized approaches such as the medication appropriateness index, which can be utilized for any medication, not just antibiotics. The index includes indication, effectiveness, dosage, directions, practicality, drug–drug interactions, drug–disease interactions, unnecessary duplication, duration and expensiveness. In a study of patients with community-acquired pneumonia, researchers found that 65% of antibiotic use was inappropriate based on medication appropriateness index criteria [31]. As mentioned above, diagnostics are an integral part of prescribing. A recent Expert Rev. Anti Infect. Ther.

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Antibiotic use in US hospitals

article utilized a RAND-modified Delphi procedure to ascertain quality indicators to measure appropriate antibiotic use, which included appropriate diagnostics: take two blood cultures, take cultures from suspected sites of infection, prescribe empiric antibiotic therapy according to local guideline, change empiric to pathogen-directed therapy, adapt antibiotic dosage to renal function, switch from intravenous to oral, document antibiotic plan, perform therapeutic drug monitoring, discontinue antibiotic therapy if infection is not confirmed [32]. The CDC has also created tools for facilities to assess the appropriateness of antibiotic use regarding UTIs, community-acquired pneumonia, resistant, Gram-positive infections and a general assessment of all inpatient antibiotics [33]. Inappropriate antibiotics use continues to be common. However, the proportion of inappropriate antibiotic use varies depending on the clinical syndrome, patient population and, importantly, the criteria for measuring appropriateness. The use of national guidelines may help standardize appropriateness measurement, but may not reflect important differences in local epidemiology. Other measurements such as those that evaluate change from parental to oral or evaluated overlapping anaerobic coverage do not give a full assessment of antibiotic use in these healthcare settings. Development of antibiotic stewardship programs in the USA

The measure of aggregate antibiotic use and inappropriate use helps define the problem. The solution relies on improving the prescribing of antibiotics in healthcare settings. ASPs have been developed not only to help track antibiotic use in healthcare settings, but also to help optimize this use [34]. President Obama’s executive order in 2014 has called for the Department of Health and Human Services to take steps such as proposing new guidelines “that require hospitals and other inpatient healthcare delivery facilities to implement robust antibiotic stewardship programs that adhere to best practices” [3]. In 2007, IDSA and Society for Healthcare Epidemiology of America guidelines for antimicrobial stewardship recommended that the composition of the multidisciplinary stewardship team includes an infectious disease (ID) physician, a clinical pharmacist with IDs training, a clinical microbiologist, an information system specialist, an infection control professional and a hospital epidemiologist [2]. The team is usually directed by an ID physician or codirected with a clinical pharmacist with IDs training. However, as ASPs are likely to be implemented in more remote acute care hospitals, some with limited ID trained personnel, the structure of these ASPs are likely to evolve in response to the resources available. However, the composition of the ASP should include expertise in clinical IDs, pharmaceuticals, clinical microbiology, infection control and information system support. In order to run an effective ASP, the support and collaboration of hospital administration, medical staff leadership and clinicians is essential. In order to gain and maintain this support for this, variety of stakeholders relies on correlating the efforts of the ASP with patient safety outcomes. informahealthcare.com

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Outcomes for measuring optimization of antibiotics

Before considering the interventions to optimize antimicrobial use, one must consider the possible measures that the interventions may affect. A number of measures have been examined in studies purporting to have optimized antimicrobial use and can be broadly categorized as economic, antimicrobial use, resistance and clinical outcomes. Economic outcomes

Often, these outcomes are the driving force for ASPs in the USA. An economic outcome is usually clear and easy to understand, generally in cost savings from one time period compared with a previous one. Direct and indirect antibiotic costs should be considered. Direct costs are those related to the cost of the antibiotic. However, even calculation of seemingly simple, direct costs must consider financial changes due to inflation or contract cost of drug acquisition over time. Indirect costs are all of the related costs to antimicrobial use, for example, cost of adverse effects, cost of therapeutic monitoring, cost of increased length of stay related to the antibiotic treatment and cost of treating resulting resistant infections. There is a substantial body of evidence that, despite the cost to run a program, the cost savings from ASP efforts in the USA are associated with very favorable economic gains [35]. Economic outcome measurement comes with some cautions. As the direct cost of antimicrobials account for less than 10% of healthcare bills for patients with infections, cost savings of these drugs should not be the only economic measure. Other financial targets such as the indirect costs need to be considered, even though these costs are more difficult to measure. Several previous studies have shown that cost savings of a new ASP are substantial in the first year or two but savings level off [36–38]. Even if the economic benefit of the program may appear murkier after a few years, a recent publication from the University of Maryland showed the dramatic negative economic impact after discontinuing an established program [39]. However, economic measurement can never be the only outcome that an ASP measures. Ultimately, the program needs credibility with prescribers. If members of the ASP are known only as the ‘cost police’, clinicians will pay little attention to recommendations and interventions. Antimicrobial use outcomes

Nearly all ASPs in the USA measure changes in antimicrobial use as an ‘outcome’. These measures, detailed above, are not actually patient outcome measures but rather process measures, according to the Donabedian model of healthcare quality measurements, the dominant model in the US healthcare [40]. However, these process measures can evaluate quality of care and have been validated to correlate with patient outcomes and costs [41]. In a review of studies among critical care patients, Kaki et al. found that 71% of 24 articles reviewed assessed the impact of antimicrobial stewardship on antibiotic use using an aggregate measure, mostly DDD/1000 patient days [42]. One difficulty with the aggregate measure of antimicrobial use is that there is doi: 10.1586/14787210.2015.1040766

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no way to use the measure to examine appropriateness of the antimicrobial. In that same study, only 5 (20%)/24 studies attempted any assessment of the appropriateness of antimicrobials, but none of these studies attempted to analyze antimicrobial appropriateness according to pre-specified clinical guidelines. Further, aggregate measures cannot link individual antimicrobial exposure to individual outcome [43]. Patient-level data, for example, case–control or cohort studies, can examine this link but suffer from greater difficulty in obtaining this information. Both aggregate and patient-level measures of use are needed for a better understanding of the effectiveness of ASPs. Antimicrobial resistance changes

In the review by Kaki et al., only 54% of the included studies examined the impact of the antimicrobial intervention of antimicrobial resistance. Many of the studies showed a reduction in resistance to a targeted antimicrobial, for example, ciprofloxacin. However, unanticipated effects on antimicrobial resistance were seen, both reductions and increases in resistance with antimicrobial interventions [42]. The opportunity to observe changes in antimicrobial resistance with antimicrobial interventions often depends on the duration of the study.

create this link but, again, suffer from greater difficulty in obtaining this information. Interventions to optimize antimicrobial use & their effectiveness

Infection control efforts are vital to control antimicrobialresistant organisms but these practices alone will not be sufficient. Optimizing antibiotic use remains essential to effectively limit antimicrobial resistance. Even though the need to optimize antimicrobial use is clear, the means to this optimization is not. A bewildering variety of interventions have been employed to optimize antimicrobial use. Ultimately, these interventions come down to changing prescriber behavior, which is in turn influenced by personal knowledge and experience, formal policy and peer behaviors [11].The means to this behavior change can be roughly divided into restrictive and persuasive approaches, each with advantages and disadvantages (TABLE 2). To assess the value of the diverse interventions that have been tried, we will focus on one measure: changes in antimicrobial use since nearly all interventions examine this measure. However, as stewardship interventions become more refined, outcomes related to the process of prescribing are likely to become more pertinent in identifying the most useful interventions.

Adverse effects of antimicrobials

Few studies have examined adverse effects of antimicrobials in the context of antimicrobial interventions [42]. One study found that fewer adverse effects and drug allergies were observed with a computerized decision support system that was designed to help optimize antimicrobial use [44]. CDI can be regarded as an adverse effect of antimicrobials. In a recent review, the effect of ASPs on C. difficile incidence was examined. Nearly all (14/16) studies reported a decrease in C. difficile incidence with ASP interventions [45]. Clinical outcomes: mortality, infection cure, length of stay, quality-adjusted life-year

An important question about ASPs relates to whether patient outcomes such as mortality, cure of infection or improvement in quality of life are improved with antimicrobial interventions. These outcome measures have been analyzed in several different ways. One study showed that restriction of third-generation cephalosporin use reduced infection-related hospital mortality in critically ill patients by examining the periods before and after the intervention [46]. A recent review showed the value of ID consultants as part of ASPs with resultant reductions in hospital length of stay, lower readmission rates and decreased mortality [47]. Many studies have examined length of stay and mortality for a hospital or the ICU comparing those receiving interventions from ASPs with those institutions or units that were not; most studies found no significant differences in overall infection rates or mortality rates [42]. Like measures of antimicrobial use, aggregate clinical outcome measures such as average length of stay or crude mortality rates cannot link individual antimicrobial exposure to individual outcome. Patientlevel data such as case–control or cohort studies are needed to doi: 10.1586/14787210.2015.1040766

Restrictive interventions

These interventions set up barriers that a prescriber would have to overcome before an antimicrobial can be prescribed. Preauthorization of antimicrobials is one of the most common interventions, usually restricting use of an antimicrobial to approval by the ASP or other trained physician, allowing unrestricted use only for the first dose (or day) in life-threatening circumstances such as in the ICU. Formulary restriction of antimicrobials is present in many US hospitals. Designed to decrease direct costs, formulary committees may limit unnecessary use of expensive agents that offer little advantage over other available agents. The restrictive measures vary in their ease of use. Formulary restrictions are simple to put in place but also require mechanisms to acquire non-formulary drugs, if needed. An approval mechanism and the acquisition time for non-formulary drugs are disadvantages, but most institutions use this form of intervention to hold down acquisition costs and drive use in certain directions. Importantly, restriction interventions in almost all studies show a significant reduction in the use of targeted antimicrobials [42]. Unfortunately, all studies using restrictive interventions also demonstrated a compensatory increase, some by as much as 300%, in the use of other agents. For example, investigators found that fluoroquinolone restriction resulted in increased use of cefepime [48]. A recent Cochrane analysis examined the difference between restrictive and persuasive interventions at 1, 6, 12 and 24 months [49]. Early on, restrictive approaches tended to decrease antimicrobial use more than persuasive approaches and appeared to be most useful when the need to change antimicrobial use was urgent, for example, an outbreak. At 24 months, evidence favored persuasive interventions for optimizing antimicrobial use. Expert Rev. Anti Infect. Ther.

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Table 2. Intervention categories to optimize antimicrobial use. Restrictive interventions

Advantages

Disadvantages

Persuasive interventions

Advantages

Disadvantages

Preauthorization

Generally effective in reducing use of a single agent in short term

Labor intensive to maintain; associated with a compensatory increase in unrestricted antimicrobials

Education: Lectures, Printed materials including Guidelines

Simple, cheap

Generally ineffective at changing prescriber behavior

Formulary restriction

Highly effective in limiting use of agents not on formulary; cost effective approach in limiting use of expensive agents with similar spectrum of activity to cheaper ones

Adjunctive methods of procurement of nonformulary agents needed; usually associated with a compensatory increase in unrestricted antimicrobials

Audit and Feedback

Variably effective

Can be labor intensive data collection

Local Opinion Leaders

Variably effective depending upon the individual

Labor intensive to maintain and resource limited

Computerized Decision Support

Consistent improvement in prescribing

Requires computerized record system with either commercial software ($$) or local programming; Improvement may be limited over time

Academic detailing

Generally effective

Limited by personnel resources; may be best utilized for consistently problematic prescribers

Formal reassessment

Consistent success in reducing inappropriate antimicrobial use

Limited by personnel resources

Antimicrobial de-escalation

Effective but the best approaches remain to be identified

Limited by personnel resources and encompasses complex issues, particularly duration of therapy

Multifaceted interventions

Effective

Can be inefficient since it is difficult to determine which intervention(s) are efficacious

Persuasive interventions

These interventions are ultimately educational tactics designed to motivate a prescriber to move in a particular direction, either not to prescribe an antimicrobial at all or toward a certain drug(s). However, the interventions vary in their overall

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effectiveness. Unlike restrictive interventions, persuasive interventions, especially computerized decision-support, formal reassessment and the impact of an ID specialist, demonstrated decreases in antimicrobial use without a compensatory increase in other agents of similar spectrum [49].

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Education: lectures, printed materials, guidelines

Multifaceted interventions

Dissemination of educational materials in printed form or via educational meetings/lectures has shown variable results. While some studies have shown this form of intervention to improve antimicrobial use, overall the effects are small [49,50].

About one-third of the reported studies that have utilized interventions to optimize antimicrobial use have been multifaceted. These studies showed consistent effectiveness but did not, on the whole, improve antimicrobial use any more than the reported successful studies using single interventions [49]. The main difficulty in assessing multifaceted interventions is that one is never sure which intervention(s) are efficacious.

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Audit & feedback

Nine studies have attempted to evaluation Audit and Feedback but have had multifaceted interventions, making it difficult to evaluate this method by itself. The success of the studies has been variably effective in optimizing antimicrobial use [49]. Local opinion leaders

The impact of ID specialists on antimicrobial prescribing in hospitals was recently reviewed [47]. In almost all studies of the 31 studies reviewed, ID specialist intervention was associated with significant improvement in the appropriateness of antimicrobial prescribing but there was great variability in the interventional approaches and compliance to fully assess the efficacy of this intervention, which is limited by personnel resources. Academic detailing

A one-on-one educational program has been shown to be effective and safe for reducing excessive antimicrobial use [51]. The value of this intervention is limited by personnel resources and may be best utilized for consistently problematic prescribers. Formal reassessment

A majority of antimicrobials are used empirically. Reassessment of empiric choices with an ASP team member has been evaluated in several studies with consistent success in reducing inappropriate antimicrobial use by identifying bug-drug mismatches, patients in whom an infection or a bacterial infection is unlikely, inappropriate double coverage, drug dosing problems or transition from parenteral to oral therapy [52]. Antimicrobial de-escalation

Most antimicrobials are initiated as empiric therapy with no knowledge of the microorganisms causing the infection, or even if there is definitive evidence for the existence of an infection. Antimicrobial de-escalation is based upon microbiology results at 48–72 h; empiric antimicrobials are stopped, reduced in number or narrowed in spectrum. Further, determination of the length of antimicrobial therapy is embedded in the concept of de-escalation. Data from a review demonstrate that de-escalation is effective but the best approaches remain to be identified [53]. Critical to this intervention is determining if an infection definitively exists or not; if an infection exists, is it bacterial? c) the duration of antimicrobial therapy for a diagnosed bacterial infection. The duration of antimicrobial therapy for most infections except for uncomplicated UTIs, traveler’s diarrhea, endocarditis and osteomyelitis is not known. Randomized controlled trials for pneumonia and pyelonephritis have suggested that shorter duration of therapy is equivalent to longer durations [30]. doi: 10.1586/14787210.2015.1040766

Role of the microbiology laboratory & use of biomarkers in antimicrobial stewardship

Rapid and sensitive diagnostic microbiologic tests can be a great help to ASPs. Technologies in the last decade permit identification of microorganisms in as little as 4 h, which can greatly limit the need for broad-spectrum agents. Resistance markers can also be identified quickly to help target antimicrobial therapy [21]. Using these tests, ASPs have helped to optimize antimicrobial selection [54]. Clinical microbiology laboratories must work closely with ASPs to test needed antimicrobials, develop antibiograms and monitor local resistance rates over time. The use of biomarkers, notably C-reactive protein (CRP) and procalcitonin, have improved diagnostic accuracy of an infection, leading to more optimal use (or discontinuation) of antimicrobials. Use of either biomarker better predicts the diagnosis of pneumonia in patients who present with acute cough than any individual or combination of clinical symptoms and signs in lower respiratory tract infection [55]. However, the use of these two biomarkers has important differences. Procalcitonin

Procalcitonin is a precursor peptide from the hormone, calcitonin that is also a cytokine mediator that becomes elevated in bacterial but not in viral infections. Studies examining the use of procalcitonin (mostly in hospitals) have shown that, without a change in clinical outcome, antimicrobial consumption was significantly reduced across different clinical settings and diagnoses, including acute respiratory infection, but also pneumonia and sepsis [56]. Monitoring with procalcitonin has also been used to help determine duration of antibiotic therapy and, to a limited extent, prognosis [57,58]. The value of procalcitonin in outpatient settings is profoundly affected by the lack of availability of a point-of-care test. C-reactive protein

Point-of-care tests have been used successfully, primarily in Europe, as a way to better optimize antibiotic prescribing and improve outcomes in outpatients [55]. While point-of-care CRP is currently available in some European countries, in the USA, point-of-care CRP testing encounters problems with regulatory agencies and/or clinical laboratories that are responsible for quality assurance/competencies, since any point-of-care testing would require a Clinical Laboratory Improvement Amendments of 1988 waiver. However, point-of-care tests such as CRP hold promise in potentially limiting antimicrobial initiation [54]. Expert Rev. Anti Infect. Ther.

Antibiotic use in US hospitals

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Role of information technology

A key element to track antimicrobial use and assess outcomes of stewardship programs is adequate information technology to improve data collection and processing. The US government has added incentives to health systems to adopt and demonstrate ‘meaningful use’ of electronic health record (EHR) through the 2009 Health Information Technology for Economic and Clinical Health (HITECH) Act. By 2011, 54% of physicians had adopted an EHR system [59]. Hospitals are increasingly adopting EHR systems with more than 80% of hospitals receiving incentive payments to improve their EHRs in 2013 [60]. The two largest EHR vendors, Epic Systems Corp. (Verona, WI, USA) and Cerner Corp. (North Kansas City, MI, USA) have limited stewardship-related capabilities in their entry-level products, however, both have been increasingly offering tools to assist local ASPs [61]. A significant limitation of both of these systems is the ability to share locally developed software enhancements. Given the limitations of these EHRs, other clinical decision support systems are being utilized, such as TheraDoc and SafetySurveillor. These products enhance the ability of ASPs in program areas including: formulary restriction and preauthorization, prospective audit and feedback, incorporation of guidelines at time of prescription and de-escalation of antimicrobial therapy. Of the studies that have evaluated computerized decision support, all have shown a significant change in prescribing of at least 5% in the intended direction [49]. A major reason cited for computerized decision support effectiveness, unlike educational lectures, printed materials or guideline dissemination, is that the former is available to the prescriber right at the time a decision is being made to order an antimicrobial. These automated systems allow ASPs to broaden the impact of their interventions without requiring continued use of resources. One study suggested that the improvement in prescribing may be limited over time [62]. Although information technology has seemingly boundless potential in improving antimicrobial utilization, significant limitations to these programs include the cost of the software, IT resources to enhance local programs and diminish returns due to ‘alert fatigue’ [61]. Information technology will continue to play an integral role of ASPs in terms of monitoring antibiotic use and in the development of interventions. Barriers to success

Nearly all healthcare workers are aware of and concerned about antimicrobial resistance as a threat in healthcare. Yet less than half of all acute healthcare facilities in the USA have ASPs [52]. The barriers to more successful implementation of practices to optimize antimicrobial use require examination of economics and attitudes. Funding/personnel for programs

A business model is necessary to present to hospital administration for facilities to develop an established program demonstrating that the hospital will get a return on its investment in informahealthcare.com

Review

a reasonable timeframe [63]. The US healthcare facilities must also recognize the importance of an existing ASP with regulators since guidelines exist as to the nature and composition of the ASPs [2]. Attitudes of prescribers

Development and maintenance of an ASP to satisfy hospital administration and/or regulators will ultimately be an ineffective use of personnel and monies. Maintaining an effective ASP requires credibility with clinical prescribers and an understanding of their attitudes toward ASPs. Nearly 20% of prescribers view ASPs as an infringement on their autonomy [64]. Acceptance of guidance can also be problematic, even if the guidance is well founded [62]. ASPs will likely need to make more than mere suggestions. No longer can clinicians’ unrestricted use of antimicrobials and ignoring suggestions from those who attempt to improve or alter antimicrobial use be tolerated [65]. In order to achieve this, ASP interventions may need to better understand prescribing practice and include process outcomes in order to understand why some interventions work and others do not. Clinicians must understand the sense of urgency about the appropriate use of antimicrobials. ASPs must also adapt to be fully integrated into quality improvement programs so that clinicians believe that ASPs are aiding in selecting the appropriate drugs to improve outcomes. Expert commentary & five-year view

Antibiotic resistance is a problem that has become a crisis and will likely remain so. The IDSA challenge of 10 new antibiotics by 2020 will likely fall short or be met with ‘new’ antibiotics that are only variations of current ones [66]. To preserve the effectiveness of antibiotics, we must use our current supply wisely. By 2020, all healthcare facilities will need effective ASPs in the USA. National benchmarking will be fully utilized since all the US healthcare facilities will have fully operational electronic medical records. Improved diagnostics and use of biomarkers will help optimize antibiotic use. Ultimately, the challenge will eventually fall on clinicians who must recognize the urgency of the problem of antibiotic resistance and treat recommendations from national and local antibiotic stewardship programs as more than mere suggestions. This may be accomplished similar to what the Center for Medicare and Medicaid Services has done with pay for performance measures with objective, universally applicable measures of antibiotic use tied to performance of healthcare facilities and may be the only way out of the current crisis. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript. doi: 10.1586/14787210.2015.1040766

Review

Reddy, Jacob, Varkey & Gaynes

Key issues .

There is a growing interest in measuring and optimizing antibiotic use in the US hospitals.

.

Recent studies from hospital networks and the CDC have utilized days of therapy per 1000-patient days to measure antibiotic consumption, rather than defined daily dose.

.

Benchmarking is currently being developed, but is not standardized in the USA. Adequate risk adjustment is an important element to benchmarking.

.

Inappropriate use of antibiotics continues to be common in the US hospitals and particular focus has been placed on improving diagnostics, optimizing use of particular classes of antibiotics and reducing redundant microbial coverage of multiple antibiotics.

Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by University of Leeds on 05/17/15 For personal use only.

.

Antibiotic stewardship programs are increasingly being developed and the ideal structure of such programs may depend on facility specific resources.

.

Measuring the effectiveness of intervention programs may include measuring costs (direct and indirect), antimicrobial outcomes (in use and resistance patterns), but optimally needs to include clinical outcomes.

.

Restrictive interventions result in more immediate decreases in antibiotic use but may shift antibiotic use to other antibiotics. Persuasive interventions have longer lasting impact without a compensatory increase in other agents with similar spectrum.

.

Improving the utilization of appropriate diagnostics can help ensure antibiotics are being utilized for true bacterial infections. Advances in diagnostics, from quicker identification of bacterial and viral pathogens to biomarkers to help rule out bacterial pathogens, are powerful new tools to improve antibiotic use in the US hospitals.

in 130 US hospitals: comparison of defined daily dose and days of therapy. Clin Infect Dis 2007;44:664-70

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