The incidence of antimicrobial resistance has risen dramatically, becoming a major public health concern over the past several years. Health care providers and patients are faced with infections caused by multidrug-resistant organisms for which few, if any, treatment options remain. The principal driver of this resistance is the use of antimicrobial agents. Not only does inappropriate antimicrobial use lead to the development of drug resistance, but also antimicrobials as a class are among the drugs commonly associated with drug toxicity and adverse effects, including collateral damage such as Clostridium difficile disease. Importantly, as much as 50% of antimicrobial use in the inpatient setting is either unnecessary or suboptimal.¹ For example, up to 80% of acute bronchitis patients are prescribed antibiotics, despite the fact that acute bronchitis is primarily the result of viruses.² Curbing the widespread misuse of antimicrobials through antimicrobial stewardship presents an opportunity to improve patient outcomes and decrease resistance. 

Systemizing Antimicrobial Stewardship
Antimicrobial stewardship is a systematic process for ensuring appropriate antimicrobial selection, dosage, route of administration, and duration, with the overall goal of improving patient outcomes while minimizing drug toxicity and the development of resistance. Secondary to these aims, implementing antimicrobial stewardship may reduce drug costs to the institution, resulting in potential annual savings of $200,000 to $900,000 in academic and community hospitals.³ State and national initiatives are underway to encourage antimicrobial stewardship programs or their components within US health care facilities. For example, in 2008, California State Bill 739 mandated that acute care hospitals implement quality assurance programs to ensure the prudent use of antimicrobials. Additionally, in October 2011, after collaborating with the Centers for Disease Control, the Centers for Medicare & Medicaid Services released new draft worksheets for accreditation by The Joint Commission that include new items to assess how each health care facility is promoting antimicrobial stewardship. Although this currently remains a draft document, these standards make it clear that antimicrobial stewardship is garnering increased recognition as a system for ensuring quality patient care.

Initiating a Sustainable Program 
Antimicrobial stewardship programs will vary depending on the hospital size, location, availability of expertise, and goals of the program. Ideally, a pharmacist and a physician, both with training in infectious diseases, should comprise the core of a successful antimicrobial stewardship program, although pharmacists and hospitalists without this specialized training have been utilized with success when this expertise has not been not available.³ Specific training in antimicrobial stewardship is available from the Society of Infectious Diseases Pharmacists (SIDP; www.sidp.org) and Making a Difference in Infectious Diseases Pharmacotherapy (MAD-ID; www.mad-id.org). To ensure a program is sustainable, those working with the antimicrobial stewardship program should be appropriately compensated for their time. Additionally, collaboration with clinical microbiologists, infection preventionists, hospital epidemiologists, hospital quality personnel, surgical specialists, and informatics specialists will strengthen the program. For example, in accordance with recommendations from the Infectious Diseases Society of America (IDSA), the antimicrobial stewardship program at The Nebraska Medical Center (TNMC) employs a full-time pharmacist and provides significant salary support to the infectious diseases division, which collaborates in coordinating the program.³

Before initiating an antimicrobial stewardship program, a concise strategic plan should be developed and discussed with hospital administrators. The plan should establish chosen strategic interventions and determine the outcomes to be measured. Conservative estimates in cost savings based on drug acquisition costs and the benefits of the program from a patient safety and regulatory standpoint should be highlighted. Gaining administration support and outlining a clear plan for the program will ensure that it will be supported financially and given authority within the organization to implement the necessary interventions. This support and authority has been proven essential to the long-term success of a program and the effectiveness of stewardship initiatives.

Maximizing Outcomes 
Strategies for conducting stewardship generally fall into two broad categories: active antimicrobial management and passive efforts. Combining both approaches is ideal to optimize efficacy and maximize intended outcomes. 

Employing formulary management techniques is one strategy with an immediate and significant effect; this may include reviewing the anti-infective agents on the formulary and eliminating redundancies/unnecessary agents. Furthermore, antimicrobial restrictions can be placed on specific agents so that their use requires approval.⁴ Most stewardship programs utilize antimicrobial restriction policies, although the number of restricted agents and the process for approval varies depending on resources at the institution. For example, at TNMC a selection of high cost and unique agents are restricted based on criteria and/or certain medical service approval (eg, daptomycin may be used for FDA-approved indications; otherwise, infectious diseases approval needs to be obtained). These restricted agents are reviewed daily by the antimicrobial stewardship team to ascertain that criteria are met or that agents have been approved. When devising restriction policies and procedures, it is essential to ensure that the restriction process does not result in delays in the administration of antimicrobial therapy, because delays to the initiation of active therapy, particularly in critically ill patients, can worsen patient outcomes.⁵ One option is to allow a 24-hour grace period in which the restricted agent can be dispensed to the patient while the appropriate approvals are obtained or alternative agents are recommended. 

Other active strategies include pharmacy-driven protocols that allow pharmacists to perform certain tasks automatically that may be related to patient safety. Examples of these programs include renal dosage adjustment of antimicrobials, pharmacokinetic consultations for vancomycin and aminoglycosides, and IV to oral switches. At TNMC, a protocol was developed that allows pharmacists to automatically convert hemodynamically stable patients with a functioning GI tract from IV to oral anti-invectives with high bioavailability (eg, fluoroquinolones, linezolid, fluconazole). IV to oral conversions will decrease drug cost and the need for continued IV access, and may even shorten length of patient stay.

The use of prospective audit and feedback is another useful strategy that typically involves the identification of patients who may benefit from modifications to their anti-infective therapy. Opportunities for intervention are identified by integrating patient clinical status, microbiology data, dosing issues (eg, anti-infective penetration to infection site), and the need to narrow or stop therapy. One advantage of employing this method is that active learning through prescriber education can occur at the time of the stewardship team’s contact with the physician. As a complement to this process, TNMC has developed clinical pathways for common infectious diseases that incorporate national guidelines, local antimicrobial susceptibility patterns, and the TNMC formulary. These clinical pathways are available on our stewardship website for all practitioners to use.

Educational activities, such as grand rounds, in-service presentations, and institution-specific written guidelines, can improve prescriber knowledge of appropriate antimicrobial use on a global level. The rapid turnover of trainees, the time commitment needed to provide educational services, and the overall shortcomings related to passive versus active learning, however, can limit the effectiveness of this approach. Despite these drawbacks, education typically is well-received and integral to a successful program, but it must be combined with other stewardship strategies to produce sustained effects.

Using Automation to Facilitate Antimicrobial Stewardship 
The increased use of CPOE creates a new window of opportunity to facilitate and expand stewardship. Depending on the sophistication of the system, CPOE potentially allows for real-time education, additional means of formulary management, and the ability to provide suggestions for preferred treatments at the time of order entry.⁶ Mandatory anti-infective indications within CPOE can be utilized as well, which can improve the ability to optimize therapy. 

Clinical decision support software (CDSS) provides another opportunity to maximize the efficiency of the antimicrobial stewardship program by identifying patients requiring intervention. CDSS mines data from multiple electronic sources such as microbiology, drug, and laboratory data to create alerts or reports of clinical situations amenable to intervention. For example, the CDSS software at TNMC identifies any patient with a bloodstream infection that is not currently being treated, as well as patients being treated with an agent to which the organism is resistant. This occurs in real time as results are updated and allows for quick intervention to optimize patient outcomes. CDSS also provides a means to record and monitor interventions, promoting continuity of care among health care providers. The availability of this type of documentation may also help to provide justification for stewardship programs.

Budgetary constraints often limit acquisition of these electronic programs, and integration of electronic medical records and data systems is a complex and time-consuming process. Implementation of CDSS also often requires the extensive involvement of information technology departments and antimicrobial stewardship staff.⁴ While automation certainly increases the prospect of expanding a stewardship program, an effective pharmacist-driven program can certainly be managed in the absence of such technology. In fact, it is important to remember that CDSS cannot identify all pertinent interventions; thus, regular reviews of patient profiles by a pharmacist should always be conducted. 

Measuring Program Effectiveness
Identifying optimal metrics for assessing the outcomes of an antimicrobial stewardship program is an area of active research. Because the primary objective of antimicrobial stewardship is to improve patient outcomes, ideally the effect of optimizing choice of agent, dose, and duration on clinical cure and survival would be tracked and reported. However, these outcomes can be difficult to assess, particularly if the resources to do so are limited. 

Tracking antimicrobial usage over time is a primary antimicrobial stewardship metric. Antimicrobial use can be measured in multiple ways; tonnage purchased, antimicrobial cost, defined daily doses (DDD)/1000 patient days, and days of therapy (DOT)/1000 patient days are the most common measurements. A DDD is determined by dividing the grams of drug given to a patient by a standard defined daily dose according to the World Health Organization. This can be a useful metric for benchmarking antimicrobial usage against other health care facilities. However, it is limited by factors such as differences in dosing among institutions, pediatric patients, or dosage adjustments (eg, a patient may receive less total beta-lactam if they have renal dysfunction, thereby resulting in an artificially low DDD measurement).⁷ DOT are simply the number of days a patient receives an antimicrobial agent; for example, a patient receiving ceftriaxone and metronidazole each for three days would have received a total of six DOT. This measurement is typically a more accurate representation of drug exposure and ideally is gleaned from administered drug databases (rather than from information on drugs dispensed or active drug orders). 

Tracking antimicrobial usage with the aforementioned metrics can assist the program in identifying important trends, such as decreases in use of a specific agent or overall antimicrobial use after the implementation of a stewardship intervention (eg, drug restriction). For example, at TNMC we track DOT/1000 patient days overall and, for individual agents of interest, through collaboration with informatics specialists. Importantly, changes in antimicrobial usage do not necessarily indicate whether that prescribing is appropriate. If an unexpected increase of an agent is seen, collaboration with hospital epidemiology and infection preventionists may help to determine if there are important trends in the point prevalence of specific pathogens that might explain the change. Additionally, when these antimicrobial-use metrics are compared between institutions, some attempt should be made to stratify them based on patient populations, case, and acuity mix.

Measuring drug acquisition costs is of particular interest to hospital administrators and is usually normalized by the number of patient days. The initial savings of an antimicrobial stewardship program in drug acquisition cost is often very significant, given that anti-infectives may comprise 20% of the pharmacy budget and that anti-infectives are so frequently misused.^1,3 However, once the program has been well-established and the low-hanging fruit has been accounted for, continued significant decreases in drug acquisition cost will be difficult. When drug use is optimized, antimicrobial drug cost on an annual basis, corrected for inflation, can serve as a measure of cost containment. For example, the baseline rate of increasing antimicrobial expenditures per patient day prior to the implementation of a stewardship program can be compared with the rate of increase after the initiation of a program adjusted for inflation in health care costs.⁸

Drug resistance and rates of Clostridium difficile infection also can be used to assess the performance of an antimicrobial stewardship program. Unfortunately, numerous other factors impact the spread of resistance, and effects may take years to manifest. In addition, clonal spread of resistant organisms or infection control issues can confound the measurement of both resistance and Clostridium difficile rates.

Preserving Antimicrobial Supply
At a time when drug resistance is ubiquitous and few new antimicrobial agents are being approved, the need for antimicrobial stewardship to preserve the finite supply of antimicrobials is clear. Depending on the setting and available resources, multiple complementary stewardship strategies can be employed that will assist facilities in improving patient outcomes and decreasing antimicrobial resistance.

Angie Huang, PharmD, currently is completing a PGY1 pharmacy practice residency at The Nebraska Medical Center, and subsequently will complete a PGY2 infectious diseases residency at the University of Michigan. She earned her PharmD from Drake University.

Trevor Van Schooneveld, MD, is an assistant professor in the Division of Infectious Disease at the University of Nebraska Medical Center (UNMC) and serves as the medical director of the Antimicrobial Stewardship Program at The Nebraska Medical Center. Trevor received his MD from UNMC, where he completed a residency in Internal Medicine and also served as a chief resident. He then completed the Creighton University Medical Center Infectious Disease fellowship. 

Alan Gross, PharmD, is a clinical assistant professor at the University of Nebraska Medical Center (UNMC) College of Pharmacy as well as an adjunct assistant professor in the Division of Infectious Disease, UNMC College of Medicine. He is currently the pharmacist coordinator for the Antimicrobial Stewardship Program at The Nebraska Medical Center. Alan received his PharmD from Purdue University and subsequently completed a PGY1 pharmacy practice residency at Henry Ford Hospital and a PGY2 infectious diseases residency at Midwestern University Chicago College of Pharmacy. 

References

1. John JF, Fishman NO. Programmatic role of the infectious diseases physician in controlling antimicrobial costs in the hospital. Clin. Infect. Dis. 1997;24:471-485.
2. Wenzel RP, Fowler AA. Acute bronchitis. N. Engl. J. Med. 2006;355:2125-2130.
3. Dellit TH, Owens RC, McGowan JE Jr, 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. Clin. Infect. Dis. 2007;44(2):159-177.
4. Drew RH, White R, MacDougall C, et al. Insights from the Society of Infectious Diseases Pharmacists on Antimicrobial Stewardship Guidelines from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Pharmacotherapy 2009;29(5):593-607.
5. Harbarth S, Nobre V, Pittet D. Does antibiotic selection impact patient outcome? Clin. Infect. Dis. 2007; 44:87–93.
6. Macdougall C, Polk RE. Antimicrobial Stewardship Programs in Health Care Systems. Clin. Microbiol. Rev. 2005;18(4):638. 
7. Polk RE, Fox C, Mahoney A, et al. Measurement of adult antibacterial drug use in 130 US hospitals: comparison of defined daily dose and days of therapy. Clin. Infect. Dis. 2007;44(5):664-670.
8. Beardsley JR, Williamson JC, Johnson JW, et al. Show me the money: long-term financial impact of an antimicrobial stewardship program. Infect. Control Hosp. Epidemiol. 2012;33(4):398-400.

Additional Resources

Suggested readings for additional information include the IDSA/SHEA guidelines3 for the development of antimicrobial stewardship programs and the Society of Infectious Diseases Pharmacists white paper.⁴ TNMC also provides multiple resources, including institutional guidelines and protocols with supporting evidence, found at: www.nebraskamed.com/asp.