Antimicrobial stewardship programs-A review for the formulary decision-maker

The spread of antimicrobial resistance, lack of novel antimicrobial agents in development, and challenges to the drug discovery process are of significant global concern today.^1-7 The state of this crisis is emphasized by published literature denoting the need for action on multiple levels as we move towards a second pre-antibiotic era or post-antibiotic era.^8-12 Antimicrobial Stewardship Programs (ASPs) have become a particular area of focus as healthcare practitioners aim to combat these issues within institutions. In 2007 the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) published guidelines for developing an institutional program to enhance antimicrobial stewardship.¹³ Since that time, a plethora of original research articles in this area as well as various reviews have been published.^14-21 In 2010 a national survey conducted by the American Society of Health-System Pharmacists (ASHP) found that 246 of 566 (43.5%) responding American hospitals had an ASP, reflecting the wide-scale utilization of these programs.²² More recently, interest has developed in the role of ASPs within long-term acute care hospitals (LTACHs) and long-term care facilities (LTCFs).^23-26  The value of each element and strategy employed by ASPs continues to be understood within various practice settings. As such, the focus of this article is to review the current state of ASPs from the perspective of a formulary decision-maker and raise awareness regarding the complex related issues.

Description of Antimicrobial Stewardship Programs

The goals of an ASP are to improve patient care and health outcomes.¹³ This may be accomplished through targeting inappropriate or suboptimal antimicrobial selection, progression of antimicrobial resistance, drug toxicity, or costs. The 2 core strategies of an ASP ([1] prospective audit with feedback and intervention and [2] formulary restriction) may be used in combination with the many potential supplemental elements of an ASP (eg, intravenous to oral conversion) to achieve individual or numerous program objectives (Table 1, page 8). Ideally, ASPs are co-directed by a physician and a pharmacist with specialty training in the area of infectious diseases (ID). These 2 core members work with epidemiologists, infection control specialists, microbiologists, information technology specialists, institutional administrators and other healthcare professionals to compose a multidisciplinary ASP team. Implementation of an Anti-Infective Subcommittee that reports to the Pharmacy and Therapeutics Committee, may be used for managing the interventions and activities of the ASP in this interdisciplinary fashion.

Antimicrobial Stewardship in Practice

For an ASP to maximize its potential benefits, incorporating a pharmacist with advanced training (residency or fellowship), extensive experience, or related certifications in the field of antimicrobial stewardship and ID is invaluable.^13,18,27 Unfortunately, realization of such positions is limited by difficulties securing funding and a lack of specialized pharmacists.^18,27 This leaves many of the more than 5,700 American hospitals in a unique position.²⁸ In current practice, ASP support from a department of pharmacy is being derived from several avenues, leading to great inconsistencies in how each is organized and managed.^16,29 Such diversity is reflective of, among other factors, variations in institution types, sizes, politics, affiliations, patient populations and obtainable financial or personnel resources. From the personnel standpoint, pharmacy students completing an introductory pharmacy practice experience or an advanced pharmacy practice experience, post-graduate year-1 or year-2 pharmacy residents, pharmacy fellows, non-ID pharmacists and pharmacy faculty members have all demonstrated the capacity to actively participate in ASP activities.^29-32 As such, institutions are getting creative. For example, a 236-bed community hospital in Bethesda, Md., implemented an ASP without a dedicated on-site ID specialist pharmacist or ID specialist physician and successfully demonstrated significant cost savings and a significant decrease in antimicrobial utilization.³³

The uniqueness of each practice location must be considered to achieve the greatest return on investment for delegated ASP resources.  When key players select which intervention(s) to pursue, motivating factors such as patient safety, the spread of antimicrobial resistance, hospital length of stay, spectrum of antimicrobial activity and costs are potential targets.^13,34,35 As a healthcare practitioner, patient care universally comes before all else; however, as a formulary decision-maker with administrative responsibilities, financial considerations are of particular interest.³⁶ Fortunately, interventions fueled by economic motivations (eg, decreasing daptomycin expenditures) should inherently contribute to additional ASP targets (eg, inappropriate use) when implemented correctly.²⁹

Drug Expenditures and Economic Impacts

During the first 9 months of 2011 within non-federal American hospitals, $2.15 billion of a total $21 billion in drug expenditures was due to systemic anti-infectives.³⁷ Of the top 15 individual drug expenditures, antimicrobial agents levofloxacin (2007), piperacillin-tazobactam (2007-2011), linezolid (2008-2011), and daptomycin (2009-2011) have all made the list during this same period each year from 2007 through 2011.^37-41 In recent years, daptomycin has gained particular notoriety for its financial successes.  From 2010 to 2011, 9-month daptomycin expenditures experienced an increase of 21.9% (a percentage increase second only to the chemotherapeutic agent oxaliplatin) to reach $305 million.³⁷ Moreover, in 2010, it was noted to be the most financially successful intravenous antibiotic in American history (in nominal dollars of sales).⁴² As administrators look to contain drug expenditures and sustain excellent patient care within their institutions, various ASP strategies have been shown to be effective.^13,34,43 Recently, Beardsley et al documented an average annual ASP cost reduction (defined as antimicrobial expenditures minus labor costs) at an 880-bed academic teaching medical center of between $920,070 and $2,064,441 (dependent upon the method of calculation of inflation that was used).⁴⁴ The noted example from Michaels et al. in Maryland occurred at a much smaller (230-bed) community hospital and produced a two-year drug cost reduction of up to $290,000.³³ Such examples reflect the capacity for an ASP to generate cost savings in a variety of settings.

Formulary Restriction and Preauthorization

The core ASP strategy of formulary restriction and preauthorization has shown to contribute to immediate and significant reductions in drug cost and use, earning it an A-II recommendation in the 2007 Stewardship Guideline.¹³ This strategy may be implemented in a number of ways, including controlling antimicrobial agents in a prospective or retrospective authorization process enforced either intermittently or 24-hours per day, 7-days per week. The target for this strategy may be an individual drug (eg, linezolid) or a selected formulary agent within a drug class (eg, doripenem as the antipseudomonal carbapenem of choice).^21,43 Target selection is dependent upon the numerous previously noted institution-specific characteristics.

Recently, Goff et al. investigated potential ASP “low-hanging fruit,” or selecting the most feasible targets given sparse resources.²¹ The authors found formulary restriction to contribute to early program successes and significant cost savings, but noted the requirement of more resources than other strategies (eg, therapeutic substitution).  This led the researchers to reject formulary restriction as a low-hanging fruit. Prior to their investigation, survey data from members from the IDSA Emerging Infections Network documented a shift over a10-year period (1999 to 2009) away from formulary restriction alone to a tailored set of strategies.³⁶ Such findings seem fitting, particularly in light of the lack of resources (including sufficiently trained personnel) institutions are faced with today.^18,27

In the setting of an LTACH or LTCF, recognizing the difficulties of maintaining formulary standards when receiving patients from outside facilities with various formulary practices is a challenge for preserving continuity of care.¹⁵ To this end, ASPs in these settings may or may not choose to incorporate the strategy of formulary restriction.^24,25

Looking forward, formulary restriction will undoubtedly remain an integral part of ASPs, but may be more effective when used in combination with other elements or in a bundled approach to influencing practice.^34,45 As such, 2 possible occurrences to be aware of when incorporating formulary restriction into an ASP are stealth prescribing and squeezing of the balloon. Stealth prescribing refers to situations in which prescribers work around the hours of the restriction program, writing for restricted drugs when their orders will not be subject to the traditional approval process.⁴⁶ Squeezing of the balloon refers to restriction of 1 antimicrobial drug or class, which in turn increases the use of another antimicrobial drug or class.⁴⁷ A classic case of this was documented by Rahal et al., who found that total cephalosporin restriction led to greater imipenem-cilastatin use and increased imipenem-cilastatin resistance in Pseudomonas aeruginosa.⁴⁸

Supplemental Strategies for Antimicrobial Stewardship

There are numerous supplemental strategies an ASP may employ (Table 1, page 8), of which many have demonstrated an impact on financial endpoints.^13,44 A complete review of these is beyond the scope of this article, but several will be noted here.

Intravenous (IV) to oral (PO) conversion of antimicrobial agents is a commonly practiced intervention that has consistently shown to be safe and effective. Additionally, it can be performed by personnel who do not require extensive training.^13,21 In 2001, Wong-Beringer et al provided a description of how an IV to PO program can be implemented, which new ASPs may find useful.⁴⁹ They suggest selecting drugs that are commonly used and for which there are substantial cost differences between the IV and PO formulations, reflecting the importance of considering the uniqueness of each institution when making decisions. With regard to financial outcomes, there have been extensive publications in this area. Recently, in 2012, Jones et al reported a potential cost savings from 2006 through 2010 of up to $4,000,000 through elimination of avoidable IV fluoroquinolone use in 128 Veterans Affairs Hospitals.⁵⁰ Although such promise is noteworthy and drug costs are not the only benefit to IV to PO transition, it is also important to recognize long-term drug cost benefits may be hampered by changes in factors such as acquisition costs (eg, levofloxacin transitioning to generic).

Dose optimization of antimicrobials refers to ensuring drug treatment is tailored to the individual patient, causative organism, infection site, and/or drug-specific characteristics (pharmacokinetic/pharmacodynamic [PK/PD] properties).¹³ Numerous interventions fall under this element, including use of PK/PD services (eg, for IV vancomycin) and extended- or continuous-infusions for drugs with time-dependant killing (eg, select beta-lactams).¹⁵ Implementation of a piperacillin-tazobactam extended-infusion protocol has become a specific area of interest in recent years, as more publications supporting its favorable safety and financial impact have come to light.^51-55 Utilizing a more prolonged infusion time allows for maximization of antimicrobial killing and a reduction in total daily doses (eg, 3.375 g every 6 hours infused over 30 minutes versus 3.375 g every 8 hours infused over 4 hours), thus preserving patient care and lowering drug costs. Three separate studies of piperacillin-tazobactam extended-infusion protocol implementation have documented financial outcomes to include annual expenditure reductions of up to 18%, $108,529, and $135,750.^53-55 Implementing this intervention has the potential to have a similar benefit at other institutions, particularly when considering that piperacillin-tazobactam has consistently been of significant cost to non-federal American hospitals for several years.^37-41

As previous points are considered, implementation of interventions targeting utilization of specific high-cost agents is likely to appear a rational starting point, particularly when there are multiple such drugs available and the goal is to establish sustainable ASP activities. While this is undoubtedly true in the short-term, McGowan notes that long-term cost savings are not supported by as robust data and that future evaluation methods are an area of concern if convincing evidence for the continuation of ASPs is to be produced.⁵⁶ As implementation and continuation of sustainable ASPs remains a challenge, nonpharmacy costs, such as those associated with increased length of hospitalization, hospital readmission, drug toxicities, and acquiring an infection with an antimicrobial resistant organism should also be kept in mind.^6,21,57,58

Patient Safety and the Progression of Antimicrobial Resistance

The primary goal of an ASP is the optimization of clinical outcomes.¹³ To achieve this, use of interdisciplinary strategies and active accounting for institution-specific outcome measures (eg, antimicrobial resistance, length of stay, 30-day readmissions, etc.) are crucial. As patient safety and antimicrobial resistance are addressed, common ground can be observed. For example, when a patient acquires an infection due to an antimicrobial-resistant organism, use of a drug with significant toxicities (eg, colistin) may become necessary.⁵⁹ The effect of resistant organisms on mortality was investigated by Neidell et al, who recently found higher death rates in patients infected with antimicrobial-resistant organisms versus antimicrobial-susceptible organisms.⁵⁸ Although this is not entirely surprising, it is tremendously concerning in light of current issues relating to antimicrobial development and resistance worldwide.^1-12

When considering these issues, collateral damage is a term worth noting. This refers to the unfavorable ecological effects of using antimicrobial therapy.⁶⁰ Two possible forms of collateral damage are selection for organisms harboring antimicrobial resistance and colonization with an antimicrobial-resistant organism. Cephalosporins (the second and third generations in particular) and fluoroquinolones are two areas of concern regarding these negative implications.^60-62 Focusing on Clostridium difficile infection, Dubberke recently published an article reviewing the scope of this significant and wide-spread health problem.⁶³ Here, the author reviews the impact on morbidity, mortality, and costs and denotes an increase in the incidence, severity, virulence, and treatment failures. As healthcare practitioners attempt to address this issue, agents associated with collateral damage may be found to be antagonistic to their efforts. One example of the impact fluoroquinolone and cephalosporin use can have may be derived from an incident that occurred in a hospital in The Netherlands.⁶¹ At this institution, an outbreak of C difficile did not end until use of cephalosporins was restricted and fluoroquinolones were completely banned. More recent literature has supported this finding, noting the restriction of these antibiotics (referred to as “high-risk antibiotics”) to contribute to a reduction in their use and the incidence of C difficile infection.⁶²  Although agents within these 2 drug classes (eg, ceftriaxone and ciprofloxacin) are not typically of particularly high cost from the drug acquisitions perspective, it is clear that they do have considerable cost implications to the healthcare system.⁶⁴

The occurrence and evolution of infections due to antimicrobial-resistant organisms will inevitably continue to impact patient safety. Therapeutic options in the antimicrobial arsenal become more limited when organisms acquire resistance mechanisms, often resulting in choices which carry a different set of toxicities. This is of particular concern for a set of organisms termed the “ESCAPE” pathogens (previously the “ESKAPE” pathogens), which have the ability to “escape” actions of available antibiotics.^2,3 This acronym stands for Enterococcus faecium, Staphylococcus aureus, C difficile, Acinetobacter baumannii, P aeruginosa, and Enterobacteriaceae.³ Agents used to treat infections caused by these pathogens (select adverse drug reaction(s) [ADRs] noted in parentheses), such as tigecycline (nausea and vomiting), daptomycin (creatinine phosphokinase [CPK] elevation), linezolid (neuropathies and bone marrow suppression), dalfopristin-quinupristin (infusion reactions and arthralgias) and colistin (nephrotoxicity and neurotoxicity) require specific consideration in regards to their tolerability.⁶⁴ Fortunately, several ASP activities exist which can help to control and prevent ADRs. One example comes from Tran et al., who investigated the impact of an institutional protocol to improve daptomycin dosing for infections caused by vancomycin-resistant enterococci (VRE). Their results demonstrated that a multidisciplinary ASP team improved the rate of safety monitoring, as CPK assessment at baseline rose from 43% to 64% (P<.05).⁶⁵ With multidrug-resistant organisms on the rise, an increase in the utilization of aforementioned medications is inevitable, thus incorporation of monitoring parameters for ADRs into ASP activities should be considered.

Antimicrobial Stewardship Resources

Numerous resources are available to healthcare practitioners looking to acquire more information about antimicrobial stewardship. The websites of organizations such as the World Health Organization, Centers for Disease Control and Prevention (CDC), and local departments of health have an enormous amount of information. The CDC in particular hosts a “Get Smart for Healthcare” campaign available at: www.cdc.gov/getsmart/healthcare (accessed November 19, 2012), whose goal is to optimize antimicrobial use in the inpatient healthcare settings. Guidelines and resources published by the IDSA, SHEA and other major organizations are extensive and many are available for free online. Further, the ASHP initiative Lead Stewardship website available at: www.leadstewardship.org (accessed November 19, 2012) hosts an array of resources. 

Available from the literature, a publication by Pagani et al in 2009 provides a review of online resources.⁶⁶ Here, researchers describe results of a search for antimicrobial stewardship resources for healthcare institutions, with a goal of identifying high-quality and readily accessible resources, such as comprehensive websites, institutional websites, and websites from societies or other organizations. Their findings present a wide array of available resources, which may be useful for anyone involved in ASP activities. More recently, Goff provided a review of medical applications (commonly referred to as “apps”) ASPs may use on the iPhone or iPad.⁶⁷ Descriptions of 17 apps are provided, which fall under a medical category of drug information, education, calculators, references, epidemiology, or news.

For practitioners looking to acquire training and exposure within the area of ID or antimicrobial stewardship, beyond completing post-graduate pharmacy residency or fellowship training, a few avenues exist. The Society of Infectious Diseases Pharmacists has an Antibiotic Stewardship Certificate Training Program, with details available at: www.sidp.org (accessed November 19, 2012). The group Making a Difference in ID Pharmacotherapy (MAD ID) also has a training program, with details available at: http://mad-id.org (accessed November 19, 2012). For practitioners looking to become distinguished among their peers, the Board of Pharmacy Specialties (BPS) offers Added Qualifications in the area of ID for Board Certified Pharmacotherapy Specialists with criteria available at: www.bpsweb.org (accessed November 19, 2012). Further, the creation of an independent BPS ID specialty is in the works.⁶⁸

Future Directions and Conclusion

Undoubtedly, antimicrobial stewardship will remain a subject of interest for healthcare practitioners across a variety of settings for years to come. Appelbaum provides a thorough summary of what can be done to address the many concerns at hand, during which he notes the importance of education, public awareness, regulatory collaboration, and funding.¹ Goff et al noted future Medicare payment penalties relating to readmissions and the Affordable Care Act, which is likely to become of great interest.^21,69 Such discussion supports the notion that improving outcomes, ASP longevity, institution-specific considerations, and other factors will remain a noteworthy challenge as we continue to attempt to hit the moving target of implementing effective antimicrobial stewardship strategies. Importantly, formulary decision-makers should continue to stay abreast of changes as further information comes to light and as we better understand how the decisions of today impact the issues of tomorrow. ■

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