The first closed system drug transfer device (CSTD) was approved by the FDA in 1998 for prevention of hazardous drug leakage into the environment. Since then, several products have been approved, each with different characteristics. A selection of available products is listed in the Figure.

		CSTDs are supplemental engineering controls designed to protect health care professionals from hazardous medications.

		CSTDs equalize the pressure gradient between the syringe and the container from which liquid medication is drawn or expelled, reducing the risk that hazardous medication will escape into the surrounding environment.

		CSTDs are used in both compounding and administration of hazardous medications.

However, CSTDs also vary in several respects, including

		The quality of data supporting each product’s performance in containing medication and reducing worksite contamination

		The type of interface between the syringe and the infusion set or vial

		Compatibility with bedside use by nurses and compounding use by pharmacists

		Plastic components in CSTDs are not compatible with all chemotherapeutic medications; reviewing compatibility before using a CSTD with reactive medications is critical to operational safety

Considering these and other factors is important in determining which CSTD is appropriate for a given institution. Because CSTDs can be used in both compounding in the pharmacy and bedside administration of chemotherapeutic drugs, selection of a CSTD is a multidisciplinary process that may involve discussions between nursing directors and pharmacy directors.

Currently, many hospitals do not have access to CSTD systems. In a 2011 survey of 1401 pharmacy directors at hospitals throughout the United States conducted by Pederson and colleagues, researchers found that CSTDs were used in 41% of all hospitals. Of these hospitals, the vast majority (92%) used CSTDs in compounding medications, while a smaller percentage (70.2%) used CSTDs during bedside administration.

In hospitals where CSTDs are unavailable, nurses administer chemotherapeutic medications to patients without the benefit of these devices. As a result, nurses may be exposed to hazardous drugs, potentially leading to adverse health effects. In the coming years, CSTDs will be used in most hospitals as a result of a provision in USP <800>. This provision mandates that nursing departments have access to CSTDs when administering chemotherapeutic medications to patients.

Recent data indicate that hospital pharmacy departments are slightly more likely to have access to CSTDs than hospital nursing departments. In a 2014 survey of US hospitals, 35% of pharmacy departments were estimated to have access to CSTDs versus 32% of nursing departments. When the provisions of USP <800> are adopted by state pharmacy boards, this difference in access is likely to reverse, with more nursing departments than pharmacy departments having access to the technology.

The potential disparity in access to CSTDs between pharmacy and nursing departments is one reason why pharmacy department leaders would be wise to discuss CSTD systems with nursing departments to ensure that all stakeholders ultimately have access to systems that are optimized for use in both pharmacy and nursing environments. Without the additional protection of CSTDs, both pharmacists and nurses may be at increased risk of health effects occurring secondary to hazardous drug exposure.

	In a 1999 study published in the Journal of Occupational and Environmental Medicine, Valanis and colleagues analyzed pregnancy outcomes in nearly 3000 nurses, pharmacists, and pharmacy technicians and compared those outcomes with those in more than 4000 women who were not health care workers. In health care workers, spontaneous abortion or stillbirth was 40% more likely (OR 1.4; 95% CI, 1.2 to 1.7) to occur in individuals who reported handling hazardous drugs.

	In 2010, McDiarmid and colleagues published a study in the Journal of Occupational and Environmental Medicine identifying a higher rate of chromosome 5 and 7 abnormalities among health care workers frequently handling antineoplastic medications than in health care workers who handled such medications less frequently.

 Researchers collected blood samples from more than 100 health care workers and analyzed the likelihood of chromosomal abnormalities related to the frequency of hazardous drug handling in each individual. Study results indicated significantly higher rates of structural chromosomal abnormalities in a high-exposure subset of health care workers than in a lowexposure group (0.18/ person vs 0.02/person, respectively; P = .04). Significant outcomes included a 24% greater risk of chromosome 5 abnormalities (P = .01) and a 20% greater risk of chromosome 5 or 7 abnormalities (P = .01) in high-exposure individuals.

	Considering that both pharmacists and nurses may have an elevated risk of adverse health outcomes as a result of exposure to hazardous drugs, both pharmacists and nurses would ideally have access to CSTDs. However, CSTD devices that may be ideal for use in the pharmacy may not be ideal for administration of medication. For some institutions, CSTDs for nursing personnel may be different from the CSTDs used by pharmacy personnel.

Because pharmacists use CSTDs in controlled compounding environment, they are less likely to be concerned about needle sticks. However, nurses administering medication at the bedside may be more amenable to using a CSTD that does not have a metal needle, which may reduce the risk of accidental puncture wounds.

	Some CSTDs may also not be compatible with a hospital’s existing intravenous administration equipment. The extra cost of these proprietary administration sets and the training required to implement their use may lead some nursing departments to find this aspect of certain CSTD systems unfavorable.

	The closing mechanism of the CSTD system, assembly requirements, and integration with automated systems are also important considerations to discuss, as the importance of these factors may vary between pharmacist and nurse stakeholders. For instance, pharmacists may be more concerned about the potential for repetitive stress injury if a product requires intensive manipulation for use, whereas nurses may be more concerned about safeguards ensuring that CSTD components are firmly joined together before use.

	Regardless of the differences between the needs of nursing departments and pharmacy departments, the primary concern with any CSTD system is the quality of the evidence showing that these systems prevent the escape of hazardous drugs. For example:	

			More than 25 published studies support the performance and efficacy of the BD PhaSeal System in protecting health care workers from hazardous drugs.

			In a 2003 study, Wick and colleagues determined that the BD PhaSeal system led to real-world reductions in personnel exposure. Before, and 6 months after implementation of BD PhaSeal CSTD use in a hospital pharmacy, all personnel were evaluated using 24-hour urine samples. Of 8 employees, 6 showed evidence of exposure to cyclophosphamide and 2 showed evidence of ifosfamide exposure prior to use of the BD PhaSeal System. After implementation, none of the 8 employees had evidence of cyclophosphamide or ifosfamide in urine samples.

			In a 2011 study, Sessink and colleagues reported levels of surface contamination of antineoplastic drugs in 22 US hospitals before and several months after adoption of the BD PhaSeal CSTD system. Researchers, however, found significantly lower levels of surface contamination for all 3 antineoplastic drugs sampled: cyclophosphamide (95% reduction; P <.0001), ifosfamide (90% reduction; P <.001), and 5-fluorouracil (65% reduction; P <.01).

			In a 2013 study, Clark and colleagues reported the efficacy of the EquaShield CSTD on reducing surface contamination at a single cancer center before and after the system’s adoption. Researchers used a kit to collect samples from 5 areas of the pharmacy, 5 areas of the infusion suite, and 2 areas in offices. Approximately half of the samples showed contamination before, but no contamination with cyclophosphamide or 5-fluorouracil in the pharmacy was identified in the final sample collection.

	Protective efficacy of CSTD systems is the most important consideration for both pharmacy and nursing stakeholders. However, other considerations may also be worth discussing. Some of these considerations are discussed in the Table.

	Although pharmacy and nursing departments share the common goal of providing optimal patient care, departments may have different priorities and needs that may affect departmental CSTD preferences. As a result, proactively discussing CSTD systems and their use across departments is an important component of smooth implementation of USP <800>. Proactive engagement now may help ensure that more pharmacies and nursing departments have access to CSTDs with qualities well suited to both practice settings.	

			Massoomi F. The Evolution of the CSTD. 

			FDA. 510(k) Premarket Notification Database. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm.

			Page MR. Protecting health care workers from chemotherapeutic medication. 

 website. www.specialtypharmacytimes.com/publications/specialty-pharmacy-times/2015/june-2015/protecting-health-care-workers-from-chemotherapeutic-medication. Published June 9, 2015. Accessed September 2015.

			Page MR. USP <800>: new regulations to protect health care workers from hazardous drugs. 

 website. www.specialtypharmacytimes.com/publications/specialty-pharmacy-times/2015/april-2015/usp-800-new-regulations-to-protect-health-care-workers-from-hazardous-drugs. Published April 15, 2015. Accessed September 2015.

			Pedersen CA, Schneider PJ, Scheckelhoff DJ. ASHP national survey of pharmacy practice in hospital settings: dispensing and administration--2011. 

			Massoomi F. USP <800> and the expected impact on health systems. http://www.pharmacyadvisor.com/resources/uploads/webinar_handouts/55/usp_800_and_the_expected_impact_on_health_systems.pdf. Accessed September 2015.

			Valanis B, Vollmer WM, Steele P. Occupational exposure to antineoplastic agents: self-reported miscarriages and stillbirths among nurses and pharmacists. 

			McDiarmid MA, Oliver MS, Roth TS, Rogers B, Escalante C. Chromosome 5 and 7 abnormalities in oncology personnel handling anticancer drugs. 

			BD Phaseal Studies. BD website. www.bd.com/pharmacy/phaseal/evidence/studies.asp. Accessed September 2015.

			Wick C, Slawson MH, Jorgenson JA, Tyler LS. Using a closed-system protective device to reduce personnel exposure to antineoplastic agents. 

			Sessink PJ, Connor TH, Jorgenson JA, Tyler TG. Reduction in surface contamination with antineoplastic drugs in 22 hospital pharmacies in the US following implementation of a closed-system drug transfer device. 

			Clark BA, Sessink PJ. Use of a closed system drug-transfer device eliminates surface contamination with antineoplastic agents. 

		- See more at: http://www.specialtypharmacytimes.com/publications/specialty-pharmacy-times/2015/october-2015/selection-of-closed-system-transfer-devices-tips-for-engaging-nursing-and-pharmacy-stakeholders-in-purchasing-decisions#sthash.bZdPTmfY.dpuf	

Articles

Health System Information

The first closed system drug transfer device was approved by the FDA in 1998 for prevention of hazardous drug leakage into the environment; since then, several products have been approved, each with different characteristics.

Selection of Closed-System Transfer Devices: Tips for Engaging Nursing and Pharmacy Stakeholders in Purchasing Decisions

The House of Representatives, and eventually the Senate, are expected to pass bill HR 592 and its companion bill, S 314, within the next 2 years. Last year, the campaign to support the bills generated strong bipartisan support.

Passage of the bills would allow patients access to, and coverage for, Medicare Part B services by statelicensed pharmacists in medically underserved communities. It is predicted that this would allow immediate billing of medication therapy management (MTM) by pharmacists, prompting most medical practices to require MTM and, in turn, ensure better medication adherence and patient outcomes. The legislation supports having pharmacists recognized as providers by Centers for Medicare & Medicaid Services, and it is hoped that commercial payers will also come on board.

Passage of the bills may also open new opportunities for pharmacists to practice in current environments and in new practice areas, serving as an incentive to seek additional professional training, residencies, and board certifications.

As the only pharmacist serving in Congress, US Representative Earl L. “Buddy” Carter (R-GA) is a critical leader of efforts to pass federal legislation pertinent to pharmacists. 

 recently spoke with the first-term US Congressman, House Community Pharmacy Caucus co-chair, and Carter’s Pharmacy, Inc, owner about HR 592. (For the full interview, see “Q&A with US Representative Buddy Carter, the Only Pharmacist in Congress” on pharmacytimes.com.)

“This legislation [HR 592] is paramount to the advancement of pharmacies and pharmacists,” said Rep. Carter. “The current pharmacy practice is light years ahead of what the practice was when I was going through school. Pharmacists now know more about clinical education for patients than ever before.”

Rep. Carter is working with US Representative Brett Guthrie (R-KY) to garner additional co-sponsors and ensure that the Energy and Commerce Committee brings the bill up for debate. “We are garnering much support for this bill, with over 200 sponsors so far. The sooner we can get this bill to the House Floor, the sooner patients will be able to take full advantage of all the important skills pharmacists have today.”

News & Highlights

The House of Representatives, and eventually the Senate, are expected to pass bill HR 592 and its companion bill, S 314, within the next 2 years.

Provider Status Update

Hospital acquisitions and mergers have become common in today’s health care environment. Reports indicate a significant increase in recent years, demonstrated by a growth from 50 in 2009 to more than 100 in 2013, with 2015 on course for the most to date.

 It is important to note that the expansion of large health systems is not new: organizations such as Hospital Corporation of America (HCA), operator of 463 hospitals in 1987, have been growing for decades.

 However, the rapid acceleration of health-system consolidation has brought this topic to the forefront. Pharmacy has the potential to be affected by these transactions.

It is evident that the increased rate of acquisitions and mergers is closely related to the significant changes in health care delivery. As health systems transition from a fee-for-service to a value-based care payment model, their size is pivotal to their success. In an environment where the expectation is to perform at higher levels of quality with fewer resources, economies of scale and purchasing power are essential to leverage cost savings.

 Consolidations allow health systems to share infrastructure, standardize clinical workflows, develop specialized services, and negotiate more competitive contracts—all while ultimately providing improved patient care.

With future payment models focusing on the management of populations, health systems need adequate resources to care for patients far beyond the walls of the acute care hospitals. It is here where pharmacy plays a role. Although significant focus has been placed on the acquisition of physician clinics by health systems, the growth of pharmacy services is arguably more crucial for monitoring patients across the continuum of care. Medications serve as a unifying aspect of the various domains of health care, and leveraging pharmacy management in each one of these domains allows continuous patient follow-up and monitoring.

The concept of health-system pharmacies operating in multiple domains across a system is nothing new. The term “pharmacy enterprise” has been used, since 2006, by the American Society of HealthSystem Pharmacists Section of Pharmacy Practice Managers executive committee and been discussed and defined multiple times in years since, most recently by Scott Knoer, PharmD, chief pharmacy officer of the Cleveland Clinic.

 In the inaugural article of the CPO Perspectives section of the 

American Journal of Health-System Pharmacy

, Knoer emphasizes that pharmacy is so much more than the term “pharmacy department” denotes, and he defines the pharmacy enterprise as “an integrated system of business units with accountability for clinical and financial outcomes related to medication use across the continuum of care in a health system.”

When exploring the concept of the pharmacy enterprise and an approach to pharmacy on a system level, 3 priorities emerge as constants: (1) improvement of patient care, (2) reduction of inevitable inpatient pharmacy costs, and (3) expansion and optimization of outpatient pharmacy revenue. A focus on each of these constants was central to the creation of Novant Health’s system pharmacy administration office.

Novant Health is no stranger to health care consolidation. Originating from a merger between Carolina Medicorp and Presbyterian Hospital in 1997, Novant Health now operates 13 medical centers, more than 400 physician clinics, 100 outpatient facilities, 9 retail pharmacies, 11 infusion centers, and 2 URAC-accredited specialty pharmacy locations in North Carolina, South Carolina, Virginia, and Georgia.

For much of Novant Health’s history, the organization has been on a journey to realize the potential of a truly integrated health system. Prior to a systemwide office known as “pharmacy administration,” a regional approach was in place, led by a regional leader. This leader had oversight of 3 hospitals, as well as clinical and medication safety. With the transition to systemwide structure, the regional leader moved into the newly created role of vice president of pharmacy. This individual represented a core principle of the pharmacy enterprise: a leader with a focused strategic plan encompassing quality of care and generation of revenue, the latter being practically unheard of in health-system pharmacy, where inpatient services have historically dominated.

The strategic plan for pharmacy administration consisted of 3 core principles: the standardization of acute care facility operations and clinical services, systemwide management of drug procurement, and the growth of Winston-Salem Health Care—Novant Health’s outpatient and mail order pharmacy. Together, these principles represent the 4 priorities of the pharmacy enterprise/integrated health-system approach around improving quality, reducing costs, maximizing earnings potential, and improving the patient experience.

To implement these core principles, pharmacy administration needed to grow. Initial additions of clinical and operational directors allowed an accelerated unification of inpatient pharmacy services throughout the system. The goal here was 2-fold: (1) standardize workflows to permit pharmacist staffing across the system and offsite coverage to serve facilities without 24/7 pharmacy support, and (2) create an identifiable pharmacy culture that provides the same level of expectations to patients, physicians, nurses, and all other health care professionals across the system.

With inpatient services on the right track, focus quickly shifted toward the outpatient market and the transformation of pharmacy from a cost center into a revenue generator. Leaders of outpatient and infusion pharmacy, along with support staff, were hired. The early goals of Winston-Salem Health Care generating revenue and the increased retail capture rate of Novant Health, team members were quickly realized. This early success bolstered senior leadership’s confidence in pharmacy administration and gave the green light for the development of Novant Health Specialty Pharmacy, which launched in 2013. This remarkable process of leadership and focused growth helped a struggling retail service evolve into a full-spectrum outpatient pharmacy service.

Following the outpatient successes, along with inpatient improvements, opportunities presented to expand beyond traditional areas of pharmacy. One area was within the system’s transitions of care and value-based care work. Pharmacy administration now monitors patients through the domains of health care. Instead of following patients along a linear path from the hospital to outpatient location, pharmacists now proactively partner with providers and patients, focusing on the ambulatory care setting of patient management. Our role is to meet patients where they are in their health care journey and help them leverage medication management to get better and stay healthy.

It is clear that innovative solutions and new models of care are critical to the success of our industry. As such, Novant Health has a responsibility to create its future and help train a new generation of pharmacists to meet this challenge. As such, pharmacy created a PGY2 in population health in 2014.

Today, Novant Health’s pharmacy administration oversees an entity consisting of far more than the sum of its parts. In addition to the physical pharmacy facilities, it manages a systemwide procurement team, regulatory affairs specialists, automation specialists, a residency and student education coordinator, and administrative support staff. These units combine to form an operative pharmacy enterprise that is successfully leveraging system integration and providing both innovative patient care and profitable results.

With a stable infrastructure now in place, it is essential to evaluate what advancements, if any, have been made possible by taking a system-integrated approach. Standardization of inpatient services has been seen as a success across the board. Standardized workflows ensure thorough pharmaceutical care at all facilities 24 hours a day, allowing pharmacists and technicians to move across the system where needed to optimize staffing and foster relationships with other members of the health care team. In addition, a systemwide pharmacy and therapeutics committee and formulary have standardized therapeutic options. This benefits the patient and significantly impacts procurement performance. Advancements in procurement—such as using a systemwide wholesaler and contracts, as well as a unified 340B management&mdash;along with operational streamlining will save an estimated $20 million in 2015 alone.

With the help of savings estimates in the millions of dollars, pharmacy administration was recently awarded 5 additional full-time equivalents for pharmacists trained in infectious disease (bringing the total to 7) to advance Novant Health’s antimicrobial stewardship program. It is through the platform of a centralized pharmacy leadership that clinical initiatives are launched and primed for future growth.

On the outpatient side, Novant Health is now operating at a completely different level than before the launch of the coordinated systemwide approach. Retail, specialty, and infusion centers provided an estimated $50 million contribution margin in 2015. Although infusion centers maintain a majority of this contribution, specialty is rapidly growing and has completed more than 50% of its 5-year business plan in just 2 years. With many successes already seen on the inpatient and outpatient sides, it is hard to imagine that only a small fraction of system initiatives have been fully enacted. Novant Health continues to pursue additional projects to help transform pharmacy services, including advanced procurement solutions (systemwide inventory management software, highspeed repackagers, and centralized distribution), clinical pharmacy initiatives (antimicrobial stewardship, transitions of care, and value-based care), and business intelligence (data use and clinical outcomes improvement projects).

The future of health care is bound to be uncertain and ever-changing. However, optimizing the benefit potential of a fully integrated health system may provide a means of stabilization and controlled growth. Novant Health has demonstrated this potential for success through its systemwide approach to pharmacy administration. This is translatable not only to other pharmacy leadership teams, but also to health systems as a whole.

David Garbarz, PharmD, is a PGY1 pharmacy resident with an administration focus at Novant Health Forsyth Medical Center in Winston-Salem, North Carolina, with plans to pursue a PGY2 in health-system administration at Novant Health.

Jeff Reichard, PharmD, MS, BCPS, is pharmacy manager at Novant Health Clemmons Medical Center, Novant Health Kernersville Medical Center, and Novant Health Medical Park Hospital. Dr. Reichard received his doctor of pharmacy degree from the University of North Carolina at Chapel Hill Eshelman School of Pharmacy. Upon graduation, he completed a combined residency and master of science degree in health-systems pharmacy administration at the University of North Carolina Hospitals.

Pharmacy Forecast: Strategic Planning Advice for Pharmacy Departments in Hospitals and Health Systems 2014-2018

. Chapter 5. ASHP Foundation website. ashpfoundation.org/MainMenuCategories/CenterforPharmacyLeadership/Pharmacy-Forecast. Accessed November 9, 2015.

		HIMSS analytics. Health Information Management Systems Society website. himssanalytics.org/stage7. Accessed November 9, 2015.

. pppmag.com/article/pppv12n8s0/State_of_Pharmacy_Automation_2015. Accessed November 9, 2015.

		50 things to know about Epic, Cerner, MEDITECH, McKesson, athenahealth and other major EHR vendors. Becker's Healthcare website. beckershospitalreview.com/healthcare-information-technology/50-things-to-know-about-epic-cerner-meditech-mckesson-athenahealth-and-other-major-ehr-vendors.html. Accessed November 9, 2015.

		Banner Health. EMR and sepsis. Banner Health website. bannerhealth.com/About+Us/Innovations/Electronic+Medical+Record/EMR+and+Sepsis.htm. Accessed November 9, 2015.

Viewpoints

Hospital acquisitions and mergers have become common in today's health care environment.

A System Approach to Pharmacy Leadership

Neuropathic pain is a chronic nerve pain that can significantly impair a patient’s functioning and quality of life. Neuropathic pain results from damaged nerves that have been affected by tissue injury due to trauma or disease. Diabetes mellitus and herpes zoster are commonly associated with the development of neuropathies. Other disease states that may result in neuropathic pain include complex regional pain syndrome, radiculopathy, and phantom limb pain. Neuropathic pain can also be medicationrelated, as in the case of nerve damage due to cancer treatment.

Neuropathic pain originates from the reduced inability of a neuron to relay messages to and from the brain because of damage to the nerve. This can cause a person to feel a variety of sensations or hypersensitivities.

 A patient may feel different types of pain, depending on the origin and cause of the pain.

Neuropathic pain can be distinguished from nociceptive pain by determining the quality of the pain. Typically, patients experience variations in sensation or hypersensitivity. Neuropathic pain symptoms can be classified as negative or positive. Negative symptoms of neuropathic pain are described as a loss of sensation or numbness. Positive symptoms are characterized by the increased perception of pain or abnormal sensations. Positive symptoms can be either induced by a stimulus or spontaneous (nonstimulus induced). Table 1 describes the types of symptoms.

Various classes of medications have shown benefit for managing neuropathic pain. Medications for neuropathic pain are not likely to completely resolve pain; therefore, health care providers should discuss realistic goals with patients prior to initiating therapy. A reduction in pain of 30% is often considered a reasonable goal, along with potential improvements in sleep and depression, depending on the specific agent used. Patients should also be informed that many agents used for neuropathic pain often require a series of dose titrations and weeks of use to see a benefit. Classes of medications used for neuropathic pain include tricyclic antidepressants (TCAs), serotonin/ norepinephrine reuptake inhibitors (SNRIs), anticonvulsants, and, potentially, opioid therapy.

TCAs are often considered first-line for treatment of neuropathic pain and have shown benefit in clinical trials for diabetic peripheral neuropathy and postherpetic neuralgia.

 Benefits include low cost, as well as potential improvement in depression and/ or insomnia, which are frequently associated with neuropathic pain. Anticholinergic adverse effects (AEs), including dry mouth, constipation, and drowsiness, are possible with TCAs, although nortriptyline and desipramine are less likely than amitriptyline to cause AEs. Due to the risk of anticholinergic AEs, it is generally recommended to avoid the use of TCAs in the elderly. Use of TCAs should also be avoided in patients with a history of cardiac arrhythmias. TCAs should be initiated at a low dose, and the dose should be increased every 3 to 5 days until a target dose is reached or AEs become intolerable.

Serotonin/Norepinephrine Reuptake Inhibitors

SNRIs is a class of antidepressant medications that can be used to treat neuropathic pain. These medications include venlafaxine, duloxetine, and milnacipran. An advantage to SNRIs, similar to TCAs, is that they can help improve comorbid depression or anxiety. SNRIs should be used cautiously with other serotonergic medications due to the risk of serotonin syndrome. The most common AE associated with this class is nausea.

The anticonvulsants gabapentin and pregabalin are frequently used in the setting of neuropathic pain management. Gabapentin has been studied for managing various types of neuropathic pain, including diabetic neuropathy and postherpetic neuralgia, and gabapentin case study results have shown a benefit to its use over placebo in managing sciatica.

 Pregabalin has also been studied for managing postherpetic neuralgia and diabetic neuropathy, and the drug has shown efficacy in treating pain due to centrally mediated neuropathic pain and due to spinal cord injury.

Along with TCAs, gabapentin is often considered a first-line agent for managing neuropathic pain. Use of pregabalin may be considered after failure with gabapentin due to a lack of efficacy or to intolerable AEs. Gabapentin and pregabalin are started at low doses and titrated every 3 to 7 days until a target dose is reached or AEs prevent further titrations. Both agents require dose adjustments in patients with renal impairment. Horizant (gabapentin enacarbil) and Gralise (gabapentin), extended-release gabapentin formulations, have been FDA-approved for management of postherpetic neuralgia and are designed to improve absorption of gabapentin; however, the cost of these medications is higher than an immediate-release gabapentin product.

Topiramate is another anticonvulsant that may be used for managing neuropathic pain; however, there is a lack of evidence to support the use of topiramate for managing neuropathic pain, and the study results are inconsistent.

 Therefore, topiramate is typically one of the last agents used to treat neuropathic pain. Other anticonvulsants, including carbamazepine, oxcarbazepine, lamotrigine, and lacosamide, have been studied for treating neuropathic pain and the results have been inconsistent, similar to those for topiramate.

Lidocaine patches are an analgesic alternative for managing localized neuropathic pain. This patch is indicated for treating postherpetic neuralgia and allodynia. One to 3 patches can be used at the same time for up to 12 hours. Because lidocaine patches are associated with a low risk of AEs, they are an option for patients at risk of AEs due to oral therapies.

Due to the risk of serious AEs, including addiction, abuse, and overdose, opioids are generally considered a last-line option for managing neuropathic pain. If used in this setting, using the lowest possible dose is prudent (Online Table 2).

Table 2: Drugs for Managing Neurophathic Pain

				Increases serotonin and norepinephrine; blocks sodium channels

				Sedation; antidepressant effects; less anticholinergic (nortriptyline)

				Sedation; anticholinergic effects (amitriptyline); drug—drug interactions; cardiac arrhythmias

				Increase by 25 mg intervals every 3-5 days

				Increase in 10- mg intervals every 3-5 days

				Serotonin/Norepinephrine Reuptake Inhibitors

				Increases concentrations of serotonin and norepinephrine by inhibiting the reuptake of serotonin and norepinephrine into the synapse

				Antidepressant and antianxiolytic effects

				Nausea; changes in behavior/mood; hepatic impairment (venlafaxine and duloxetine); renal impairment (venlafaxine and milnacipran); blood pressure changes (venlafaxine and milnacipran)

				Increase by 37.5 mg in the first week, then increase by 75 mg weekly

Chronic Care Focus

Neuropathic pain is a chronic nerve pain that can significantly impair a patient's functioning and quality of life.

Neuropathic Pain

The Centers for Disease Control and Prevention (CDC) has reported that 20% to 50% of all antibiotics prescribed in US acute care hospitals are either unnecessary or inappropriate, resulting in avoidable adverse effects, bacterial resistance, and an increased incidence of 

 The evolution of multidrug resistant organisms has limited the available antimicrobial treatment choices, making the improvement of antibiotic use a public health priority.

 As a result, there has been increased interest in establishing antimicrobial stewardship programs, nationwide.

Antimicrobial stewardship is a coordinated approach that aims to improve the appropriate use of antimicrobials, thereby reducing antimicrobial resistance and improving patient outcomes through targeted interventions. Effective antimicrobial stewardship programs have substantially improved clinical outcomes, decreased use of unnecessary antimicrobials, reduced 

 infections, and reduced drug resistance.

 Although these programs are also associated with potential annual savings in antimicrobial expenditures, such financial gains are often seen early in program development and may plateau over time.

 Comparatively, the clinical effects of these programs have lasting benefits for institutions.

NATIONAL ACTION PLAN FOR COMBATING ANTIBIOTICRESISTANT BACTERIA

In response to the antibiotic resistance crisis, the White House has published the National Action Plan for Combating Antibiotic-Resistant Bacteria.

President Barak Obama issued an Executive Order on Combating Antibiotic-Resistant Bacteria in September 2014. The National Action Plan was developed as guidance for implementing the Executive Order, with goals to slow the emergence of ment of diagnostic tools to identify resistant bacteria, promote and accelerate research for new antibiotics and vaccines, and strengthen surveillance efforts.

 Importantly, the plan establishes that, by 2020, antimicrobial stewardship programs should be active in all acute care hospitals, and inappropriate antibiotic use should be reduced by 50% in outpatient settings and 20% in inpatient settings.

 To do this, the plan recommends a regulatory requirement for antimicrobial stewardship be in place by 2017.

ANTIBIOTIC STEWARDSHIP PROGRAM CORE ELEMENTS

To establish a successful antimicrobial stewardship program at an institution, the CDC recommends 7 core elements, which can be found in Table 1

The foundation of any antibiotic stewardship program is a multidisciplinary stewardship team. Ideally, the stewardship team consists of an infectious diseases physician, an infectious diseases pharmacist, a clinical microbiologist, an infection control professional, and an information system specialist.

 Embedded within this team are the first 3 core elements for an antimicrobial stewardship program. Leadership commitment is evidenced by the support of hospital administration, such as dedicating the necessary personnel, financial resources, and information technology resources. Accountability and drug expertise can be achieved by appointing a single leader to be responsible for program outcomes and a single pharmacist leader to be responsible for improving antibiotic use. Figure 1

 shows the ideal stewardship team. Table 2

 provides the types of stewardship interventions.

After the stewardship “dream team” is established, the next step is to implement at least 1 intervention. Many types of interventions exist, and each has advantages and disadvantages:

: One intervention is to develop institution- specific guidelines that are modeled after national guidelines and take local susceptibility patterns into consideration, and to make these guidelines available to all providers. This can guide appropriate empiric antibiotic regimens and duration of treatment for common disease states (eg, instituting hospital guidelines for the treatment of communityacquired pneumonia and urinary tract infections). One advantage is the ability to adapt institution guidelines to the hospital’s antibiogram and population. However, this type of intervention requires buy-in by prescribers, and adherence to the guidelines is not required. Incorporation of guidelines and treatment pathways into computerized physician support systems can increase adherence to recommendations.

: Antibiotic restriction is a commonly used strategy to control antimicrobial use and can be implemented as front-end restricted, back-end restricted, or a combination of both.		

: With frontend restriction, certain antimicrobials are considered restricted and require preauthorization for use from an antimicrobial stewardship team member or based on a set of preauthorization criteria reviewed by a pharmacist. For example, an antibiotic such as daptomycin may require preauthorization from an infectious diseases consultant based on predefined prescribing criteria before it can be dispensed.

: Back-end restriction refers to review and intervention after the antimicrobial is prescribed. Typically, an antimicrobial steward reviews current antibiotic orders and provides prescribers with recommendations to continue, adjust, change, or discontinue the therapy, based on the available microbiology results and clinical features of the case.

: Front- and back-end formulary restrictions can coexist with the use of prospective auditing, as well as intervention and feedback. Figure 2

 shows the advantages and disadvantages of front- and back-end formulary restrictions.

: Another intervention is to empower pharmacists to switch highly bioavailable antimicrobials from IV to oral formulations for clinically stable patients who are able to take oral medications. IV-to-oral conversion can reduce costs and the incidence of catheter- related infections. Table 3

 lists highly bioavailable antimicrobials, which are good candidates for IV-to-oral switch programs.

: For expensive antibiotics that come as singleuse vials, writing and establishing dose-rounding protocols can reduce waste and costs. These protocols can be made available on an institution’s intranet for into computer ordering systems to maximize adherence.

: With careful consideration of the institution’s antibiogram and the necessary antimicrobials to keep on formulary, therapeutic substitutions may be made by maintaining 1 antimicrobial per class, such as a single carbapenem or fluoroquinolone, on formulary to reduce inventory and costs.

Antibiotic “timeout” at 72 hours after antibiotic initiation

: An antibiotic timeout is a pause during interdisciplinary rounds to verify that each antimicrobial is appropriately indicated, check for updated culture and sensitivity results, and de-escalate therapy, when appropriate. An antibiotic timeout helps ensure appropriate use, dosing, and duration for every antimicrobial and allows discussion by the team.

: This strategy sets a scheduled rotation of antimicrobials to reduce resistance by changing selective pressure. For example, an intensive care unit may use piperacillin/ tazobactam as the preferential gram-negative agent of choice for one quarter and switch to cefepime for the next quarter. However, there are few studies on the effectiveness of this approach; many patients are excluded on the basis of past culture data or surveillance cultures, and antimicrobial cycling is not currently recommended by the Infectious Diseases Society of America Antimicrobial Stewardship Guidelines.

Another core element of antimicrobial stewardship is to measure the effects of the antimicrobial stewardship actions by using performance measures to track antibiotic prescribing, use, and resistance.

 Institutions can monitor this in several different ways, depending on which interventions were implemented. For example, an institution can measure rates of 

 infection, compile and publish antibiograms on antibiotic susceptibility reports, and assess adherence to antimicrobial guidelines and interventions.

In addition to tracking, the antimicrobial steward should report the findings on antibiotic use and resistance to doctors, nurses, and other relevant staff.

 Sharing facility-specific reports on antibiotic use with providers allows direct communication on how providers can improve antibiotic prescribing and raise awareness for areas of improvement.

The last core element recommends that antimicrobial stewardship programs regularly provide education to health care providers about resistance and improving antibiotic prescribing.

 Education can be provided in various formats, such as presentations, printed flyers, or electronic messages. In addition, case presentations at grand rounds or case conferences can demonstrate examples of appropriate de-escalation of therapy.

The growing problem of antimicrobial resistance has been recognized nationally. To combat this issue, all acute care institutions should implement antimicrobial stewardship programs. Each institution may employ different interventions according to its size, antibiotic use, antimicrobial resistance patterns, and available information technology. With the implementation of successful antimicrobial stewardship programs and the support of hospital administration, we can slow the antibiotic resistance crisis at the institutional level, as well as nationally.

Kathy Tang, PharmD, is a PGY-1 pharmacy resident at the University of Maryland Medical Center in Baltimore, Maryland. Emily Heil, PharmD, BCPS-AQ ID, AAHIVP, is a clinical pharmacy specialist in infectious diseases at the University of Maryland Medical Center in Baltimore, Maryland.

		Get Smart for Healthcare. Centers for Disease Control and Prevention website. cdc.gov/getsmart/healthcare. Accessed December 10, 2015.

		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. 

		National Action Plan for Combating Antibiotic-Resistant Bacteria. The White House Forum on Antibiotic Stewardship. whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf. Accessed December 10, 2015.

		MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems.

		Doron S, Davidson LE. Antimicrobial stewardship. 

. 2011;86(11):1113-1123. doi: 10.4065/mcp.2011.0358.

		Flanders SA, Saint S. Why does antimicrobial overuse in hospitalized patients persist? 

Clinical Care Focus

The CDC has reported that 20% to 50% of all antibiotics prescribed in US acute care hospitals are either unnecessary or inappropriate, resulting in avoidable adverse effects, bacterial resistance, and an increased incidence of infection.

Antimicrobial Stewardship: A Primer for Hospital Pharmacists

The Centers for Disease Control and Prevention (CDC) estimated that during the 2013-2014 influenza season, the influenza vaccination prevented approximately 7.2 million illnesses and 90,000 influenza-associated hospitalizations. Despite this preventive measure, the influenza virus remains an imperative health concern. Three neuraminidase inhibitors (NAIs) have been approved to treat influenza in the United States: oseltamivir (Tamiflu), peramivir (Rapivab), and zanamivir (Relenza).

NAIs inhibit neuraminidase, which is the enzyme that releases viral particles from infected cells. Thus, NAIs disable the influenza virus by preventing infected cells from releasing viral progeny. Each NAI has the same end result yet different binding characteristics and chemical structures. Because of these differences, NAIs may have varying resistance patterns, as mutations in the neuraminidase active site are responsible for the development of resistance.

All 3 NAIs are indicated for the treatment of influenza; oseltamivir and zanamivir are also indicated for prophylaxis. For treatment, a patient should initiate therapy within 2 days of symptom onset, as NAIs have not been shown effective if initiated past that point. Oseltamivir may be used to treat patients at least 2 weeks of age and for prophylaxis in patients older than 1 year. Peramivir is indicated for influenza treatment in patients at least 18 years. For treatment and prophylaxis, zanamivir may be used in patients at least 7 years and 5 years, respectively.

Each NAI is available as a unique dosage form. Oseltamivir is formulated for oral administration as capsules and as a powder for suspension. Adult patients should be treated with 75 mg twice daily for 5 days. For prophylaxis, the dose should be 75 mg once daily for at least 10 days. Oseltamivir may be administered without regard to meals, but taking it with food can improve tolerance. Specific dosing guidelines are available for pediatric patients and those with a creatinine clearance less than 60 mL/min.

For uncomplicated illness in the outpatient setting, peramivir is administered as a single 600-mg intravenous (IV) infusion over 15 to 30 minutes. However, for the 2015-2016 influenza season, the CDC has recommended that hospitalized patients receive at least 5 days of IV treatment. Peramivir should be diluted to a maximum volume of 100 mL with 0.9% or 0.45% sodium chloride, 5% dextrose, or lactated Ringer’s solution.

Zanamivir is administered via oral inhalation. A Diskhaler device is included with individual blisters containing medication. For treatment, 10 mg (2 inhalations) should be administered twice daily for 5 days. For prophylaxis in the household setting, 10 mg should be used once daily for 10 days. If zanamivir is being used in response to a community outbreak, 10 mg should be continued for 28 days.

Each NAI was approved on the basis of placebo-controlled studies. The primary outcome of these studies was time to improvement of symptoms (typically self-assessed by the patient). All studies initiated treatment within 48 hours of symptom onset. Oseltamivir, peramivir, and zanamivir trials reported similar results and reduced the time to improvement by 1.3 days, 21 hours, and 1 day, respectively. Thus, when initiated quickly after the onset of symptoms, NAIs may reduce influenza duration by approximately 1 day.

In addition, a multicenter observational study compared the efficacy of zanamivir and oseltamivir in treating influenza A and influenza B. The study enrolled 1113 patients and assessed the duration of fever in patients who received zanamivir, oseltamivir, or no anti-influenza treatment within 48 hours of symptom onset. Zanamivir and oseltamivir did not significantly differ in the duration of fever in patients with influenza A (49.7 + 21.7 hours and 52.5 + 25.6 hours, respectively), although they did vary significantly from the group that did not receive treatment (75.4 + 24.2 hours; P <.001 for both). However, zanamivir treatment of influenza B resulted in a significantly shorter duration of fever compared with oseltamivir treatment or no anti-influenza treatment (53.9 + 26.4 hours, 69.4 + 32.9 hours, 75.3 + 27.3 hours, respectively; P <.001 for both). Overall, zanamivir and oseltamivir are considered equally effective for the treatment of influenza A, but zanamivir is more effective (using fever reduction as a surrogate) than oseltamivir for treating influenza B.

Although adverse effects (AEs) associated with NAIs are generally mild, there are a few rare and severe AEs. These agents may cause serious skin and/or hypersensitivity reactions. Also, it is important to note that influenza may be associated with neurologic and behavioral symptoms. Therefore, although these AEs are rare and the contribution of NAIs to them is unknown, patients should be monitored for abnormal behavior.

In addition, the use of zanamivir is not recommended in patients with underlying airway disease (eg, asthma, chronic obstructive pulmonary disease) because serious cases of bronchospasm have been reported. Less serious AEs associated with these agents include fatigue, nausea/vomiting, diarrhea, and headache.

Minimal drug interactions are observed with NAIs. The main concern associated with these agents is the concomitant use of certain influenza vaccines. Inactivated influenza vaccines do not interact and can be administered at any time. However, antiviral drugs may inhibit the replication of a live vaccine virus, thus making live attenuated influenza vaccines less effective if administered 2 weeks before or 48 hours after these antiviral agents.

When patients are receiving the oral suspension of oseltamivir, an appropriate measuring device should be provided and patients should be instructed based on the milliliter unit. Additionally, because zanamivir is administered via inhalation, the technique and ability of the patient to selfadminister should be evaluated before prescribing.

Jennifer L. Cruz, PharmD, BCPS, is an assistant professor of clinical education at UNC Eshelman School of Pharmacy. Katherine Summers is a PharmD candidate at UNC Eshelman School of Pharmacy.

		Reed C, Kim IK, Singleton JA, et al; Centers for Disease Control and Prevention. Estimated influenza illnesses and hospitalizations averted by vaccination—United States, 2013-2014 influenza season. 

		Tamiflu [package insert]. South San Francisco, CA: Genentech, Inc; 2014.

		Rapivab [package insert]. Durham, NC: BioCryst Pharmaceuticals; 2014.

		Relenza [package insert]. Philadelphia, PA: GlaxoSmithKline; 2013.

		Spanakis N, Pitiriga V, Gennimata V, Tsakris A. A review of neuraminidase inhibitor susceptibility in influenza strains. 

. 2014;12(11):1325-1336. doi: 10.1586/14787210.2014.966083.

& comparisons eAnswers. online.factsandcomparisons.com. Accessed November 6, 2015.

		Kawai N, Ikematsu H, Iwaki N, et al. A comparison of the effectiveness of zanamivir and oseltamivir for the treatment of influenza A and B. 

		Lexicomp [online database]. Hudson, OH: Wolters Kluwer Health; 2015.

Formulary Drug Review

During the 2013-2014 influenza season, the influenza vaccination prevented approximately 7.2 million illnesses and 90,000 influenza-associated hospitalizations.

March 2016

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Provider Status Update

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Antimicrobial Stewardship: A Primer for Hospital Pharmacists

Influenza Antiviral Therapies