 (VRE) is a common nosocomial pathogen associated with significant morbidity and mortality.

 tends to be the more common organism causing infection. However, 

 is intrinsically more resistant to antimicrobials. About 80% of 

Aminopenicillins may maintain susceptibility in select cases, but when 

 isolates are resistant to both aminopenicillins and vancomycin, choosing the optimal agent can be challenging. Not surprisingly, VRE bacteremia has been associated with a 2.5-fold higher mortality rate compared with vancomycin-susceptible enterococcal bacteremia.

The 2 most commonly used antibiotics for VRE bacteremia are linezolid and daptomycin. Both agents are recommended by professional guidelines for the treatment

of VRE bloodstream infections, including infective endocarditis and intravascular catheter-related bacteremia.

 However, despite widespread use of each agent, there is still conflicting evidence and controversy regarding the therapeutic efficacy of daptomycin versus linezolid. This article reviews the body of literature and comparative advantages and disadvantages of each antibiotic for the treatment of VRE bacteremia.

Linezolid is an oxazolidinone antibiotic with broad gram-positive bacterial activity, including VRE. It is available in both intravenous and oral formulations with excellent

bioavailability and the recommended dose is 600 mg twice daily. Linezolid is the only agent with an FDA-approved indication for VRE infections, including bacteremia.

 It is also recommended by professional guidelines as a first-line treatment option for bacteremia secondary to infective endocarditis, because of ampicillin-resistant VRE.

 Despite the clinical data supporting its use, a theoretical issue with linezolid lies in its bacteriostatic nature, which may hinder its activity against VRE, especially in cases of bacteremia with high inoculum burden or complicated by endovascular seeding. Treatment failures with linezolid have been reported, particularly in cases of infective endocarditis.

 Additionally, a mortality imbalance was noted in a study comparing linezolid with vancomycin for catheter-related bloodstream infections,

although enterococcal bacteremia accounted for less than 10% of all cases.

Toxicities may arise with long-term use of linezolid exceeding 2 weeks. These include lactic acidosis, peripheral neuropathy, optic neuritis, and thrombocytopenia. There are also concerns regarding serotonin syndrome as a result of potential drug-drug interactions with serotonergic agents, given linezolid’s weak monoamine oxidase inhibition properties.

Daptomycin is a lipopeptide antibiotic with rapid bactericidal activity against enterococci. It is only available as an intravenous formulation and is FDA approved for complicated skin and skin structure infections and 

 bacteremia, at doses ranging from 4 to 6 mg/kg/day. Although not FDA approved for VRE bacteremia, it has demonstrated both clinical and in vitro efficacy in this particular setting.

 As with linezolid, there are concerns with daptomycin that may affect its efficacy for VRE bacteremia. These include elevated daptomycin minimum inhibitory concentrations (MICs) that may hinder optimal pharmacodynamic target attainment, emerging resistance, and lack of standardized dosing for VRE bacteremia.

Prior to 2019, the susceptible breakpoint for daptomycin against 

 spp was ≤4 mg/L. However, 2 major cohort studies concluded that daptomycin MICs of 3 to 4 mg/L were predictive of microbiological failure, suggesting that the breakpoint did not correlate with therapeutic efficacy.

 In early 2019, the Clinical and Laboratory Standards Institute updated daptomycin breakpoints against E faecium, removing the susceptible breakpoint for daptomycin and assigning all isolates with MICs ≤4 mg/L as “susceptible dose dependent.”

 Higher daptomycin doses of 8 to 12 mg/kg are recommended for susceptible dosedependent isolates of 

, particularly in the blood, to achieve clinical efficacy.

The benefit of “high dose” daptomycin for the treatment of VRE bacteremia has been demonstrated in clinical studies.

 For instance, Britt et al showed that higher doses (≥10 mg/kg) were associated with improved survival and microbiological clearance compared with lower doses (6 to 8 mg/kg) of daptomycin.

 Similarly, Chuang et al suggested that higher-dose daptomycin (≥9 mg/kg) was associated with decreased mortality compared with lower-dose daptomycin (<9 mg/kg) for VRE bacteremia. The majority of their VRE isolates (70%) possessed MICs of 4 mg/L.

The main toxicity issue with daptomycin is creatine phosphokinase (CPK) elevations during the course of therapy, which may be asymptomatic or can progress to myopathy or rhabdomyolysis. It is recommended to discontinue daptomycin therapy in patients with signs and symptoms of myopathy and a CPK level >5 times the upper limit of normal (ULN) or >1000 units/L or in asymptomatic patients with a CPK ≥10 times ULN or >2,000 units/L.

 It is also recommended to temporarily discontinue therapy with other agents associated with rhabdomyolysis (eg, HMG-CoA reductase inhibitors) during daptomycin therapy. Myopathy and rhabdomyolysis occur more frequently in patients with renal impairment, and therefore, dosage adjustment in the setting of dysfunction is warranted. Finally, eosinophilic pneumonia may develop in rare instances, typically within 2 to 4 weeks after daptomycin initiation.

A literature review (table) was conducted to identify studies comparing daptomycin with linezolid for VRE bacteremia. These included 4 meta-analyses and systematic reviews, 2 retrospective studies, and 1 prospective study. It is clear that linezolid demonstrates superior survival outcomes compared with daptomycin when suboptimal doses of the latter are used. The majority of studies that demonstrated increased mortality with daptomycin used a median dose of ~6 mg/kg/day. These findings indicate that daptomycin is likely most effective for VRE bacteremia when dosed at the 8- to 12-mg/kg/day range.

Both daptomycin and linezolid are potential options for the management of VRE bacteremia. The literature supports the use of linezolid over daptomycin if suboptimal doses of daptomycin are used, implying that daptomycin doses in VRE bacteremia should be optimized (8-12mg/kg/day). In VRE bacteremia that is complicated by endovascular seeding, such as infective endocarditis, it may be prudent to use a bactericidal agent such as daptomycin over linezolid with consideration for even higher doses (10-12 mg/kg/day). The ultimate decision to choose daptomycin or linezolid for VRE bacteremia will depend on considerations for adverse effects of each respective antibiotic, comorbidities, patient-specific factors, and the source of infection.

, is a PGY-2 infectious diseases pharmacy resident, and 

Shin-Pung Jen, PharmD, BCPS-AQ ID, AAHIVP

, is a clinical pharmacotherapy specialist, infectious diseases, at NYU Langone Health in New York, New York.

Song X, Srinivasan A, Plaut D, Perl TM. Effect of nosocomial vancomycin-resistant enterococcal bacteremia on mortality, length of stay, and costs. I

. 2003;24(4):251-256. doi: 10.1086/502196.

Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010. 

O’Driscoll T, Crank CW. Vancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management. 

. 2015;8:217-230. doi: 10.2147/IDR.S54125.

Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. 

. 2015;132(15):1435-1486. doi: 10.1161/CIR.0000000000000296.

Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. 

Zyvox (linezolid) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada Inc; February 2018.

Tsigrelis C, Singh KV, Coutinho TD, Murray BE, Baddour LM. Vancomycinresistant Enterococcus faecalis endocarditis: linezolid failure and strain characterization of virulence factors.

Wilcox MH, Tack KJ, Bouza E, et al. Complicated skin and skin-structure infections and catheter-related bloodstream infections: noninferiority of linezolid in a phase 3 study. 

. 2009;48(2):203-212. doi: 10.1086/595686.

Hall AD, Steed ME, Arias CA, Murray BE, Rybak MJ. Evaluation of standard-and high-dose daptomycin versus linezolid against vancomycin-resistant enterococcus isolates in an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations. 

. 2012;56(6):3174-3180. doi: 10.1128/AAC.06439-11.

Levine DP, Lamp KC. Daptomycin in the treatment of patients with infective endocarditis: experience from a registry. 

Shukla BS, Shelburne S, Reyes K, et al. Influence of minimum inhibitory concentration in clinical outcomes of enterococcus faecium bacteremia treated with daptomycin: is it time to change the breakpoint? 

 2016;62(12):1514-1520. doi: 10.1093/cid/ciw173.

Moise PA, Sakoulas G, McKinnell JA, et al. Clinical outcomes of daptomycin for vancomycin-resistant enterococcus bacteremia. 

 2015;37(7):1443- 1453.e1442. doi: 10.1016/j.clinthera.2015.04.008.

CLSI. Daptomycin breakpoint revision. Revision memo to CLSI supplement M100, 29th ed. Wayne, PA: Clinical and Laboratory Standards Institute; 2019. clsi.org/media/2663/m100ed29_sample.pdf. Accessed February 6, 2020.

Moise PA, Hershberger E, Amodio-Groton MI, Lamp KC. Safety and clinical outcomes when utilizing high-dose (> or =8 mg/kg) daptomycin therapy. 

. 2009;43(7):1211-1219. doi: 10.1345/aph.1M085.

Britt NS, Potter EM, Patel N, Steed ME. Comparative effectiveness and safety of standard-, medium-, and high-dose daptomycin strategies for the treatment of vancomycin-resistant enterococcal bacteremia among Veterans Affairs patients. 

. 2017;64(5):605-613. doi: 10.1093/cid/ciw815.

Chuang YC, Lin HY, Chen PY, Lin CY, Wang JT, Chang SC. Daptomycin versus linezolid for the treatment of vancomycin-resistant enterococcal bacteraemia: implications of daptomycin dose. 

 2016;22(10):890. e891-890.e897. doi: 10.1016/j.cmi.2016.07.018.

Chuang YC, Lin HY, Chen PY, et al. Effect of daptomycin dose on the outcome of vancomycin-resistant, daptomycin-susceptible enterococcus faecium bacteremia. 

. 2017;64(8):1026-1034. doi: 10.1093/cid/cix024.

Werth BJ, Steed ME, Ireland CE, et al. Defining daptomycin resistance prevention exposures in vancomycin-resistant Enterococcus faecium and E. faecalis. 

. 2014;58(9):5253-5261. doi: 10.1128/AAC.00098-14.

Daptomycin [prescribing information]. Schaumburg, IL: Sagent Pharmaceuticals; August 2019. medlibrary.org/lib/rx/meds/daptomycin-5/. Accessed February 4, 2020.

Whang DW, Miller LG, Partain NM, McKinnell JA. Systematic review and meta-analysis of linezolid and daptomycin for treatment of vancomycin-resistant enterococcal bloodstream infections. 

 2013;57(10):5013-5018. doi: 10.1128/AAC.00714-13.

Balli EP, Venetis CA, Miyakis S. Systematic review and meta-analysis of linezolid versus daptomycin for treatment of vancomycin-resistant enterococcal bacteremia. 

. 2014;58(2):734-739. doi: 10.1128/AAC.01289-13.

Chuang YC, Wang JT, Lin HY, Chang SC. Daptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bacteremia: systematic review and meta-analysis. 

 2014;14:687. doi: 10.1186/s12879-014-0687-9.

Britt NS, Potter EM, Patel N, Steed ME. Comparison of the effectiveness and safety of linezolid and daptomycin in vancomycin-resistant enterococcal bloodstream infection: a national cohort study of Veterans Affairs patients. 

. 2015;61(6):871-878. doi: 10.1093/cid/civ444.

Zhao M, Liang L, Ji L, et al. Similar efficacy and safety of daptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bloodstream infections: a meta-analysis. 

. 2016;48(3):231-238. doi: 10.1016/j.ijantimicag.2016.06.010.

Narayanan N, Rai R, Vaidya P, Desai A, Bhowmick T, Weinstein MP. Comparison of linezolid and daptomycin for the treatment of vancomycin-resistant enterococcal bacteremia. 

. 2019;6:2049936119828964. doi: 10.1177/2049936119828964.

Articles

Health-System Edition

What are the advantages and disadvantages of linezolid versus daptomycin for vancomycin-resistant enterococcus bacteremia?

It Is a "VRE" Serious Controversy

There is a lot going on in health care, with the industry changing more rapidly than it has in decades, and every change has a ripple effect.

For the 340B program, those changes have led to an increased call for transparency that often puts a burden on covered entities and compromises their ability to serve vulnerable populations.

This is part 2 of a 2-part article on this topic. Part 1, in the January issue provided an overview of the economic, political, social, and technological trends shaping health care and illustrated how the 340B program fits into that landscape.

Although the government and pharmaceutical manufacturers are calling for increased transparency and reporting from covered entities, we have seen very little transparency on the part of manufacturers. This is where “fair” comes into play.

For example, consider the Civil Monetary Penalties ruling, in which the online posting of 340B ceiling prices was delayed 5 times over the course of 10 years before the information was made public.

After a very long road, on April 1, 2019, the Health Resources and Services Administration (HRSA) made available online a way for covered entities to view the ceiling prices, or maximum amount drug manufacturers are allowed to charge, for drugs under the 340B program.

 The requirement for such a website was enacted into law in 2010 under the Obama administration, and the final regulation implementing the changes was issued in January 2017, but it encountered many delays since then.

This is just 1 example in which stakeholders are not exercising “transfairency” or the open sharing of information on all sides. Some additional information that would be beneficial to covered entities in the interest of “transfairency” include the following:

Manufacturers often contact covered entities to inquire why purchasing on certain drugs in the 340B space may have gone up. The HRSA encourages covered entities to respond to these “good faith” inquiries, yet may have no idea how often they are occurring among their peers. Are there certain manufacturers who look for this information more than others? Do they send out 200 such inquiries a year or 2000?

 Covered entities have no insight into how often manufacturer audits occur. Although manufacturers must notify the Office of Pharmacy Affairs when they conduct an audit, covered entities have no way to know how their frequency of audits compares with their peers or which manufacturers tend to conduct such audits more frequently.

Whenever a manufacturer increases the price of a 340B drug more quickly than the rate of inflation, it is subject to a “penny pricing” penalty—that is, it is then required to sell that drug to covered entities the following quarter at a price of 1 penny. Manufacturers claim this happens frequently, which is a reason they say that the 340B program is costing them money, yet we have no way to know how often this really occurs, as there are limitations in the recently developed online reporting tool from the HRSA. There is no publicly available report to demonstrate the frequency of this penalty.

On July 1, 2019, the Office of Inspector General released a report in which it found that in 2014, pharmacy benefit managers (PBMs) missed out on potential rebates of up to $74.7 million on Medicare Part D prescriptions, because those drugs were filled through the 340B program.

 PBMs, or “sponsors,” typically receive rebates from drug manufacturers in exchange for offering those drugs on their formularies and playing middleman between insurance companies and manufacturers. However, when Medicare Part D drugs are filled through the 340B program, manufacturers are required to sell those 340B drugs to covered entities at a deep discount and, in an effort to avoid paying out double or stacked rebates, the manufacturers therefore do not offer rebates on those 340B drugs to the PBMs. Yet covered entities cannot know for certain how many rebates manufacturers are refusing to pay out in circumstances like these, because, again, no reporting requirements or transparency exist on the manufacturer side.

Many manufacturers have been limiting access to certain drugs by distributing them only through specialty pharmacies. When this happens, it becomes more difficult for covered entities to access these drugs, and when they do access them, it may not be at the 340B price. We know that the number of drugs being put into this limited-distribution, specialty-pharmacy category has been increasing over the years, as noted by the Office of Pharmacy Affairs’ online posting of letters from manufacturers. What we do not know is how many drugs actually fall into that category at any given time. There is no requirement for pharmaceutical manufacturers to provide a list.

These examples illustrate that transparency can and should go both ways. When calling for more reporting and transparency, government entities, pharmaceutical manufacturers, and other stakeholders must think about the limits of what is fair, not a burden, and practical.

As the push for transparency around 340B continues, covered entities must be prepared. It will be imperative to keep track of 340B savings, how they are being used whether to build oncology clinics or provide prescriptions at discounts, and how they can prove compliance. To execute these responsibilities with confidence, covered entities should engage with partners that have not only the right technology but also the right level of 340B program expertise.

As hospital leaders think about the future of the 340B program and what reporting will look like, the role of the 340B vendor is 3-fold: to develop a reporting infrastructure to match the needs of the future; to integrate and centralize information to create efficiencies and protect sensitive data; and to engage with stakeholders on the health system’s behalf to help the covered entity understand the elements of the 340B program that are most important for empowering it to meet the community needs.

With the right partners in one’s corner, maintaining 340B program compliance and integrity is possible, regardless of the changes faced. Transparency is a team effort.

, is head of industry relations at Sentry Data Systems in Deerfield Beach, Florida, a 340B management and compliance company.

340B Office of Pharmacy Affairs information system. Health Resources & Services Administration website. hrsa.gov/opa/340b-opais/index.html. Updated March 2019. Accessed January 31, 2020.

US Department of Health and Human Services. Medicare Part D rebates for prescriptions filled at 340B contract pharmacies. Office of Inspector General website. oig.hhs.gov/oas/reports/region3/31600002.asp. Published July 1, 2019. Accessed February 3, 2020.

What should covered entities do to prepare for increased reporting requirements?

340B Program Transparency: Is It "Transfairency"?

Abuse-deterrent formulations (ADFs) of opioid medications were first marketed in 2010 when a reformulated version of OxyContin (extended-release oxycodone) was

released at the mandate of the FDA in an effort to address the nationwide opioid epidemic.

This product was created with both chemical and physical barriers to its manipulation.

 The intention was to reformulate traditional opioid medications in ways that would make it more difficult to chemically and physically alter the delivery of their active pharmaceutical ingredient in an effort to reduce the potential for abuse. These efforts were particularly directed at extended-release and long-acting formulations, which are especially attractive to abusers of opioid medications because of the high-milligram content in a single-dose unit.

Prescription opioid abuse is not limited to taking intact tablets by mouth. Rather, those who abuse prescription opioids chew, crush, dissolve, and otherwise manipulate the tablets to take them intranasally, intravenously, orally, via inhalation, and by other routes of administration. By altering the route of administration and delivery systems, users are able to achieve different pharmacokinetics with preference toward increasing peak concentration and decreasing time to peak. Manipulation causes a “dose-dumping” effect in which higher serum levels are achieved more rapidly, resulting in enhanced psychoactive effects.

 Because of this, abuse via intranasal and intravenous routes is associated with more severe individual and societal risks.

Abuse-deterrent formulations have been created with alternate bases or harder outer shells, or coformulated with opioid antagonists to make manipulation and abuse more difficult.

 No amount of reformulation can completely deter all forms of manipulation, eliminate the potential for drug diversion, or deter users from taking more medication than prescribed. But the creation of ADFs was intended only as 1 component of a multifaceted approach to reducing opioid abuse and misuse.

Since the introduction of ADFs, the products have only gradually seen enough use in the market to preliminarily demonstrate decreased diversion and rates of intentional abuse.

 However, there is a dearth of knowledge regarding patients with chronic pain and their experiences with and opinions about ADFs. Further, those patients and their caregivers have historically reported concerns regarding the stigma associated with chronic opioid therapy. There is potential for further apprehension

and stigma associated with opioids in general and with the prescription of ADFs in particular—specifically, being labeled or thought of as an abuser. Health care providers, in turn, may be concerned about patients having a false sense of security when they issue a prescription for an ADF instead of a traditional opioid formulation.

The American Chronic Pain Association (ACPA), with support from Collegium Pharmaceutical, conducted an anonymous needs assessment/survey of ACPA members to gather information on patient experience with ADFs and their knowledge and perceptions about the medications. Until this point, patients’ knowledge and opinions regarding ADFs had not been explored. Of the 1154 respondents to the survey, 936 completed it in full. As participants were recruited through the ACPA and more than 98% of them were people living with chronic pain, it is likely that they had a higher baseline knowledge regarding opioids and safe medication practices than the general population. Therefore, conclusions about the generalizability of survey results should be filtered through this lens.

The survey addressed patients’ knowledge on topics ranging from the existence of ADFs to safety and tampering. Further questions assessed patients’ behaviors and beliefs associated with ADFs. Respondents were stratified based on whether they were currently prescribed an ADF, and additional questions were posed to those patients with the goal of assessing their actual use. More than half of the survey respondents had never heard of an ADF. Therefore, 1 of the most significant findings of this study is a large knowledge gap regarding ADFs in the community of people living with pain.

Notably, the vast majority of respondents from both groups believed that it is not safe to take more ADFs than prescribed or to share an ADF with others. Most respondents who are currently prescribed an ADF reported that they do not crush, cut, or dissolve their tablets in water, whereas respondents not currently prescribed an ADF were more likely to report that they did not know whether tablets could be crushed, cut, or dissolved. Importantly, most respondents who are prescribed an ADF answered that they did not feel their prescriber was concerned about possible abuse when they prescribed the ADF. Those who take an ADF were divided as to

whether it is as effective as other opioids they have been prescribed.

This survey and an educational video have begun to fill a void in the literature regarding patients with chronic pain and their beliefs, experiences, and knowledge about ADF opioid medications. Certainly, some respondents voiced negative attitudes about incurring additional costs for ADFs when they do not personally think they are at risk for abuse or manipulation of the dose form. Others worried about the stigma, wondering if their physicians felt they were abusers. These views were not universal, however, and some respondents understood the potential need for ADFs in the context of continuing concerns related to the opioid epidemic. Thus, a potential takeaway for those who prescribe or dispense ADFs is that these patients are not uniformly concerned with stigma or as negatively inclined toward ADFs as some clinicians have thought. Rather, any apprehension or misgivings on the part of patients could be attributable to a lack of knowledge. This can be managed through individualized education and sensitivity to the patients’ pre-existing attitudes.

Clinicians can also be advised that both groups of patients were largely aware that they should not take more ADFs than prescribed nor should they share their ADFs with others. This advice could serve to assuage some concern for the potential false sense of security that some providers fear when prescribing ADFs.

The authors conclude that, concerning ADFs, patients who suffer from chronic pain have neither a commonly held negative view nor a commonly held positive view, and that this population respects and understands opioid safety, overall. These findings support the notion that ADFs can be a valuable part of a comprehensive approach to managing the opioid epidemic. As practitioners on the frontlines of both patient and provider education, pharmacists are poised to impart this important information regarding ADFs to their medical colleagues and patients alike.

, is a PGY-2 pain and palliative care pharmacy resident at the Albany Stratton VA Medical Center in Albany, New York.

Jeffrey Fudin, PharmD, FCCP, FASHP, FFSMB

, is chief executive officer and founder of Remitigate, LLC and the owner and managing editor of paindr.com. He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts, an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences in Albany, New York, and the director of the PGY-2 pain residency at Albany Stratton VA Medical Center.

 is the founder and chief executive officer of the American Chronic Pain Association in Rocklin, California.

, is a research assistant and evaluations specialist at the Native American Rehabilitation Association of the Northwest, Inc, in Portland, Oregon.

Adler JA, Mallick-Searle T. An overview of abuse-deterrent opioids and recommendations for practical patient care. 

. 2018;11:323-332. doi: 10.2147/JMDH.S166915.

FDA. Abuse-deterrent opioid analgesics. FDA website. www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm600788.htm. Updated June 11, 2019. Accessed February 20, 2020.

Green JL, Bucher Bartelson B, Le Lait MC, et al. Medical outcomes associated with prescription opioid abuse via oral and non-oral routes of administration [published online March 28, 2017]. 

. 2017;175:140-145. doi: 10.1016/j.drugalcdep.2017.01.039.

Pergolizzi JV Jr, Raffa RB, Taylor R Jr, Vacalis S. Abusedeterrent opioids: an update on current approaches and considerations [published online January 10, 2018]. 

. 2018;34(4):711-723. doi: 10.1080/03007995.2017.1419171.

Dart RC, Iwanicki JL, Dasgupta N, Cicero TJ, Schnoll SH. Do abuse deterrent opioid formulations work? 

. 2017;13(6):365-378. doi: 10.5055/jom.2017.0415.

Pharmacists can extend education to prescribers and provide important guidance on abuse-deterrent opioid formulations.

Offer Patients Counseling on ADFs

About 218,000 new cases of lung cancer were reported in 2016 and more than 148,000 people died from this disease, according to the CDC.

More individuals die from lung cancer each year than from breast, colon, and prostate cancer combined.

 Cigarette smoking is the biggest risk factor for developing lung cancer, as it is responsible for 80% to 90% of lung cancer deaths.

 The 2 main types of lung cancer are non—small cell lung cancer (NSCLC) and small cell lung cancer.

 The majority of lung cancer cases are NSCLC, however, representing about 80% to 85% of cases.

 Additionally, NSCLC has 3 main subtypes: adenocarcinoma, large cell carcinoma, and squamous cell carcinoma (see Figure 14). For patients with localized NSCLC, the overall 5-year survival rate is about 60%. For regional NSCLC, the 5-year survival rate is about 33%. If the cancer has spread to distant sites of the body (metastatic lung disease), the 5-year survival rate precipitously declines to just 6%. However, with the advent of earlier interventions and newer, more effective therapies, these survival percentages are improving.

The choice of first-line agents used initially in patients with NSCLC depends on multiple factors (see Figure 14). The expression of programmed cell death ligand 1 (PD-L1) greatly influences therapy decisions.

 In patients with a low PD-L1 expression of less than 50% and no other genetic mutations, pembrolizumab, an immunotherapy agent, in combination with carboplatin and pemetrexed, are the preferred therapy options.

 In patients with a high PD-L1 expression, pembrolizumab monotherapy can be used in the absence of rapidly progressing disease. For instance, in rapidly progressive disease, pembrolizumab with chemotherapy is preferred.

First-line agents depend on a variety of genetic test results that could display certain mutations, according to the most recent National Comprehensive Cancer Network NCSLC guidelines.

Mutations are biomarkers and act as predictive and prognostic markers for therapy efficacy. For example, the firstline agents in patients with a known epidermal growth factor receptor mutation prior to starting any chemotherapy are afatinib, erlotinib, or gefitinib. Additionally, the presence or absence of PD-L1, anaplastic lymphoma kinase, B-raf proto-oncogene, and c-ros oncogene 1 are all examined to establish initial therapy.

New types of treatment options are being tested in clinical trials, which include chemoprevention and other investigational options.

Despite advances in lung cancer treatment, including biologic therapy and targeted treatment, survival rates have not dramatically improved, primarily because by the

time most patients present with symptoms, the disease has metastasized to an advanced stage. Chemoprevention involves using dietary or pharmacologic agents to prevent or slow the growth of cancer, and it is classified as either primary, secondary, or tertiary chemoprevention, depending on the target population

Although antioxidants and vitamins have not been successful as agents for primary chemoprevention, incidental observations regarding the use of inhaled corticosteroids and low-dose aspirin have shown more promising results. In a cohort study of 10,474 US veterans diagnosed with chronic obstructive lung disease and no history of lung cancer, there was a dose-dependent decrease in lung cancer associated with the use of inhaled corticosteroids.

 Additional randomized controlled trials with extended follow-up periods are warranted to further validate these findings. In a retrospective cohort study of nearly 13 million individuals in the Korean National Health Institute, low-dose aspirin (less than 100 mg) was associated with a reduced risk of lung cancer, which was even more apparent in participants 65 years and older and those diagnosed with diabetes.

Secondary and tertiary chemoprevention, such as oral iloprost and celecoxib, displayed promising results in phase II trials,

 but the end points used were not validated, and future larger trials are necessary to confirm supportive data.

Early detection confers better treatment outcomes in most malignancies and NSCLC is no exception.

Low-dose chest computed tomography screening is recommended for patients aged 55 to 77 years, who are asymptomatic smokers and former smokers who have smoked for 30 pack-years or more and either continue to smoke or have quit within the past 15 years. Asymptomatic is defined as the absence of symptoms suggesting the presence of lung cancer.

A promising alternative to chemotherapy and pembrolizumab in patients with low or unknown PD-L1 expression is the immunotherapy combination of nivolumab plus ipilimumab. In the CheckMate-227 trial, the results indicated superior survival outcomes over chemotherapy alone.

 Durvalumab and tremelimumab were also studied in a phase 3 trial, MYSTIC, versus chemotherapy alone.

Although preliminary results did not show improved outcomes, post hoc exploratory analysis displayed improved outcomes in patients with a higher tumor mutational burden.

Radiosensitizers, substances that work to enhance the effect of radiation on tumors without increasing the effect on normal tissue, are being investigated in patients with NSCLC.

 Vicenin-2, a substance that has been reported to possess a wide variety of pharmacologcal activities, has been proven effective in lowering cancer cell survival while promoting expression of proapoptotic genes, making it an effective radiosensitizing agent.

Although there have been numerous advancements in the treatment of NSCLC, early detection, public education, and smoking cessation are the most important cornerstones of preventing the disease and improving patient survival outcomes. Additional research and targeted therapy will continue to improve survival, but tobacco

avoidance and early intervention are the key areas of opportunity for combating this lethal malignancy.

Glenn Schulman, PharmD, MS, BCPS, BCACP, BCG BCIDP

, are clinical pharmacists in Pensacola, Florida.

 is a PharmD candidate at the Universityof Florida in Gainesville.

Leading cancer cases and deaths, male and female, 2016. CDC website. gis.cdc.gov/Cancer/USCS/DataViz.html. Accessed January 5, 2020.

Key statistics for lung cancer. American Cancer Society website. cancer.org/cancer/lung-cancer/about/key-statistics.html. Updated January 8, 2020. Accessed February 11, 2020.

What are the risk factors for lung cancer? CDC website. cdc.gov/cancer/lung/basic_info/risk_factors.htm. Updated September 18, 2019. Accessed January 5, 2020.

Non-small cell lung cancer treatment (PDQ)-patient version. National Cancer Institute website. cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq. Updated October 6, 2019. Accessed January 5, 2020.

Lung cancer - non-small cell: statistics. Cancer.Net website. cancer.net/cancer-types/lung-cancer-non-small-cell/statistics. Published January 2019. Accessed January 5, 2020.

Management of advanced non-small cell lung cancer lacking a driver mutation: immunotherapy. UpToDate website. uptodate.com/contents/management-of-advanced-non-small-cell-lung-cancer-lacking-a-driver-mutation-immunotherapy. Accessed January 5, 2020.

Non-small cell lung cancer. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology website. nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed January 5, 2020.

New M, Keith R. Early detection and chemoprevention of lung cancer. F1000Research website. ncbi.nlm.nih.gov/pmc/articles/PMC5770990/. Published January 16, 2018. Accessed January 5, 2020.

Keith RL, Miller YE. Chemoprevention of lung cancer. UpToDate website. uptodate.com/contents/chemoprevention-of-lung-cancer. Updated April 10, 2019. Accessed January 5, 2020.

Parimon T, Chien JW, Bryson CL, McDonell MB, Udris EM, Au DH. Inhaled corticosteroids and risk of lung cancer among patients with chronic obstructive pulmonarydisease. 

Ye S, Lee M, Lee D, Ha EH, Chun EM. Association of long-term use of lowdose aspirin as chemoprevention with risk of lung cancer. 

. 2019;2(3):e190185. doi:10.1001/jamanetworkopen.2019.0185.

Keith RL, Blatchford PJ, Kittelson J, et al. Oral iloprost improves endobronchial dysplasia in former smokers. 

(Phila). 2011;4(6):793-802. doi:10.1158/1940-6207.CAPR-11-0057.

Kim ES, Hong WK, Lee JJ, et al. Biological activity of celecoxib in the bronchial epithelium of current and former smokers. 

 (Phila). 2010;3(2):148-159. doi:10.1158/1940-6207.CAPR-09-0233.

Mazzone PJ, Silvestri GA, Patel S, et al. Screening for lung cancer: CHEST guideline and expert panel report. 

. 2018;153(4):954-985. doi: 10.1016/j.chest.2018.01.016.

Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non—small-cell lung cancer. 

. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231.

Peters S, Cho BC, Reinmuth N, et al. Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): blood and tissue TMB analysis from MYSTIC, a phase III study of first-line durvalumab ± tremelimumab vs chemotherapy. 

. 2019;79(13). doi: 10.1158/1538-7445.AM2019-CT074.

Van Belle S. Do radiosensitizers enhance the treatment of patients with NSCLC? The need for better models and alternative methods of treatment. 

Baruah TJ, Kma L. Vicenin-2 acts as a radiosensitizer of the non-small cell lung cancer by lowering Akt expression. 

. 2019;45(2):200-210. doi: 10.1002/biof.1472.

Despite numerous treatment advances, early detection, public education, and smoking cessation are the best bets. 

Prevention is Key for Non-Small Cell Lung Cancer

Morristown Medical Center, a member of Atlantic Health System, is a 735-bed community teaching hospital located in New Jersey.

The pharmacy department of Morristown Medical Center operates 24 hours a day and has 165 employees verifying about 1.6 million medication orders per year. The area-based pharmacist (ABP) model, which was reviewed and approved by pharmacy leadership as the future state of pharmacy services, was designed to transition a traditional staff pharmacist to a hybrid, clinical/staff pharmacist.

Pharmacy models within an institution may be centralized (within the main pharmacy or satellite), decentralized (directly on the nursing units themselves), or a combination of the 2.

The first steps were to identify the main goals of the model, measurable outcomes, and staff scheduling logistics for implementation. A 2-day proof-of-concept trial took place, which was followed with a 6-week pilot on the nursing units. The working team comprised assistant managers, an educator, a manager, pharmacist supervisors, and the transition-of-care clinical pharmacist. A targeted positive outcome was to improve communication, as 70% of adverse events can be attributed to poor communication in health care. Nursing leadership was instrumental during the ABP model design and was supportive of its implementation.

The ABP pharmacist was primarily responsible for discharge counseling, medication history reconciliation when possible, order entry and clarification(s), patient education, and participation in multidisciplinary patient care rounds. Training competencies and manuals were created to provide clinical training, whereas positions and responsibilities were redistributed to use the current staffing resources. These goals were to be accomplished while maintaining order entry turnaround time and routine pharmacy operations.

The team selected 2 units, adult general medicine and neurology, which were selected based on their lower-than-hospital-average Hospital Consumer Assessment of Healthcare Providers and Systems Scores, manageable volume of patient beds-to-pharmacist ratio (combined 104 beds: 1 pharmacist), and proximity to each other. The pharmacy reviewed the current staffing model and reallocated a position with existing resources, designated as the new ABP.

A 2-day proof-of-concept trial confirmed that the locations, patient volume, and workload were manageable for 1 pharmacist. For the 6-week pilot, 3 pharmacists with interest in being directly involved volunteered to optimize the overall model structure and provide real-time feedback. A list of responsibilities was created, including discharge counseling, medication education, medication history collection and review, order clarification, and prioritization of order entry. In real time, the pharmacist addressed urgent missing medications, optimized therapy recommendations, and provided answers to drug information questions during morning huddles. Staff pharmacists expanded their roles to increase direct patient care involvement (see Table 1).

Morristown Medical Center’s area-based pharmacist program leads to an increase in direct patient contact and opportunities for interventions.

March 2020

It Is a "VRE" Serious Controversy

340B Program Transparency: Is It "Transfairency"?

Offer Patients Counseling on ADFs

Prevention is Key for Non-Small Cell Lung Cancer

Hybrid Models Can Transform Team Chemistry

How Do Pharmacies Evaluate Cleanroom Automation Systems?

Crohn Disease Management Presents Challenges

CDC Makes Recommendations for Preserving Brain Health

How Secure Is the US Drug Supply?

Dietary Interventions Build a Healthy Brain