Pharmacy Practice News (July 2020)

The Best-Read Pharmacist’s News Source

pharmacypracticenews.com

UP FRONT

Is compounding really all that risky? .....................

4

CLINICAL

Taming CINV via texts ..............................

16

CMS is a powerful agent of change for ABx stewardship ............

18

POLICY

Waste management in the COVID-19 era ....

22

OPERATIONS & MGMT

HHS green-lights COVID-19 testing by pharmacists ....................

32

REVIEW ARTICLES

See insert after page 18.

C

ritical care teams still grappling with COVID-19 cases in hotspots around the country should remain wary of the sharp increase in ICU delirium that many hospitals reported at the height of the pandemic.

The spike in delirium occurred as more mechanically ventilated patients with COVID-19 were kept under deep and prolonged sedation, often without the evidence-based interventions that could decrease their confusion and agitation and shorten ventilator time.

“We’ve reduced delirium down from 70% in ventilated patients to around 40% in the last 20 years,” said E. Wesley Ely, MD, MPH, a professor of medicine and critical care at Vanderbilt University Medical Center in Nashville, Tenn.

“But COVID-19 has got it back up to 80%. So in three months, we’ve erased 20 years of progress.”

Blank NMBA Cap Poses Lethal Med Error Risk

Article starts on page 26.

NEW PRODUCT PeridoxRTU® Sporicidal Disinfectant and Cleaner.

See page 30.

Transition-of-Care Pharmacists Fill Gaps During COVID-19 At Dignity Health Northridge Hospital Medical Center, in Calif., transitional care pharmacists help nurse practitioners and medical residents administer COVID-19 tests at the hospital’s drive-thru testing site.

R

ials of neuromuscular blocking agents lacking the usual “Warning: Paralyzing Agent” label on their caps have increased the risk for serious and potentially fatal medication errors, the Institute for Safe Medication Practices (ISMP) cautioned in its latest Medication Safety Alert!.

ISMP issued the alert (bit.ly/ 37QabQa) after an FDA decision in early June to temporarily allow manufacturers of rocuronium and vecuronium to distribute vials of the paralyzing agents without the required cautionary cap labels. The

ecently, the pharmacy team led by Michael Korczynski, PharmD, at Allegheny Health Network (AHN) in Pittsburgh, reached out to a healthy 22-year-old patient. The patient had visited an AHN emergency department for shortness of breath and was diagnosed with COVID-19. He was scared.

As part of a multidisciplinary partnership with AHN Case Management, a transition-ofcare (TOC) pharmacist at AHN called the patient within 48 hours of discharge and explained how to take his new medications, including an inhaler, and answered questions, such as the purpose of the medications and any potential side effects. Before hanging up, the pharmacist reminded the patient to follow up with his primary care provider in a few weeks. That was when the patient said, “I don’t have a doctor.”

Many health systems have TOC pharmacists who can help fill such care gaps in patients with diabetes, heart failure and other chronic diseases. But doing so while tackling a new virus that experts still do not fully understand presents a new challenge—one that pharmacists are rising to meet.

“Pharmacists are learning about COVID-19 with the rest of the system,” Toni Fera, PharmD, a senior consultant based in Pittsburgh, said. “They’re right on the front lines and they know what’s going on. They’re filling in the gaps in knowledge for patients and physicians.”

Still, there is no typical COVID-19 patient. Many people who end up seeking medical help have preexisting conditions that are managed by an existing network of providers, but others

Continued on page 14

Continued on page 31

V HD Surface Contamination Monitoring Guidance

COVID-19 Triggers Spike In ICU Delirium

Continued on page 6

Rapid Diagnostic Testing and Biomarkers Affecting Stewardship

Volume 47 • Number 7 • July 2020

Special Focus:

COVID-19 Pandemic More coverage on pages 8-13, 20, 22, 32, 33

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Up Front

Pharmacy Practice News • July 2020

3

Opinion

Getting Patients the Medications They Need

By Susan A. Cantrell, RPh, CAE

M

ed i ci nes t ha t m i g ht a i d i n the fight against COVID-19 are flooding our newsfeeds. As health care researchers around the world seek treatments and vaccines, the health care system must be ready to identify those therapies that demonstrate the greatest value and expedite them to patients as quickly as possible. To do this, we must effectively share data on promising products with the health plans and other payor organizations that provide health care coverage for hundreds of millions of Americans.

These organizations rely on health care decision makers (HCDMs), experts in formulary development and benefit design, who have the unique know-how to examine new drugs and consider their efficacy, safety and cost-effectiveness.

HCDMs’ ultimate goal is to get patients the medications they need at costs they can afford—health systems and patients expect that. The process includes working with formulary committees to make timely recommendations about new medications and treatments. Therefore, HCDMs require access to clinical and

economic information “before” new products are approved for marketing or expanded indications.

The current situation with COVID-19 offers a clear example of why sharing early information on medications in the pipeline is so important: Payors need new treatment data from manufacturers as early as possible. For example, the FDA recently authorized the emergency use of remdesivir, which early evidence shows may reduce recovery times in patients with the coronavirus. Another example is Utah’s move to spend $800,000 to build a stockpile of chloroquine and hydroxychloroquine without rigorous evidence that the therapies helped patients recover faster from COVID-19. The state later canceled its order. (In mid-June, the FDA revoked emergency use authorization for hydroxychloroquine due to a lack of efficacy and known safety concerns.)

These examples highlight the need to examine drugs’ evidence early. Such an approach is inherent in a process called pharmaceutical information exchange (PIE).

PIE gives manufacturers and HCDMs the ability to proactively share certain nonpromotional health care economic and scientific information on products “ahead of” FDA approval, including for both initial and subsequent indications. PIE has the potential to accelerate

‘Given the current global pandemic, it is even more critical to urge Congress to introduce and pass bipartisan legislation that allows manufacturers and HCDMs to exchange preapproval information.’

patient access to emerging pharmaceuticals and devices, including those granted breakthrough designation by the FDA, by expediting coverage decisions.

Given the current global pandemic, it is even more critical to urge Congress to introduce and pass bipartisan legislation that allows manufacturers and HCDMs to exchange preapproval information.

While the FDA has guidance regarding PIE, writing it into law provides a firm and clear basis that will ensure manufacturers that they can lawfully share truthful and non-misleading clinical and economic information about medications in their development pipelines, as well as new uses of approved products, prior to FDA approval.

EDITORIAL BOARD

To be clear, PIE is not to be used for promotional communications about unapproved products, which is prohibited by the FDA. Rather, it is designed specifically for HCDMs to obtain the information they need to evaluate medical products and make population-based coverage and reimbursement decisions quickly and effectively.

Patients are waiting for lifesaving drugs to combat COVID-19. Passing legislation and providing valuable tools that enable and facilitate PIE can help.

Ms. Cantrell is the CEO of AMCP, a professional association that advocates for access to high-quality, cost-effective medications and other therapies.

Craig Wilson, Sales Associate, Classified Advertising cwilson@mcmahonmed.com

ADMINISTRATION Robert Adamson, PharmD, Livingston, NJ

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4 Up Front

Pharmacy Practice News • July 2020

Letters

Have We Conflated Low- and High-Risk Compounding?

To the Editor: Re: “Lessons Learned From a Once Not-So-Sterile CR” (bit.ly/3cqg7jD): [It seems] to me that there is far too much energy and resources devoted to surrogate end points in sterile compounding.

Have we entered an era where we “can’t see the forest for the trees”?

The legitimate end point is product contamination. Where are the studies showing that the USP’s [U.S. Pharmacopeial Convention’s] surrogate end points make a difference in the end product?

This is especially true for low-risk compounding (which is mostly what hospitals do) involving the simple transfer of a sterile drug solution to a sterile diluent (IV piggybacks). Risk for contamination is minimal because the sterile

Before recent USP updates, compounding practices showed a lack of understanding of proper aseptic technique.

ingredients are sequestered within sterile syringes, needles and closed system drug-transfer devices. Indeed, the only study I could find comparing traditional and sterile room influences concluded: “The most important variable affecting microbial contamination of admixtures was the aseptic technique of personnel, not the environment in which the drugs were compounded” (Am J Health Syst Pharm 2005;62[22]:2386-2392).

Have we conflated low-risk compounding with the problems of high-risk compounding? Should we be asking who profits from perpetuating a culture of regulatory extremism? How much has it cost us? Does anybody care?

—Ray Vella, PharmD Central Coast, Calif.

Jerry Siegel, PharmD, one of the sources interviewed in the story, responds: I can’t speak for USP on the issue of surrogate end points, but I can speak to the main question underlying Dr. Vella’s letter: whether fully outfitted and USPcompliant cleanrooms are necessary or overkill. As both a microbiologist and pharmacist, I, too, often have questioned the need for the increasing requirements of USP <797> for compounding sterile products. Certainly, these requirements are a far stretch from the practices of the 1970s, when I first started working as a

hospital pharmacist. We didn’t use key personal protective equipment, such as gloves, and we just started employing laminar airflow in cleanrooms, but typically not in any type of buffer room— so basically, compounding in street clothes, with no guidelines on hand hygiene. I participated in studies to wear scrubs and move our “hoods” to separate rooms but not with measured air pressures. Morever, validation testing to document changes in nosocomial infections were not done.

The wake-up call was the New England Compounding Center disaster in 2012, when nearly 800 people were sickened and more than 100 died from fungal contamination in compounded sterile products. The lawsuits that followed, along with CDC and FDA investigations, prompted a stern look at the in-hospital and outsourced pharmacy compounding state of affairs.

In my own work with cleanrooms, I saw many deplorable conditions in hospital compounding facilities. Practices and facilities were inconsistent across every state as well as any level of enforcement. Although USP was and is still trying to set standards that are enforceable, not all states have or will accept this standard. As a result, I have seen not only poor facilities but very poor practices as well. I have so many examples of sinks in compounding areas leaking water contaminated with Pseudomonas spp, with compounded IVs stacked up right next to them, that the chance of not infecting the patient is relatively small in that situation.

As for the financial burden that cleanroom renovations can pose—and the pushback that often results—I understand those concerns. Still, I am in favor of risk reduction for patient care; it’s hard to put a price on that!

Jerry Siegel, PharmD Vice President of Safe Medication Management Associates Inc. East Greenwich, R.I.

Promised Safety Solutions Fall Short To the Editor: Re: “Preventing Medication Errors At Small and Rural Hospitals” (bit.ly/3cqmcwt) Humans make mistakes, but computers should catch them. Despite the fact that insulin dosages change and new orders are generated, the “chain of custody” referring to the original order should always be maintained back to the first patient-specific order for that medication. This might have been problematic

in 1985, but not today.

The workaround that was cited in the article—creating a “dummy order with the patient’s ID but no dose information, which generated a patient-specific barcode that stayed with that patient, even if dosing information changed”— is a solution that embarrasses the software vendor, the hospital and the pharmacist, and is dangerous for the patient.

Pharmacy Practice News does everyone a disfavor by not identifying the electronic health record (EHR) vendor and following up with them as to why such an important safety net is unavailable in their system. I'll even give the EHR vendor the benefit of the doubt because this may be a configuration issue that the people who bought this system are unaware of, but critically need to know how to fix. If not, it behooves the vendor to fix the problem as soon as possible and provide the promised safety solution that the customer thought they were purchasing in the first place.

—Bruce Kiacz, BSPharm Toledo, Ohio

ISMP Responds: Thank you for your interest in our work.

Health care practitioners working in smaller hospitals with fewer resources are often compelled to be creative with the tools that are available to ensure the safest care for our patients. The function identified as a contributing factor in the case described is not unique to one EHR vendor. This issue and potential solutions were in fact discussed with the EHR vendor. ISMP's advocacy efforts include regular discussions with EHR (and other medication-related technology) vendors when medication safety risks for which they should be aware are identified. ISMP offers vendors safe practice recommendations based on our experience investigating and analyzing medication errors, that can be used in a plan of action to prevent further events.

We disagree, however, that any disfavor was done by not providing the name of the EHR vendor in the article. In fact, one might argue that if the vendor name were included, those who do not use that vendor may have dismissed the importance of the message being conveyed.

It is important to learn and use information about medication safety risks and errors that have occurred outside one’s organization. Establishing a process for learning from external risks helps to

assess an organization’s vulnerability to similar events and can trigger them to take preventative action. It is our hope that through sharing this event and the challenges that are specific to those practicing in small and/or rural hospitals, not only practitioners, but also vendors will be motivated to investigate their insulin use in the hospital setting and take action to implement processes that will make it harder for us to err.

Christina Michalek, BS, RPh, FASHP Medication Safety Specialist Institute for Safe Medication Practices Horsham, Pa.

Deborah Sadowski, RPh, MHA Director of Pharmacy Services Deborah Heart and Lung Center Browns Mills, N.J.

Vendor Offers More Information On Telepharmacy To the Editor: Re: “Trying Telepharmacy?

Here’s What You Need to Know” (bit.ly/3gI9oop) As a representative of TelePharm, the proprietary HIPAA-compliant software used by the Medicap telepharmacy provider described in this article, I thought it might be worth mentioning that the main barrier listed in the article—that all communications have to be conducted via HIPAA-compliant software—can be addressed by using available software.

Additionally, as noted correctly in the article, regulations governing telepharmacy vary state to state. So it may be worth mentioning that we at TelePharm have comprehensive resources fully briefing pharmacists from every state as to the regulatory landscape for telepharmacy.

We also have a full-time regulatory affairs staff available to help efforts in both states where the practice is and is not allowed.

As noted in the article, reimbursement is a critical component of a successful telepharmacy operation. As far as the standard practice of remote dispensing using telepharmacy goes, the scope of practice is exactly the same as in a traditional pharmacy, and thus reimbursement works the same way. Pharmacists are not reimbursed for their consultations in a traditional setting, and that remains the same in telepharmacy.

Indeed, the issue of reimbursement is not unique in the telepharmacy versus traditional fields of pharmacy operation.

—Mitch Larson Senior Marketing Specialist, TelePharm Iowa City, Iowa

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6 Clinical

Pharmacy Practice News • July 2020

COVID-19 Pandemic

ICU Delirium

50 of 58 patients

continued from page 1

A major factor in the resurgence was the growing shortage of first-line medications for managing the pain, agitation and confusion that patients on ventilators typically experience, and the increasing use of benzodiazepines for sedation.

By mid-June, those shortages were still widespread. Indeed, many of the first-line agents used for COVID-19 patients on mechanical ventilation— cisatracurium, fentanyl, ketamine, vecuronium and midazolam—were still in shortage, according to the FDA (bit.ly/ 2YoXBEH). Shortages of ketamine, propofol, lorazepam, morphine and fentanyl also were reported.

In the absence of such agents, many clinicians are turning to benzodiazepines—and that’s a problem, Dr. Ely noted. Given the risks these agents pose, “when possible, we really need to get away from them,” he said.

That’s easier said than done. A recent New England Journal of Medicine study (doi: 10.1056/NEJMc2008597) found that 50 of 58 patients (86%) with COVID-19 received a benzodiazepine (midazolam).

“We stopped using benzodiazepines years ago because of how deliriogenic they are,” Dr. Ely said. “To see 86% of people on a ventilator getting a benzodiazepine is like going back to how we practiced in 1995.”

(86%) with COVID-19 received a benzodiazepine despite the drug’s deliriogenic effects.

Source: NEJM doi: 10.1056/NEJMc2008597.

“People are just scared,” said Joanna L. Stollings, PharmD, a critical care pharmacy specialist at Vanderbilt University Medical Center. “It’s a new virus and we don’t completely understand how it’s transmitted. Providers are sometimes afraid to go in and see the patients, not necessarily because they are afraid of contracting the virus but because they are afraid of transmitting it to someone else, and are trying to conserve PPE. Because of that, we’re having trouble implementing some of the letters in the bundle.”

‘COVID-19 has got [ICU delirium] back up to 80%. So in three months, we’ve erased 20 years of progress.’

—E. Wesley Ely, MD, MPH

Dr. Ely is an advocate for the ICU Liberation Bundle (A-F) protocol (formerly known as the A-F bundle), which focuses specifically on the prevention and treatment of delirium. “This is a six-step approach to taking care of patients in the ICU, where we modify sedation, try to avoid benzodiazepines, and try to wake people up and get them out of the bed,” he said.

ARDS Causing Hardships The increasing number of COVID-19 patients with acute respiratory distress syndrome has stretched the ability of some hospitals to keep up with the shortages of drugs, personal protective equipment (PPE), and critical care physicians and nurses needed to treat them. Some hospitals find it easier to keep patients deeply sedated instead of implementing the A2F Bundle. Another factor is fear of viral transmission occurring at the bedside of COVID-19 patients.

These include the spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs) described in the letter B of the ABCDEF bundle, Dr. Stollings said, and the early mobility and exercise called for in letter E. Both steps have been shown to facilitate a reduced need for sedation and earlier removal from the ventilator.

The importance of family involvement and empowerment in ICU patient recovery (letter F) has been another casualty in the delirium reduction protocol, as hospitals with COVID-19 in their ICUs bar family visits out of fear of transmission. “When people become delirious [letter D], we know medications typically don’t work to prevent or treat this,” Dr. Stollings said. “So one intervention that we might use is to have the family reassure and calm the patient.” But that option has been virtually eliminated by the need to curb transmission of the virus.

“We have had to get creative and use

things like phones and tablets to allow patients to communicate with their families,” she added.

Forced Substitutions Dr. Stollings cited other factors in the resurgence of ICU delirium, including the growing shortage of medications used to induce sedation in ventilated patients. She noted that guidelines for managing pain, agitation and delirium recommend the use of dexmedetomidine or propofol for sedation—two drugs that, as of mid-June, were still listed in the current shortages section of the ASHP’s tracking site (bit.ly/2MohoNK), dovetailing with what the FDA reported. Because of this, she added, critical care physicians are forced to use benzodiazepines, such as midazolam or lorazepam, to induce sedation. “We’ve done a fair amount of research to show that these agents can cause delirium,” Dr. Stollings said.

“Then there’s the shortage of PPE,” she added, including the N95 respirators and powered air-purifying respirators that reduce the risk for viral exposure among physicians and nurses when they enter patients’ rooms.

In early June, the FDA reported that PPE shortages continued to affect hospitals nationwide. Part of the challenge for some facilities is how PPE is distributed. “We have received information from health care organizations that some distributors may have placed certain types of [PPE] on allocation, basing the quantity available to the health care organization on previous usage, not projected use,” the agency stated (bit.ly/2XXw3EI).

“Increased use may exceed the available supply of PPE, resulting in shortages at some health care organizations.”

Dr. Stollings works in the ICU every day, rounding with physicians and helping them to decide what medications to prescribe and what not to prescribe. “I look for drug interactions and make sure

everything is cost-effective,” she said.

“I’m wearing scrubs for the first time and wearing a mask. We’ve had a shortage of fentanyl, for example, so I help them figure out different pain medications we can use so patients have adequate [relief ].”

An Algorithm for Delirium Rx So far, Vanderbilt Medical Center has avoided the surge in critically ill COVID-19 patients that has struck other health systems. Dr. Stollings has developed a tiered algorithm for the use of ventilation medications “as we get more of these patients and experience more shortages.”

The algorithm, she said, has been submitted for publication and hopefully will be available soon for others to use to guide alternative treatment of pain and agitation. It suggests different options to consider, for example, when first-line sedation drugs and even less optimal second-line agents, such as the benzodiazepines, become unavailable. “When you get deeper into the algorithm,” Dr. Stollings said, “you’re thinking about things like antipsychotics,” such as haloperidol or drugs like ketamine, “which have limited data in critically ill patients.”

Speaking of alternative therapies for delirium, Dr. Ely said: “What doctors in hotbeds of COVID-19 are telling me they are doing is transitioning to shorter-acting drugs for less time, even antipsychotics, though not for delirium—they don’t treat delirium—but at least they can calm the patient and they won’t cause respiratory suppression. They won’t keep patients on the ventilator longer. So, antipsychotics, the alpha-2 agonists—clonidine and dexmedetomidine—these choices will at least not suppress the respiratory drive and won’t build up as much.”

—Bruce Buckley The sources reported no relevant financial relationships.

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8 Clinical

Pharmacy Practice News • July 2020

COVID-19 Pandemic Benefits do not outweigh risks

FDA Pulls COVID-19 EUAs for Antimalarial Drugs

S

aying that the benefits no longer outweigh the potential risks, the FDA revoked the emergency use authorization (EUA) for hydroxychloroquine sulfate (HCQ) and chloroquine phosphate (CQ) to treat COVID-19.

The EUA allowed hydroxychloroquine and chloroquine to be donated to the Strategic National Stockpile to be used to treat certain hospitalized patients

with COVID-19 when a clinical trial was unavailable, or participation in a clinical trial was not feasible. The agency determined that the legal criteria for issuing an EUA were no longer met.

“Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that chloroquine and hydroxychloroquine are unlikely to be effective in treating COVID-19 for the

authorized uses in the EUA,” the agency said in a statement.

“It was not surprising to see the announcement,” said Michael Ganio, PharmD, the director of Pharmacy Practice and Quality at ASHP. “There’s been mounting evidence that the drug is not effective in treating hospitalized COVID-19 patients. And at some point the amount of evidence about the lack

of benefit outweighs the risk of treating patients with hydroxychloroquine or chloroquine.”

In April, just four weeks after granting the EUA, the FDA issued a warning about reports of serious arrhythmias in patients with COVID-19 treated with either drug, especially when prescribed with azithromycin and other QT-prolonging medicines. The warning noted that the EUA was not a new drug approval, but allowed the drug to be used in clinical trials. “We are also aware of increased use of these medicines through outpatient prescriptions. Therefore, we would like to remind health care professionals and patients of the known risks associated with both hydroxychloroquine and chloroquine,” the agency said in a statement at the time, adding that it would continue to investigate the reports, which included arrythmias, such as QT interval prolongation and ventricular tachycardia.

As of May 6, 347 HCQ and 38 CQ cases with possible adverse events (AEs) were identified, according to the FDA. Most of the cases were among men in their early 60s. Five cases reported HCQ use through the EUA. QT prolongation was the most commonly reported AEs for both HCQ and CQ. There were 109 cases with serious cardiac AEs, some reporting one or more of the following: • 80 reported QT prolongation; • four reported torsades de pointes; • 14 reported ventricular arrhythmia, ventricular tachycardia or ventricular fibrillation; and • 25 had a fatal outcome.

Among the 109 cases, 92 (84%) reported concomitant use of at least one other medication that prolongs the QT interval, and 75 (69%) reported concomitant use of azithromycin.

There were 113 cases with serious noncardiac AEs, and among those, hepatitis, increased liver enzymes and hyperbilirubinemia were the most common AEs.

RECOVERY Data In addition to the AEs reported, the FDA said it considered many factors before rescinding the EUA, including an announcement by the chief investigators of the RECOVERY trial, which closed the hydroxychloroquine arm of its study on June 5, due to a lack of benefit.

Sponsored by Oxford University in England, the RECOVERY trial (www. recoverytrial.net; Clinical Trials.gov: NCT04381936) is assessing the effectiveness of different potential COVID-19 treatments on their ability to reduce all-cause mortality within 28 days. More than 11,000 patients have been enrolled. The study randomized

Clinical

Pharmacy Practice News • July 2020

9

COVID-19 Pandemic

Mortality in patients treated with HCQ was

25.7% versus

23.5% in the usual care arm.

CQ, chloroquine phosphate; HCQ, hydroxychloroquine sulfate.

Source: FDA (bit.ly/2UWZdmW).

1,542 patients to HCQ and 3,231 to the usual care comparator, and an interim analysis found that mortality trends favored the usual care comparator. In the HCQ arm, mortality was 25.7%, versus 23.5% in the usual care arm (hazard ratio, 1.11; 95% CI, 0.98-1.26).

The agency said several studies are still looking at the use of HCQ or CQ in COVID-19. Dr. Ganio said rescinding the EUA would not stop any of the trials.

However, institutional review boards overseeing those trials might request preliminary data to decide whether they should be continued.

This is what happened at the National Institutes of Health and the World Health Organization (WHO). The NIH halted its hydroxychloroquine trial after an interim analysis found that while there was no harm, it was “very unlikely to be beneficial in hospitalized patients with COVID-19.”

In addition, the WHO suspended the hydroxychloroquine treatment arm from the SOLIDARITY trial.

Relief from Shortages The FDA’s decision to pull the EUAs for hydroxychloroquine and chloroquine promises to ease shortages of the medications that developed when they were being touted as potential cures for COVID-19. At the height of that promotion, first-time prescriptions for the agents poured into community pharmacies at more than 46 times the average weekly rate, industry figures showed (bit.ly/3dc46yt). As a result, patients who take the drugs for chronic diseases, such as rheumatoid arthritis (RA) and lupus, had difficulty obtaining the medications. Access for malaria prophylaxis also was adversely affected.

Dr. Ganio said he hoped that as a result of the EUA cancellation, fewer outpatient prescriptions would be written for people trying to use the drugs as a COVID-19 prophylaxis, increasing the number of patients with RA and lupus who can regain access to the medications.

Dr. Ganio said pharmacists are going to be asked about hydroxychloroquine and chloroquine, and they need to have a discussion about the drugs’ risks and benefits, especially for people who still want to take them prophylactically.

They should consider the patient’s medical history, what medications they might be taking, and their risk for infection for COVID-19, he suggested.

Thomas M. File Jr, MD, president of the Infectious Diseases Society of America, which has issued COVID-19 treatment guidelines, agreed that a cautious approach is needed. “As our body of knowledge expands in response to the COVID-19 pandemic, our nation must remain committed to following the science and ensuring policies that protect the health of residents as we investigate

effective treatments to counter this insidious virus,” he said in a statement.

In related news: • The FDA said that HCQ or CQ could reduce the antiviral activity of remdesivir, another drug being tested for COVID-19 (bit.ly/3fMwKIj).

• Two widely publicized COVID-19 papers have been retracted following questions about the accuracy of the Surgisphere database used by the investigators (see pages 10-11).

—Marie Rosenthal

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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. * When prepared as directed, each 5 mL of solution contains vancomycin hydrochloride equivalent to approximately 250 mg of vancomycin. † Vancomycin Hydrochloride for Oral Solution USP [package insert]. Baudette, MN: ANI Pharmaceuticals, Inc. ‡ Content of vancomycin per bottle.

Vancocin® is a registered trademark of ANI Pharmaceuticals, Inc.

Copyright © 2019 ANI Pharmaceuticals, Inc. All rights reserved.

Please see Brief Summary of Prescribing Information on adjacent page.

10 Clinical

Pharmacy Practice News • July 2020

COVID-19 Pandemic

Retractions Question Claims Database

T

he recent retraction of two papers that used the Surgical Outcomes Collaborative registry, a database developed and maintained by Surgisphere Corp., to evaluate the impact of drugs in COVID-19 patients is a cautionary tale, according to C. Michael White, PharmD, who was not involved in both studies but was asked his thoughts about them.

The authors of the two papers, which appeared in The New England Journal of

Medicine and the Lancet, retracted the papers after concerns were raised about the data set used in the studies.

“By their nature, studies based on claims data or other databases do not provide a high quality of evidence to answer clinical questions, such as the risks versus benefits of a therapy for a condition,” said Dr. White, the department head and a professor of pharmacy in the Department of Pharmacy

Practice at University of Connecticut School of Pharmacy, in Storrs. Dr. White recently co-authored a review about the use of hydroxychloroquine for COVID-19 (Ann Intern Med 2020 May 27.

[Epub ahead of print]).

The retraction of the Lancet paper likely will reverberate most, given the ongoing controversy surrounding the antimalarial drugs at the center of the research. Published online on May 22, the study found

Vancomycin Hydrochloride for Oral Solution USP Important Safety Information

Contraindications Vancomycin Hydrochloride for Oral Solution is contraindicated in patients with known hypersensitivity to vancomycin.

Warnings and Precautions • Significant systemic absorption has been reported in some patients (e.g., patients with renal insufficiency and/or colitis) who have taken multiple oral doses of vancomycin hydrochloride for C. difficile-associated diarrhea. In these patients, serum vancomycin concentrations reached therapeutic levels for the treatment of systemic infections. Some patients with inflammatory disorders of the intestinal mucosa also may have significant systemic absorption of vancomycin. These patients may be at risk for the development of adverse reactions associated with higher doses of vancomycin oral solution; therefore, monitoring of serum concentrations of vancomycin may be appropriate in some instances, e.g., in patients with renal insufficiency and/or colitis or in those receiving concomitant therapy with an aminoglycoside antibacterial drug.

• Nephrotoxicity (e.g. reports of renal failure, renal impairment, blood creatinine increased) has occurred following oral vancomycin hydrochloride therapy in randomized controlled clinical trials, and can occur either during or after completion of therapy. The risk of nephrotoxicity is increased in patients over 65 years of age. In patients over 65 years of age, including those with normal renal function prior to treatment, renal function should be monitored during and following treatment with vancomycin oral solution to detect potential vancomycin induced nephrotoxicity.

• Ototoxicity has occurred in patients receiving vancomycin. It may be transient or permanent. It has been reported mostly in patients who have been given excessive intravenous doses, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent, such as an aminoglycoside. Serial tests of auditory function may be helpful in order to minimize the risk of ototoxicity.

• Use of vancomycin may result in the overgrowth of non-susceptible bacteria. If superinfection occurs during therapy, appropriate measures should be taken.

• Prescribing vancomycin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.

• Hemorrhagic occlusive retinal vasculitis, including permanent loss of vision, occurred in patients receiving intracameral or intravitreal administration of vancomycin during or after cataract surgery. The safety and efficacy of vancomycin administered by the intracameral or intravitreal route have not been established by adequate and well-controlled studies. Vancomycin in not indicated for prophylaxis of endophthalmitis.

Adverse Reactions The most common adverse reactions include C. difficile colitis, nausea, vomiting, hypokalemia, and nephrotoxicity. This is not a complete list of side effects and others may occur. Please see the Full Prescribing Information for a complete list of adverse reactions.

To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800-308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

This Important Safety Information does not include all the information needed to use Vancomycin Hydrochloride for Oral Solution USP safely and effectively. See full Prescribing Information for Vancomycin Hydrochloride for Oral Solution USP. For additional information, please call 1-800-434-1121 or visit www.anipharmaceuticals.com.

Copyright © 2019 ANI Pharmaceuticals, Inc. All rights reserved.

10239 Rev 10/19

that mortality was higher gher in people receiving hydroxychloroquine, hloroquine, chloroquine, or either of these drugs with ith a macrolide antibiotic versus those treated without them. In addition, the investigators reported that patients treated with hydroxychloroquine or chloroquine were far more likely to experience ventricular arrhythmias than their counterparts who had not received the drugs.

The NEJM paper reported that the use of angiotensin-converting enzyme inhibitors and statins were not associated with worse outcomes in patients with COVID-19.

Surgisphere Data Come Under Fire In early June, a group of researchers outlined their concerns about the integrity of the Surgisphere data set in a letter to the editor of NEJM (2020 May 1. doi: 10.1056/NEJMoa2007621). They noted, for example, that in some countries that contributed to the data set, “a relatively small number of hospitals are reported to have provided electronic patient record data to Surgisphere, yet these reports describe a remarkably high proportion of all confirmed cases in the respective countries.”

Based on such concerns, an independent auditor was to review the raw data and the studies, but apparently could not obtain the necessary information from Surgisphere, so the authors withdrew the papers.

“Because all the authors were not granted access to the raw data and the raw data could not be made available to a thirdparty auditor, we are unable to validate the primary data sources underlying our [NEJM] article, ‘Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19.’

We therefore request that the article be retracted,” wrote Mandeep R. Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center, in Boston, and lead author of the studies.

The retraction for the NEJM study was signed by all four authors, including Sapan S. Desai, MD, PhD, the president and CEO of Surgisphere.

The Lancet retraction, which came about an hour before the NEJM retraction, was not signed by all of the authors.

Although longer, it essentially noted the same difficulty in analyzing the raw data.

“We launched an independent third-party

Clinical

Pharmacy Practice News • July 2020

‘The big issue is that while you might be able to statistically correct for the impact of some demographic factors [in claims data or other databases], you cannot correct for those factors you do not know at the time are important.’

—C. M Michael White, PharmD peer review of Surgisphere with the pe cconsent of Sapan Desai to evaluate the origination of the database elements, to or confirm the completeness of the database, con and to replicate the analyses presented in an the paper. Our independent peer reviewers informed us that Surgisphere would not transfer the full dataset, client contracts, and the full ISO audit report to their servers for analysis as such transfer would violate client agreements and confidentiality requirements,” Dr. Mehra; Frank Ruschitzka, MD; and Amit N. Patel, MD, wrote. “As such, our reviewers were not able to conduct an independent and private peer review and therefore notified us of their withdrawal from the peerreview process.

“We always aspire to perform our research in accordance with the highest ethical and professional guidelines,” the researchers added, noting that they “no longer vouch for the veracity of the primary data sources.”

The researchers said they collaborated in good faith and apologized for the papers.

11

COVID-19 Pandemic legitimate, there are inherent weaknesses in this type of study that should be noted, said Dr. White, who is a member of the Pharmacy Practice News editorial advisory board. “The big issue is that while you might be able to statistically correct for the impact of some demographic factors [in claims data or other databases], you cannot correct for those factors you do not know at the time are important, and you cannot factor in the thought processes of the treating clinicians as they are making treatment choices.”

More rigorous data began pointing

people away from hydroxychloroquine for COVID-19. The U.K.’s Randomized Evaluation of COVid-19 thERapY (RECOVERY) trial reported that there was no beneficial effect of hydroxychloroquine in hospitalized COVID-19 patients. The researchers compared 1,542 patients taking hydroxychloroquine with 3,132 patients receiving usual care alone. “There was no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs. 23.5% usual care; hazard ratio 1.11 [95% confidence interval 0.98-1.26];

P=0.10). There was also no evidence of beneficial effects on hospital stay duration or other outcomes,” the researchers said in a statement.

As a result, the FDA withdrew its emergency use authorization for hydroxychloroquine and chloroquine, and the National Institutes of Health and the World Health Organization stopped their hydroxychloroquine treatment studies.

—Marie Rosenthal The sources reported no relevant financial relationships.

DRIVEN TO FULFILL THE PROMISE OF BIOSIMILARS— THE PFIZER WAY The Pfizer Promise is simple: To help you provide patients with more treatment options while delivering the largest portfolio of potentially cost-saving biosimilars.1-3

Claims Data Sets Problematic

Breadth of offerings

However, even if the trial data sets were

Pfizer has the largest portfolio of oncology biosimilars on the market, including both cancer therapies and supportive care products, to give patients more treatment options.2,3

A Conversation With Dr. C. Michael White

Quality focused Pfizer oncology biosimilars are all produced to meet the same high-quality standards as its biologics—using the same robust protocols for monitoring quality throughout every stage of the manufacturing process.4

Manufacturing and supply experience Pfizer leverages more than 30 years of state-of-the-art manufacturing and supply-chain experience in biologics to reliably deliver biosimilars to patients.4

To learn more about Pfizer’s oncology biosimilars, visit us online at PfizerBiosimilars.com Although the evidence points away from hydroxychloroquine as a treatment for COVID-19, it is still being considered as a prophylaxis. In a ZOOM interview, C. Michael White, PharmD, talked with us about what that could mean for patients.

Watch at bit.ly/2Nphwgc-PPN.

References: 1. IMS Institute for Healthcare Informatics. Delivering on the Potential of Biosimilar Medicines: The Role of Functioning Competitive Markets. Parsippany, NJ: IMS; March 2016. 2. Drugs.com. How many biosimilars have been approved in the United States? https://www.drugs.com/medical-answers/many-biosimilars-approved-united-states-3463281/. Updated December 8, 2019.

Accessed April 6, 2020. 3. McGowan S, Jesse M. Biosimilars Pipeline Report. AmerisourceBergen. https:/www.amerisourcebergen.com/-/ media/assets/amerisourcebergen/biosimilars-pipeline-report_0420_v3.pdf?la=en&hash=1071304C7B66ED62628201B8268C0B633 627CB6B. Updated May 1, 2020. Accessed June 4, 2020. 4. Data on file. Pfizer Inc., New York, NY.

PP-BIO-USA-0633

© 2020 Pfizer Inc.

All rights reserved.

June 2020

12 Q & A

Pharmacy Practice News • July 2020

The following advertorial is provided by Visante. It is designed to support the advertisement below.

Q & A: Steve Rough, Senior Vice President, Visante Q: Hospitals and health systems are faced with serious financial challenges post COVID-19. How will this impact pharmacy leaders and their departments?

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consultants (many with minimal pharmacy expertise and understanding) to help lead financial recovery efforts. Pharmacy occupies a large expense in most organizations, therefore pharmacy leaders will likely be asked to critically evaluate how services are provided, and pharmacy departments will likely be targets for labor and non-labor savings mandates.

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A: In general, broad-scale reductions in pharmacy workforce are shortsighted and can negatively impact the quality of patient care as well as health-system financial performance. However, post COVID-19, it is advisable that every pharmacy leader proactively identifies opportunities for improved labor efficiency without compromising quality, and that every pharmacy leader has a plan to gain efficiency of between 5% and 20% in a worst-case scenario. Visante is able to help pharmacy leaders with centralization and remote services strategy as well as with leveraging technology and skill mix enhancements to improve productivity and lower labor costs if needed. Some examples include work-from-home and remote dispensing to help match resources with workload, for example. It is vital that any pharmacy workforce savings strategy does not negatively impact patient care, and we offer innovative approaches in this regard.

Mr. Rough has more than 20 years of hospital pharmacy and health care leadership experience, in which he successfully built and led all aspects of strategic, operational, clinical, programmatic and financial performance for a large health-system pharmacy enterprise.

He has delivered more than 145 presentations to national pharmacy audiences and has served in countless volunteer leadership positions within professional pharmacy organizations.

Clinical

Pharmacy Practice News • July 2020

13

COVID-19 Pandemic

COVID-19 Takes a Global Toll on Oncology Practice

O

ncology pharmacy practices around the world are struggling to cope with the numerous supply and safety challenges brought on by the COVID-19 pandemic, according to a global survey by the International Society of Oncology Pharmacy Practitioners (ISOPP).

Among these practitioners’ top concerns, the survey found, is the impact of shortages in medications and personal protective equipment (PPE) on the delivery of therapy to cancer patients, who are already at higher risk for coronavirus infection and worse outcomes than the general population.

“Oncology pharmacists are looking for guidance,” said Alexandre Chan, PharmD, MPH, a professor and the founding chair of the Department of Clinical Pharmacy Practice at the University of California, Irvine. “We wanted to come up with data that could help them make decisions.”

Dr. Chan told Pharmacy Practice News that the snapshot survey, covering the period from April 10 to April 20 when the worldwide infection rate was rapidly increasing, was just the “first step” in ISOPP’s long-term objective to develop evidence-based pandemic response guidelines for oncology pharmacy practitioners.

The survey, with responses from 42 oncology pharmacy leaders worldwide, found that more than eight out of 10 respondents (82%) had changed their treatment practices to adjust to the new realities brought by the pandemic (doi.org/10.1177/1078155220927450; bit.ly/3hzgoEN).

The practice changes were hardly uniform across the 28 countries and five regions surveyed. The most common changes were fewer clinical trial referrals, reported by respondents in 10 of 28 countries; increased use of supportive care medications (nine of 28); and timing changes or delays in treatments or transplants (nine of 28). In the palliative care setting, the most frequent changes involved the use of more oral cancer therapies (12 of 28); switches to less myelosuppressive cancer therapy regimens (eight of 28); and a reduction in clinical trial referrals (eight of 28).

In 12 of the 28 countries, the survey found that shortages of PPE—particularly N95 masks—had put a strain on the compounding and administration of hazardous antineoplastic agents. To cope with the shortfall, some practices extended pharmacists’ and technicians’ work hours. Others altered their hours to facilitate split shifts or team separation. A handful of practices were forced to reduce hours because of illness or quarantine. Longer shifts helped to extend PPE supplies, but the trade-off

was the potentially negative effect on workers’ mental health and quality of life, Dr Chan noted.

Medication shortages also took a toll on oncology practice, with the impact felt most acutely in Africa, where importation has been an ongoing challenge. Of responding African countries, 86% reported experiencing shortages of both anticancer and supportive care medications, and 71% have had

problems importing anti-infectives.

Dr. Chan said this survey report was published because “a lot of oncology pharmacists around the world are looking for guidance on how to ensure occupational safety during the pandemic.

ISOPP’s mission is to support not just members, but the entire oncology pharmacy profession. We want to come up with data that can help decision making.”

Moving forward as a society, he added,

“we’re going to use some of the best practices being developed around the world to inform practitioners. But ultimately, we need research to develop evidencebased guidelines. That is what is in shortage right now, which is why everyone is scrambling and doing different things.”

—Bruce Buckley Dr. Chan reported no relevant financial relationships.

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14 Clinical

Pharmacy Practice News • July 2020

Medication Safety

NMBA Caps Pose Risk continued from page 1

agency said the short-term measure was necessary to ease severe supply disruptions caused by the high demand for agents needed to immobilize critically ill COVID-19 patients on mechanical ventilation. Specially marked warning caps also have been in short supply, the FDA reported.

Figure 1.

Images of currently approved cap (left) and temporary cap (right) for vecuronium bromide injection 10-mg vial and 20-mg vial.

The easement was scheduled to continue through July 2020 for rocuronium and through September 2020 for vecuronium.

To ensure safe use of these high-alert medications in the meantime, ISMP published images of the approved and temporary blank caps (Figures 1, 2) and urged pharmacists and nurses to exercise extreme vigilance in storing the unmarked vials (Figure 3) and selecting and preparing them for administration.

“There may be other vials of the same size that also have a gray cap or nearly gray cap,” said Michael R. Cohen, MS, RPh, the president of ISMP. If they’re stored next to each other and below eye level with only the caps visible, he said, the odds of choosing and injecting the wrong medication greatly increase.

Deadly Versed Error

Figure 2.

Images of currently approved cap (left) and temporary cap (right) for rocuronium bromide injection, 50 mg per 5 mL and 100 mg per 10 mL.

Figure 3.

When vials are standing upright in storage, staff may select a vial based on cap color and may not notice if they have the wrong vial in hand (tranexamic acid, left, ropivacaine, right).

Photo credit: ISMP.

As an example of the risks, Mr. Cohen cited a December 2017 case at a Tennessee hospital where a nurse, who was supposed to administer the sedative Versed (midazolam) to a patient with anxiety, typed “VE” into the computer instead of “MID” for midazolam, and vecuronium popped up. The result was she prepared and injected the paralyzing agent, and the patient died (bit.ly/2zVn8M2-PPN). “We’ve had these accidents from time to time with these agents given in error,” Mr. Cohen said.

One way to reduce the risk, he suggested, is to attach auxiliary “warning: paralyzing agent” labels to the tops of the unmarked vials. “They’re readily available from different medical supply houses,” he said.

Other suggestions highlighted in the safety alert included reminding staff of the importance of barcode scanning before drug preparation and administration. Another strategy is to make sure vials “are lying down so that labels are visible in automated dispensing cabinet drawers, anesthesia trays, or in other storage containers or shelving, particularly on low shelves in a refrigerator.”

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The FDA has temporarily allowed manufacturers of rocuronium and vecuronium to distribute vials of the paralyzing agents without the required cautionary cap labels.

The agency said the measure was necessary to ease severe supply disruptions caused by the high demand for agents needed to immobilize critically ill COVID-19 patients on mechanical ventilation.

Deb Saine, MS, RPh, the director of the quality program at Valley Partners in Winchester, Va., emphasized the critical importance “for pharmacists to ensure safe processes are in place, and followed, for storing and dispensing these high-alert medications.

“It’s also a good time,” she said, “to physically visit each area where neuromuscular blockers are stored or used so you can resolve any inconsistencies and take the opportunity to provide education to keep patients safe from harm.”

Rush University’s Approach Many health systems and hospitals have already taken special safety precautions with paralyzing agents in response to the growing number of ventilated COVID-19 patients with severe acute respiratory syndrome.

Drayton A. Hammond, PharmD, a critical pharmacy specialist at Rush University Medical Center in Chicago, said the center’s adult medical ICU “has been vigilant with barcode scanning at the bedside to help reduce the likelihood of

an error involving any medications, but especially high-risk medications, at the time of administration.”

Dr. Hammond said the ICU also changed its “process to use intravenous push neuromuscular blockade in critically ill adults in response to COVID-19, which involved pharmacists reeducating all registered nurses on the agents and their risks, as well as monitoring parameters.”

Additionally, an alert now goes off whenever a neuromuscular blocking agent is removed from an automatic dispensing cabinet “to remind the nurse of the care needed when administering these agents.

“These are not foolproof measures,” Dr. Hammond said, “but we do believe they’ve allowed us to feel comfortable with short-term use of the vials that do not have the labeling on the cap. We do remain vigilant with these agents and, thankfully, have not had any issues so far with this change.”

—Bruce Buckley The sources reported no relevant financial relationships.

Keep it coming!

Go to PharmacyPracticeNews.com/renew to renew or start your complimentary subscription to the best-read newsmagazine for hospital pharmacists.

16 Clinical

Pharmacy Practice News • July 2020

Oncology

Tracking CINV Via Texts Cuts Admissions, Urgent Care

A

pharmacist-led remote monitoring program to track cancer patients experiencing chemotherapy-induced nausea and vomiting (CINV) using text messaging resulted in a marked reduction in urgent care and emergency department (ED) visits, according to researchers at the University of Michigan.

“We were very excited about this,” said lead study author Shannon Hough, PharmD, the pharmacy manager for

oncology clinical services at the university’s Rogel Cancer Center, in Ann Arbor.

“When you’re looking to modify a metric like ED use, any movement improves patient outcomes and the overall quality of care we’re providing. We were thrilled to see that this intervention looks like it makes a difference in those outcomes.”

During their pilot program, Dr. Hough and her colleagues sent text messages to nearly 400 chemotherapy patients

and intervened if patients reported severe symptoms, she reported at the 2020 virtual annual meeting of the American Society of Clinical Oncology (abstract 2001). After eight months of the program, they found that combined hospitalization, ED visits and urgent care use were nearly halved in this population. Visits fell from 234 before the program started to 118 during the program (P=0.029).

Dr. Hough’s team started the program to reduce the number of patients seeking unplanned care, which often is related to nausea and vomiting. Patients at the main infusion center who were receiving chemotherapy agents likely to induce nausea and vomiting and given an NK-1 antagonist were asked to enroll in the program, which sent a daily text message for seven days after treatment.

The text included questions based on

Clinical

Pharmacy Practice News • July 2020

17

Oncology the validated MASCC (Multinational Association for Supportive Care in Cancer) anti-emesis tool (MAT), asking if patients experienced vomiting, how many times, and how bad their nausea was on a 1-10 scale. Their responses were tracked in the electronic health record (EHR), and patients who reported significant difficulties were flagged in an email to the team pharmacists. From there, pharmacists called patients to assess whether they could adjust medications, refer their call to a nurse or provider, or ask the patient to come to the clinic.

Of 652 patients who received an NK-1 antagonist, 387 (59%) enrolled in the pilot program. Each patient participated

for an average of 1.8 chemotherapy cycles. The text message response rate was 94% (18,143 responses to 19,256

messages sent). During 861 cycles of therapy (51.7% with curative intent; 48.3% palliative), 7% of responses noted vomiting and 33% reported nausea.

Comparing health care utilization before and after the service began, hospital admissions (ED, inpatient and observation units) declined from 124 to 80 visits; nausea-related admissions dropped from 22 to seven visits; urgent care visits dropped from 110 to 38 visits; and nausea-related urgent care visits dropped from 23 to seven visits.

Feedback has been positive, Dr. Hough said. “When I call patients, they are so relieved that I’m reaching out to them.

I think patients sometimes feel bad calling, like they’re bothering somebody and they don’t know if something is bad enough to call. We’re removing that worry by just reaching out to them.”

The team plans to expand the service to satellite infusion centers, Dr. Hough said.

“People don’t always think about pharmacists as your front-line and triage team member, but modifying medications already prescribed to patients, providing education and breaking down barriers” when patients may hesitate to take medications that have been prescribed “is something that we frequently do in these visits, and that’s a perfect role for our clinical pharmacists,” she said.

Linking to Electronic Record Beneficial Using the MAT tool in this program is helpful because nausea and vomiting can be subjective, commented Cindy O’Bryant, PharmD, a professor of clinical pharmacy at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, in Aurora.

“This will help sort out which patients are really having issues and which may not be, and can eliminate bringing in people who may not need additional health care resources.”

Linking to the EHR also is helpful because the entire health care team can see results, Dr. O’Bryant said. Because half of the study population was receiving curative treatment, that helped the team stay on top of treating adverse events so patients remained adherent to their prescribed therapies.

More information, including interventions used to prevent admissions, provider workload and other programmatic resources, as well as the total economic impact of the program, would have been helpful, Dr. O’Bryant said, adding that this information could help determine the feasibility of implementing a similar program at other institutions.

—Karen Blum The sources reported no relevant financial relationships.

18 Clinical

Pharmacy Practice News • July 2020

Infectious Disease

CMS a Powerful Agent of Change for ABx Stewardship T

his year’s March 30 deadline to meet the Centers for Medicare & Medicaid Services (CMS) conditions of participation regarding antibiotic stewardship programs (ASPs) has come and gone. But the positive effects of the new rules remain, not the least of which is confirmation that policy revisions can be a powerful agent for change in facilities that are open to process improvement.

In fact, most hospitals showed they were ready for the change, having been primed by both the CDC’s 2019 Core Elements for Hospital Antibiotic Stewardship Programs and the Joint Commission’s 2017 standards for antimicrobial stewardship. According to the CDC’s 2018 National Healthcare Safety Network survey (bit.ly/2sK02nV), 85% of hospitals in the United States have met the agency’s recommended core elements for ASPs. “Antimicrobial stewardship is a great case study for how policy can reform practice,” said Anna Legreid Dopp, PharmD, the director of clinical guidelines and quality improvement at ASHP. “CDC is in close communication with CMS, and we have seen the results of this with the number of institutions that have an ASP doubling within five years’ time,” Dr. Dopp said, referring to how the number of hospitals with ASPs went from 41% in 2014 to more than 90% in 2019. “The CMS final rule recognized that there is still a gap to fill in reaching compliance.”

Leadership Shines Through As outlined in the CDC core elements, pharmacists have taken leadership positions in their hospitals’ ASPs, and in doing so, have brought their hospitals into compliance with the CMS requirements. For example, they have been leading ASP committees to ensure the programs are multidisciplinary, said Susan Davis, PharmD, the

president-elect of the Society of Infectious Diseases Pharmacists. One of the CMS requirements is to demonstrate coordination among all staff responsible for antibiotic use and resistance. “[Pharmacist-led ASPs] have been updating the ASP committees to make sure not only nurses, but relevant specialists, are at the table,” said Dr. Davis, a professor in the Department of Pharmacy Practice at Wayne State University’s Eugene Applebaum College of Pharmacy and Health Sciences, in Detroit. “For instance, if they are at a cancer center,

they make sure oncologists are represented. Pharmacists are often the ones bringing people together.”

Dr. Davis also is a clinical pharmacy specialist at Henry Ford Hospital, the flagship hospital of the five-hospital Henry Ford Health System. In 2018, the system received a grant through CDC’s Antibiotic Resistance Solutions Initiative to improve antibiotic selection and reduce excessive treatment duration through pharmacist-led prescription reviews at the time of discharge.

This effort dovetailed with the CMS

requirements to document evidencebased use of antibiotics and demonstrate improvements in proper antibiotic use. It also presented a challenge, as each of the five hospitals in the system had its own way of doing things.

“In my hospital, the pharmacist does most of the bedside management, but in another hospital, a generalist [physician] and an infectious diseases pharmacist work behind the scenes. We had to design something that worked across different models,” Dr. Davis said.

The project involved designing

To Bring ASPs Up to Speed, Build on Existing Foundation

P

harmacists in hospitals that are still struggling to meet all of the antibiotic stewardship requirements should keep in mind that each hospital has its own needs, experts noted. So what works for one may not work for another.

“Antibiotic stewardship isn’t one-size-fits-all,” said Susan Davis, PharmD, the president-elect of the Society of Infectious Diseases Pharmacists.

“You can learn from what other sites are doing, but your practice model has to dictate what your interventions are and depends on how your pharmacists are deployed.”

Dr. Davis, a clinical pharmacy specialist at Henry Ford Hospital System and a professor in the Department of Pharmacy Practice at Wayne State

University’s Eugene Applebaum College of Pharmacy and Health Sciences, in Detroit, suggested building on the foundation that’s already there, especially with transitions of care.

“Most hospital pharmacists already have some degree of involvement in transitions of care, but it’s focused on medications for chronic illnesses like COPD [chronic obstructive pulmonary disease], congestive heart failure or diabetes. If you’re already doing that kind of care, start thinking of how you would do it for infectious diseases and antibiotics,” Dr. Davis said.

Buy-in from all levels is crucial to a well-rounded ASP, as Dr. Davis and her colleagues learned when they undertook an initiative to improve

appropriate antibiotic use through a CDC grant.

“We had to get approval from C-suite leaders, but we also had to get buy-in from the physician and nurse leaders on the floor. We asked them what would work for their patient care flow.”

Lisa Dumkow, PharmD, a clinical pharmacist in antimicrobial stewardship at Mercy Health St. Mary’s, in Grand Rapids, Mich., suggested breaking down the plan into manageable chunks. “Start with one or two goals at a time, and make sure you’ve tackled those goals before you move on to the next,” she said. “Two or three goals in a year is enough. It’s a marathon, not a sprint.”

—T.D.

Clinical

Pharmacy Practice News • July 2020

19

Infectious Disease

Resistance Benchmarking Tool Available D

oes your hospital need to battle the growing problem of antibiotic resistance? If so, a metric for measuring antibiotic use developed by the CDC— the Standardized Antimicrobial Administration Ratio (SAAR)—may be useful.

“When administrators look at data, nobody wants to be the outlier, especially to their peers,” said Jason Newland, MD, MEd, a professor of pediatrics at Washington University in St. Louis and St. Louis Children’s Hospital, where administrators were convinced to hire a pharmacist in 2015, after seeing comparative data similar to the SAAR and requirements being set forth by the Joint Commission.

SAAR 101 More than 20,000 health care facilities are enrolled in the CDC’s National Healthcare Safety Network (NHSN), an internet surveillance system that collects mandated and voluntarily reported data on health care–associated infections, antimicrobial use and resistance, health care personnel influenza vaccination and blood safety. The system provides facilities with the SAAR data that can be used for inter- and intra-facility comparisons and local quality improvement activities (Clin Infect Dis 2018;67[2]:179-185).

“It lets us find out where we are out of line with others, and then we use that to

protocols and procedures that would not only identify patients scheduled to go home on antibiotics, but also incorporate institutional guides on antibiotic selection and duration to allow pharmacists on rounds to recommend the discharge antibiotic and cue up the appropriate order so it was ready for physician review.

“We had a massive improvement in getting the right duration of therapy,” Dr. Davis said. “If a patient was supposed to get seven days of antibiotics, we knew what they already had in the hospital and could give them only what they needed for the rest of their treatment.”

Mercy Health St. Mary’s, part of the Trinity Health System in Michigan, uses a split model with both clinical and staff pharmacists. Each floor has a clinical pharmacist who rounds with nurses, case managers and other clinicians, such as respiratory therapists at the bedside.

That kind of collaboration not only aligns with the CMS requirements, but improves care in ways that are

improve,” Dr. Newland said.

Hospitals reporting to the NHSN Antimicrobial Use Option submit aggregated antibiotic use data electronically, providing antimicrobial usage data monthly, including days of therapy.

“Days present” in the SAAR refers to the period during which a given patient is at risk for antimicrobial exposure for a given patient location. Patient location number is the number of patients present, regardless of patient status (e.g., inpatient, observation), for any portion of each day of a calendar month for a patient care location.

This includes admission, discharge and transfer days. On a day when a patient is transferred from a medical critical care unit to a medical ward, the patient will be recorded as one day present on the medical critical care unit and one day on the medical ward. “In one day, you can be in three different locations in your denominator,” Dr. Newland said, so interpreting the data can be challenging.

Consistency, Uniqueness, Avoiding Paralysis The SAAR’s strengths are that it includes nationally represented data and has risk-adjusted/benchmarking data that can be used for improvement, he said. The metric’s weaknesses are that it is based on quantitative data; risk

adjustment is not at a patient level; it does not include all drugs; and it might not be effective for certain populations.

The key to benchmarking is consistency. “You should follow a metric and be consistent. If you are doing 1,000 patientdays and you can get that and use that, continue to use that,” he cautioned.

Learn from best practices and impleple ment interventions that have worked rked at other hospitals, and rememberr a team effort is best for effective ve antimicrobial stewardship. “A key piece of the SAAR is it doesn’t measure ure appropriateness. If your guy says there is something going on there, you should go look,” Dr. Newland said.

Elizabeth Dodds Ashley, PharmD, an associate professor of medicine at Duke University School of Medicine,, in Durham, N.C., said the SAAR is used throughout the Duke Antimicrocrobial Stewardship Outreach Network. k.

“Being able to benchmark antibiotic use in a risk-adjusted way is a tremendous tool for the stewardship team when discussing use with individual provider groups at the local level,” she said.

—Kate O’Rourke The sources reported no relevant financial relationships.

The number of hospitals with ASPs went from

41% in 2014 to more than

90% in 2019.

Source: ASHP

meaningful to the patient, said Lisa Dumkow, PharmD, a clinical pharmacist in antimicrobial stewardship at Mercy Health St. Mary’s, in Grand Rapids, Mich.

“Nurses especially are important. They are with the patient and family and they know the patient’s concerns intimately.

They can tell you if a patient isn’t tolerating [metronidazole] or another antibiotic

well,” Dr. Dumkow said.

Beyond that, the pharmacists work with the emergency department and urgent care center, and the team includes student pharmacists and residents. “[Lack of ] time and resources can be barriers [to successful antibiotic stewardship], and our residents and students are vital in helping us tackle challenges in

Adult SAAR Agent Category • All antibacterial agents • Broad-spectrum antibacterial agents predominantly used for hospital-onset infections • Broad-spectrum antibacterial agents predominantly used for a community-acquired infections com • Antibacterial An agents predominantly used for resistant grampositive infections (e.g., MRSA) • Narrow-spectrum beta-lactam agents • Antifungal agents predominantly used for invasive candidiasis • Antibacterial agents posing highest risk for CDI CDI, Clostridioides difficile icile inf infection; MRSA, methicillin-resistant methicil stant Staphylococcus Staphyloco aureus; SAAR, Standardized Stand rdized Antimicrobial Adm Administration Ratio

Source: CDC. DC.

Dr. Newland repo reported financial relationships with Merck and Nabriva Therapeutics.

Dr. Dodds Ashley reported research funding to determine the impact of the Standardized Antimicrobial Administration Ratio on antibiotic use.

the ER and urgent care and assisting with data collection,” Dr. Dumkow said.

As a leader in antibiotic stewardship, Dr. Dumkow uses her expertise to work with physicians, specialists and other prescribers to make sure they follow best practices, even if it means having a difficult conversation. “Some are not really open to stopping or deescalating their patients’ antibiotics, especially if their patient is really sick, or they don’t understand why they can’t order a carbapenem without an infectious diseases consult,” she said. “But every antibiotic you add, or every extra day a patient is on it, is an extra risk for adverse drug events such as [Clostridioides] difficile.

So we have to be diligent, especially as a patient is discharged to make sure that they have the appropriate antibiotic and duration of therapy.”

—Terri D’Arrigo The sources reported no relevant financial relationships.

20 Policy

Pharmacy Practice News • July 2020

Reimbursement Matters

Medicare Advantage, Part D Plans 2021 and 2022 Final Rule

R

ecent columns have been preparing you for the reimbursement environment in the upcoming fiscal and calendar years covering a variety of practice sites. Although many issues will be covered in this rule along with additional releases, in this column, we’ll hone in on a few key provisions.

We’ll also review several reimbursement policy updates related to the ongoing COVID-19 pandemic.

Let’s start with the final rule that revises regulations for the Medicare Advantage (MA) or Part C program, the Medicare Prescription Drug Benefit (Part D) program, and the Medicare Cost Plan program. These revisions are part of an effort to implement certain sections of the Bipartisan Budget Act of 2018 and the 21st Century Cures Act. The rule also enhances the Part C and D programs, codifies several existing CMS policies,

and implements other technical changes, notably targeting telehealth.

Under the revisions, MA plans have been given greater flexibility to offer and discount telehealth for specialty care, including dermatology, psychiatry, cardiology, ophthalmology, nephrology, primary care, gynecology, endocrinology and infectious diseases. The rule allows CMS to expand benefits for these services and advances and expands the availability of

“Reimbursement Matters” is a tool for maintaining your health system’s fiscal health.

Please email the author at bonniekirschenbaum@ gmail.com with suggestions on reimbursement issues that you would like to see covered.

Bonnie Kirschenbaum, MS, FASHP, FCSHP

340B Hospitals, Be Aware!

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CMS Position: The survey will make sure Medicare pays the same amount for drugs covered under the program as hospitals pay to acquire those drugs.

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A Reimbursement Lexicon

telehealth. It’s important to note, however, that the revised regulations also require providers to meet CMS network adequacy standards. (For an overview of the final rule on Parts C and D, see the Federal Register at go.aws/3cWgSkU.)

Capping Out-of-Pocket Insulin Costs for Medicare CMS is capping out-of-pocket insulin costs for Medicare beneficiaries at $35 per month as of Jan. 1, 2021. The cap applies to both pen and vial dosage forms for rapid-acting, short-acting, intermediate-acting and long-acting insulin. It will extend from the beginning of the year and through the Part D coverage gap. Participation by Medicare Part D prescription drug and MA plans with prescription drug coverage has been robust. More than 1,750 stand-alone Medicare Part D and MA prescription drug plans will offer the lower insulin copays through the Part D Senior Savings Model for the 2021 plan year. (To familiarize yourself with this new innovation model, visit bit.ly/3cPTVQ3.)

The change to insulin copays in 2021 for beneficiaries in participating plans will cover “all common forms of insulin,” CMS

Policy

Pharmacy Practice News • July 2020

21

Reimbursement Matters CMS is capping out-of-pocket insulin costs for Medicare beneficiaries at $35 per month as of Jan. 1, 2021. The $35 per month cap applies to both pen and vial dosage forms for rapid-acting, short-acting, intermediate-acting and long-acting insulin.

Administrator Seema Verma said during a press conference. “If it goes well, we’ll extend that to other drugs. We’re starting with insulin, but depending on the progress of this, we will consider offering this flexibility to manufacturers and plans with other drugs, depending on the results. We think that this creates a foundation and a platform to fix ... some of the problems that we have in the Part D plans.

It’s time for that program to be updated.

A lot of the provisions just don’t work anymore, and it’s standing in the way of free-market completion and negotiation that can lower prices for seniors.”

CMS anticipates releasing the premiums and costs for specific Medicare health and drug plans for the 2021 calendar year in September 2020, including final information on the model, the agency noted (go.cms.gov/3cRlcSm).

Action Step: Know who the payor is for each patient; this applies to Part D and U.S. MA patients in the Senior Savings Model. Examine your policy for inpatient insulin use as well as transitions of care for diabetic patients using insulin, and make sure you’re taking into consideration the need to keep the patient on a product with insurance plan–capped copays.

including physicians, hospitals and rural health clinics. These cover outpatient therapy, telehealth and appropriate

coding, and federally qualified health centers. For a COVID-19 FAQ on Medicare fee-for-service billing, see go.cms.gov/3hd3Ane. For an overview on COVID-19 management, see the CDC’s resource page at bit.ly/3ff2mpB. Another useful COVID-19 resource is CMS’s current emergencies website, at go.cms. gov/3dPPoi7. And the AHA has posted updates as well (aha.org/COVID19).

COVID-19 Medicare Condition Codes. CMS recently clarified when to use the catastrophe/disaster-related modifier as well as the disaster-related condition code for Medicare claims submission. The resource includes a chart of when to use each code for waivers and flexibilities, and includes past code changes related to COVID-19 (go.cms. gov/2XNPEbx).

Action Step: Ensure you’re compliant if pharmacy is involved in testing or telehealth or any other incident to services that may be affected.

■

Choose the Amgen difference

HISTORY of reliable supply1

Be Aware of These Updates!

Local Coverage Determinations (LCDs): This recently published update on thrombolytic agents is well worth downloading. It covers all the requirements for getting paid for the agents in a clear, concise manner.

1. Billing and Coding: Thrombolytic Agents (A55237): go.cms.gov/3cOOWzf 2. LCD: Thrombolytic Agents (L35428): go.cms.gov/3cRDQt6.

Action Step: Download these two documents and determine whether your current procedures, computerized provider order entry and revenue cycle coding support the path to reimbursement.

Broad nationwide coverage:

88

%

of Medicare Part B lives3 and

of commercially insured patients pay $0 OOP costs per dose of Neulasta® Onpro®2,*

COVID-19 Resources FDA compenduim. The FDA has posted an online compendium page of COVID-19 resources for health care professionals, which it will regularly update. Information is categorized into emergency use authorizations, including investigational drug products/uses; personal protective equipment; and medical products. Fraudulent devices are addressed as well (bit.ly/3fbtpCl).

New COVID-19 FAQs on Medicare Fee-for-Service Billing. CMS released additional FAQs on recent COVID-19– related waivers to help providers,

100% 93%

*Data based on quarterly SHS medical claims data of 20,862 commercial medical claims collected at the national level between January 2017 and December 2017. Physician service claims and hospital claims were included in this analysis. Neulasta® OOP is calculated using the sum of deductible, V «>Þ] > ` V ÃÕÀ> Vi >vÌiÀ Ì i w > «>ÞiÀ has paid their share of the cost. Each claim represents a single dose of Neulasta®.2

v V iÀV > Li iwÌ Ûià V ÛiÀi`3

Learn more about Neulasta® Onpro® by visiting Ì i vwV > ÜiLÃ Ìi\ www.neulastahcp.com References: 1. Data on file, Amgen; [1]; 2018. 2. Data on file, Amgen; [1]; 2019. 3. Data on file, Amgen; [2]; 2019.

OOP, out of pocket; SHS, Symphony Health Solutions.

© 2019 Amgen Inc. All rights reserved.

USA-003-80525 08/19

22 Policy

Pharmacy Practice News • July 2020

Waste Management

Safe Disposal in the COVID-19 Era C

hallenges persist in managing waste for hospitals treating COVID-19 patients and aiming to limit the spread of the virus.

Institutions must now complete more steps on-site to safely collect, prepare and dispose of regulated medical and

hazardous waste and sharps, while simultaneously protecting workers and the public, according to agency, state and waste hauler guidelines. These recommendations could change further as COVID-19 cases continue in hot spots throughout the United States and

personal protective equipment nt (PPE) remains in short supply. “‘How do I dispose of (fill ll in the blank) from a COVID-19 patient?’ nt?’ is the single question I’ve been asked ked most on waste management during this pandemic,” said Cara Simaga, thee director

Best Practices for Waste During a Pandemic

T

he challenges of COVID-19-related waste management led Stericycle to reinforce best practices and add temporary changes to its Packaging Guidelines and Waste Acceptance Policies. The revisions include: • Hospitals must line shipping containers with red bags for regulated medical waste, and close and tie bags with a knot. This Department of Transportation regulation protects workers who open these containers to recycle cardboard or place tubs into the tub washer for reuse. Also, stay under the 50-pound limit per container for safe loading (exceptions are roll-up boxes or carts), and double-bag and absorb or solidify all liquid waste.

• Stericyle drivers won’t accept improperly packaged waste for pickup or assist in packaging it. All containers must be properly labeled, closed and ready for removal, with no red bags visible. Nonconforming waste discovered at the facility will be returned to the hospital or redirected elsewhere for disposal.

• Hospitals that don’t want to sign shipping documents can have the drivers print “Generator refused to sign COVID-19,” sign and date their section, and leave a copy for the hospital’s file.

• Stericycle technicians don’t service sharps or comingled sharps and pharmaceutical containers in any hospital isolation rooms, regardless of airborne, droplet or contact precautions taken. Instead, Stericycle provides sufficient containers for hospital staff to put clean ones in patient rooms, removing the used ones and putting them in carts for pickup. “We believe it is prudent to limit the number of people that enter such rooms to limit disease

•

•

•

•

•

spread and preserve scarce PPE,” said Cara Simaga, maga, e. the director of government affairs at Stericycle. efore Service technicians check with nursing stations before reatservicing a department to learn if there are any treatD-19. ment areas they shouldn’t enter because of COVID-19. ste Don’t place other waste types besides solid waste into red bags or sharps containers. Other typess iof waste could pose danger to workers. “Chemiders cal waste, batteries, aerosol cans and gas cylinders pcould react dangerously in our processing equipon ment. We cannot accept [Resource Conservation active and Recovery Act] hazardous waste and radioactive waste at our regulated medical waste facilities,”” said Ms. Simaga, noting y of that other Stericycle divisions can handle many these wastes. s.

Don’t place pharmaceutical waste into red bags.

Continue to use blue and black pharmaceutical waste containers for that service. nRegulated medical waste and sharps should continue to be autoclaved. Incineration is needed only e and for pathology waste, trace chemotherapy waste dical nonhazardous pharmaceutical waste. Once medical waste is treated, it can still be landfilled or sent to waste-to-energy sites.

Stericycle has established a business continuity plan to ensure ongoing services, and centrally commu-nicates COVID-19 updates to health care facilities via its Knowledge Center (see main article).

—A.H.

The sources reported no relevant financial relationships.

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COMPOUNDING HEALTH™

of government affairs at Stericycle, in a webinar she hosted with Selin Hoboy, the company’s vice president of government affairs and compliance.

Ms. Simaga assured listeners that “[generally, if you put waste] in the red bag before COVID-19, it still goes in the red bag today. If you put waste in the trash before COVID-19, it can still go in the trash today …. If you put something in a pharmaceutical waste container before COVID-19, it will still go there today.” Yet, she and Ms. Hoboy also characterized this pandemic period as a dynamic one,

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with process changes possibly ahead as scientists uncover new disease insights.

On one hand, Ms. Hoboy explained, the “enveloped virus is easily destroyed with normal disinfection procedures and typical waste treatment methods we use today. It is spread by close contact, so [social distancing is key].” On the other hand, SARS-CoV-2’s highly contagious nature and surface-sticking ability make waste management risky. The COVID-19 virus remains viable in aerosols for three hours, on plastic and steel for 48 to 72 hours, on cardboard for less than 24 hours, and on copper less than four hours (N Engl J Med 2020;382:1564-1567).

Stericycle imposed safety changes despite the CDC’s position that “medical waste (trash) coming from health care facilities treating COVID-19 patients is no different than waste coming from facilities without COVID-19 patients,” and despite a lack of federal guidance on managing regulated medical waste (sidebar).

Instead, “there’s a patchwork of regulations we must follow on a stateby-state basis,” said Ms. Hoboy, who urged those involved in waste management to “check regularly because [the

Policy

Pharmacy Practice News • July 2020

23

Waste Management regulations] might be changing.” Those tweaks, she said, might provide “regulatory relief, enforcement discretion, or fast-tracking medical waste generator registrations or waiving fees.”

Ms. Hoboy steered

‘There’s a patchwork of regulations we must follow on a state-by-state basis.

Check regularly because they might be changing.’

—Selin Hoboy

updated sources for the latest policies and recommendations.

She shared Knowledge Center links from the CDC and the Occupational Safety and Health Administration on waste: bit.ly/3gtPUnv; bit.ly/2ZKHYZe;

health care professionals, hospital safety directors and administrators toward state health department websites, the Healthcare Waste Institute of the National Association for Healthcare Waste Companies, and Stericycle’s own Knowledge Center (www. stericycle.com/knowledgecenter) as reliable,

bit.ly/2B2nwsj; and bit.ly/2yDbAfM. For further CDC/EPA guidance, visit bit.ly/3gxJEv2.

“Having managed Ebola in 2014, I’ve never seen anything of this magnitude.

We certainly are in an unprecedented

time,” Ms. Hoboy said. Actual direct waste from COVID-19 patients is “minimal,” with less blood and bodily fluids than during the Ebola outbreak, but there is “a lot more PPE and other solid waste generated” in hospitals as well as at pop-up testing sites, clinics, patient triage areas and quarantine sites in unconventional settings.

—Al Heller The sources reported no relevant financial relationships.

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24 Policy

Safe Handling

NIOSH 2020: Big Changes Are Afoot!

Charlotte A. Smith, RPh, MS Senior Regulatory Advisor

Kathleen Skibinski, RPh, MS Manager, Regulatory and Compliance

Monica Livingston Senior Implementation Manager PharmEcology Services Waste Management Sustainability Services Brookfield, Wis.

A

s of June 15, 2020, the National Institute for Occupational Safety and Health (NIOSH) has received 23 separate comments on its much-awaited waited document, “NIOSH List of Hazardous ardous Drugs in Healthcare Settings, 2020.”

The comments range from short paragraphs to relatively lengthy entries. s. The NIOSH document was published in the Federal Register May 1 (bit.ly/2UYrFoq). rFoq).

Some of the comments address ss one or two areas of concern, whereas others include a variety of suggestions, clarifications, opposing viewpoints and simple grammatical revisions. More feedback back is coming: At press time, NIOSH extended ended the comment period to 90 days, ending nding July 30, 2020.

Before delving into the comments, s, let’s review the key documents involved. ed. In addition to the NIOSH list, the Federal Register announcement also included cluded the “Procedures for Developingg the NIOSH List of Hazardous Drugs ugs in Healthcare Settings” (bit.ly/3fVXdDv).

Dv).

Of more practical importance to the health care community is an n 87-page document titled “Managging Hazardous Drug Exposures: Information for Healthcare Settings,” which can be accessed in the online version of the Federal Register under “Enhanced content” (bit.ly/2Z20iLd). Your safe handling team should become familiar with the key changes that NIOSH made in these various documents. Here are a few highlights.

Guidance on Engineering Controls

Serving managed care health-system and specialty pharmacy decision makers SpecialtyPharmContinuum

@SpecialtyPharm

Pharmacy Practice News • July 2020

In the NIOSH 2016 list, Table 5 provided valuable guidance in terms of when specific levels of engineering controls, personal protective equipment (PPE) and so forth should be used. However, there were gaps that health care facilities had to navigate on their own to develop and implement a risk management plan. The new document on managing hazardous drug exposures goes into much greater detail regarding the process of evaluating potential exposures, and assessing and mitigating risk, through the hierarchy of controls: elimination, substitution, engineering controls, administrative controls and PPE. These steps are summarized in

a more robust table (yet still not representative of all handling scenarios) titled “Control Approaches for Safe Handling of Hazardous Drugs by Activity and Formulation” (bit.ly/3dudldy).

As part of the process of segregating the list itself from the implementation of safe handling practices, the “Procedures” document was created. This document describes in detail the processes and procedures used, including an evaluation of the molecular properties of the drug, which may prevent absorption absorp ption through g routes other than deliberate injection. The NIOSH defini-

NIOSH’s 5 Risk Management Elements 1. Elimination 2. Substitution 3. Engineering Controls 4. Administrative Controls 5. Personal Protective Equipment

tion also includes the restriction to only drugs that have been approved for use in humans by the FDA’s Center for Drug Evaluation and Research (CDER).

A footnote indicates that biological products, including vaccines, gene therapy and several others are not included because they are approved for use by the FDA’s Center for Biologic Evaluation and Research (CBER). A summary of the processes for identifying, screening, evaluating and reviewing drugs for placement on the list is provided in Figure 1 (page 21) of the document.

What They Had to Say Those highlights cover just a few of the changes contained in the new documents. For a more in-depth summary, see pharmacypracticenews.com (bit.ly/ 37WycoS). So, let’s move on to the public comments.

Regarding two questions asked about the NIOSH proposed list of hazardous drugs, there appeared to be agreement that 1) the generic name of the drug was the most useful unique ingredient

Policy

Pharmacy Practice News • July 2020

25

Safe Handling identifier, and 2) botulinum toxins should continue to be evaluated. In those comments was a recommendation that NIOSH should include biological drugs that are approved for use by the CBER, in addition to those approved by the CDER. As for more general comments, we’ve summarized and divided them into eight categories:.

1. Request for additional information or inclusion of information. These comments covered several areas, including a request for more detailed guidance in establishing an assessment of risk in nonacute practices—for example, when retail pharmacies reconstitute an oral liquid drug such as fluconazole. Additional guidance also was requested regarding the risk to an employee from crushing tablets in a hood relative to the risk to nurses from administration of that crushed dosage form. More evidence for PPE recommendations was requested, along with inclusion of DailyMed and Drug Bank as references.

2. Clarification of information. Questions were raised regarding some of the recommendations for PPE requirements, including the use of sleeve covers, closed system drug-transfer devices for subcutaneous/intramuscular administration, and PPE recommendations when withdrawing injections from a vial during administration. There also was a suggestion that an overt statement regarding the handling of “investigational drugs as hazardous drugs until adequate information becomes available to exclude them” should be included as a formal source of guidance 3. Discussion of information. Various suggestions about language used in describing the priming of IVs and current closed system drug-transfer device usage by nurses were made. There were additional suggestions to require the use of sterile gloves during sterile compounding. One commenter suggested that the PPE requirements should not apply for manufacturer-prepared kits that are selfadministered by the patient 4. Language suggestions. Several commenters provided alternative language in some areas, including engineering controls and compounding practices.

5. Statements. Concern was expressed that by including illustrations, the equipment featured was outdated or selection of a specific item demonstrated product bias. To address this concern, it was suggested that no pictures be included, as has been the case in the past. Another suggestion was to refer to the new ASTM (American Society for Testing and Materials) gown standard, which should be available by the end of June.

6. Omissions. The ommission of mitomycin and 5-fluorouracil in ophthalmology surgery and their concomitant risks were pointed out. Another commenter noted that a large group of relatively

new oral antineoplastics, although not cytotoxic, have manufacturers’ cautions but are not on the new list. And concern was raised by the NIOSH statement that a drug was not listed because there was insufficient toxicity information available. The concern is that this could lead to a drug being on the market that does pose a significant risk but has not been identified as such.

7. Consideration of placement of certain drugs on NIOSH’s list or assignment to specific tables. Several commenters were concerned that potential systemic side

effects upon injection for certain drugs were determining the listing, rather than the risks to employees from inhalation or skin contact. Several suggestions were made regarding moving some drugs from Table 1 to Table 2, including hormonal agents such as estrogens, gonadotropins and progestins. Another area of concern was the criteria used to determine reproductive risks, including black box warnings for ingestion as opposed to occupational risk, with divalproex and warfarin being called out relative to statins and angiotensin-converting enzyme inhibi-

tors, which are not listed.

8. Support for efforts. A very positive comment was made regarding radiopharmaceuticals continuing to be excluded from the list since their storage, handling and compounding are regulated by the U.S. Nuclear Regulatory Commission under very different circumstances and risks. General acknowledgment was made of the value the NIOSH documents bring to compliance efforts and the degree to which they are relied upon by health care professionals to ensure a safe working environment.

■

26 Clinical

Pharmacy Practice News • July 2020

Review Article

Best Practices for Monitoring Hazardous Drug Surface Contamination A Guidance for Health Care Institutions KATHERINE SARNA, PHARMD, BCPS Clinical Assistant Professor University of Illinois at Chicago College of Pharmacy Chicago, Illinois

O

ccupational exposure to hazardous chemicals affects an estimated 13 million workers in the United States, with upwards of 8 million US health care personnel in clinical and

nonclinical roles potentially exposed to hazardous drugs (HDs).1,2

The characteristics of HDs, along with adverse health effects from workplace exposure, are well described in the literature.1,3 Several factors determine the likelihood and severity of harm caused by exposure to HDs, including the drug toxicity profile and formulation, workplace handling procedures, and routes of exposure.1 Dermal contact is a critical route of exposure to hazardous chemicals, including HDs, in the workplace, because substances may remain unnoticed on work surfaces for extended periods.2,4 Contact dermatitis constitutes the vast majority of all cases of occupational skin disorders, with estimated annual costs exceeding $1 billion.2

There are no established minimum or safe HD exposure limits.1 Therefore, those who come into contact with HDs are required to follow strict precautions. Numerous federal agencies and professional organizations have published recommendations and guidelines to control occupational exposure to HDs (Table 1).1,3,5-11 Most recently, the CDC and National Institute for Occupational Safety and Health released a draft publication summarizing risk management information pertinent to HD management in health care settings; the finalized document will be posted after the period for public comment ends.1 (See related article, page 24.)

Collectively, available guidelines and

Table 1. Publications Presenting Best Practices In Hazardous Drug Management1,3,5-11 • CDC/NIOSH: Managing Hazardous Drug Exposures: Information for Healthcare Settings (Draft, 2020)1 • ASCO Safe Handling of Hazardous Drugs: ASCO Standards (2019)5 • ONS/HOPA Ensuring Health Care Worker Safety When Handling Hazardous Drugs (2019)6 • USP General Chapter <800> (2019)7 • ASHP Guidelines on Handling Hazardous Drugs (2018)8

recommendations have been adopted by state and federal enforcement agencies and are used by health care facilities to create policies and procedures to mitigate occupational risk associated with HD handling.

Along with a positive safety culture within the organization, effective HD risk management includes hazard identification, exposure assessment, risk assessment, and risk management.1 Periodic monitoring of the effectiveness of risk management efforts also is paramount.

Unfortunately, not all aspects of HD management are explicitly described in published standards to allow for standardization. Particularly in the arena of risk management, best practices concerning surface contamination monitoring are limited.

This paper summarizes best practices related to monitoring workplace surface contamination, with a focus on surface wipe sampling for HDs. An upcoming 2020 consensus conference that plans to provide more detailed guidance for HD surface contamination monitoring also is introduced. A publication summarizing recommendations from this conference is planned for early 2021.

• ONS Safe Handling of Hazardous Drugs (2017)9 • OSHA Technical Manual: Controlling Occupational Exposure to Hazardous Drugs (2016)10 • USP General Chapter <797> (2008)11 • NIOSH Alert: Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs (2004; hazardous drug list is updated every 2 y)3 ASCO, American Society of Clinical Oncology; CDC, Centers for Disease Control and Prevention; HOPA, Hematology/Oncology Pharmacy Association; NIOSH, National Institute for Occupational Safety and Health; ONS, Oncology Nursing Society; OSHA, Occupational Safety and Health Administration; USP, United States Pharmacopeia.

Surface Contamination Numerous studies in the last 30 years have demonstrated widespread HD contamination of workplace surfaces in national and international health care facilities.3,8,10,12-14 Using wipe samples, investigators have detected measurable concentrations of HDs—notably cyclophosphamide, cytarabine, fluorouracil, ifosfamide, methotrexate, and paclitaxel—on

surfaces within and adjacent to the pharmacy, in patient care areas, and in other locations. Common surfaces that contain HD residue include drug vials, biological safety cabinets and isolators, worktops, floors, storage areas, and tables and chairs.3,12,13 Overall, these studies indicate that the potential for accidental dermal exposure to HDs in the workplace continues to be an issue, and warrants the development of practice standards aimed at preventing occupational exposure.14

Controlling Exposure Table 2 summarizes administrative and engineering controls used to control HD surface contamination in the workplace.1 Both engineering and administrative controls, along with personal protective equipment (PPE), are recommended as part of a risk management plan to protect health care workers from HD exposure.1,3,7 Details regarding these controls are described in other publications.1,7 Briefly, engineering controls isolate workers from HDs, usually by physical barriers, whereas administrative controls rely on workers who handle HDs to follow workplace practices intended to minimize exposure.1 Because engineering controls generally require minimal or no effort by health care workers to be effective, they are preferred to administrative controls whenever possible. However, engineering controls have more significant up-front costs.

Other methods for controlling HD exposure, such as physical removal or replacement of the HD, are highly

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Review Article

effective but difficult to implement in existing processes without major changes in equipment and procedures.1 Furthermore, because HDs usually cannot be eliminated or substituted for, reducing occupational exposure to these agents is a critical component of decreasing adverse health effects in health care workers.

The application of administrative and engineering controls reduces, but does not completely eliminate, HD exposure in the workplace.7,8,10 Therefore, implementing methods to monitor workplace surface contamination is prudent when creating and evaluating institutional policies and procedures that are intended to minimize occupational risk.1 Because occupational exposure limits are not available to guide safe levels of HD exposure based on health effects, following an ALARA (as low as reasonably achievable) approach similar to that used for radiation exposure has been suggested.1,8,15

at evaluating work practices, engineering controls, and PPE.1,15 As previously noted, wipe sampling has been used extensively in studies evaluating locations of HD residue in health care facilities.3,16 Unfortunately, published data supporting regular wipe sampling for decreasing HD surface contamination are scarce. In the 2013 MEWIP (Monitoring-Effect Study of Wipe Sampling in Pharmacies) study, 130 pharmacies in Germany were randomly assigned to 1 of 2 surface wipe sampling plans.17 The test group conducted wipe sampling at 3-month intervals for 5 cycles, while the control group only conducted sampling at the beginning and end of the investigation. The wipe samples across both groups were from similar locations throughout the pharmacy, and 774 of 1,269 samples (61%) were positive for HD residue.

An important finding in this study was the consistent decrease in surface contamination observed in the group that performed regular wipe sampling; there was a 13% reduction in contaminated samples between first and fifth cycles compared with no change between sample 1 and 2 in the control group.

A more recent study retrospectively analyzed 5,842 individual surface wipe samples from 338 pharmacies, mostly in the United States, over 6 years.18 Approximately 40% of sites performed more than 1 wipe sample during this time.

Results showed that, depending on the specific location and surface tested, between 3.94% and 25.96% of samples had high levels of HD contamination. Furthermore, overall HD contamination was lowered with repeat wipe sampling; 45.24% of samples detected HDs with the first wipe compared with 31.64% for subsequent wipes. Since contamination was not completely eliminated even with repeated sampling, the authors suggested that continued monitoring is required to minimize exposure.

Surface Wipe Sampling Surface wipe sampling, along with wipe sample analysis, is the method of choice for identifying and determining the level of workplace surface contamination where hazardous chemicals such as lead, asbestos, pesticides, and antineoplastics are handled.8,16 Although this method does not directly measure workers’ exposure to hazardous substances, the information provided is helpful in identifying contaminated surfaces that may contribute to accidental dermal exposure. Therefore, surface wipe sampling can be used as part of a quality assurance program aimed

Sampling Procedure Best practices concerning surface wipe sampling for HDs are limited and lack detail to allow for standardization.15,19,20 Therefore, there is considerable variation in how sampling is performed and how results are reported.16 The following information provides an overview of sampling methods specifically for HDs. Wipe sampling begins by choosing a surface area and determining whether the drugs of concern can be identified with an available test kit or analytical method.15,16 Commonly assayed drugs include

Table 2. Administrative and Engineering Controls To Minimize HD Exposure1 Administrative Controls

Engineering Controls

• Education and training

Primary controls

• Limiting access to areas containing HDs

• Biological safety cabinets

• Limiting the time workers handle HDs • Good housekeeping practices (cleaning, etc) • Handwashing before and after handling HDs • Continuous monitoring of compliance with workplace practices

• Compounding aseptic containment isolators

Secondary controls • Proper ventilation and negative pressure rooms

Supplemental controls (to be used in combination with primary engineering controls) • Closed system drug-transfer devices • Robotic drug preparation system • Needleless systems

HD, hazardous drug

Table 3. Advantages and Disadvantages Of Analytical and Immunochemical Wipe Sample Analyses16 Test

Advantages

Disadvantages

Analytical

• Sensitive, specific, and accurate results

• Time-consuming and costly to complete

• Quantitative results

• Requirement for specially trained personnel to run analyses • Results take weeks to return • Equipment variations resulting in differences in lower limits of detection

Immunochemical using a LFIA

• Portable and easyto-use device

• Can only test for selected HDs

• Quick to run

• Qualitative results only

• Sensitive results that correlate well to analytical methods HD, hazardous drug; LFIA, lateral flow immunoassay

cyclophosphamide, ifosfamide, methotrexate, fluorouracil, and platinum-based antineoplastic agents.

Next, a suitable solvent is applied either directly to the surface to be sampled or to the sampling material (swabs, etc). The surface then is wiped in one direction followed by wiping perpendicular to that direction. The size of the areas sampled generally range from 100 to 500 cm2, and a supplementary sample can be taken from the same location using a second wipe to ensure a better recovery. Once the sample has been collected, the next steps are determined by whether an analytical or immunochemical technique is employed for detecting

HDs. The advantages and disadvantages of each of these technologies are summarized in Table 3.16

Detection Using Analytical Methods Conventional analytical methods require that wipe samples are placed in labeled containers and shipped to a laboratory for analysis.16 The most common analytical method for detecting HDs includes high-performance liquid chromatography and in combination with mass spectrometry (MS). Other methods used in combination with MS or tandem MS include gas chromatography and ultra-high-performance see HD BEST PRACTICES, page 28

28 Clinical

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Review Article

HD BEST PRACTICES continued from page 27

liquid chromatography; inductively coupled plasma MS has been used to detect platinum compounds. Few laboratories in the United States can perform these analyses; therefore, there is a significant lag time between sending samples and obtaining results using analytical methods for HD detection. The delay in obtaining results also means that HD residue may remain on work surfaces for extended periods of time before decontamination is initiated.

Table 4. Barriers to Implementation 0f Wipe Sampling Plans for HDs7,15,22 • Lack of regulatory requirements • Incomplete guidance concerning sampling methodology • Time and/or cost associated with available sampling methods • Limitations of HD panels in available test kits • A lack of certifying agencies for vendors of wipe sample kits • Uncertain effectiveness of a specific number or size of wipe samples in determining levels of HD contamination • Unknown acceptable limits, if any, for HD surface contamination • Lack of experience by sampling personnel HD, hazardous drug

Detection Using Immunochemical Techniques A novel strategy that allows for on-site detection of HD residue on work surfaces involves immunochemical techniques.16 Unlike analytical analyses that require complex laboratory equipment and specially trained personnel, immunochemical techniques employ competitive lateral flow immunoassay (LFIA) technology, similar to that found in point-of-care tests, to detect the presence of HDs through antibody interactions quickly and easily. The BD HD Check system is the only rapid HD detection system on the market to use competitive LFIA technology, according to BD (bit.ly/ 2YHZ3Rx). The system contains a template to place over the testing location, a collection kit that includes a swab used to collect the sample, assay cartridges to hold the sample, and an analyzer to test the sample. A positive or negative result (ie, the HD is or is not present at a level above the detection threshold) can be obtained in less than 10 minutes, allowing for immediate corrective action against surface contamination. Cyclophosphamide, doxorubicin, and methotrexate are the only HDs that can be detected using the BD HD Check system, according to the company.

Creating and Implementing An HD Wipe Sampling Plan Surface wipe sampling procedures are recommended for all facilities that manage HDs as part of a comprehensive HD risk management plan.6-8,11,21 General considerations for creating an HD wipe sampling plan have been published, but lack detailed sampling procedures (number of wipe samples, etc) and application of available technologies.15,19,20,22 Health care institutions should consider the HDs their workers are handling when choosing a wipe sampling kit.7 A robust wipe sampling plan may include a combination of

Table 5. Development of Hazardous Drug Surface Contamination Monitoring Guidelines: 2020 Conference Objectives • To understand other health care disciplines’ standards and best practices for the handling of hazardous substances within their respective practices, which may have applicability to hazardous drug surface contamination monitoring • To understand the current state of hazardous drug surface contamination monitoring within the medication-use system for all dosage forms across all patient care sites • To assess the capabilities, current utilization, benefits, and challenges of commercially available surface contamination monitoring technologies and systems • To promulgate best-practice recommendations for the monitoring of hazardous drug surface contamination • To produce a conference consensus statement on the topic of hazardous drug surface contamination monitoring, suitable for publication in an appropriate peer-reviewed journal

sampling techniques, such as frequent LFIA analyses for continuous monitoring and periodic quantitative analytical measurements for more comprehensive information related to surface contamination.23 There are no certifying agencies for vendors of HD wipe sample kits; however, suggested questions for institutions when considering a vendor have been published in a previous issue of Pharmacy Practice News.21 USP General Chapters <797> and <800> recommend routine wipe sampling, including assessments at baseline and at least every 6 months thereafter.7,11 USP provides

recommended locations for sampling that include multiple locations in pharmacy, nursing, and patient care areas where HDs are received, prepared, stored, and administered.

Sampling worker PPE also may be considered in light of data showing HD contamination on the gloves of nurses and pharmacists.13 More frequent monitoring (eg, monthly) and rotation of wipe sample sites have been implemented by some institutions.21 If contamination is found using wipe sampling, a designated person should identify, document, and contain the cause of contamination.7

Corrective action may include thorough deactivation, decontamination, cleaning, and improvement of administrative and engineering controls.

To validate that corrective actions have been effective, wipe sampling should be repeated. The use of LFIA for detection of remaining HD residue may be particularly beneficial for this purpose.23

Addressing Implementation Challenges Widespread implementation of wipe sampling protocols has been slow in US and international health care facilities. 22,24 Table 4 summarizes some of the known barriers to implementation of sampling plans.7,15,22 To address some of the knowledge gaps in this arena, a formal consensus conference (Safe to Touch) has been planned for October 2020 in Chicago, Illinois, with the purpose of providing guidance for HD surface contamination monitoring. The conference was planned in cooperation with a multidisciplinary group of nursing and pharmacy experts in the field of oncology, medication safety, and hazardous materials environmental testing, and is supported by Visante Inc. Table 5 lists the objectives of this conference.

Conclusion An effective HD risk management plan can reduce occupational exposure to HDs and related adverse health outcomes.1 Administrative and engineering controls and PPE have demonstrated effectiveness in reducing HD exposure; however, these strategies do not completely eliminate risk. Therefore, the implementation of processes to assess workplace surface contamination are critical to identifying and minimizing occupational risk. Wipe sampling is the preferred method to identify the need for, and effectiveness of, available controls and what type of PPE is required while handling HDs.8,15 Newer immunochemical techniques, while currently limited in scope, have provided an opportunity for more timely and less costly measurements of surface contamination compared with traditional analytical techniques.16 The creation of wipe sampling protocols that incorporate these newer technologies has been encouraged by professional organizations, although uptake has been limited due to knowledge gaps and lack of detailed guidance.21,22,24 A formal consensus conference has been planned to harmonize available recommendations and provide detailed guidance for HD surface contamination monitoring.

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Review Article References 1.

Hodson L, Ovesen J, Couch J, et al. Managing hazardous drug exposures: information for healthcare settings. Department of Health and Human Services, CDC, National Institute for Occupational Safety and Health. www.regulations.gov/ document?D=CDC-2020-0046-0004.

May 1, 2020. Accessed June 12, 2020.

2. CDC. Skin exposures & effects. www.cdc. gov/niosh/topics/skin/default.html.

July 2, 2013. Accessed June 12, 2020.

3. CDC. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. www.cdc.gov/ niosh/docs/2004-165. September 2004.

Accessed June 12, 2020.

4. US Department of Labor, Occupational Safety and Health Administration.

Dermal exposure. www.osha.gov/SLTC/ dermalexposure/index.html. Accessed June 12, 2020.

5. Celano P, Fausel CA, Kennedy EB, et al.

Safe handling of hazardous drugs: ASCO standards. J Clin Oncol. 2019;37(7):598-609.

6. Oncology Nursing Society. Ensuring healthcare worker safety when handling hazardous drugs. Joint position statement from the Oncology Nursing Society and the Hematology/Oncology Pharmacy Association. www.ons.org/ make-difference/ons-center-advocacyand-health-policy/position-statements/ ensuring-healthcare. July 2019. Accessed June 12, 2020.

7. USP. USP General Chapter <800> Hazardous Drugs—Handling in Healthcare Settings. www.usp.org/compounding/ general-chapter-hazardous-drugshandling-healthcare. December 1, 2019.

Accessed June 12, 2020.

8. Power LA, Coyne JW. ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm. 2018;75(24):1996-2031.

9. Polovich M, Olson MM, eds. Safe Handling of Hazardous Drugs. 3rd ed. Oncology Nursing Society; 2017.

10. US Department of Labor, Occupational Safety and Health Administration. OSHA Technical Manual. Controlling occupational exposure to hazardous drugs. www.osha. gov/SLTC/hazardousdrugs/controlling_ occex_hazardousdrugs.html. February 1, 2016. Accessed June 12, 2020.

11. USP. USP General Chapter <797> Pharmaceutical Compounding—Sterile Preparations. www.usp.org/compounding/ general-chapter-797. Updated 2008.

Accessed June 12, 2020.

12. Davis J, McLauchlan R, Connor TH. Exposure to hazardous drugs in healthcare: an issue that will not go away.

J Oncol Pharm Pract. 2011;17(1):9-13.

13. Call E, Bill B, McLean C, et al. Hazardous drug contamination of drug preparation devices and staff: a contamination study simulating the use of chemotherapy drugs in a clinical setting. Hosp Pharm.

2017;52(8):551-558.

14. Marie P, Christophe C, Manon R, et al.

Environmental monitoring by surface sampling for cytotoxics: a review. Environ Monit Assess. 2017;189(2):52.

15. Connor TH, Zock MD, Snow AH. Surface wipe sampling for antineoplastic (chemotherapy) and other hazardous drug residue in healthcare settings: methodology and recommendations. J Occup Environ Hyg. 2016;13(9):658-667.

16. Connor TH, Smith JP. New approaches to wipe sampling methods for antineoplastic and other HDs in healthcare settings.

Pharm Technol Hosp Pharm. 2016;1(3): 107-114.

17. Kiffmeyer TK, Tuerk J, Hahn M, et al.

Application and assessment of a regular environmental monitoring of the antineoplastic drug contamination level in pharmacies - the MEWIP project. Ann Occup Hyg. 2013;57(4):444-455.

18. Salch SA, Zamboni WC, Zamboni BA, et al.

Patterns and characteristics associated with surface contamination of hazardous drugs in hospital pharmacies. Am J Health Syst Pharm. 2019;76(9):591-598.

19. US Department of Labor, Occupational Safety and Health Administration.

Evaluation guidelines for surface sampling methods. www.osha.gov/dts/sltc/methods/ surfacesampling/surfacesampling.html.

2001. Accessed June 12, 2020.

20. US Department of Labor, Occupational Safety and Health Administration. OSHA Technical Manual. Section II: chapter 2.

Surface contaminants, skin exposure, biological monitoring and other analyses. www.osha.gov/dts/osta/otm/otm_ii/ otm_ii_2.html#:~:text=Biological%20 monitoring%20results%20can%20 be,chemical%20of%20concern%20has%20 occurred. Updated February 14, 2007.

Accessed June 12, 2020.

21. Shaw G. Making a plan for surface wipe sampling. Pharmacy Practice News. www.pharmacypracticenews.com/ Operations-Management/Article/04-20/ Making-a-Plan-for-Surface-WipeSampling/58126?ses=ogst. May 5, 2020.

Accessed June 12, 2020.

22. Engel J. Implement an HD wipe sampling program. Pharmacy Purchasing & Products. 2018;15(11):26. www.pppmag. com/article/2314. Accessed June 12, 2020.

23. Peeples L. The hunt for hazardous drug residues: surface wipe sampling a part of USP <800>. Pharmacy Practice News. www.pharmacypracticenews.com/Policy/ Article/02-19/The-Hunt-for-HazardousResidues/54003. February 14, 2019.

Accessed June 12, 2020.

24. Mathias PI, MacKenzie BA, Toennis CA, et al. Survey of guidelines and current practices for safe handling of antineoplastic and other hazardous drugs used in 24 countries. J Oncol Pharm Pract.

2019;25(1):148-162.

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30 Operations & Management

Pharmacy Practice News • July 2020

Finance

Many U.S. Hospitals Already in the Red—Then COVID-19 Hit

C

OVID-19 has created a financial crisis for many U.S. hospitals, with no easy way out.

The math is simple: During the pandemic, hospitals lost a huge source of revenue from elective surgeries while experiencing a dramatic uptick in costs, as facilities purchase more gear to cope with the surge of infected patients, some of whom are uninsured.

“They are increasing unanticipated

costs and decreasing any revenue you have to offset it,” said Halee Fischer-Wright, MD, the president and CEO of the Medical Group Management Association, one of the marquis health care associations in the United States. “I think this is the definition of the perfect storm.”

Although the federal government has taken some early actions to flood the health care system with financial relief, experts worry about the long term.

“No hospital is going to come through this unscathed,” said Jacqueline Barton True, MSW, MPH, the vice president of rural health programs at the Washington State Hospital Association.

“I have a lot of concern about our ability to weather this financial crisis, and what we look like on the other side. I think it is very possible that without significant help from the federal government, there will be closures.”

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Bad Timing Even before COVID-19 hit, many hospitals were struggling, particularly those in rural areas. According to a February 2020 report from the Chartis Center for Rural Health, 19 rural hospitals had to shut their doors in 2019, the largest number of closures in a year since tracking began in 2010. The analysis identified more than 450 additional facilities in rural areas that are at risk for closure.

One of the hardest-hit states is Texas, where 20 rural hospitals have been forced to shut down since 2010, and 50% of the remaining facilities are vulnerable to closure, according to the Chartis report. Thankfully, small and rural facilities in the state haven’t been hit by a surge of COVID-19 patients and some elective surgeries are starting to resume, but they lost a huge source of income from the prolonged pause on those procedures, as well as the usual influx of post-acute care from larger urban facilities, according to Nancy Dickey, MD, the executive director of the Texas A&M Rural and Community Health Institute.

“Many rural facilities are, in fact, extraordinarily challenged right now,” she said.

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Operations & Management

Pharmacy Practice News • July 2020

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Ambulatory Care

TOC Pharm continued from page 1

are young and relatively healthy and may not have been to a physician in years.

Some research indicates including pharmacists in care transitions makes a difference. A 2015 study (J Manag Care Spec Pharm 2015;21[3]:256-260) showed that patients discharged from the hospital who had follow-up clinic appointments with a multidisciplinary team coordinated by a clinical pharmacist practitioner were significantly less likely to be readmitted within 30 days than discharged patients whose follow-up team consisted solely of physicians (14.3% vs. 34.3%; P=0.010).

Starting in the ED Transitions of care at AHN can take on different forms. At the end of March, as the pandemic began to take hold, the network asked ambulatory care pharmacists led by Dr. Korczynski, who is the manager of clinical services, pharmacy–ambulatory care, to join the network’s COVID ED decompression service. As part of the program, nurses and social workers call patients after they’ve left the emergency room or hospital; if patients have questions about their medications, the providers refer them to one of two members of Dr. Korczynski’s team of pharmacists: Gina Lee, PharmD, or Kara Stiely, PharmD, both in the AHN ambulatory pharmacy residency program. Since March 23, he estimated that both pharmacists have reached out to roughly a dozen patients.

A Larger Effort The COVID-19 TOC program at Dignity Health Northridge Hospital Medical Center in Northridge, Calif., has a much bigger scope. Pharmacists follow COVID-19 patients discharged from the hospital and those diagnosed during drive-thru testing at Northridge’s testing location. Northridge TOC nurse practitioners, physicians and pharmacists have called hundreds of COVID-19 patients since the pandemic began. The pharmacists check in at least once per week for up to 30 days to ensure patients understand their medications, and recommend over-the-counter medications for symptom management. The pharmacists also ensure patients leave with the proper tools to monitor their symptoms, such as a thermometer, pulse oximeter and blood pressure monitor.

What’s more, the transitional care pharmacists help nurse practitioners and medical residents administer COVID-19 tests at the hospital’s drive-thru testing.

Much of what TOC pharmacists provide is education, said Jasmen Esfandi, PharmD, a Northridge team member.

Patients have lots of questions about how to successfully quarantine themselves and engage in social distancing, she said, as well as protect their loved ones. Many

didn’t even know the safest way to get groceries. This is not something many pharmacists were trained to do, Dr. Esfandi said, but they can do it. “We saw the demand and we saw the need, and we redesigned our [approach] to accommodate our community.”

In the pandemic’s early stages, AHN also saw a need for patient education and met it, said Dr. Korczynski, adding that the team used this outreach to reduce the burden on primary care offices. “Patients in the early stages of the lockdown were captive and willing to engage with the pharmacy team,” he said. “If they’re engaging with us, then they’re not calling the doctor’s office.”

Some COVID-19 patients may receive medications they’ve never heard of, and will have questions on how to get them, take them and integrate them into their existing regimen. Pharmacists can help patients with such questions, Dr. Esfandi noted. They also can help patients manage existing chronic conditions, which “often get overlooked” while they’re battling the coronavirus, she added.

Care transition teams are used to managing complex disease states, but COVID-19 is not like other chronic diseases, noted Casey Barbiera, RN, MSN, the senior director of acute rehabilitation, transitional and palliative care, diabetes and pain management at Dignity Health.

So much about the new virus remains elusive. Although COVID-19 initially presented as a respiratory disease, patients are now testing positive with just a rash or intestinal symptoms, she noted. “The biggest challenge is managing the unknown,” she stressed. “We live in a world where we like to be really concrete when we give patients instructions. With COVID-19, there’s somewhat of a gray area and we have to navigate around that.”

Still, some of the TOC struggles that arise with COVID-19 match those of other chronic diseases, such as poor patient compliance with follow-up visits. Up to one-fourth of patients who request an appointment for testing at Northridge’s testing location don’t show up, and a handful who came and tested positive provided incorrect contact information, so pharmacists and other team members struggle to reach them to let them know they are infected, Ms. Barbiera said. (For more challenges with pharmacist-assisted testing and follow-up, see article, page 32.)

Many COVID-19 patients are older and may have problems with using telecommunications or text messaging, which makes access to health information even more difficult, she said.

Like other transitional care patients, people infected with COVID-19 may have issues related to insurance coverage and paying for medications. “With almost every COVID patient, we were addressing access issues,” Dr. Korczynski said. “They are probably our No. 1 gap

Patients given follow-up clinic appointments coordinated by a clinical pharmacist had a

14.3% rate of 30-day hospital readmissions, versus

34.3% in patients without such care.

Source: J Manag Care Spec Pharm 2015;21[3]:256-260.

to close. Because if the patient can’t get their medicine, all bets are off.” Even if patients had adequate access to health care, in the early stages of the pandemic, many primary care offices were closed, leaving follow-up uncertain.

As for young, otherwise healthy patients such as the 22-year-old customer, they may not have felt the need to seek medical care before falling ill with a potentially deadly disease. So, before ending the call with the young patient, the AHN pharmacist connected him with a primary care provider who was part of the AHN network, at a practice with an embedded pharmacy resource to ensure he could continue receiving his medications. “This is always a challenge with transition of care,” Dr. Korczynski said. “Where does this patient go after they leave the hospital?”

Pharmacists are well suited to make sure that the primary care gap is closed and address any other concerns patients may have, said Dr. Fera, who mentors providers at Dignity Health Northridge as part of the A3 collaborative, an initiative that supports implementation of valuebased ambulatory pharmacy programs.

“Helping patients with COVID-19 is in the pharmacists’ wheelhouse. We have hugely stepped up to the plate with trying to navigate all the issues in medications related to COVID-19.”

—Alison McCook The sources reported no relevant financial relationships.

HHS rule furthers COVID-19 testing, but roadblocks remain.

See story, page 32

32 Operations & Management

Pharmacy Practice News • July 2020

Ambulatory Care

Reimbursement, PPE shortages remain barriers

Pharmacists Get Green Light for COVID-19 Testing T

o many Americans across the country, one sight has become increasingly familiar: a tent pitched outside a community pharmacy, advertising drive-thru testing for COVID-19. People who want to schedule an appointment often simply go to the retailer’s website and receive a time slot, with no doctor’s authorization required.

And yet, significant barriers remain to pharmacists’ ability to order and administer tests for COVID-19. At a time when experts say increased testing is one of the key components o off reopening reo openiing the country as safely as possible, pharmacy ossiblee, pha arm macyy groups—including those ose representing repressenttingg health-system pharmacy—are asking macy— —are ask kingg officials to make it easier to let this thiis highly skilled workforce screen patients ce scr reen p atieentts for the coronavirus.

On May 19, the Department Health artmen nt of Hea alth h and Human Services (HH (HHS) tried HS) tr ried d to o remove some of those existing barriers. existting ba arrie ierss.

The move came in thee form new m of a n ew w advisory opinion, which concluded ch h con ncludeed tthat haat the Public Readiness and Eme Emergency erg r encyy Preparedness (PREP) Act gives pharph harrmacists the ability to provide authorized rovidee autho horizzed d COVID-19 diagnostic ttests patients ests to p atieentss without a doctor’s supervision, preemptervisio on, preem mptting any state or local barriers.

HHS’s arrrierss. The HH HS’’s guidance “highlights the administraadmin inisttraation’s confidence in pharmacists proharmaacists tto op ro ovide expanded and widespread testing capacity in the United States,” said Eric Maroyka, PharmD, the senior director of the Center for Pharmacy Practice Advancement at ASHP. But the HHS advisory opinion did not address the major obstacle to pharmacists’ ability to test for COVID-19: reimbursement, noted Starlin HaydonGreatting, BSPharm, the director/owner of SHG Clinical Programming and Population Health, in Springfield, Ill. In too many states, the path to payment for pharmacists providing any aspect of diagnostic testing for COVID-19 is unclear and riddled with roadblocks, she said.

The new HHS missive may permit pharmacists to perform these services, but if they can’t cover the costs, what’s the point? “Billing and reimbursement are the No. 1 barrier for adding any of these services,” Dr. Haydon-Greatting said.

More Than 40 States on Board The HHS guidance clarified that pharmacists can, in theory, order and administer a diagnostic test for COVID-19, without involving a doctor or nurse practitioner. This is not unprecedented: According to the National Association of Chain Drug Stores (NACDS), more than 40 states have opened doors to pharmacists performing point-of-care

testing for several diseases, such as HIV, hepatitis C, flu and tuberculosis; in some of those states, pharmacists also can initiate treatments for certain conditions.

But when it comes to pharmacists and COVID-19 testing, it’s not full speed ahead. Similar to almost every other health care worker, pharmacists are limited by ongoing shortages of personal protective equipment (PPE). To collect a nasopharyngeal sample, for instance, pharmacists must wear a gown, nonsterile gloves, a protective mask (rated N95

extended wait times for the results—and the logistics of getting the results back to the patient—are another challenge in community pharmacist–coordinated COVID-19 testing and follow-up, she noted.

It’s not clear how that arrangement— collecting specimens and sending them to a lab versus actually administering and reading the tests—will play out for pharmacists in terms of reimbursement, Dr. Maroyka said. “Reimbursement for a specified test may be determined by

A new report commissioned

by America’s Health Insurance Plans estimates that

diagnostic testing for COVID-19 could cost up to

$25 billion per year.

or higher), and a face shield. Even the swabs used to collect samples have been in short supply. “There aren’t enough supplies in the system to provide all the COVID-19 testing supplies, and all the PPE supplies, for everybody to have everything,” Ms. Haydon-Greatting said.

“That’s a major limiting factor.”

Impediments From Medicare And Medicaid Then there’s the issue of payment.

A new report commissioned by the trade group America’s Health Insurance Plans estimates that diagnostic testing for COVID-19 could cost up to $25 billion per year. But Medicare won’t pay for COVID-19 diagnostic testing unless pharmacies enroll as a laboratory certified by the Clinical Laboratory Improvement Amendments. In many states, Medicaid won’t pay pharmacists for COVID-19 testing at all. Some chain pharmacy– and health-system pharmacy–run ambulatory care practices (see page 1) are offering testing, but pharmacists often do not administer the test or read the results, Ms. Haydon-Greatting said. Instead, they oversee self-administered tests, in which they train patients to take the nasopharyngeal sample themselves, and the specimen is sent to an external lab for processing. The

the requirements of the different payors and whether the payor requires processing and payment of the claim under the medical or prescription benefit,” he said.

Federal and state rules also can affect the billing process, and pharmacies need proper coding and billing infrastructure to receive reimbursement, he noted, as well as assurances of coverage for patients without adequate health insurance.

In the Health System Setting For some health-system pharmacists, the persistent barriers to ordering and conducting diagnostic tests for COVID-19 aren’t a big issue: As members of a hospital network, they likely have access to a laboratory that’s qualified to process the samples, and can bill through the hospital. Yet, few are doing it.

In a May ASHP survey of hospital pharmacists, only 1% of respondents said pharmacists are performing COVID-19 testing at their location. Another 9% are exploring adding this service. “We are not seeing much of this activity within health systems,” Dr. Maroyka said. In a hospital setting, most patients will likely be tested at their bedside or sent to the hospital-affiliated lab, he noted. “The capability and capacity of COVID-19 testing in hospital settings is largely an

interprofessional effort, and primary responsibility may be coordinated with the facility's laboratory services, which can support moderate- to high-complexity molecular and serological testing.”

If hospital pharmacists do expand testing for COVID-19, they could collect specimens in or outside a registered pharmacy, such as in an ambulatory care setting, and then send the specimen to a lab for analysis, Dr. Maroyka said. In states where pharmacists are allowed to read test results, that final step won’t be necessary, he added. “In some states, pharmacists may interpret and analyze COVID-19 or COVID-19 antibody test results and provide the results to patients, with appropriate guidance for follow-up care.”

Ideally, more states will move in that direction, loosening up the restrictions on diagnostic testing by pharmacists, said Kathleen Jaeger, BS Pharm, JD, the senior vice president of pharmacy care and patient advocacy at NACDS. “We mainly want to acknowledge the Department of Health and Human Services, and certainly Secretary Alex Azar, for expressing clearly the sense that pharmacists and pharmacies are critical for the deployment of COVID-19 testing,” she said. NACDS also appreciates the efforts that state governments are taking to make it even easier for pharmacists to provide COVID-19 testing, she added. “We are working directly with the federal and state governments on any barriers that persist.”

Other groups are also reaching out to lawmakers about remaining issues, including reimbursement, Dr. Maroyka said. “The pharmacy association partners, including ASHP, have been meeting with CMS [Centers for Medicare & Medicaid Services] and congressional staff to get clarity and make these payment pathways more clear, predictable and financially supportable as a business model.”

Hopefully, opening doors to participation in diagnostic testing for COVID-19 will also ease the way for pharmacists to pitch in with other looming health issues, such as ordering and administering diagnostic tests and treatments for seasonal flu, and providing vaccinations for COVID-19 when they become available, Dr. Maroyka said. “If allowed to test, treat and vaccinate, pharmacists can improve capability and capacity of response. Pharmacy fits as a patient educator and a connector to treatment within the broader health care system.”

—Alison McCook The sources reported no relevant financial relationships.

Read Pharmacy Practice News Anywhere, Anytime!

www.pharmacypracticenews.com

34 Operations & Management

Pharmacy Practice News • July 2020

Finance

IN THE RED continued from page 30

are generally older, have a lower socioeconomic status, and have more chronic diseases than people living in urban areas, according to a report from the Kaiser Family Foundation. What’s more, they are more likely to be uninsured, and that disparity will likely increase, Dr. Dickey said. “When people lose their jobs, they tend to lose their health insurance. So the number of people who are uninsured is probably going to go up across the country.”

“What we’re seeing now in this crisis is that 50% of our rural health care centers were already operating in the red. This is probably the thing that’s going to push them to close,” Dr. Fischer-Wright said.

Steven J. Martin, PharmD, the dean and a professor at the Rudolph H. Raabe College of Pharmacy, Ohio Northern University, in Ada, agreed that rural hospitals are facing unprecedented pressures as a result of the COVID-19 pandemic. But those pressures aren’t necessarily a function of treating COVID-19 patients. Due to stay-at-home orders, he explained, patients are unable to get to hospitals for elective procedures, and the facilities are unable to perform outpatient visits that generate revenue. As a result, “these critical access hospitals are struggling to survive,” he said.

If large numbers of critical access hospitals succumb to these pressures, the public health consequences could be dire, Dr. Martin stressed. The facilities “provide much-needed health services for large sections of the country,” he said. “Especially now, rural Americans need access to health care services in their communities.”

Bigger Is Sometimes Safer Even larger urban facilities are struggling, said Kerry McKean Kelly, the vice president of communications and member services at the New Jersey Hospital Association. Northern New Jersey has been a “true hot spot” in the nation for COVID-19 patients, and unexpected costs have risen substantially, as hospitals struggle to purchase more—and more expensive—personal protective equipment and add perdiem staff. “Both of those line items have increased significantly,” she noted. Although there now is a billing code for COVID-19, “I don’t think anybody fully understands reimbursement for those patients,” Ms. Kelly said. “Right now, hospitals are just providing the care.”

According to one estimate, each infection results in a median of $3,045 direct medical costs (Health Aff 2020 Apr 23. [Epub ahead of print]. doi: 10.1377/ hlthaff.2020.00426); another suggests the

cost of hospitalization to private insurers could reach $20,000 per infection.

Still, the larger the hospital, the more likely it is to survive the pandemic, as well as any other waves of cases that appear in the coming months, as stay-athome orders begin to ease, Dr. FischerWright said. Large facilities likely have bigger cash reserves, and can sell off assets or redistribute costs in a way that isn’t possible at small hospitals, many of which only keep 45 days of cash on hand, she said. “And that is not enough to get through this crisis.”

Some Help, but Not Enough?

Starting April 10, hospitals and other providers fighting the pandemic began receiving $30 billion, 30% of the total amount allocated under the $2.2 trillion

coronavirus relief bill, to provide them with an immediate influx of cash. To calculate the payments, Congress considered Medicare payments and gave each hospital its portion of that total. On April 23,

Indication and Usage HYPERRAB® (rabies immune globulin [human]) is indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies.

Limitations of Use Persons who have been previously immunized with rabies vaccine and have a confirmed adequate rabies antibody titer should receive only vaccine.

For unvaccinated persons, the combination of HYPERRAB and vaccine is recommended for both bite and nonbite exposures regardless of the time interval between exposure and initiation of postexposure prophylaxis.

Beyond 7 days (after the first vaccine dose), HYPERRAB is not indicated since an antibody response to vaccine is presumed to have occurred.

Important Safety Information For infiltration and intramuscular use only.

Severe hypersensitivity reactions may occur with HYPERRAB. Patients with a history of prior systemic allergic reactions to human immunoglobulin preparations are at a greater risk of developing severe hypersensitivity and anaphylactic reactions. Have epinephrine available for treatment of acute allergic symptoms, should they occur.

HYPERRAB is made from human blood and may carry a risk of transmitting infectious agents, eg, viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

The most common adverse reactions in >5% of subjects during clinical trials were injection-site pain, headache, injection-site nodule, abdominal pain, diarrhea, flatulence, nasal congestion, and oropharyngeal pain.

Do not administer repeated doses of HYPERRAB once vaccine treatment has been initiated as this could prevent the full expression of active immunity expected from the rabies vaccine.

Other antibodies in the HYPERRAB preparation may interfere with the response to live vaccines such as measles, mumps, polio, or rubella. Defer immunization with live vaccines for 4 months after HYPERRAB administration.

Please see brief summary of Prescribing Information on adjacent page or visit HyperRAB.com for full Prescribing Information.

Operations & Management

Pharmacy Practice News • July 2020

35

Finance the government passed an additional $484 billion bill, which includes $75 billion for hospitals.

However, the formula for the first round of payments under the bill disadvantaged small and rural hospitals, which don’t have the same volume of Medicare patients as larger facilities but still have fixed costs, Ms. True said. One hospital in Washington state told her the funding they received only covered six days of operation. “It was good to get the cash, but it isn’t enough.”

The first round of funding also didn’t

consider a state’s burden of COVID-19 patients, Ms. Kelly said. New Jersey has the second-highest case count in the nation, and the payment formula applied equally to the state with the lowest count.

The rest of the funding allocated to health providers by the end of April—the remaining $70 billion in the bill and the $75 billion from the second bill—aims to help fill the gaps in coverage, focusing for instance on hard-hit areas, uninsured patients and rural areas, but the larger goal of the bailout should be finding ways to make hospitals “whole” enough

to survive the crisis over the long term, Ms. True said. “These initial rounds of funding provided just enough to help hospitals limp along. But if each one is just barely making it, what does that do to our viability as a health system and our ability to respond to a future crisis?

That’s the concern.”

Dr. Fischer-Wright agreed. “The federal support during the initial weeks of the pandemic is certainly laudable, but it will need to continue throughout the remainder of and beyond the pandemic to help our nation’s providers recover

HyperRAB®

-----------DOSAGE FORMS AND STRENGTHS---------300 IU/mL solution for injection supplied in 1 mL, 3 mL and 5 mL single-dose vials.

HIGHLIGHTS OF PRESCRIBING INFORMATION

--------------------CONTRAINDICATIONS--------------------None.

Rabies Immune Globulin (Human) These highlights do not include all the information needed to use HYPERRAB® safely and effectively.

See full prescribing information for HYPERRAB. HYPERRAB [rabies immune globulin (human)] solution for infiltration and intramuscular injection Initial U.S. Approval: 1974 ----------------INDICATIONS AND USAGE------------------HYPERRAB is a human rabies immune globulin indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies.

Limitations of Use Persons previously immunized with rabies vaccine that have a confirmed adequate rabies antibody titer should receive only vaccine.

For unvaccinated persons, the combination of HYPERRAB and vaccine is recommended for both bite and nonbite exposures regardless of the time interval between exposure and initiation of postexposure prophylaxis.

Beyond 7 days (after the first vaccine dose), HYPERRAB is not indicated since an antibody response to vaccine is presumed to have occurred.

--------------DOSAGE AND ADMINISTRATION------------For infiltration and intramuscular use only.

Administer HYPERRAB within 7 days after the first dose of rabies vaccine.

Postexposure HYPERRAB • Administer as soon as possible after 20 IU/kg prophylaxis, exposure, preferably body weight along with at the time of the first OR rabies vaccine, after 0.0665 mL/kg rabies vaccine dose. body weight • Infiltrate the full suspected exposure to dose of HYPERRAB Single dose rabies thoroughly in the area around and into the wound(s), if anatomically feasible.

• Inject the remainder, if any, intramuscularly.

-------------WARNINGS AND PRECAUTIONS-------------• Severe hypersensitivity reactions, including anaphylaxis, may occur with HYPERRAB. Have epinephrine available immediately to treat any acute severe hypersensitivity reactions.

• HYPERRAB is made from human blood; it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

--------------------ADVERSE REACTIONS--------------------The most common adverse reactions in >5% of subjects in clinical trials were injection site pain, headache, injection site nodule, abdominal pain, diarrhea, flatulence, nasal congestion, and oropharyngeal pain.

To report SUSPECTED ADVERSE REACTIONS, contact Grifols Therapeutics LLC at 1-800-520-2807 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

--------------------DRUG INTERACTIONS------------------• Repeated dosing after administration of rabies vaccine may suppress the immune response to the vaccine.

• Defer live vaccine (measles, mumps, rubella) administration for 4 months.

Grifols Therapeutics LLC Research Triangle Park, NC 27709 USA U.S. License No. 1871

3054805 Revised: 11/2019

and meet patient needs.”

The need is indeed acute. Just consider the cost of support for front-line hospital workers in COVID-19 hotspots.

The American Hospital Association estimates those costs to be $2.2 billion through the end of June, or just under $550 million per month. This includes the costs of providing child care, housing, transportation, and medical screening and treatment for COVID-19 for front-line workers (bit.ly/2Y836qU).

—Alison McCook and Marie Rosenthal

Introducing greater dosing convenience with a new 3-mL (900-IU) vial

When protecting your patients with HRIG

DELIVER MORE OF THE TOTAL DOSE AT THE WOUND SITE. HyperRAB® (rabies immune globulin [human]) 300 IU/mL The first and only high-potency human rabies immune globulin (HRIG) that offers:

the volume of medication administered in a total dose, potentially resulting in fewer injections the concentration of rabies antibodies per mL at the wound site

HIGH-POTENCY FORMULA

REDEFINING HRIG ADMINISTRATION REDEFINING HRIG ADMINISTRATION

LOWEST VOLUME PER DOSE

MORE RABIES ANTIBODIES PER mL

Please see Important Safety Information and brief summary of Prescribing Information for HyperRAB on adjacent pages, or visit www.HyperRAB.com for full Prescribing Information. n.

HyperRAB® (rabies immune globulin [human]) is indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies.

HyperRAB is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent that can cause disease. There is also the possibility that unknown infectious agents may be present in such products.

#1 Prescribed HRIG in the US

For more information, visit www.HyperRAB.com © 2020 Grifols

All rights reserved

March 2020

US-HB3-2000016

PRINTER-FRIENDLY VERSION AVAILABLE AT PHARMACYPRACTICENEWS.COM

The Changing Antimicrobial Landscape Rapid Diagnostic Testing and Biomarkers Affecting Stewardship

KAREN FONG, PHARMD, BCIDP, AAHIVP

TRISTAN T. TIMBROOK, PHARMD, MBA, BCPS

Clinical Pharmacist, Infectious Diseases and Antimicrobial Stewardship Department of Pharmacy at University of Utah Health Salt Lake City, Utah

Assistant professor, University of Utah Health Salt Lake City, Utah, when he co-wrote this review article. He has since accepted a position at BioFire Diagnostics.

A

ntimicrobial stewardship programs (ASPs) have demonstrated their immense value by improving clinical outcomes and mitigating adverse events through the optimization of antimicrobial use.1,2

Hospital ASPs have been able to concomitantly improve the cure rates of infections and combat challenges with Clostridioides difficile infections, antimicrobial resistance, adverse effects, length of stay, and costs.2-4

As a syndrome-based intervention, rapid diagnostic tests (RDTs) combined with ASP intervention, particularly for bloodstream infections (BSIs), have been revolutionary in providing consistently meaningful results on antimicrobial optimization and patient outcomes.5,6 Additionally, the implementation of RDTs may enable better fulfillment or alignment with the Core Elements

of Hospital Antibiotic Stewardship Programs, which are the key structural and procedural components of ASPs associated with success in hospitals regardless of size and types of care.5,7 The CDC released its core elements in 2014 to serve as guidance for the goal of nationwide implementation of ASPs.7 In 2015, the US National Action Plan for

MCMAHON PUBLISHING GROUP

1

T ECHNICAL EFFICACY • Resource constraints • Turnaround time

DI AGN OSTI C ACCURACY EFFICACY • Specificity and sensitivity • Positive and negative predictive values

DI AG N OSTI C T HINKING EFFICACY • Facilitates determining diagnosis

T H ERA PEUTI C EFFICACY • Therapy change • Procedure change

PATI EN T OUTCOME EFFICACY • Morbidity and procedures avoided • Patient improvement with test

Combating Antibiotic Resistant Bacteria set the intent for the core elements to be implemented in all federally funded hospitals.8 In 2017, the Joint Commission and Centers for Medicare & Medicaid Services mandated ASPs, grounding the core elements as part of accreditation and conditions of participation, respectively.9,10 In 2019, after 5 years of experience, the CDC updated its core elements based on new evidence published on antimicrobial stewardship.7 Wenzler et al summarize barriers to RDT implementation and provide justification strategies based on the 2014 core elements for the addition and optimization of RDTs in ASPs.5 We have refined these justification strategies based on the updated core elements (Table, page 3).

Although RDTs may provide a promising level of diagnostic accuracy, combination with routine ASP efforts has been found to be imperative, as supported by data on BSIs, to observe translational outcomes.6,11-13 Evaluations in the clinical efficacy of RDTs beyond BSIs are still evolving and may benefit by evaluation in the context of a hierarchical model of efficacy. Fryback and Thornbury describe a hierarchical 6-tiered model of efficacy in diagnostic imaging that can be applied to nearly all diagnostic technologies, including RDTs. This model emphasizes the assessment of diagnostic technologies beyond their quality or accuracy, but considers the ultimate value or benefit resulting from the technologies.14 Level 2 addresses diagnostic accuracy efficacy, which is characterized by measures associated with interpretation of tests, such as positive and negative predictive values, sensitivity, and specificity.14 These measures highlight the important concept that diagnostic accuracy efficacy is a joint function of the test and an observer who controls both the specificity in the clinical practice environment and sensitivity to the extent that it varies with the spectrum of disease.14 Additionally, asymmetry in relationships exists among adjacent levels in the continuum of efficacy. For efficacy to be observed at a higher level in this hierarchy, efficacy must be observed at lower levels, but the reverse is not true.14 Perhaps this model alludes to the performance variability of RDTs, as outcomes observed at levels 4 to 6 are usually suboptimal without consistent ASP intervention.6,11-13 This model may be helpful as we discuss novel RDTs including respiratory, biomarkers and sepsis diagnostics, advances in blood culture testing, and prospects of outpatient point of care and their performance with current diagnostic stewardship practices (Figure).

Respiratory

S O C I ETA L EFFICACY • Cost-effectiveness

Figure. Efficacy hierarchy of microbiology diagnostics.

2

MCMAHON PUBLISHING GROUP

In the United States, pneumonia has been a major contributor of morbidity and mortality, estimating 63,000 annual deaths and 1.2 million annual hospitalizations.15,16 The American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) recommendations for empiric antimicrobial therapy in community-acquired pneumonia (CAP) are based on selecting agents targeted against the major treatable respiratory bacterial pathogens.17 Unfortunately, overuse of antibiotics is

Table. Achieving Compliance With CDC Core Elements With the Use of RDTs Core Element Hospital Leadership Commitment

2014

2019

RDT Justification

Dedicate necessary human, financial, and information technology resources

Financial support and allocation of human resources including information technology dedicated to implementation from administration as a display of leadership commitment

Accountability

Appointing a single leader responsible for program outcomes; experience with successful programs shows that a physician leader is effective

Appoint a leader or co-leaders, such as a physician and pharmacist, responsible for program management and outcomes

Addition of pharmacy expertise as accountable for the implementation, prioritization of daily interventions, tracking and reporting, and outcomes

Pharmacy Expertise

Appointing a single pharmacist leader responsible for working to improve antibiotic use

Appoint a pharmacist, ideally as the co-leader of the stewardship program, to lead implementation efforts to improve antibiotic use

Emphasizing the engagement of pharmacy expertise to lead implementation, perform daily interventions, improve efficiency of optimal antibiotic administration from pharmacy, and decrease suboptimal antimicrobial use

Implementing at least 1 recommended action, such as systemic evaluation of ongoing treatment need after a set period of initial treatment (ie, “antibiotic time-out” after 48 h)

Implement interventions, Cornerstone of daily infection-specific such as prospective audit and or microbiology-based prospective feedback or preauthorization, to audit and feedback improve antibiotic use Facilitate priority interventions

Monitoring antibiotic prescribing and resistance patterns

Monitor antibiotic prescribing, impact of interventions, and other important outcomes (eg, Clostridioides difficile infection and resistance patterns)

(Previously Drug Expertise)

Action

Tracking

Ease of tracking and reporting directed interventions Addition of tracking the impact of priority interventions Allows tracking targeted and clinically significant outcomes Acceptance of intervention as process measure to demonstrate compliance Outcome measures may include mortality, length of stay, and time to appropriate or optimal therapy

Reporting

Regularly reporting information on antibiotic use and resistance to doctors, nurses, and relevant staff

Regularly report information on antibiotic use and resistance to prescribers, pharmacists, nurses, and hospital leadership

Outcomes reported to key stakeholders including pharmacists and leadership Demonstrate accountability and strengthen leadership support Emphasize value of clinical pharmacy input Gaps may be recognized and prompt quality improvement by specific prescriber groups

Education

Educating clinicians about resistance and optimal prescribing

Educate prescribers, pharmacists, and nurses about adverse reactions from antibiotics, antibiotic resistance, and optimal prescribing

Education at pre- and postimplementation will improve intervention acceptance Outcome measures may improve confidence in ASP recommendations Empower clinicians and providers to encourage and utilize optimal prescribing patterns

ASP, antimicrobial stewardship program; RDT, rapid diagnostic test

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common in lower respiratory tract infections (LRTIs), as there is difficulty in distinguishing between bacterial and viral etiologies due to similar manifestations.18 Antibiotic therapy may be safely withheld in patients with isolated viral pneumonia if these infections can be identified easily from those with concomitant bacterial etiology.19 Procalcitonin (PCT) is a component of the innate pro-inflammatory response that is released in response to bacterial challenge, discriminating between viral and bacterial infections.20 The ATS/IDSA guidelines for the diagnosis and treatment of adults with CAP were updated in 2019 and included recommendations for the use of PCT. Empiric antibiotic therapy is recommended to be initiated in adults with clinically suspected and radiographically confirmed CAP regardless of initial serum PCT level.17 This recommendation acknowledges the findings of a recently updated Cochrane Review assessing the safety and efficacy of using PCT for initiating or discontinuing antibiotics among patients with varying severity of acute respiratory infections (ARIs) from different clinical settings. Thirty-two randomized controlled trials of adults with ARIs who received an antibiotic treatment either based on a PCT-guided antibiotic stewardship algorithm or usual care were included for analysis.

Most of the PCT algorithm used levels of less than 0.1 mg/L to indicate a high likelihood of viral infection, whereas levels more than 0.25 mg/L indicate a high likelihood of bacterial pneumonia. Mortality was significantly lower (8.6% vs 10.0%; adjusted odds ratio [aOR], 0.83; 95% CI, 0.70-0.99; P=0.037) with PCT guidance compared with usual care, respectively.21 Procalcitonin guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 vs 8.1 days; 95% CI, –2.71 to –2.15; P<0.001) and lower risk for antibiotic-related adverse effects (16.3% vs 22.1%; aOR, 0.68; 95% CI, 0.57-0.82; P<0.001).21 Results were similar among different types of ARIs and clinical settings, supporting syndrome-specific PCT use with antimicrobial stewardship.

However, Self et al recently evaluated the association between serum PCT concentration with pneumonia etiology in a multicenter prospective surveillance study of adults hospitalized with CAP.22 The investigators were unable to identify a PCT threshold that allowed perfect discrimination between viral and bacterial detection, a challenging goal. Although results established that there was a lower frequency of bacterial pathogens in patients

with PCT below both the 0.1- (6%) and 0.25ng/mL (8%) thresholds, this finding also supports that clinicians cannot solely rely on PCT to guide antibiotic treatment decisions.22 Furthermore, Huang et al did not demonstrate a reduction in mean antibiotic days in patients with LRTIs with PCT use compared with usual care in a recent multicenter randomized controlled trial. Outcomes may have been limited by subpar adherence with the PCT antibiotic prescribing guideline and lack of real-time prospective audit and feedback.18 Therefore, implementation may have failed to demonstrate benefit in the absence of ASP intervention.

Given the mixed results of PCT efficacy, respiratory viral polymerase chain reaction (PCR) assays, BioFire FilmArray respiratory panel (BioFire Diagnostics) and eSensor respiratory viral panel (GenMark Diagnostics), may be useful as an adjunctive RDT. Moradi et al explored the use of respiratory viral PCR (RVP) combined with PCT and an automated antimicrobial stewardship provider alert in a multicenter quasi-experimental study. If three criteria were met PCT <0.25 ng/mL, virus detected on RVP, and active use of systemic antibiotics the automated alert would prompt de-escalation by communicating “antimicrobial stewardship alert: your patient has a positive viral PCR + negative procalcitonin + one or more antibiotics ordered. These results suggest viral infection— please reassess necessity of antibiotics as indicated.”23 Antibiotic-days of therapy were significantly reduced in the intervention group by a mean of 2.2 days (5.8 vs 8.0 days; P<0.001). In addition, there were significantly more patients having antibiotics discontinued within 24 hours of initiation (37.8% vs 18.6%; P<0.001) and fewer patients discharged on antibiotics (20.0% vs 47.8%; P<0.001).23 In the absence of ASP intervention, previous evidence observed low rates of antibiotic discontinuation in patients with negative PCT and positive RVP.24 The findings from this study emphasize the importance of its real-world implementation strategy by leveraging indirect ASP intervention through an automated alert, which may be especially worthy for minimal resource settings.23,25 Similarly, Lee et al examined the clinical impact of combining the RVP with PCT in older adults with severe ARIs through a prospective multicenter observation study.26 Outcomes were compared between the intervention group and a propensity score–matched historical cohort. Patients in the

Prompt initiation of appropriate antifungal therapy and source control has been associated with as much as

50% reduction

in candidemia-attributed mortality.

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intervention group had significantly more antibiotic de-escalation (21.9% vs 13.2%; P=0.007), a shorter duration of IV antibiotic use (median, 10.0 days; interquartile range [IQR], 5.3-14.6 days vs median, 14.5 days; IQR, 7.2-22.0 days; P<0.001), and a shorter hospital length of stay (median, 14.0 days; IQR, 5.0-20.5 days vs 16.1 days; IQR, 6.0-24.5; P=0.030).26 The investigators did not incorporate formal ASP in their study but had a study nurse promote antibiotic stewardship by communicating the tests results and reminding the physicians of the antibiotic treatment recommendations based on different testing results.26 Reduction in antibiotic days of therapy observed with RVP and PCT combination with a varying level of ASP intervention appears to be similar, if not greater and more consistent, compared with solely PCT or RVP utilization with ASP intervention, but more robust head-to-head comparisons are needed to confirm such speculations.18,21,23,26,27

LRTI PANELS Multiple syndromic molecular testing panels for LRTIs have been cleared by the FDA, including the BioFire FilmArray pneumonia panel and Curetis Unyvero lower respiratory tract (LRT) panel. These panels offer increased sensitivity compared with clinical cultures. Additionally, the panels may offer benefit over conventional microbiology cultures by providing the presence of resistance markers within as little as 1 to 5 hours from specimen collection and testing.

The BioFire panel offers detection of 8 viruses, 8 resistance genes, 3 atypical bacterials using qualitative targets, and 15 bacterial targets with semiquantitative analysis, which can assist in evaluating colonization versus infection. The Curetis Unyvero LRT panel includes detection of 29 bacterial pathogens and 19 resistance genes. Both panels are able to be used with multiple specimen types (sputum, endotracheal aspirates, bronchoalveolar lavage fluid). A recent validation and hypothetical impact study of the BioFire FilmArray pneumonia panel compared conventional microbiology cultures among ICU patients.28 The positive and negative percent agreement was high at 90% (95% CI, 73.5%-97.9%) and 97.4% (95% CI, 96.0%-98.4%), respectively. Similarly, the overall agreement was high at approximately 80%. Of note, there was a concordance rate of 100% for 5 targets including Enterobacter cloacae complex, Escherichia coli, Haemophilus influenzae, Serratia marcescens, and Streptococcus pneumoniae. However, substantial discrepancies were found in the detection of antimicrobial resistance genes. The results of testing had the potential of affecting antibiotic prescriptions in 40.7% of patient cases.

The Curetis Unyvero LRT panel also has reported robust diagnostic accuracy. Moreover, in a hypothetical impact study, the LRT panel offered results 2.7 days faster than culture, which could have affected 63% of cases being overtreated, translating into a decrease of $2,538 cost per day in treatment.29 Clinical outcomes

evaluations of these panels are ongoing.

CLINICAL UTILITY OF SURVEILLANCE MRSA NASAL PCR SCREENING Methicillin-resistant Staphylococcus aureus (MRSA) nasal screens, such as the Cepheid GeneXpert SA Nasal, have evolved beyond use for infection prevention and control practices to having clinical utility for routine use in de-escalations of MRSA therapy, predominantly in patients with suspected or confirmed pneumonia. Robust evidence has reflected more than 95% negative predictive value for use of the test in ruling out MRSA pneumonia.30 Therefore, the ATS/IDSA guidelines endorsed the routine use of MRSA nasal PCR screening for the de-escalation of MRSA coverage.17 ASP implementation of this approach has been associated with a median decrease of 2.1 days of vancomycin (P<0.01).31 Other implementation results of nasal screening for vancomycin avoidance in suspected or confirmed pneumonia among ICU patients has been associated with $108 per patient in cost avoidance based on the cost of surveillance testing, vancomycin, and vancomycin therapeutic drug monitoring levels.32 Reviews of implementation considerations suggest fidelity of the nasal testing for 7 days after results and lack of impact of vancomycin exposure in affecting results of testing.33,34 A systematic review and meta-analysis also supported the use of the screen for negative predictive value beyond pneumonia, such as in skin and soft tissue infections.35 A recent national study from the Veterans Affairs system has supported this concept in the largest cohort to date including clinical cultures (n=561,325).36 These data showed a high overall negative predictive value for all infection types (96.5%) and among specific infections including BSIs (96.5%), intraabdominal infections (98.6%), respiratory infections (96.1%), wound cultures (93.1%), and urinary tract infections (99.2%). Whereas the surveillance of gram-negative resistance using rectal swab testing (eg, Streck ARM-D resistance detection kits) among some settings may be standard, the clinical utility of these tests in directing therapy has yet to demonstrate significant promise.37,38

BIOMARKERS

AND

SEPSIS DIAGNOSTICS

Candidemia is one of the most common hospitalacquired BSIs in the United States, associated with up to 47% attributable mortality, and even higher among patients who develop septic shock. Prompt initiation of appropriate antifungal therapy and source control has been associated with as much as 50% reduction in mortality. However, this is often delayed due to blood culture insensitivity, prolonged turnaround time (median time to positivity, 2-3 days, ranging from 1 to â&#x2030;Ľ7 days) needed to yield growth, and the possibility of negative growth with invasive abdominal candidiasis.39 These limitations propagate overuse of empiric antifungal therapy for suspected invasive candidiasis, a practice of unproven clinical value.40 Nonculture diagnostic tests,

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such as the Fungitell ß-D-glucan (BDG; Associates of Cape Cod) detection assay and the T2Candida panel (T2 Biosystems), have a much shorter turnaround time (8-12 hours) and entered clinical practice as adjunctive RDT to cultures.39,41 BDG is a component of the cell wall in Candida species, Aspergillus species, and Pneumocystis jiroveci.

Therefore, true positive results have limited specificity for candidemia due to cross-reactivity with other organisms. Another concern is false positivity, which may be caused by physiologic changes, selected antimicrobials, hemodialysis, albumin or immunoglobulin therapy, or use of surgical materials containing glucan.39 A few studies have explored the use of BDG in suspected candidemia and shown de-escalation of antifungal therapy through avoidance and reduction, but they were limited by sample size and did not incorporate active ASP intervention.42,43 Rautemaa-Richardson et al developed a local ASPdriven guideline for the diagnosis and management of suspected or proven invasive candidiasis in nonneutropenic adult patients.44 BDG was used as a ruleout test to guide the discontinuation of therapy in the absence of other microbiological evidence at 48 to 96 hours. The researchers retrospectively evaluated the compliance of the ICU with the invasive candidiasis guideline in patients initiated on micafungin and ASP impact on mortality through a 4-month audit period in 2014 with active ASP intervention and 2016 without ASP intervention.44 Additionally, antifungal consumption was evaluated over a 2-year period between 2014 and 2016. Results demonstrated that there were significant changes between 2014 and 2016 in patients categorized as “proven or probable invasive candidiasis,” “appropriately suspected but candidiasis excluded,” and “inappropriately suspected” (P=0.01). A 90% reduction in inappropriately initiated antifungal courses was observed between 2014 and 2016. All-cause mortality due to proven or probable invasive candidiasis decreased from 45% to 19% in the study period compared with the historical cohort in 2003 to 2007, respectively. Furthermore, a decrease in micafungin consumption by 49% was observed.44 Although reduction of micafungin consumption was likely attributed to BDG, improvements in inappropriate initiation of antifungals and mortality were more likely influenced by assessment of risk factors, source removal, and further workup of invasive candidiasis as recommended by the guideline. There was improvement with guideline compliance and micafungin utilization from 2014 even though active ASP intervention was withdrawn in 2016.

Moreover, Ito-Takeichi et al observed mixed results in their single-center prospective cohort study evaluating the impact of implementing antifungal daily reviews

by ASP through prospective audit and feedback combined with BDG (Wako by Wako Pure Chemical Industries) monitoring on antifungal consumption and clinical outcomes of patients with candidiasis.45 The ASP recommended stopping antifungal therapy in cases with

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negative BDG, but testing appeared to be at physician discretion. Overall antifungal use was not significantly decreased after intervention, but there was a significant reduction in the 60-day clinical failure rate (80.0% vs 36.4%; P<0.001) and 60-day mortality (42.9% vs 18.2%; P=0.004) in patients with proven candidiasis. This was likely due to most ASP interventions on choice of antifungal (104/223; 47%) followed by dosage adjustment (77/223; 35%). There were minimal interventions on BDG guidance and de-escalation (8/223; 4%).45 Molecular Candida platforms such as the T2Candida panel and the Karius Test (Karius) detecting Candida species DNA from whole blood also have emerged. While sensitivity and specificity seem to be much more promising compared with blood cultures, the role of these technologies in the early diagnosis and management of candidemia remains unclear with minimal available data.39 Patch et al evaluated the impact of the T2Candida panel combined with active ASP intervention through positive culture review in a 2-phase retrospective analysis on timing of appropriate antifungal initiation for patients with candidemia and micafungin duration of therapy in patients without microbiological evidence of invasive candidiasis.46 The investigators observed a significant decrease in time to appropriate therapy in the post-T2Candida group (34 vs 6 hours; P=0.0147). Despite a lack of mycological evidence in the pre-T2Candida group, average duration of therapy was 6.7 days compared with 2.4 days in patients with negative T2Candida without mycological evidence in the post-T2Candida group. This resulted in a total antifungal

in diagnosing BSIs caused by Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and E. coli were 90% (95% CI, 76%-96%) and 90% (95% CI, 88%-91%), respectively.47 Negative predictive value was 99.7%. Limited to only 5 bacteria, sensitivity and specificity for any organism were 43% (95% CI, 32%-54%) and 89% (95% CI, 87%-91%). Time from initiation of testing to detection and identification of pathogens was shorter for T2Bacteria (mean, 7.70 [SD, 1.38] hours) than for blood cultures (mean, 71.7 [SD, 39.3] hours). However, a 10% false-positive rate was observed for its targeted organisms.47 These results do not address whether T2Bacteria adds any additional value to the management or outcomes of patients with suspected BSIs. Further studies are needed to justify its role along with ASPs in patient care.48 Karius testing has offered a new potential tool in the antimicrobial stewardship armamentarium of microbiologist testing. This novel metagenomic microbiologic diagnostic test uses plasma microbial cell-free DNA sequencing which is able to identify 1,250 bacteria, fungi, parasites, and viruses.49,50 While clinical data are fairly limited presently, this new technology has shown promise in diagnosing and identifying causative infectious etiologies for pneumonia, bacteremia, and general sepsis. In particular, its role may be useful in immunocompromised hosts where a broader range of pathogens may be associated with illness. cost savings of $48,440 (or $280/tested patient).46 Of concern, discordance was observed in 3 patients with unpaired positive blood cultures and negative T2Candida results.46 In patients without microbiological evidence of candidemia, negative T2Candida results were compared with negative BDG, along with active ASP intervention in both groups, in a retrospective quasi-experimental study on their facilitation in antifungal discontinuation.41 During the study period, there was a systemwide guideline on the standard of care for invasive candidiasis, which included either BDG or T2Candida as RDT. Negative results for either were encouraged to discontinue echinocandin therapy. In addition, the ASP reviewed BDG and T2Candida results for patients on anidulafungin (Eraxis, Pfizer) during both periods. Among 206 ICU patients, median duration of therapy was 2 (1-5) compared with 1 (1-2) in the BDG and T2Candida groups, respectively (P<0.001). Moreover, T2Candida was the only independent predictor of early anidulafungin discontinuation (aOR, 3.0; 95% CI, 1.7-5.6; P<0.001).41 Gill et al conducted the first active comparison between distinct RDT-based antifungal stewardship strategies, reinforcing the potential advantage of T2Candida use in minimizing unnecessary antifungal exposure with the presence of active ASP intervention.41 The T2Bacteria panel made its debut detecting bacteria DNA by T2 magnetic resonance technology from whole blood to improve early initiation of appropriate antibiotic therapy in BSIs. Paired with a single set of blood cultures, T2Bacteria sensitivity and specificity

RDT for Blood Culture Testing Molecular RDT has fundamentally changed the management of BSIs and blood culture contaminants (eg, coagulase-negative staphylococci) by providing actionable information much earlier in the course of treatment than conventional microbiology cultures. Implementation of PCR-based technologies (eg, BioFire FilmArray and GenMark ePlex blood culture identification panels), nanoparticle probe technology (eg, Verigene [Luminex] gram-positive and -negative blood culture nucleic acid tests), or matrix-assisted laser desporption/ionization time-of-flight mass spectrometry (eg, bioMĂŠrieux, BD Bruker) have been associated with decreases in time to effective therapy, hospital length of stay, and mortality when associated with ASP interventions.6 Similar to the clinical impacts observed, cost-effectiveness analysis has also reflected benefits of molecular RDTs in BSIs.11 These data also highlight the strong synergy of stewardship and RDT: RDT has an 80% chance of cost-effectiveness with an ASP but only 41.1% without it.

Further potential changes in the management of BSIs have developed with the introduction of automated rapid phenotypic testing systems, such as the Accelerate Pheno system (Accelerate Diagnostics). This system is able to yield organism identification, minimum inhibitory concentration (MIC), and susceptibility interpretation with a turnaround time of approximately 7 hours after a positive blood culture. Two recent hypothetical impact studies have been performed with this platform.51,52 In the first study among 167 patients with

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positive blood cultures tested by both rapid molecular testing and rapid phenotypic testing, the Accelerate platform may have resulted in earlier de-escalations in 31% of patients, resulting in a median decrease of time to definitive therapy by 25.4 hours. Similarly, in a study at the same institution among 61 patients with drug-resistant gram-negative BSIs, nearly half of patients would have potential improvements in time to effective and/ or definitive therapy with the Accelerate Pheno system.

At IDWeek 2019, results of a randomized controlled trial of the Accelerate Pheno system in gram-negative BSIs were presented and reflected significantly faster antibiotic changes (median decrease of approximately 25 hours for gram-negative antibiotics, P<0.01) compared with culture-based methods.53 Although susceptibility interpretation may have a high degree of variability with MIC testing,54 the introduction of rapid phenotypic testing may be of particular importance to ASPs in terms of the ability to optimize therapeutic dosing to maximize pharmacokinetic and pharmacodynamics (PK/PD) parameters in the setting of a known MIC. Optimal drug exposures have been associated with improved outcomes in achieving the enhanced PK/PD targets.55 Prospective evaluations of critically ill patients have shown that under dosing for PK/PD targets is common.56 Therefore, the use of rapid phenotypic technologies, such as the Accelerate Pheno system, combined with therapeutic drug monitoring among critically ill patients likely has the potential to significantly affect patient outcomes.

Outpatient Antimicrobial Prescribing And Diagnostic Potential Antimicrobial stewardship in the outpatient setting is relatively new. Population database evaluations of antimicrobial prescribing in the United States suggests at least one-third of prescribing is inappropriate, the majority attributed to respiratory infections.57 Following this finding, the CDC released the Core Elements of Outpatient Antibiotic Stewardship, which recommends a variety of interventions, such as commitment posters, to decrease inappropriate antibiotic prescribing.58 A systematic review on interventions to influence prescriber behavior in acute respiratory infections in primary care demonstrated that C-reactive protein testing, shared decision making, and PCT-guided management have promise for decreasing inappropropriate use of antibiotics.59 In contrast, conclusions could not be made on the utility of respiratory diagnostics, as studies were of low or very low quality.

Respiratory RDTs in outpatient settings are evolving. Although influenza testing with digital lateral flow immunoassays, such as BD Veritor Plus, in the primary care setting is widely available, the use of point-of-care molecular testing has been limited due to regulations on who and where testing can be performed (Clinical Laboratory Improvement Amendments [CLIA] waivers) and logistical issues of achieving turnaround time during clinic visits. The first CLIA-waived nucleic acid

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amplification test, the Alere i influenza A & B test, was approved in 2015. In 2016, the BioFire FilmArray respiratory panel EZ (RP EZ), a CLIA-wavied respiratory panel, became available to allow for multiplex respiratory inclinic testing. These advances in technologies have the potential to change outpatient health care.

A recent study implemented the RP EZ panel in a pediatric clinic among 430 patients at 2 clinics. In clinic A, the RP EZ panel was routinely used at provider discretion, whereas in clinic B, if antigen testing was performed for influenza or respiratory syncytial virus, samples were also tested using FilmArray, but results were blinded to patients and providers. In clinic A, at least 1 organism was detected in 70.4% of patients, leading to appropriate treatment in 93.6% of patients compared with 87.9% of patients in clinic B without the panel (P=0.0445). Significant increases in neuraminidase inhibitor use (75% vs 31.6%; P<0.01) occurred among patients in clinic A compared with clinic B, although this may have been related to differences in patient presentations and related indication for therapy. The RP EZ panel was associated with a decrease in clinic appointment duration when used (mean check-in to checkout time, 48 vs 55 minutes; P<0.01). Although promising, these results are very likely limited by the turnaround time of the CLIA-waived test of approximately 1 hour.

The importance of turnaround time in yielding clinically actionable information in the outpatient setting cannot be overstated. A post hoc analysis of randomized controlled trial data of the use of a respiratory viral panel for patients presenting to emergency departments with respiratory symptoms has shown that faster turnaround times are associated with improved patient management compared with longer turnaround times.60 As mean office visit times for respiratory tract infections are often 15 minutes, the logistics of primary care require technologies that can accommodate these time constraints.61 With the development of such technologies, determination will be needed of which patient population to target, which targets provide clinical utility (antibiotic avoidance, antiviral use, lab and imaging utilization, and subsequent health care utilization), and the optimal implementation strategies of these panels.62 Utilization of clinical decision support may be of benefit in directing front-line clinicians in the optimal use of RDT results, particularly as the resources for prospective audit and feedback from antimicrobial stewardship may be limited in the outpatient setting.25

Conclusion A revolution in antimicrobial stewardship continues with the changing landscape of RDTs. As a critical component of ASPs, RDTs have shown the greatest impact on patient outcomes for BSIs. However, many advances are occurring in technologies available for the management of severe respiratory infections, sepsis, candidiasis, PK/PD optimization opportunities, and outpatient respiratory infections. Many of these technologies show

promise in their potential to positively impact patient care. However, efficacy evaluations of these technologies are critically important and should be approached with considerable contemplation to ensure they are not only improving the accuracy and speed of diagnosis but also affecting the diagnostic thinking of clinicians, changing clinical management, affecting patient outcomes, and yielding overall cost-effectiveness.

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51. Henig O, Cooper CC, Kaye KS, et al. The hypothetical impact of Accelerate Pheno system on time to effective therapy and time to definitive therapy in an institution with an established antimicrobial stewardship programme currently utilizing rapid genotypic organism/resistance marker identification. J Antimicrob Chemother. 2019;74(suppl 1):i32-i39.

36. Mergenhagen KA, Starr KE, Wattengel BA, et al. Determining the utility of methicillin-resistant Staphylococcus aureus nares screening in antimicrobial stewardship. Clin Infect Dis. 2019 Oct 1. [Epub ahead of print]. doi: 10.1093/cid/ciz974 37. Lindblom A, Karami N, Magnusson T, et al. Subsequent infection with extended-spectrum beta-lactamase-producing Enterobacteriaceae in patients with prior infection or fecal colonization. Eur J Clin Microbiol Infect Dis. 2018;37(8):1491-1497.

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Dr Fong reported no relevant financial relationships.

Dr Timbrook reported several relationships, but has since taken a position with BioFire Diagnostics.