48 minute read

HHS green-lights COVID-19 testing by pharmacists

Next Article
UP FRONT

UP FRONT

Reimbursement, PPE shortages remain barriers

Pharmacists Get Green Light for COVID-19 Testing

To 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 of reopening the of reopening the country as safely as possible, pharmacy ossible, pharmacy groups—including those representing ose representing health-system pharmacy—are asking macy—are asking officials to make it easier to let this easier to let this highly skilled workforce screen patients ce screen patients for the coronavirus.

On May 19, the Department of Health artment of Health and Human Services (HHS) tried to (HHS) tried to remove some of those existing barriers. existing barriers. The move came in the form of a new e form of a new advisory opinion, which concluded that ch concluded that the Public Readiness and Emergency and Emergency Preparedness (PREP) Act gives pharAct gives pharmacists the ability to provide authorized rovide authorized COVID-19 diagnostic tests to patients tests to patients without a doctor’s supervision, preemptervision, preempting any state or local barriers. The HHS’s arriers. The HHS’s guidance “highlights the administrathe administration’s confidence in pharmacists to proharmacists to provide 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

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 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

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

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.

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 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

HyperRAB ®

Rabies Immune Globulin (Human)

HIGHLIGHTS OF PRESCRIBING INFORMATION

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

-----------DOSAGE FORMS AND STRENGTHS----------

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

--------------------CONTRAINDICATIONS---------------------

None.

-------------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.

The Changing Antimicrobial Landscape

Rapid Diagnostic Testing and Biomarkers Affecting Stewardship

KAREN FONG, PHARMD, BCIDP, AAHIVP

Clinical Pharmacist, Infectious Diseases and Antimicrobial Stewardship Department of Pharmacy at University of Utah Health Salt Lake City, Utah TRISTAN T. TIMBROOK, PHARMD,

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 Additionally, the implementation of RDTs may enable better fulfillment or alignment with the Core Elements MBA, BCPS

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

Antimicrobial 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

on antimicrobial optimization and patient outcomes. 5,6 Diagnostics. 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

TECHNICAL EFFICACY • Resource constraints • Turnaround time

DIAGNOSTIC ACCURACY EFFICACY • Specifi city and sensitivity • Positive and negative predictive values

DIAGNOSTIC THINKING EFFICACY • Facilitates determining diagnosis

THERAPEUTIC EFFICACY • Therapy change • Procedure change

PATIENT OUTCOME EFFICACY • Morbidity and procedures avoided • Patient improvement with test

SOCIETAL EFFICACY • Cost-effectiveness

Figure. Efficacy hierarchy of microbiology diagnostics.

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

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

Core Element 2014 2019 RDT Justification

Hospital Leadership Commitment Dedicate necessary human, fi nancial, 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

Pharmacy Expertise (Previously Drug Expertise) Appointing a single pharmacist leader responsible for working to improve antibiotic use

Action 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)

Tracking Monitoring antibiotic prescribing and resistance patterns

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

Education Educating clinicians about resistance and optimal prescribing 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

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 effi ciency of optimal antibiotic administration from pharmacy, and decrease suboptimal antimicrobial use

Implement interventions, such as prospective audit and feedback or preauthorization, to improve antibiotic use Cornerstone of daily infection-specifi c or microbiology-based prospective audit and feedback Facilitate priority interventions Ease of tracking and reporting directed interventions

Monitor antibiotic prescribing, impact of interventions, and other important outcomes (eg, Clostridioides diffi cile infection and resistance patterns) Addition of tracking the impact of priority interventions Allows tracking targeted and clinically signifi cant 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

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 specifi c prescriber groups

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 confi dence in ASP recommendations Empower clinicians and providers to encourage and utilize optimal prescribing patterns

ASP, antimicrobial stewardship program; RDT, rapid diagnostic test

common in lower respiwith PCT below both ratory tract infections (LRTIs), as there is difPrompt initiation of the 0.1- (6%) and 0.25- ng/mL (8%) threshficulty in distinguishing between bacterial and viral etiologies due appropriate antifungal therapy and source olds, this finding also supports that clinicians cannot solely rely on to similar manifestations. 18 Antibiotic control has been PCT to guide antibiotic treatment decisions. 22 therapy may be safely withheld in patients associated Furthermore, Huang et al did not demonstrate a with isolated viral pneumonia if these with as much as reduction in mean antibiotic days in patients infections can be identified easily from those 50% reduction with LRTIs with PCT use compared with usual with concomitant bacterial etiology. 19 in candidemia-attributed care in a recent multicenter randomized conProcalcitonin (PCT) is a component of the mortality. trolled trial. Outcomes may have been limited innate pro-inflammaby subpar adherence tory response that is with the PCT antibiotreleased in response to bacterial challenge, discrimic prescribing guideline and lack of real-time prospecinating between viral and bacterial infections. 20 The tive audit and feedback. 18 Therefore, implementation ATS/IDSA guidelines for the diagnosis and treatment may have failed to demonstrate benefit in the absence of adults with CAP were updated in 2019 and included of ASP intervention. recommendations for the use of PCT. Empiric antibiotGiven the mixed results of PCT efficacy, respiic therapy is recommended to be initiated in adults with ratory viral polymerase chain reaction (PCR) clinically suspected and radiographically confirmed CAP assays, BioFire FilmArray respiratory panel regardless of initial serum PCT level. 17 This recommen(BioFire Diagnostics) and eSensor respiratory viral panel dation acknowledges the findings of a recently updat(GenMark Diagnostics), may be useful as an adjunced Cochrane Review assessing the safety and efficacy tive RDT. Moradi et al explored the use of respiratory of using PCT for initiating or discontinuing antibiotics viral PCR (RVP) combined with PCT and an automatamong patients with varying severity of acute respiratoed antimicrobial stewardship provider alert in a multiry infections (ARIs) from different clinical settings. Thircenter quasi-experimental study. If three criteria were ty-two randomized controlled trials of adults with ARIs met PCT <0.25 ng/mL, virus detected on RVP, and who received an antibiotic treatment either based on active use of systemic antibiotics the automated alert a PCT-guided antibiotic stewardship algorithm or usual would prompt de-escalation by communicating “anticare were included for analysis. microbial stewardship alert: your patient has a positive

Most of the PCT algorithm used levels of less than viral PCR + negative procalcitonin + one or more anti0.1 mg/L to indicate a high likelihood of viral infection, biotics ordered. These results suggest viral infection— whereas levels more than 0.25 mg/L indicate a high please reassess necessity of antibiotics as indicated.” 23 likelihood of bacterial pneumonia. Mortality was signifiAntibiotic-days of therapy were significantly reduced cantly lower (8.6% vs 10.0%; adjusted odds ratio [aOR], in the intervention group by a mean of 2.2 days (5.8 0.83; 95% CI, 0.70-0.99; P=0.037) with PCT guidance vs 8.0 days; P<0.001). In addition, there were significompared with usual care, respectively. 21 Procalcitocantly more patients having antibiotics discontinued nin guidance was associated with a 2.4-day reducwithin 24 hours of initiation (37.8% vs 18.6%; P<0.001) tion in antibiotic exposure (5.7 vs 8.1 days; 95% CI, –2.71 and fewer patients discharged on antibiotics (20.0% to –2.15; P<0.001) and lower risk for antibiotic-relatvs 47.8%; P<0.001). 23 In the absence of ASP intervened adverse effects (16.3% vs 22.1%; aOR, 0.68; 95% CI, tion, previous evidence observed low rates of antibi0.57-0.82; P<0.001). 21 Results were similar among differotic discontinuation in patients with negative PCT and ent types of ARIs and clinical settings, supporting synpositive RVP. 24 The findings from this study emphasize drome-specific PCT use with antimicrobial stewardship. the importance of its real-world implementation strat

However, Self et al recently evaluated the association egy by leveraging indirect ASP intervention through an between serum PCT concentration with pneumonia etiautomated alert, which may be especially worthy for ology in a multicenter prospective surveillance study of minimal resource settings. 23,25 Similarly, Lee et al examadults hospitalized with CAP. 22 The investigators were ined the clinical impact of combining the RVP with PCT unable to identify a PCT threshold that allowed perfect in older adults with severe ARIs through a prospective discrimination between viral and bacterial detection, a multicenter observation study. 26 Outcomes were comchallenging goal. Although results established that there pared between the intervention group and a propenwas a lower frequency of bacterial pathogens in patients sity score–matched historical cohort. Patients in the

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

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 ≥7 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,

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

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

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 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.

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, bioMérieux, 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

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 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.

References

1. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases

Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44(2):159-177.

2. Davey P, Marwick CA, Scott CL, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane

Database Syst Rev. 2017;2:CD003543.

3. Karanika S, Paudel S, Grigoras C, et al. Systematic review and meta-analysis of clinical and economic outcomes from the implementation of hospital-based antimicrobial stewardship programs.

Antimicrob Agents Chemother. 2016;60(8):4840-4852.

4. Baur D, Gladstone BP, Burkert F, et al. Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis. Lancet Infect Dis. 2017;17(9):990-1001.

5. Wenzler E, Timbrook TT, Wong JR, et al. Implementation and optimization of molecular rapid diagnostic tests for bloodstream infections. Am J Health Syst Pharm. 2018;75(16):1191-1202.

6. Timbrook TT, Morton JB, McConeghy KW, et al. The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infections: a systematic review and meta-analysis. Clin

Infect Dis. 2017;64(1):15-23.

7. CDC. Core Elements of Hospital Antibiotic Stewardship Programs. bit.ly/2u1LAIPidse. Accessed June 22, 2020.

8. CDC. U.S. National Action Plan for combating antibiotic-resistant bacteria (National Action Plan). bit.ly/2RUCTYEIDSE. March 2015.

Accessed June 22, 2020.

9. Joint Commission. New antimicrobial stewardship standard. Joint

Commission Perspectives. 2016;36(7). bit.ly/2CXz1jSidse. Accessed

June 22, 2020.

10. Centers for Medicare & Medicaid Services. Medicare and Medicaid programs; hospital and critical access hospital (CAH) changes to promote innovation, flexibility, and improvement in patient care.

Federal Register. 2016;81(116). www.govinfo.gov/content/pkg/

FR-2016-06-16/pdf/2016-13925.pdf. Accessed June 22, 2020.

11. Pliakos EE, Andreatos N, Shehadeh F, et al. The cost-effectiveness of rapid diagnostic testing for the diagnosis of bloodstream infections with or without antimicrobial stewardship. Clin Microbiol Rev. 2018;31(3). pii: e00095-17.

12. Bookstaver PB, Nimmich EB, Smith TJ 3rd, et al. Cumulative effect of an antimicrobial stewardship and rapid diagnostic testing bundle on early streamlining of antimicrobial therapy in gram-negative bloodstream infections. Antimicrob Agents Chemother. 2017;61(9). pii: e00189-17.

13. Avdic E, Wang R, Li DX, et al. Sustained impact of a rapid microarray-based assay with antimicrobial stewardship interventions on optimizing therapy in patients with gram-positive bacteraemia.

J Antimicrob Chemother. 2017;72(11):3191-3198.

14. Fryback DG, Thornbury JR. The efficacy of diagnostic imaging.

Med Decis Making. 1991;11(2):88-94.

15. Kung HC, Hoyert DL, Xu J, et al. Deaths: final data for 2005. Natl

Vital Stat Rep. 2008;56(10):1-120. 17. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67.

18. Huang DT, Yealy DM, Angus DC, et al. Procalcitonin-guided antibiotic use. N Engl J Med. 2018;379(20):1973.

19. Ruuskanen O, Lahti E, Jennings LC, et al. Viral pneumonia. Lancet. 2011;377(9773):1264-1275.

20. Gilbert DN. Procalcitonin as a biomarker in respiratory tract infection. Clin Infect Dis. 2011;52(suppl 4):S346-S350.

21. Schuetz P, Muller B, Christ-Crain M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections.

Cochrane Database Syst Rev. 2012;(9):CD007498.

22. Self WH, Balk RA, Grijalva CG, et al. Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia.

Clin Infect Dis. 2017;65(2):183-190.

23. Moradi T, Bennett N, Shemanski S, et al. Use of procalcitonin and a respiratory polymerase chain reaction panel to reduce antibiotic use via an EMR alert. Clin Infect Dis. 2019 Oct 22. [Epub ahead of print]. doi: 10.1093/cid/ciz1042

24. Timbrook T, Maxam M, Bosso J. Antibiotic discontinuation rates associated with positive respiratory viral panel and low procalcitonin results in proven or suspected respiratory infections. Infect Dis

Ther. 2015;4(3):297-306.

25. Timbrook TT. Antimicrobial stewardship and implementation of rapid multiplex respiratory diagnostics: is there method in the madness? Clin Infect Dis . 2019 Oct 22. [Epub ahead of print]. doi: 10.1093/cid/ciz1046

26. Lee CC, Chang JC, Mao XW, et al. Combining procalcitonin and rapid multiplex respiratory virus testing for antibiotic stewardship in older adult patients with severe acute respiratory infection.

J Am Med Dir Assoc. 2020;21(1):62-67.

27. Srinivas P, Rivard KR, Pallotta AM, et al. Implementation of a stewardship initiative on respiratory viral PCR-based antibiotic deescalation. Pharmacotherapy. 2019;39(6):709-717.

28. Lee SH, Ruan SY, Pan SC, et al. Performance of a multiplex PCR pneumonia panel for the identification of respiratory pathogens and the main determinants of resistance from the lower respiratory tract specimens of adult patients in intensive care units.

J Microbiol Immunol Infect. 2019;52(6):920-928.

29. Mopuru H, Powell K, Sims MD. Potential impact of rapid diagnostics in management of suspected pneumonia. Presented at: ASM

Microbe 2017; June 1-5, 2017; New Orleans, LA.

30. Parente DM, Cunha CB, Mylonakis E, et al. The Clinical utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening to rule out MRSA pneumonia: a diagnostic meta-analysis with antimicrobial stewardship implications. Clin Infect Dis. 2018;67(1):1-7.

31. Willis C, Allen B, Tucker C, et al. Impact of a pharmacist-driven methicillin-resistant Staphylococcus aureus surveillance protocol.

Am J Health Syst Pharm. 2017;74(21):1765-1773.

32. Smith MN, Erdman MJ, Ferreira JA, et al. Clinical utility of methicillin-resistant Staphylococcus aureus nasal polymerase chain reaction assay in critically ill patients with nosocomial pneumonia.

J Crit Care. 2017;38:168-171.

33. Smith MN, Brotherton AL, Lusardi K, et al. Systematic review of the clinical utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening for MRSA pneumonia. Ann Pharmacother. 2019;53(6):627-638.

34. Carr AL, Daley MJ, Givens Merkel K, et al. Clinical utility of methicillin-resistant Staphylococcus aureus nasal screening for antimicrobial stewardship: a review of current literature. Pharmacotherapy. 2018;38(12):1216-1228.

35. Butler-Laporte G, De L’Etoile-Morel S, Cheng MP, et al. MRSA colonization status as a predictor of clinical infection: a systematic review and meta-analysis. J Infect. 2018;77(6):489-495.

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.

38. Rottier WC, Bamberg YR, Dorigo-Zetsma JW, et al. Predictive value of prior colonization and antibiotic use for third-generation cephalosporin-resistant Enterobacteriaceae bacteremia in patients with sepsis. Clin Infect Dis. 2015;60(11):1622-1630.

39. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-e50.

40. Clancy CJ, Nguyen MH. Rapid diagnosis of invasive candidiasis: ready for prime-time? Curr Opin Infect Dis. 2019;32(6):546-552.

41. Gill CM, Kenney RM, Hencken L, et al. T2 Candida versus beta-Dglucan to facilitate antifungal discontinuation in the intensive care unit. Diagn Microbiol Infect Dis. 2019;95(2):162-165.

42. Nucci M, Nouer SA, Esteves P, et al. Discontinuation of empirical antifungal therapy in ICU patients using 1,3-beta-d-glucan. J Antimicrob Chemother. 2016;71(9):2628-2633.

43. Posteraro B, Tumbarello M, De Pascale G, et al. (1,3)-ß-d-Glucanbased antifungal treatment in critically ill adults at high risk of candidaemia: an observational study. J Antimicrob Chemother. 2016;71(8):2262-2269.

44. Rautemaa-Richardson R, Rautemaa V, Al-Wathiqi F, et al. Impact of a diagnostics-driven antifungal stewardship programme in a

UK tertiary referral teaching hospital. J Antimicrob Chemother. 2018;73(12):3488-3495.

45. Ito-Takeichi S, Niwa T, Fujibayashi A, et al. The impact of implementing an antifungal stewardship with monitoring of 1-3, ß-D-glucan values on antifungal consumption and clinical outcomes. J Clin Pharm Ther. 2019;44(3):454-462.

46. Patch ME, Weisz E, Cubillos A, et al. Impact of rapid, cultureindependent diagnosis of candidaemia and invasive candidiasis in a community health system. J Antimicrob Chemother. 2018;73(suppl 4):iv27-iv30.

47. Nguyen MH, Clancy CJ, Pasculle AW, et al. Performance of the

T2Bacteria Panel for diagnosing bloodstream infections: a diagnostic accuracy study. Ann Intern Med. 2019;170(12):845-852.

48. Weinrib DA, Capraro GA. The uncertain clinical benefit of the T2Bacteria Panel. Ann Intern Med. 2019;170(12):888-889.

49. Goggin KP, Gonzalez-Pena V, Inaba Y, et al. Evaluation of plasma microbial cell-free DNA sequencing to predict bloodstream infection in pediatric patients with relapsed or refractory cancer.

JAMA Oncol. 2020;6(4):552-556. 50. Hogan CA, Yang S, Garner OB, et al. Clinical impact of metagenomic next-generation sequencing of plasma cell-free DNA for the diagnosis of infectious diseases: a multicenter retrospective cohort study. Clin Infect Dis. 2020 Jan. 14 [Epub ahead of print].

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.

52. Henig O, Kaye KS, Chandramohan S, et al. The hypothetical impact of Accelerate Pheno on time to effective therapy and time to definitive therapy for bloodstream infections due to drug-resistant gram-negative bacilli. Antimicrob Agents Chemother. 2019;63(3). pii: e01477-18.

53. Banerjee R, Komarow L, Virk A, et al. Randomized clinical trial evaluating clinical impact of RAPid IDentification and Antimicrobial Susceptibility Testing for Gram-Negative Bacteremia (RAPIDS-GN). Paper presented at: IDWeek 2019; October 2-6, 2019; Washington, DC.

54. Mouton JW, Muller AE, Canton R, et al. MIC-based dose adjustment: facts and fables. J Antimicrob Chemother. 2018;73(3):564-568.

55. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis. 2007;44(3):357-363.

56. Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072-1083.

57. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA. 2016;315(17):1864-1873.

58. Sanchez GV, Fleming-Dutra KE, Roberts RM, et al. Core elements of outpatient antibiotic stewardship. MMWR Recomm Rep. 2016;65(6):1-12.

59. Tonkin-Crine SK, Tan PS, van Hecke O, et al. Clinician-targeted interventions to influence antibiotic prescribing behaviour for acute respiratory infections in primary care: an overview of systematic reviews. Cochrane Database Syst Rev. 2017;9:CD012252.

60. Brendish NJ, Malachira AK, Beard KR, et al. Impact of turnaround time on outcome with point-of-care testing for respiratory viruses: a post hoc analysis from a randomised controlled trial. Eur Respir

J. 2018;55(1). doi: 10.1183/13993003.00555-2018

61. Linder JA, Singer DE, Stafford RS. Association between antibiotic prescribing and visit duration in adults with upper respiratory tract infections. Clin Ther. 2003;25(9):2419-2430.

62. Kozel TR, Burnham-Marusich AR. Point-of-care testing for infectious diseases: past, present, and future. J Clin Microbiol. 2017;55(8):2313-2320.

Dr Fong reported no relevant fi nancial relationships. Dr Timbrook reported several relationships, but has since taken a position with BioFire Diagnostics.

This article is from: