Rapid Diagnostic Testing and Biomarkers Implementation The Starring Role of Antimicrobial Stewardship

Rapid Diagnostic Testing and Biomarkers Implementation:

The Starring Role of Antimicrobial Stewardship

BY KAREN FONG, PHARMD, BCIDP

In the clinical microbiology laboratory, there have been truly exciting advances in microbiological diagnoses using rapid diagnostic tests (RDTs). The management of bacterial, viral, and fungal diseases has been fundamentally transformed by providing early clinical decision making through technological growth with the prospect of significantly affecting clinical outcomes, antimicrobial use, and cost savings.1-3 Although there are still shortcomings with antimicrobial susceptibility testing for bacterial and fungal cultures, RDTs provide valuable information to the clinical presentation, facilitating selection of empiric antimicrobial coverage by the prediction of susceptibility patterns based on local antibiograms.

In the early stages of sepsis, every hour of delay in commencing effective antimicrobial therapy increases the risk for death.4 The distinction between viral and bacterial infection, determination of specific bacterial etiology, and antimicrobial susceptibility testing must be available to quickly achieve maximum clinical benefit. In a proposed series by Inglis and Ekelund, 3 linked decision-making milestones with specific goals may resolve a trade-off between diagnostic confidence and therapeutic efficacy (Figure).5 The integration of RDTs into the initial investigation for sepsis and clinical laboratory workflow may expedite optimal disease management.

RDT results must be actionable and promptly addressed with appropriate clinical interpretation and corresponding antimicrobial therapy adjustment. The role of antimicrobial stewardship programs (ASPs) may be exploited to correctly interpret and rapidly communicate results, directing clinicians to appropriate antimicrobial therapy.6 ASPs have continuously demonstrated their value through the improvement of clinical outcomes and reduction of adverse events by optimizing antimicrobial use.7,8 Inpatient ASPs have concomitantly improved the rates of infection

cures and combat challenges with Clostridioides difficile infections, antimicrobial resistance, adverse effects, length of stay (LOS), and costs.8-10 RDTs combined with ASP intervention, particularly bloodstream infections (BSIs), have consistently provided meaningful results on antimicrobial optimization and patient outcomes.1,2 Rapid testing for broad panels of respiratory viruses also has been deemed by ASP guidelines as an important intervention to reduce the inappropriate use of antibiotics.11

Bauer et al created a checklist to highlight the role of ASPs as an active messenger and educator in the implementation and incorporation of RDTs (Table).12 Among the array of newer diagnostic approaches, tests, and platforms, collaboration between clinical microbiologists and ASPs is essential to determine which tests are appropriate and which cost justification and implementation strategies are effective at an institution level.12,13 The impact of RDTs is contingent on clinical context, patient flow, and access and timing. Therefore, emphasis should be placed on deriving their maximal benefit through the implementation of efficient evidence-based ASP interventions.2,14,15 In this review, we discuss novel RDTs including respiratory, biomarkers and sepsis diagnostics, advances in blood culture testing, and prospects of outpatient point of care as well as their performance with current diagnostic stewardship practices.

Respiratory

Procalcitonin and Respiratory Viral Panels

In the United States, pneumonia has been a major contributor of morbidity and mortality, causing an estimated 63,000 deaths and 1.2 million hospitalizations annually.16,17 The American Thoracic Society/ Infectious Diseases Society of America (ATS/IDSA) recommendations for empiric antimicrobial therapy in community-acquired pneumonia (CAP) are based on selecting agents targeted against the major treatable respiratory bacterial pathogens.18 Unfortunately, overuse of antibiotics is common in lower respiratory tract infections (LRTIs), as there is difficulty in distinguishing between bacterial and viral etiologies due to similar manifestations.19 Antibiotic therapy may be safely withheld in patients with isolated viral pneumonia if these infections can be easily identified from those with concomitant bacterial etiology.20

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.21 The ATS/IDSA CAP guidelines for adults, updated in 2019, include recommendations for the use of PCT. Empiric antibiotic therapy is recommended for adults with clinically suspected and radiographically confirmed CAP, regardless of initial serum PCT level.18 This recommendation acknowledges the findings of an updated Cochrane review assessing the safety and efficacy of using PCT for initiating or discontinuing antibiotics among a variety of patients with acute respiratory infections (ARIs) from different clinical settings. Thirty-two randomized trials of adults with ARIs who received an antibiotic based on either a PCT-guided antibiotic stewardship algorithm or usual care were included for analysis. Most of the PCT algorithm used levels less than 0.1 mg/L to indicate a high likelihood of viral infection, whereas levels

Initial Clinical Assessment

Using a clinical score (eg, qSOFA) Goal time <10 min ➧

Initial Sepsis Investigation

Baseline laboratory tests Empiric antimicrobial therapy Basic resuscitation Goal time <1 h ➧

Infectious Disease Management

Defi nitive antimicrobial susceptibility testing Corresponding antimicrobial therapy adjustment Goal time <8 h

Figure. Three linked decision-making milestones for sepsis in relation to infectious disease management.

qSOFA, quick Sequential Organ Failure Assessment

greater 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.22 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).22 Results were similar among different types of ARIs and clinical settings, supporting syndromespecific PCT use with antimicrobial stewardship. However, Self et al evaluated the association between serum PCT concentration with pneumonia etiology in a multicenter prospective surveillance study of adults hospitalized with CAP.23 The authors were unable to identify a PCT threshold that allowed perfect discrimination between viral and bacterial detection—a challenging goal. While results established that there was a lower frequency of bacterial pathogens in patients with PCT below both the 0.1-ng/mL (6%) and 0.25-ng/mL (8%) thresholds, this also indicates that clinicians cannot solely rely on PCT to guide antibiotic treatment decisions.23 This was further supported by a meta-analysis of 12 studies including 2,408 CAP patients, demonstrating that PCT sensitivity and specificity are too low and variable at 0.55 (95% CI, 0.37-0.71; I2=95.5%) and 0.76 (95% CI, 0.62-0.86; I2=94.1%), respectively. Thus, PCT is unlikely to provide reliable evidence that will enable clinicians to confidently address whether the infection is bacterial or viral.24 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 multicenter randomized controlled trial. Outcomes may have been limited by subpar adherence to the PCT antibiotic prescribing guideline and lack of real-time prospective audit and feedback.19 Therefore, implementation may have failed to demonstrate benefit in the absence of ASP intervention.

Serial PCT measurement also has been recognized by the ATS/IDSA as likely useful to primarily reduce duration of therapy (DOT) where the average LOS for patients with CAP exceeds the expected duration of 5 to 7 days.18 However, PCT may have little role in decreasing antibiotic duration for CAP if prospective audit and feedback is designed to target a specific DOT. In a retrospective cohort at 2 community teaching hospitals, PCT with routine audit and feedback compared with a 5-day course recommendation for uncomplicated CAP as targeted audit and feedback

resulted in similar DOT (5.4 vs 5.5 days; P=0.8, respectively) without differences observed in patient outcomes.25 In a single-center, retrospective, observational pre-post study of inpatients with CAP, a standardized order set with a single dose of IV ceftriaxone followed by an automatic transition to oral cefuroxime for a total antibiotic duration of 5 days coupled with active antimicrobial stewardship and provider feedback led to significantly shorter length of IV and total antibiotic therapy and 20% cost reduction with similar clinical outcomes.26 Although PCT was ordered once on admission as part of the pathway, this was unlikely to be the driver of the robust improvements in antibiotic use and decreased costs. The respiratory viral polymerase chain reaction (PCR) assays, the FilmArray Respiratory Panel (BioFire Diagnostics) and eSensor Respiratory Viral Panel (GenMark Diagnostics), Respiratory may be useful in reducing the use of inappropriate antibiotics. Antimicroviral and PCR bial stewardship guidelines advocate rapid testing for broad panels of respiassays may ratory viruses.11 However, use of respiratory viral testing in the inpatient and outpatient settings remains low—pribe useful marily for influenza and rhinovirus testing. Antibiotic prescribing pracin reducing tices based on test results were also inconsistent.27,28 Combination with antibiotic PCT may be more likely to exclude bacterial coinfection with confidence in a meaningful period.14 Moradi et al prescribing. explored the use of respiratory viral panel (RVP) combined with PCT and an automated ASP provider alert in a multicenter quasi-experimental study. If 3 criteria were met—PCT less than 0.25 ng/mL, virus detected on RVP, and active use of systemic antibiotics—the automated alert would prompt de-escalation.29 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).29 In addition, antibiotics were discontinued within 24 hours of initiation for significantly more patients (37.8% vs 18.6%; P<0.001), and fewer patients were discharged on antibiotics (20.0% vs 47.8%; P<0.001).29 In the absence of ASP intervention, previous evidence observed low rates of antibiotic discontinuation in patients with negative PCT and positive RVP.30 This real-world implementation strategy leveraged indirect ASP intervention through an automated alert, which may be especially worthwhile for minimal-resource settings.29,31 Similarly, Lee et al examined the clinical effect of combining the RVP with PCT in older adults with severe ARIs through a prospective multicenter observation study.32 Outcomes were compared between the intervention group and a propensity score–matched

historical cohort. Patients in the intervention group had significantly more antibiotics de-escalated (21.9% vs 13.2%; P=0.007), a shorter duration of IV antibiotics used (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 shorter LOS (median, 14.0; IQR, 5.020.5 days vs median, 16.1 days; IQR, 6.0-24.5 days; P=0.030).32 The authors did not incorporate formal ASP in their study but had a study nurse promote stewardship by communicating the test results and reminding the physicians of the antibiotic treatment recommendations based on different testing results.32 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.19,22,29,32-34

LRTI Panels

Multiple syndromic molecular testing panels for LRTIs, including the BioFire FilmArray Pneumonia Panel and Curetis Unyvero Lower Respiratory Tract (LRT) Panel, offer increased sensitivity over clinical cultures and provide 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 bacteria using qualitative targets, and 15 bacterial targets with semiquantitative analysis that can assist in evaluating colonization versus infection. The Curetis panel includes detection of 29 bacterial pathogens and 19 resistance genes. Both panels can be used with multiple specimen types (sputum, endotracheal aspirates, and bronchoalveolar lavage fluid). Although semiquantitative analysis may improve the clinical specificity, neither molecular testing panels nor culture separate airway colonizers from invasive pathogens. The possibility of a downstream effect of paradoxically increasing antimicrobial use should be a notable concern. These panels may be most useful in situations where patients have new or worsening lung infiltrates, are moderately to severely ill, have received empiric antibiotics prior to obtaining cultures, and/or there is concern for multidrug-resistant bacteria or a polymicrobial infection.14 The BioFire FilmArray Pneumonia Panel demonstrates a positive percent agreement (PPA) and negative percent agreement (NPA) of 98.1% and 96.2%, respectively, for the identification of bacterial targets on bronchoalveolar lavage specimens compared with culture.35 Similarly, a high overall agreement of 99.2% (95% CI, 98.4%-99.6%) for viral detection is observed between the FilmArray panel and culture.36 The excellent sensitivity of the pneumonia panel may be useful to rule out bacterial coinfections and avoid inappropriate prescribing of antibiotics, but positive results should be interpreted with caution. In a multinational study of 52 laboratories, the largest to date, the panel identified significantly more positive specimens (76.1%) than standard-of-care (SOC) testing (56.03%; P≤0.0001) and more potential pathogens than SOC (P≤0.0001) independent of specimen type with the largest discrepancies for fastidious pathogens.37 Lower SOC bacteria detection may be explained by local reporting guidelines and testing of specimens from patients on antibiotics.37 Yoo et al accurately detected resistance genes using the pneumonia panel, showing concordant results for the resistant organisms identified by culture; however, the genetic marker of antimicrobial resistance, particularly the CTX-M and carbapenemase genes, could not be definitively linked to the microorganisms detected.38 Thus, culture testing is essential to confirm susceptibility or resistance.

In summary, the panel carries interpretation challenges including understanding the increased detection rates, colonization and infection differentiation, and the presence of resistance markers without linkage to a specific pathogen.37 A recent study prospectively examined sputum specimens in 70 patients with pneumonia, and the potential for antibiotic optimization was observed in 56 of 70 patients.39 Nine bacteria in 9 patients were not covered by empiric therapy, and 70 antibiotics in 49 patients could have been discontinued.39 Likewise, a retrospective multicenter study observed antimicrobial de-escalation in 63 of 159

Table.Antimicrobial Stewardship Program Checklist for Rapid Diagnostic Tests

Pre-implementation

• Identify most useful RDT based on hospital pathogen prevalence • Identify hospital cost of infection based on ICD-10 code mortality data, LOS, and 30-day readmission • Time to effective therapy • Time to infectious diseases specialist consult

Implementation

• Microbiologist-validated RDT instrument • Determine whether test is done in real time 24/7 or batch • Establish communication of RDT results from microbiology to physician and ASP pharmacist • Education of medical staff by ASP pharmacist and physician • Document interventions and acceptance rate by ASP

Post-implementation

• Time to effective therapy • Time to antimicrobial discontinuation or de-escalation • Time to infectious diseases specialist consult • LOS • 30-day readmission • Mortality

ASP, antimicrobial stewardship program; ICD-10, International Classification of Diseases, 10thRevision; LOS, length of stay; RDT, rapid diagnostic test (40%) and escalation in 35 (22%) of hospitalized pneumonia patients based on FilmArray panel results.40 This reinforces the panel’s potential to reduce unnecessary antimicrobial exposure and increase the appropriateness of empiric antibiotic therapy.

The Curetis Unyvero LRT Panel also has reported robust diagnostic accuracy. In an evaluation by Collins et al, the PPA and NPA for the bacterial targets was 96.5% and 99.6%, respectively.41 Also, Klein et al found a high overall PPA and NPA with culture, but 21.7% of specimens had additional potential pathogens identified by the panel.42 The positive predictive value for antibiotic resistance markers compared with antibiotic susceptibility testing ranged from 80% to 100%.42 For the resistance targets, interpretation challenges were observed, as not all genes could be attributed to an organism, highlighting that current culture methods with antimicrobial susceptibility testing must be maintained while pursuing consistency in technological advances.41 Moreover, the Curetis panel had the potential to earlier initiation of effective antibiotic therapy in 20 of 95 patients (21%) and de-escalation in 37 patients (39%) with ventilator-associated pneumonia in a prospective study.43 Pickens et al predicted antibiotic de-escalation from unnecessary methicillinresistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa coverage in 65.9% (405/615) of patients.44 Challenges with interpretation of newer RDTs, especially with resistance genes, are of concern but may be potentially mitigated by ASP intervention, requiring further exploration.

Clinical Utility of Surveillance Screening MRSA Nasal PCR

MRSA nasal screens, such as the Cepheid GeneXpert SA Nasal, have evolved beyond use for infection prevention and control practice to have 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 (NPV) for the use of the test in ruling out MRSA pneumonia.45 Therefore, the ATS/ IDSA CAP guidelines endorsed the routine use of MRSA nasal PCR screening for the de-escalation of MRSA coverage.18 ASP implementation of this approach has been associated with a median decrease of 2.1 days of vancomycin (P<0.01).46 Other implementation results of nasal screening in suspected or confirmed pneumonia among ICU patients have been associated with $108 per patient in cost avoidance based on the cost of surveillance testing, vancomycin, and vancomycin therapeutic drug monitoring levels.47 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.48,49 Systematic reviews and meta-analyses also have supported the use of the screen for NPV beyond pneumonia, such as in

skin and soft tissue infections.50 A national study from the Veterans Affairs system has supported this concept in the largest cohort to date including clinical cultures (N=561,325).51 These data showed a high overall NPV 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%). In contrast, while the surveillance of gramnegative 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 show significant promise.52,53

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 a 50% reduction in mortality. However, this is often delayed due to blood culture insensitivity, the prolonged turnaround time (median time to positivity of 2-3 days, ranging from 1 to ≥7 days) needed to yield growth, and the possibility of negative growth with invasive abdominal candidiasis.54 These limitations propagate overuse of empiric antifungal therapy for suspected invasive candidiasis, which is a practice of unproven clinical value.55 Nonculture diagnostic tests such as the Fungitell beta-D-glucan (BDG) detection assay (Associates of Cape Cod) and the T2Candida Panel (T2 Biosystems) have a much shorter turnaround time (3-5 hours) and entered clinical practice as adjunctive RDT to cultures.54-57 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, and there is concern for false positivity in some circumstances.54 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 did not incorporate active ASP intervention.58,59

Rautemaa-Richardson et al developed a local ASPdriven guideline for the diagnosis and management of suspected or proven invasive candidiasis in nonneutropenic adult patients.60 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 authors 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 then without ASP intervention, in 2016.60 Antifungal consumption also was evaluated over a 2-year period between 2014 and 2016. Results demonstrated that there were significant changes in that time 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 to 19% from 45% in the study period compared with the historical cohort in 2003-2007, respectively. Furthermore, a decrease in micafungin consumption by 49% was observed.60 While 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 use 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 monitoring on antifungal consumption and clinical outcomes of patients with candidiasis.61 The ASP recommended stopping antifungal therapy in cases with negative BDG, but testing appeared to be at the physician’s discretion. Overall antifungal use was not significantly decreased after intervention, but there was a significant reduction in 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 being 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%).61 However, in 197 oncologic patients and solid-organ transplant recipients, a pre-post study observed that serial BDG on days 1, 3, and 5 of antifungal treatment complemented with ASP bedside advice resulted in reduced median days of empiric antifungal therapy (9 vs 5 days; P=0.04) compared with ASP bedside advice alone.62 Probable or proven fungal infections and allcause mortality were similar in both periods.

Although false-negative BDG results are considered rare, a retrospective study of 148 adult patients with proven candidemia found 26 (17.6%) patients with persistently negative BDG tests. In a multivariable analysis, persistently negative BDG tests were independently associated with better prognoses (OR, 0.12; 95% CI, 0.03-0.49; P=0.003), probably due to lower systemic fungal burden.63

Molecular Candida platforms, such as the T2Candida Panel and Karius Test, detecting Candida species

In the early stages of sepsis, every hour of delay in starting eff ective antimicrobial therapy increases the risk for death.

DNA from whole blood have emerged. While sensitivity and specificity seem to be more promising compared with blood cultures, the role of these technologies in the early diagnosis and management of candidemia remains unclear.54 Patch et al evaluated the effect of T2Candida 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 DOT in patients without microbiological evidence of invasive candidiasis. The authors 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 DOT was 6.7 days compared with 2.4 days in patients with negative T2Candida results without mycological evidence in the post-T2Candida group. This resulted in a total antifungal cost savings of $48,440 (or $280 per tested patient).64 Of concern, discordance was observed in 3 patients with unpaired positive blood cultures and a negative T2Candida result.64 In a more recent retrospective review, Bomkamp et al found in 433 paired T2Candida cultures that overall antifungal DOT improved after implementation of the panel, but micafungin use continued to decline after the panel was removed.65 This was likely due to the concomitant increased stewardship resources including physician-directed prospective audit and feedback around implementation. In contrast, Steuber et al observed different results while retrospectively evaluating 628 T2Candida results at a large community hospital with prospective audit and feedback performed on negative results typically within 24 hours. An antifungal was ordered in 265 (42.4%) of cases, and appropriate de-escalation/optimization (ie, discontinuation) of therapy occurred in 143 (54%) of these cases. There were 120 (53.3%) of 225 negative results where antifungal therapy was not discontinued within 48 hours, despite being negative. In the regression model, ICU LOS was predictive of failure to discontinue antifungal therapy within 48 hours of negative results (OR, 0.96; 95% CI, 0.94-0.99; P=0.002). Patients with negative results had significantly fewer days of antifungal therapy compared with positive tests (4.9±6.3 vs 10±10 days, respectively; P=0.03).66 Unfortunately, antifungal discontinuation with negative tests was unexpectedly low even with antimicrobial stewardship intervention. Further study is warranted to assess whether negative results would provide any additional value to patients already at substantially high risk for fungal infections.

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 quasiexperimental study on their facilitation in antifungal discontinuation.56 During the study period, there was a systemwide guideline on the SOC for invasive candidiasis, which included either BDG or T2Candida. Negative results for either were encouraged to discontinue echinocandin therapy. In addition, the ASP reviewed BDG and T2Candida results for patients on anidulafungin (Eraxis, Roerig) during both periods. Among 206 ICU patients, median DOT was 2 (1-5) days compared with 1 (1-2) day in the BDG and T2Candida group, 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).56

The T2Bacteria Panel (T2 Biosystems) recently made its debut detecting bacteria DNA by T2 magnetic resonance 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, Staphylococcus aureus, Klebsiella pneumoniae, P. aeruginosa, and Escherichia coli were 90% (95% CI, 76%-96%) and 90% (95% CI, 88%-91%), respectively.67 The NPV was 99.7%. Limited to only 5 bacteria, the sensitivity and specificity for any organism was 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.67 Voigt et al examined 137 emergency department patients from 2 centers in a prospective noninterventional T2Bacteria clinical study.68 Relative to blood culture, T2Bacteria showed 100% PPA and 98.4% NPA. The panel detected 25% more positive results associated with evidence of infection and identified bacteria 56.6 hours faster, on average, compared with blood culture. T2Bacteria could have potentially

de-escalated therapy in 8 patients, reduced time to species-directed therapy in 4 patients, and reduced time to effective therapy in 4 patients.68 A substudy of a larger prospective multicenter clinical trial evaluated the significance of positive T2Bacteria cases with negative blood cultures to determine whether these results were false positives or potentially associated with an infection. Among 233 participants, 20 were identified with 21 (9%) discordant results.Eleven (52.5%) cases had probable BSIs, 4 (19%) had possible BSIs, and 6 (28.5%) were presumptive false positives.69 The discrepancies observed for probable and possible BSIs appeared to be associated with closed space and localized infections, such as pyelonephritis and abscess, and recent use of active antibiotics.69 Further prospective, ideally interventional, studies are needed to justify its role along with ASPs in patient care.70

Karius testing has offered a new potential tool in the ASP armamentarium of microbiologist testing. This novel metagenomic microbiological diagnostic test uses plasma microbial cell–free DNA sequencing to identify 1,250 bacteria, fungi, parasites, and viruses.71,72 While expensive and clinical data are fairly limited, this new technology has shown promise in diagnosing and identifying causative infectious etiologies for pneumonia, bacteremia, and general sepsis despite pretreatment with antibiotics. Next-generation sequencing (NGS) may be most useful in mitigating the delay of targeted treatment and excessive broad-spectrum antimicrobial use in immunocompromised hosts where a broader range of pathogens is on the differential. However, Niles et al observed little diagnostic value with NGS compared with conventional testing (CT).73 There was 61% positive agreement and 58% negative agreement between NGS and CT among 60, most being immunocompromised pediatric patients. On average, CT provided the same result as NGS, but 3.5 days earlier. Antimicrobial therapy was only changed 26% of the time when additional organisms were identified by NGS.73 Larger studies are needed to validate these findings.

RDTs 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 microbiological cultures. Implementation of PCR-based technologies (eg, BioFire FilmArray BCID, GenMark ePlex BCID), nanoparticle probe technology (eg, VERIGENE BC-GP and BC-GN), or matrix-assisted laser desporption/ionization time of flight (eg, bioMérieux, BD Bruker) have been associated with decreases in time to effective therapy, hospital LOS, and mortality when associated with ASP interventions.2 Similar to the clinical impacts observed, a cost-effectiveness analysis also has reflected benefits of molecular RDTs in BSIs.74 These data also highlight the strong synergy of stewardship and RDT has an 80% chance of cost-effectiveness with an ASP, but only 41.1% without.

The introduction of automated rapid phenotypic testing systems such as the Accelerate Pheno system (Accelerate Diagnostics) can yield organism identification, minimum inhibitory concentration (MIC), and susceptibility interpretation with a turnaround time of approximately 7 hours after positive blood culture. Several studies have explored the Accelerate Pheno system coupled with ASP intervention. Results of 448 patientswith gram-negative BSIs in a randomized controlled trial with prospective audit and feedback in both arms reflected significantly faster antibiotic changes (median decrease of approximately 25 hours for gram-negative antibiotics; P<0.001) with the Accelerate Pheno system compared with culture. Antibiotic escalation also was significantly faster with the Accelerate Pheno system relative to culture-based methods for antimicrobial resistant BSIs (median decrease of approximately 43 hours; P=0.01). There were no differences between arms in patient outcomes, including LOS and mortality.75 Four quasi-experimental beforeand-after observational studies analyzed integration of Accelerate Pheno with ASP intervention with variable results in patient outcomes.76,77 Dare et al included 496 bacteremic episodes at a single center with routine prospective audit and feedback on positive blood cultures.77 Median LOS was significantly

Although there are still shortcomings, RDTs provide valuable information to the clinical presentation of patients.

shorter (6.3 and 6.7 days vs 8.1 days; P=0.001) with Accelerate Pheno with or without real-time notification (RTN) compared with the historical cohort of culture-based methods. Median antimicrobial DOT also was significantly shorter in both intervention arms compared with the historical cohort (6 each vs 7 days; P=0.011).77 Although LOS and DOT significantly improved after Accelerate Pheno implementation, the addition of RTN did not show further improvement in the setting of an active ASP, suggesting integration may omit resources to include RTN.

Ehren et al observed in 204 patients that median time from Gram stain to optimal therapy (7 vs 11 hours; P=0.024) and step-down antimicrobial therapy (12 vs 27.8 hours; P=0.019) were significantly shorter in the use of Accelerate Pheno with bedside ASP intervention compared with conventional diagnostics with or without ASP intervention; however, groups did not differ in DOT or LOS.76 Similarly, Walsh et al found time to definitive therapy improved with the Accelerate Pheno system bundled with ASP intervention in 206 non-critically ill patients with gram-negative BSIs.78 Post-intervention was associated with shorter median total DOT (9.5 vs 14.2 days; P<0.001) and mean hospital LOS (5.3 vs 7.9 days; P=0.047) compared with preintervention, respectively.78 Robinson et al observed median time to institutional preferred antimicrobial therapy decrease by 21.2 hours (P<0.001) with Accelerate Pheno compared with SOC in 514 patients with gram-negative BSIs.79 Antibiotic use (days of therapy/1,000 days present) improved with Accelerate Pheno by decreasing broad-spectrum agents (655.2 vs 585.8; P=0.043) and increasing narrow-spectrum beta-lactams (69.1 vs 141.7; P<0.001).79 Of concern, discrepant results occurred in 69 of 250 cases (28%) with the Accelerate Pheno system, resulting in incorrect ASP recommendations in 10 of 69 cases (14%).79 No differences in DOT, LOS, and mortality between the groups were observed. In 55% of these cases, the most common impact was continuation of unnecessarily broad therapy.

Although susceptibility interpretation may have a great deal of variability associated with MIC testing,80 the introduction of rapid phenotypic testing may be of particular importance to ASPs in the critically ill related to 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.81 Prospective evaluations of critically ill patients have reflected common underdosing for PK/PD targets.82 Therefore, the use of rapid phenotypic technologies, such as Accelerate Pheno, combined with therapeutic drug monitoring among critically ill patients likely has the potential to significantly affect patient outcomes.

Outpatient Antimicrobial Prescribing And Diagnostic Potential

The focus of antibiotic stewardship on the outpatient setting is relatively new. Population database evaluations of antimicrobial prescribing in the United States suggest at least one-third of prescribing is inappropriate, the majority attributed to respiratory infections.83 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.84 A systematic review on interventions to influence prescriber behavior in ARIs in primary care demonstrated that C-reactive protein testing, shared decision making, and PCT-guided management hold promise for decreasing inappropriate use of antibiotics.85 In contrast, conclusions could not be made on the utility of respiratory diagnostics, as studies were few or of very low quality.

Respiratory RDTs in outpatient settings are evolving. While influenza testing using digital lateral flow immunoassays, such as the BD Veritor Plus system, in the primary care setting are widely available, the use of point-of-care molecular testing has been limited related to regulations about where testing can be performed (Clinical Laboratory Improvement Amendments [CLIA] waivers), and by whom, as well as logistical issues of achieving turnaround time during clinic visits. The first CLIA-waived nucleic acid amplification test, Alere i influenza A&B, was approved in 2015. In 2016, the BioFire FilmArray Respiratory Panel EZ (RP EZ), a CLIA-waived 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 BioFire FilmArray RP EZ panel in a pediatric clinic among 430 patients at 2 clinics. In clinic A, the RP EZ was used routinely at provider discretion, while 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).86 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.86 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).86 Although promising, these results are very likely limited by the turnaround time of the CLIAwaived test of approximately 1 hour. Additional uncertainty arises from their second-phase study where the implementation of RP EZ did not reduce the use

of downstream health care resources including tests, telephone calls, and follow-up appointments.87

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 RVP use 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.88 As mean office visit times for RTIs are often 15 minutes, the logistics of primary care require technologies that can accommodate these time constraints.89 With the development of such technologies, determination will be needed of what patient population to target, which targets provide clinical utility (antibiotic avoidance, antiviral use, lab and imaging use, and subsequent health care use), and the optimal implementation strategies of these panels.90 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 in the outpatient setting may be limited.31

Conclusion

For severe RTIs, sepsis, candidiasis, BSIs, PK/PD optimization opportunities, and outpatient respiratory infections, a multitude of advances are occurring in the realm of RDT technology. These technologies, along with evidence-based ASP interventions, have demonstrated promise in improving patient care. Since RDTs are complex interventions with their effect contingent on clinical context, patient flow, and access and timing, critical importance should be placed on performing RDT efficacy evaluations. ASPs may be successfully engaged in this essential role to maximize appropriateness and effectiveness of RDTs at the institution-specific level. The goal should be to improve diagnostic accuracy and speed, influence diagnostic thinking of clinicians, change subsequent clinical management, affect patient outcomes, and yield overall cost-effectiveness.

References

1. 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.

2. 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.

3. Brendish NJ, Malachira AK, Armstrong L, et al. Routine molecular point-of-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (ResPOC): a pragmatic, open-label, randomised controlled trial. Lancet Respir Med. 2017;5(5):401-411.

4. Kumar A, Zarychanski R, Light B, et al. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit Care

Med. 2010;38(9):1773-1785. 5. Inglis TJJ, Ekelund O. Rapid antimicrobial susceptibility tests for sepsis; the road ahead. J Med Microbiol. 2019;68(7):973-977.

6. Messacar K, Parker SK, Todd JK, et al. Implementation of rapid molecular infectious disease diagnostics: the role of diagnostic and antimicrobial stewardship. J Clin Microbiol. 2017;55(3):715-723.

7. 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.

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

Database Syst Rev. 2017;2(2):CD003543.

9. 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.

10. 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.

11. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: Guidelines by the Infectious Diseases

Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62(10):e51-e77.

12. Bauer KA, Perez KK, Forrest GN, et al. Review of rapid diagnostic tests used by antimicrobial stewardship programs. Clin Infect Dis. 2014;59(suppl 3):S134-S145.

13. Morency-Potvin P, Schwartz DN, Weinstein RA. Antimicrobial stewardship: How the microbiology laboratory can right the ship.

Clin Microbiol Rev. 2017;30(1):381-407.

14. Hanson KE, Azar MM, Banerjee R, et al. Molecular testing for acute respiratory tract infections: clinical and diagnostic recommendations from the IDSA’s Diagnostics Committee. Clin Infect

Dis. 2020;71(10):2744-2751.

15. Patel SV, Pulcini C, Demirjian A, et al. Rapid diagnostic tests for common infection syndromes: less haste, more speed.

J Antimicrob Chemother. 2020;75(8):2028-2030.

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

Natl Vital Stat Rep. 2008;56(10):1-120.

17. Ramirez JA, Wiemken TL, Peyrani P, et al. Adults hospitalized with pneumonia in the United States: incidence, epidemiology, and mortality. Clin Infect Dis. 2017;65(11):1806-1812.

18. 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.

19. Huang DT, Yealy DM, Angus DC, the Pro ACTI. Procalcitoninguided antibiotic use. N Engl J Med. 2018;379(20):1973.

20. Ruuskanen O, Lahti E, Jennings LC, et al. Viral pneumonia.

Lancet. 2011;377(9773):1264-1275.

21. Gilbert DN. Procalcitonin as a biomarker in respiratory tract infection. Clin Infect Dis. 2011;52 Suppl4:S346-S350.

22. 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.

23. 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.

24. Kamat IS, Ramachandran V, Eswaran H, et al. Procalcitonin to distinguish viral from bacterial pneumonia: A systematic review and meta-analysis. Clin Infect Dis. 2020;70(3):538-542.

25. Clark LT, Beuschel TS, Buss PM, et al. Comparison of procalcitonin testing to a targeted audit-and-feedback strategy on prescribed durations of therapy for community-acquired pneumonia. Diagn Microbiol Infect Dis. 2021;99(1):115202.

26. Ciarkowski CE, Timbrook TT, Kukhareva PV, et al. A pathway for community-acquired pneumonia with rapid conversion to oral therapy improves health care value. Open Forum Infect Dis. 2020;7(11):ofaa497.

27. Burrowes SAB, Rader A, Ni P, et al. Low uptake of rapid diagnostic tests for respiratory tract infections in an urban safety net hospital. Open Forum Infect Dis. 2020;7(3):ofaa057.

28. Klompas M, Imrey PB, Yu PC, et al. Respiratory viral testing and antibacterial treatment in patients hospitalized with communityacquired pneumonia. Infect Control Hosp Epidemiol. 2020:1-9.

29. 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. 2020;71(7):1684-1689.

30. 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.

31. Timbrook TT. Antimicrobial stewardship and implementation of rapid multiplex respiratory diagnostics: Is there method in the madness? Clin Infect Dis. 2020;71(7):1690-1692.

32. 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.

33. 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.

34. Covert K, Bashore E, Edds M, et al. Utility of the respiratory viral panel as an antimicrobial stewardship tool. J Clin Pharm Ther. 2021;46(2):277-285.

35. Buchan BW, Windham S, Balada-Llasat JM, et al. Practical comparison of the BioFire FilmArray pneumonia panel to routine diagnostic methods and potential impact on antimicrobial stewardship in adult hospitalized patients with lower respiratory tract infections. J Clin Microbiol. 2020;58(7):e00135-20.

36. Webber DM, Wallace MA, Burnham CA, et al. Evaluation of the

BioFire FilmArray pneumonia panel for detection of viral and bacterial pathogens in lower respiratory tract specimens in the setting of a tertiary care academic medical center. J Clin

Microbiol. 2020;58(7):e00343-20.

37. Ginocchio CC, Garcia-Mondragon C, Mauerhofer B, et al. Multinational evaluation of the BioFire(R) FilmArray(R) pneumonia plus panel as compared to standard of care testing. Eur J Clin

Microbiol Infect Dis. 2021 Mar 2. doi:10.1007/s10096-021-04195-5.

38. Yoo IY, Huh K, Shim HJ, et al. Evaluation of the BioFire

FilmArray pneumonia panel for rapid detection of respiratory bacterial pathogens and antibiotic resistance genes in sputum and endotracheal aspirate specimens. Int J Infect Dis. 2020;95:326-331.

39. Zacharioudakis IM, Zervou FN, Dubrovskaya Y, et al. Evaluation of a multiplex PCR panel for the microbiological diagnosis of pneumonia in hospitalized patients: experience from an academic medical center. Int J Infect Dis. 2021;104:354-360.

40. Monard C, Pehlivan J, Auger G, et al. Multicenter evaluation of a syndromic rapid multiplex PCR test for early adaptation of antimicrobial therapy in adult patients with pneumonia. Crit Care. 2020;24(1):434. 41. Collins ME, Popowitch EB, Miller MB. Evaluation of a novel multiplex PCR panel compared to quantitative bacterial culture for diagnosis of lower respiratory tract infections. J Clin Microbiol. 2020;58(5):e02013-19.

42. Klein M, Bacher J, Barth S, et al. Multicenter evaluation of the

Unyvero platform for testing bronchoalveolar lavage fluid. J Clin

Microbiol. 2021;59(3):e02497-20.

43. Peiffer-Smadja N, Bouadma L, Mathy V, et al. Performance and impact of a multiplex PCR in ICU patients with ventilator-associated pneumonia or ventilated hospital-acquired pneumonia.

Crit Care. 2020;24(1):366.

44. Pickens C, Wunderink RG, Qi C, et al. A multiplex polymerase chain reaction assay for antibiotic stewardship in suspected pneumonia. Diagn Microbiol Infect Dis. 2020;98(4):115179.

45. 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.

46. 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.

47. 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.

48. 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.

49. 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.

50. 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.

51. 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;71(5)1142-1148.

52. 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.

53. 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.

54. 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):e1-50.

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

56. Gill CM, Kenney RM, Hencken L, et al. T2 Candida versus beta-

D-glucan to facilitate antifungal discontinuation in the intensive care unit. Diagn Microbiol Infect Dis. 2019;95(2):162-165.

57. Mylonakis E, Clancy CJ, Ostrosky-Zeichner L, et al. T2 magnetic resonance assay for the rapid diagnosis of candidemia in whole blood: a clinical trial. Clin Infect Dis. 2015;60(6):892-9.

58. 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.

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

60. 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.

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

62. Machado M, Chamorro de Vega E, Martinez-Jimenez MDC, et al. Utility of 1,3 beta-d-Glucan Assay for Guidance in Antifungal

Stewardship Programs for Oncologic Patients and Solid Organ

Transplant Recipients. J Fungi (Basel). 2021;7(1):59.

63. Agnelli C, Bouza E, Del Carmen Martinez-Jimenez M, et al. Clinical relevance and prognostic value of persistently negative (1,3)-beta-D-glucan in adults with candidemia: a 5-year experience in a tertiary hospital. Clin Infect Dis. 2020;70(9):1925-1932.

64. 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(suppl4):iv27-iv30.

65. Bomkamp JP, Sulaiman R, Hartwell JL, et al. Evaluation of a rapid fungal detection panel for identification of candidemia at an academic medical center. J Clin Microbiol. 2020;58(3):e01408-19.

66. Steuber TD, Tucker-Heard G, Edwards J, et al. Utilization and impact of a rapid Candida panel on antifungal stewardship program within a large community hospital. Diagn Microbiol Infect

Dis. 2020;97(4):115086.

67. 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.

68. Voigt C, Silbert S, Widen RH, et al. The T2Bacteria assay Is a sensitive and rapid detector of cacteremia that can be initiated in the emergency department and has potential to favorably influence subsequent therapy. J Emerg Med. 2020;58(5):785-796.

69. Kalligeros M, Zacharioudakis IM, Tansarli GS, et al. In-depth analysis of T2Bacteria positive results in patients with concurrent negative blood culture: a case series. BMC Infect Dis. 2020;20(1):326.

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

71. 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.

72. 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. 2021;72(2):239-245.

73. Niles DT, Wijetunge DSS, Palazzi DL, et al. Plasma metagenomic next-generation sequencing assay for identifying pathogens: a retrospective review of test utilization in a large children’s hospital. J Clin Microbiol. 2020;58(11):e00794-20.

74. 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):e00095-17.

75. Banerjee R, Komarow L, Virk A, et al. Randomized trial evaluating clinical impact of RAPid IDentification and Susceptibility testing for Gram Negative bacteremia (RAPIDS-GN). Clin Infect Dis. 2020 May 7. doi:10.1093/cid/ciaa528. 76. Ehren K, Meissner A, Jazmati N, et al. Clinical impact of rapid species identification from positive blood cultures with same-day phenotypic antimicrobial susceptibility testing on the management and outcome of bloodstream infections. Clin Infect Dis. 2020;70(7):1285-1293.

77. Dare RK, Lusardi K, Pearson C, et al. Clinical impact of Accelerate PhenoTM rapid blood culture detection system in bacteremic patients. Clin Infect Dis. 2020 May 28. doi:10.1093/cid/ciaa649

78. Walsh TL, Bremmer DN, Moffa MA, et al. Impact of an antimicrobial stewardship program-bundled initiative utilizing Accelerate

Pheno system in the management of patients with aerobic gramnegative bacilli bacteremia. Infection. 2021 Feb 2. doi:10.1007/ s15010-021-01581-1

79. Robinson ED, Stilwell A, Attai AE, et al. Implementation of a rapid phenotypic susceptibility platform for gram-negative bloodstream infections with paired antimicrobial stewardship intervention: Is the juice worth the squeeze? Clin Infect Dis. 2021

Feb 13. https://doi.org/10.1093/cid/ciab126

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

81. 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.

82. 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.

83. 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.

84. Sanchez GV, Fleming-Dutra KE, Roberts RM, Hicks LA. Core elements of outpatient antibiotic stewardship. MMWR Recomm

Rep. 2016;65(6):1-12.

85. 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(9):CD012252.

86. Beal SG, Posa M, Gaffar M, et al. Performance and impact of a

CLIA-waived, point-of-care respiratory PCR panel in a pediatric clinic. Pediatr Infect Dis J. 2020;39(3):188-191.

87. Fenton J, Posa M, Kelly M, et al. Impact of a point-of-care respiratory PCR panel in a pediatric clinic on postvisit communication and follow-up visits. Pediatr Infect Dis J. 2020;39(9):e282-e283.

88. 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;52(2):1800555.

89. 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.

90. 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 financial disclosures.

About the author

Karen Fong, PharmD, BCIDP, is a clinical pharmacist, Infectious Diseases and Antimicrobial Stewardship, Department of Pharmacy, at the University of Utah Health, in Salt Lake City, Utah.