Implementing Rapid Diagnostic Tests to Augment Antimicrobial Stewardship Programs The Time Is Now

BY SARAH M. WIECZORKIEWICZ, PHARMD, FIDSA, BCPS, BCIDP

For hospitalized, critically ill patients with sepsis, accurate and timely administration of antimicrobial agents is essential to prevent mortality.1,2 Rapid diagnostic tests (RDTs) have revolutionized the treatment of these patients and become one of the most powerful tools for antimicrobial stewardship programs (ASPs). Although routinely used laboratory methods, such as Gram stains, can provide helpful guidance in some clinical circumstances—such as stopping gram-positive coverage when a gram-negative organism is identified for a generally monomicrobial infection, de-escalating antipseudomonal coverage if ruled out, and so forth—they do not predict antimicrobial susceptibility patterns. In addition, routine laboratory methods often result in prolonged use of unnecessarily broad-spectrum antimicrobials or, even more concerning, ineffective therapy.

RDTs provide actionable details, even those without rapid susceptibility results, such as the ability to predict resistance patterns. When combined with the use of local antibiograms, knowledge of intrinsic resistance, and genotypic resistance marker detection, RDTs allow a more rapid, targeted approach to antimicrobial therapy.

The impact of RDTs can be largely attributed to reduced duration of empiric antimicrobial therapy. Prolonged broad-spectrum empiric therapy can lead to an increased burden of Clostridioides difficile infection, antimicrobial resistance, and adverse events, such as acute kidney injury. On the contrary, erroneous empiric antimicrobial coverage can delay effective therapy to detrimental effects and lead to dramatic increases in mortality among critically ill patients.1-8 A recent study found delays in antimicrobial therapy in patients with carbapenem-resistant and -susceptible Enterobacteriaceae infections are more important for mortality than multidrug resistance (MDR).7

However, MDR had been identified as an independent predictor of delays in time to effective therapy (TTET), likely as a result of providing inadequate empiric coverage,9 highlighting the need for RDTs with either genotypic resistance marker detection or rapid antimicrobial susceptibility testing (AST) for geographic areas with problematic multidrug-resistant organisms (MDROs). When combined with ASPs, RDTs demonstrate substantial benefit on patient outcomes, including mortality10 and attributable cost.11

With the availability of many RDT options, diagnostic stewardship is an essential component of ASPs enabling the teams to select the right test, for the right patient, at the right time.12 Furthermore, practical concerns for specific sites should be considered by the ASP, ideally comprising a multidisciplinary group that includes infectious diseases physicians and pharmacists, microbiologists, nurses, infection preventionists, information technology specialists, hospital epidemiologists, and other pertinent invested frontline providers.13 Global considerations to assess when choosing RDT platforms include, but are not limited to, institutional or regional problematic pathogens, the patient population served (ie, pediatric, adult, and/ or geriatric; immunocompromised vs general community), laboratory hours, location (ie, centralized or decentralized), operations and workflow, and leadership support. Specific practical considerations for FDA-cleared RDTs are outlined in the Table.

Barriers to RDT implementation and solutions that are justified by the CDC Core Elements of leadership commitment, accountability, pharmacy expertise (previously drug expertise), action, tracking, reporting, and education have been described.14 This article provides a clinically practical overview on the selection of RDTs for infectious syndromes, including bloodstream infections (BSIs), respiratory tract infections (RTIs), central nervous system (CNS) infections, and gastrointestinal (GI) infections.

Bloodstream Infections

Rapid blood culture identification technologies are among the most commonly used RDTs, and are endorsed by the Infectious Diseases Society of America (IDSA) guidelines for implementing ASPs to optimize antimicrobial use.13 This endorsement is supported by a substantial number of studies that demonstrate ASPs combined with molecular RDTs have favorable clinical outcomes, including a significant reduction in mortality in a meta-analysis of 31 mostly quasi-experimental studies.10,15-23 Available technologies identify organisms through genotypic (eg, nucleic acid amplification testing [NAAT]) and/or phenotypic (eg, biochemical assays, mass spectrometry, nuclear magnetic resonance [NMR] spectrometry) methods. FDA-cleared rapid assays from various manufacturers include peptic nucleic acid fluorescent in situ hybridization, matrix-assisted laser desorption/ionization time-offlight mass spectrometry (MALDI-TOF MS), polymerase chain reaction (PCR), multiplex PCR panels, nanoparticle probe technology, and NMR. Although most RDTs require organism isolation before identification, and previously included none or minimal genotypic resistance testing, this strategy is rapidly evolving with the need to further close the gap between broadspectrum empiric and targeted therapy.

This evolution is exemplified by the T2 Magnetic Resonance (T2MR) technology by T2 Biosystems that can detect the presence of organisms directly from a whole blood specimen without prior isolation. T2Candida, T2Bacteria, T2Resistance, and T2SARSCoV-2 (T2 Biosystems) panels are rapid detection panels that use this strategy. T2Resistance is not available for clinical use in the United States but has been granted a “breakthrough device” designation by the FDA in response to combating resistant infections, and will be useful in immunocompromised patients, as well as patients or regions with a high burden of MDROs. T2Resistance can identify gram-negative markers including KPC,OXA-48, NDM/VIM/IMP, CTX-M, and 14/15AmpC (CMY/DHA), as well as gram-positive markers including vanA/B and mecA/C. The T2SARSCoV-2 test was granted emergency use authorization from the FDA in 2020 to assess patients with signs and symptoms of COVID-19 by detecting nucleic acid from SARS-CoV-2 in upper respiratory secretions and may, in theory, allow earlier discontinuation of unnecessary empiric antimicrobial use in this patient population. T2Bacteria and T2Candida are FDA-cleared, commercially available assays that use a miniaturized MR diagnostic technique that assesses the reaction of water molecules in the presence of magnetic fields, and can detect various targets in 3 to 5 hours.24 Candidemia mortality rates are as high as 30% to 40%, and increase by approximately 50% each day therapy is delayed.24 This is concerning, as prompt antifungal initiation can be inadvertently missed, given the overall sensitivity of blood cultures in diagnosing invasive candidiasis is around 50%.25 The T2Candida assay can be incredibly useful in facilities with high rates of fungal infections (eg, immunocompromised patient population), as it not only detects organisms at densities of 1 colony-forming unit (CFU)/mL compared with 100 to 1,000 CFU/mL required for PCR-based detection,24 but also has the ability to substantially reduce TTET once detected.26 Patients with positive blood cultures identified by T2Candida noted a 27-hour reduction in time to appropriate antifungal therapy (P=0.01).27 Conversely, ASPs can use negative tests to shorten antifungal therapy. Previous data demonstrate this can be associated with a 4.3-day reduction in micafungin use, resulting in a cost savings of $48,440 on antifungals.27

The T2Bacteria assay uses multiplex detection to

When combined with use of local antibiograms and other resistance data, RDTs allow a more rapid, targeted approach to antimicrobial therapy.

identify common ESKAPE organisms (ie, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli) that pose clinical challenges due to their propensity for MDR.28,29 In a performance assessment study, the T2Bacteria assay identified organism species in 3.61±0.2 to 7.7±1.38 hours, with a per-patient sensitivity of 90% (95% CI, 76%-96%), specificity of 90% (95% CI, 88%-91%), and negative predictive value of 99.7% for proven BSIs.29 Another study duplicated the negative predictive value of 99.8% and further demonstrated the mean time to detection and species identification was 5.5±1.4 hours.28 The T2Bacteria panel has demonstrated the ability to detect pathogens approximately 55 hours faster than standard methods (eg, blood culture) in patients with sepsis.30 Given the previous benefit of RDTs including reductions in TTET, time to optimal therapy, mortality, and the observation of ASP intervention being an independent predictor of survival in MDR infections,31 the T2Bacteria assay is expected to demonstrate favorable clinical outcomes. While T2MR technology reduces time to organism identification by eliminating the need for prior organism isolation, other technologies target rapid phenotypic AST to prevent delays in therapy and avoid unnecessarily prolonged broad-spectrum therapy. One such technology is the Accelerate Pheno system (Accelerate Diagnostics), which uses rapid phenotypic methods to provide AST within 7 hours. Conventional identification with AST can take as long as 90 hours.32 This is particularly important when clinicians are concerned about prolonged exposure of insufficient antimicrobial concentrations (eg, patients with unpredictable pharmacokinetics/pharmacodynamics, augmented renal clearance, or pathogens with a high minimum inhibitory concentration), as inappropriate exposure can result in poor outcomes.32,33 A recent multicenter, randomized controlled trial comparing rapid identification plus phenotypic AST (RAPID; Accelerate Pheno) with standard of care (SOC; MALDI-TOF MS) plus AST using broth microdilution or agar dilution was conducted in patients with gram-negative BSIs.34 The primary outcome measure was time to first antimicrobial modification within 72 hours of randomization. First antimicrobial modification was 6.3 hours faster in the RAPID group compared with the SOC group for overall antimicrobials (median [interquartile range], 8.6 [2.6-27.6] vs 14.9 [3.3-41.1] hours; P=0.02), and 24.8 hours faster for antimicrobials targeted against gramnegative organisms (median [interquartile range], 17.3 [4.9-72] vs 42.1 [10.1-72] hours; P<0.001). Among a subset of 40 patients in the RAPID group and 44 in the SOC group with resistant organisms, time to antimicrobial escalation was 43.3 hours faster in the RAPID group than the SOC group (P=0.01), while no difference was observed in de-escalations. Although the study authors report no significant differences in clinical outcomes, such as length of stay (LOS) and mortality, the ability to escalate therapy more rapidly and reduce time to effective therapy is clinically meaningful nonetheless.34 One recent quasi-experimental study of 830 bacteremic cases, however, has demonstrated a shorter median LOS (6.3-6.7 vs 8.1 days) when the Accelerate Pheno is used, regardless of whether it is paired with or without real-time notification when compared with historical controls lacking rapid diagnostics or antimicrobial stewardship intervention.36 Overall, rapid blood culture identification systems demonstrate a substantial benefit when paired with ASPs for both clinical and economic outcomes.10,11 Probabilistic analyses of RDTs combined with ASPs show an 80% chance of being cost-effective versus a 41% chance without ASPs.11 These data suggest RDTs should be the SOC across all hospitals and continue to evolve with public health needs to slow the progression of resistance and ensure antimicrobial therapy is optimized.

Karius testing is a blood test based on next-generation sequencing of microbial cell-free DNA, allowing it to quantify more than 1,000 clinically relevant pathogens that include viruses, bacteria, fungi, and parasites. It may be useful for patients with severe illness, those who are immunocompromised, and/or those with a lack of pathogen identification after standard attempts via other methodologies.37 A prospective pilot study explored the utility of Karius testing as a BSI prediction tool among 47 pediatric patients with relapsed or refractory cancers. Sixteen BSI episodes (15 bacterial) were available for predictive sampling, and a predictive sensitivity of 80% (n=12/15; 95% CI, 55%-93%) was identified for bacterial BSIs.37 Hogan et al performed a retrospective cohort study to determine the real-world impact of the Karius test ordered for all suspected infectious diseases indications.38 Approximately 65% of patients were immunocompromised and 52.4% were children. A total of 82 Karius tests were evaluated with a positivity rate of 61%. The Karius test results led

Table. Selected FDA-Approved Rapid Diagnostic Tests and Clinical Practice Considerations a

Resistance Detection Practical Considerations for Clinical Practice

Detection Time

(Pre-blood culture)

Example Systems (Manufacturer) Organisms on Panel

Technology Type Blood Cultures

• Potential benefit for patients requiring rapid PK/PD dose adjustments (eg, augmented renal clearance) • Ability to rapidly detect resistance patterns • Unreliable MIC for bacteria with multiple morphologies or polymicrobial infections

MRSA and macrolide- lincosamide- streptogramin B phenotypically reported

~1.5 h to identify, and 7 h to antimicrobial susceptibility

Staphylococcus Staphylococcus aureus , lugdunensis ,CoNS, Enterococcus faecalis , Enterococcus faecium , Streptococcus species, Escherichia coli , Klebsiella species, Enterobacter species, Proteus species, Citrobacter species , Pseudomonas aeruginosa , Serratia marcescens , Acinetobacter baumannii, Candida albicans, Candida glabrata CoNS 20 min None • Previously associated with reduction in LOS in CoNS-positive cultures, and reduced TTET in enterococcal bacteremia • Limited number of targets per panel

E. faecalis, E. faecium, Enterococcus species 20 min None 20 min None • Limited number of targets per panel • Useful among community hospitals with low resistance rate

E. coli, Klebsiella pneumoniae, P. aeruginosa

PNA-FISH Accelerate Pheno (Accelerate Diagnostics) Staphylococcus QuickFISH (AdvanDx) Enterococcus QuickFISH (AdvanDx) Gram-negative QuickFISH (AdvanDx) 90 min None • Useful for hospitals with high fungal infections (eg, immunocompromised)

C. albicans, C. glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis

Yeast Traffic Light (AdvanDx) • Prompt identification of MRSA • May miss MRSA with non-mecA resistance

mecA • Prompt differentiation between MRSA and MSSA can facilitate faster TTET

SCCmec, mecA • Limited number of targets

mecA

None 20 min

XpressFISH mecA (AdvanDx) 1 h 2 h

S. aureus

PCR Xpert MRSA/SA BC (Cepheid) S. aureus

StaphSR (BD GeneOhm) • Comprehensive number of targets • Multiple primers allow for identification of multiple organisms • Identifies polymicrobial infections that may be missed by other technologies

mecA, vanA/B, KPC

1 h

A. baumannii, C. albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, E. coli, Enterobacter , Enterobacteriaceae , cloacae complex Enterococcus species, Haemophilus influenzae, Klebsiella oxytoca, K. pneumoniae , Listeria monocytogenes, Proteus species , P. aeruginosa, Neisseria meningitidis, S. marcescens, Staphylococcus species, S. aureus, Streptococcus species, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus

mPCR FilmArray BCID (BioFire Diagnostics) pyogenes

• Most comprehensive organism and resistance detection panels currently available on the market • Gram-positive and gram-negative panels contain pan targets to ensure organism inclusivity • Identifies polymicrobial infections that may be missed by other technologies

mecA, mecC, vanA/B

1.5 h CTX-M, IMP, KPC, NDM, OXA (OXA 23 and -48), OXA VIM

1.5 h 1.5 h None

Bacillus cereus group , Bacillus subtilis group, Corynebacterium, Cutibacterium acnes, Enterococcus, E. faecalis, E. faecium, Lactobacillus, Listeria, L. monocytogenes, Micrococcus, Staphylococcus, S. aureus, Staphylococcus epidermidis, S. lugdunensis, Streptococcus, S. agalactiae

(Group B Streptococcus anginosus Streptococcus ), , S. pneumoniae, S. pyogenes (Group A group Streptococcus ), Pan targets: pan–gram-negative and panCandida A. baumannii, Bacteroides fragilis, Citrobacter, Cronobacter sakazakii, Enterobacter (non- complex, E. coli, cloacae complex), E. cloacae Fusobacterium nucleatum, Fusobacterium necrophorum, H. influenzae, K. oxytoca, K. pneumoniae group , Morganella morganii, N. meningitidis, Proteus, Proteus mirabilis, P. aeruginosa, Salmonella, Serratia, S. marcescens, Stenotrophomonas maltophilia Pan targets: pan–gram-positive and panCandida C. albicans, Candida auris, Candida dubliniensis, Candida famata, C. glabrata, Candida guilliermondii, Candida kefyr, C. krusei, Candida lusitaniae, C. parapsilosis, C. tropicalis, Cryptococcus gattii, Cryptococcus neoformans, Fusarium, Rhodotorula

ePlex BCID-GP panel (GenMark Diagnostics) ePlex BCID-GN panel (GenMark Diagnostics) ePlex BCID-FP panel (GenMark Diagnostics) All organisms 30 min None • Ability to detect a vast array of bacterial and fungal microbes • Useful for facilities with patients at risk for uncommon infections (eg, immunocompromised population, transplant centers) • Lacks ability to detect resistance markers or provide susceptibility reports

MALDI-TOF MALDI-TOF (bioMérieux and Brucker) • Can reduce TTET and unnecessary antimicrobial utilization • Unreliable for detection in polymicrobial bacteremia

CTX-M, IMP, KPC, NDM, OXA, VIM mecA, vanA/B

2.5 h 2.5 h

Acinetobacter species , Citrobacter species , E. coli, Enterobacter species, K. oxytoca, K. pneumoniae, species P. aeruginosa, Proteus

VERIGENE BC-GN (Luminex)

Nanoparticle probe technology S. aureus, S. epidermidis, S. lugdunensis, S. anginosus, S. agalactiae, S. pneumoniae, S. pyogenes, E. faecalis, E. faecium

VERIGENE BC-GP (Luminex)

a Not an all-inclusive list. Table adapted and refined from reference 68. gastrointestinal; LOS, length of stay; MALDI-TOF, matrix-assisted laser ASP, antimicrobial stewardship program; CNS, central nervous system; CoNS, coagulase-negative Staphylococcus ; GI, multiplex polymerase chain reaction; MRSA, methicillin-resistant Staphylococcus aureus ; minimum inhibitory concentration; mPCR, desorption/ionization time of flight; MIC,

(Pre-blood culture) 3-5 h None • Detects presence of organisms directly from blood specimen (ie, prior isolation not required) substantially expediting time to identification • Low limit of detection can detect

mecA/C, vanA/B

3-5 h

pathogens missed by standard testing that is reliant on blood cultures.

Example Systems (Manufacturer) Organisms on Panel

Technology Type

E. faecium, S. aureus, K. pneumoniae, P. aeruginosa, E. coli

NMR T2Bacteria C. albicans, C. tropicalis, C. krusei, C. glabrata, C. parapsilosis

T2Candida • T2Bacteria Panel detects 90% of all ESKAPE pathogens and T2Candida detects the 5 most common sepsis-causing fungal pathogens 1 h None • Implementation may be most useful for hospitals with pediatric and neonatal patients • Associated with a rapid time to diagnosis of viral infections • Not intended to replace traditional diagnostic testing for CNS infections

Central Nervous System

E. coli (K1 serotype only), H. influenzae, L. monocytogenes, N. meningitidis (encapsulated strains only) , S. agalactiae, S. pneumoniae, C. neoformans/gattii , cytomegalovirus, enterovirus, herpes simplex viruses 1 and 2, human herpesvirus 6, human parechovirus, and varicella-zoster virus

mPCR FilmArray ME (BioFire Diagnostics)

Gastrointestinal

1 h None • Cannot differentiate between live and dead organisms • Infants and young children <3 y likely test positive for C. difficile due to high rates of colonization; pediatric centers may blind C. difficile results or include clinical decision support to interpret positives in this population with caution • Many GI pathogens may be shed asymptomatically for prolonged periods complicating positive results • Should not be used as a test of cure • Can detect multiple pathogens; h owever, the clinical significance to polymicrobial GI infections is unknown

5 h None • Consider implementing in high-prevalence units (eg, pediatrics)

<2 h None

Campylobacter species ( jejuni, coli, upsaliensis ), Clostridioides difficile (toxin A/B), Plesiomonas shigelloides,Salmonella species, Yersinia enterocolitica , Vibrio species ( parahaemolyticus, vulnificus ), Vibrio cholerae , enteroaggregative E. coli , enteropathogenic E. coli , enterotoxigenic stx1/ , Shiga-like toxin–producing E. coli E. coli E. coli 0157, Shigella /enteroinvasive E. stx2, coli , adenovirus F 40/41, astrovirus, norovirus GI/GII, rotavirus A, Sapovirus (I, II, IV, V), Cryptosporidium , Cyclospora cayetanensis , Giardia lamblia Entamoebahistolytica ,

mPCR FilmArray GP (BioFire Diagnostics) Campylobacter species ( jejuni, coli, lari ) , C. difficile toxin A/B,enterohemorrhagic E. coli , enterotoxigenic E. coli , E. coli O157, Salmonella species, Shigella species (boydii, sonnei, flexneri, dysenteriae ), Vibrio species( cholerae ), Y. enterocolitica (not in US), adenovirus F40/41, Norovirus GI/GII, rotavirus A, Cryptosporidium species ( parvum, hominis), E. histolytica, G. lamblia

xTAG GPP (Luminex Corp) Salmonella species, Campylobacter group, Shigella species, Vibrio group, Yersinia enterocolitica , Shiga toxin 1 (stx1), Shiga toxin 2 (stx2), norovirus, rotavirus

VERIGENE Enteric Pathogens Test in the Gastro (Luminex) Rotavirus, astrovirus, adenovirus 2.5 h None

InGenius Gastrointestinal Viral Elite Panel (ELITechGroup)

• Implementation encouraged in institutions with high rates of inappropriate prescribing for respiratory tract infections • Can rule viral etiologies in or out • In conjunction with procalcitonin, can assist ASP in reducing antimicrobial utilization

mecA/C and MREJ KPC, NDM, OXA- 48-like, VIM, IMP, CTX-M • First pneumonia panel with 15 bacterial isolated and resistance detection capabilities

1 h 1 h None 90 min None <2 h None

Adenovirus, coronavirus, human metapneumovirus, human rhinovirus/enterovirus, influenza A, influenza B, parainfluenza virus, Acinetobacter calcoaceticus-baumannii RSV, E. coli, H. influenzae, complex, E. cloacae complex, Klebsiella aerogenes, K. oxytoca, K. pneumoniae group, Moraxella catarrhalis, , P. aeruginosa, S. marcescens, species Proteus S. aureus, S. agalactiae, S. pneumoniae, S. pyogenes, Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae Adenovirus, coronavirus HKU1, coronavirus NL63, coronavirus 229E, coronavirus OC43, human metapneumovirus, human rhinovirus/enterovirus, influenza A, influenza A/H1, influenza A/H3, influenza A/H1-2009, influenza B, parainfluenza virus 1, parainfluenza Virus 2, parainfluenza virus 3, parainfluenza virus 4, RSV, Bordetella pertussis, C. pneumoniae, M. pneumoniae; RP2 panel adds Bordetella parapertussis

Respiratory

mPCR The BioFire FilmArray Pneumonia (PN) panel FilmArray RP and RP2 (BioFire Diagnostics) Adenovirus, coronavirus (229E, HKU1, NL63, OC43), human metapneumovirus, human rhinovirus/enterovirus, influenza A, influenza A H1, influenza A H1-2009, influenza A H3, influenza B, parainfluenza 1, parainfluenza 2, parainfluenza 3, parainfluenza 4, RSV A, RSV B, C. pneumoniae, M. pneumoniae

ePlex Respiratory Pathogen Panel (GenMark Diagnostics) Adenovirus, human metapneumovirus, influenza A, influenza A (subtype H1), influenza A (subtype H3), influenza B, parainfluenza 1, parainfluenza 2, parainfluenza 3, parainfluenza 4, rhinovirus, RSV A, RSV B, Bordetella pertussis, Bordetella parapertussis/B. bronchiseptica, Bordetella holmesii

VERIGENE Respiratory Pathogens Flex Test (Luminex) <3 h None

Influenza A, influenza A H1, influenza A H3, influenza B, RSV A, RSV B, rhinovirus/ enterovirus, parainfluenza virus 1, parainfluenza virus 2, parainfluenza virus 3, parainfluenza virus 4, human metapneumovirus, adenovirus, coronavirus HKU1, coronavirus NL63, coronavirus 229E, coronavirus OC43, human bocavirus, Chlamydophila pneumoniae, M. pneumoniae

NxTAG Respiratory Pathogens Panel (Luminex)

a Not an all-inclusive list. Table adapted and refined from reference 68. gastrointestinal; LOS, length of stay; MALDI-TOF, matrix-assisted laser ASP, antimicrobial stewardship program; CNS, central nervous system; CoNS, coagulase-negative Staphylococcus ; GI, methicillin-resistant Staphylococcus aureus ; multiplex polymerase chain reaction; MRSA, minimum inhibitory concentration; mPCR, desorption/ionization time of flight; MIC, peptic nucleic acid fluorescent in situ hybridization; pharmacokinetic/pharmacodynamic; PNA-FISH, nuclear magnetic resonance; PK/PD, ; NMR, methicillin-sensitive S. aureus

MSSA,

to a positive clinical impact in 7.3%, negative clinical impact in 3.7%, no clinical impact 86.6%, and indeterminant in 2.4%. Cases with a positive Karius result and clinical impact, bacteria, and/or fungi were involved compared with viruses or parasites. Karius testing was evaluated in 55 patients with febrile neutropenia.39 Sensitivity and specificity were 85% (41/48) and 100% (14/14), respectively. Time to diagnosis was shorter compared with traditional blood culture methodology (87%) and could have allowed early antimicrobial optimization in 47% of patients (ie, addition of antimicrobials [20%] mostly against anaerobes [12.7%], antivirals [14.5%], and/or antifungals [3.6%] and antimicrobial de-escalation [27.3%]). These data suggest that Karius testing may have a future role in enabling prompt initiation of antimicrobials specifically in immunocompromised hosts, although a clear role including optimal patient population has yet to be fully elucidated.

Respiratory

Acute RTIs are most commonly caused by viral organisms. However, differentiating between viral and bacterial pneumonia is a significant challenge, and often results in unnecessary antimicrobial use for viral infections,40 especially when bacterial coinfection cannot be ruled out. To date, no single test exists to make this differentiation, but several RDTs together can assist ASPs in the clinical decision-making process such as respiratory pathogen (viral/bacterial) panels, methicillin-resistant S. aureus (MRSA) nasal PCR, and biomarker expression (eg, procalcitonin). Procalcitonin is a pro-inflammatory biomarker previously associated with a reduction in antimicrobial therapy for lower RTIs,41 and may be useful for ruling out bacterial coinfections.42 However, a clear cutoff between bacterial and viral pneumonia remains to be elucidated,43 and interpretation is limited among some patient populations (eg, those needing hemodialysis).44 In the future, other promising biomarker approaches assessing host gene expression to categorize acute RTIs as either viral or bacterial may become more readily available for ASPs.45 Nonetheless, when ordering respiratory diagnostic assays, it is important to consider whether the test will affect clinical management. For example, influenza is the only respiratory virus of which treatment is available, suggesting identification by NAAT can facilitate prompt initiation or discontinuation of anti-influenza therapy during influenza season. However, ordering the same test for a mildly ill patient not expected to receive treatment, or during a period of low prevalence, does not provide value. Of note, NAAT is favored over traditional influenza antigen–based

diagnostic tests, as they are significantly more sensitive, resulting in more accurate and usable results.46 More recently, multiplex PCR panels for respiratory viruses have become more common, and are able to optimize anti-influenza therapy.47 Clinical and economic outcomes vary across respiratory diagnostic studies, largely due to heterogeneity and variability in the quality of currently available data. Nonetheless, reduced antimicrobial utilization with rapid viral panels has been described among pediatric48 and adult patients.49 Overall, respiratory pathogen panels play an important role in RTI diagnostics. Novel bacterial panels have become available, but clinical outcomes have yet to be assessed. The IDSA Diagnostics Committee recently released clinical and diagnostic recommendations for management of acute RTIs.50 When bacterial pneumonia is diagnosed in patients with risk factors for resistance or CNS infections require at high risk for mortality, grampositive coverage for MRSA is prompt diagnostic often empirically initiated. Because S. aureus is a pathogen routinely identifi cation and implicated in pneumonia, and a common colonizer of the nares, a antibiotics, if MRSA nasal PCR can be used to appropriate. help discontinue unnecessary vancomycin. A meta-analysis of 22 studies and 5,163 patients idenSource: Clin Infect Dis. 2004;39(9):1267-1284. tified a positive predictive value of 44.8% and negative predictive value of 96.5% using 10% prevalence,51 indicating a negative result can be particularly useful to rule out MRSA pneumonia thereby decreasing days of vancomycin therapy, especially among patients who are not critically ill. ASPs can use a combination of these RDTs in conjunction with a patient’s clinical picture to help ensure that those who require antibiotics are treated effectively and those who have solely viral infections are spared unnecessary antimicrobials.

Central Nervous System

CNS infections are medical emergencies that are associated with considerable mortality and rapid decline that requires prompt diagnostic identification and antimicrobial administration.52 Diagnostic testing for CNS infections is particularly challenging, as more than 20 available diagnostic tests exist and various testing combinations are ordered in clinical practice.53 ASPs are incredibly important for such scenarios, as they can help guide medical teams, especially when a limited amount of cerebrospinal fluid (CSF) volume is obtained. Low-volume yield of CSF during lumbar puncture is commonly seen, especially among pediatric patients. Identifying viral etiologies by PCR can facilitate diagnostics, reduce hospital LOS, and reduce duration of unnecessary antimicrobial therapy.54 However, rapid

bacterial identification expedites appropriate antimicrobial utilization and improves clinical outcomes.55,56

The only clinically used, FDA-approved rapid panel is the BioFire FilmArray meningitis/encephalitis (ME) panel (BioFire Diagnostics), with a turnaround time of 1 hour and only 2 minutes of hands-on time. It is a nucleic acid–based panel that requires a small volume of CSF (0.2 mL), and has 14 total targets, including E. coli (K1 serotype only), Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis (encapsulated strains only), Streptococcus agalactiae, Streptococcus pneumoniae, Cryptococcus neoformans/gattii, cytomegalovirus, enteroviruses, herpes simplex viruses 1 and 2, human herpesvirus 6, human parechovirus, and varicella-zoster virus.57 In a study of 1,560 CSF samples, the ME panel established an 84.4% positive and greater than 99% negative agreement to traditional testing methods.56,58 The ME panel also results in a faster time to diagnosis by 10.3 hours compared with pathogen-specific PCR testing.54 There have been reports of both false-positive and false-negative results leading to concerns for institutions when deciding on implementation. A recent meta-analysis was performed to determine the sensitivity and specificity of the ME panel.59 The investigators pooled data from 8 studies (N=3,059) and reported a sensitivity and specificity with confidence intervals of 90% (95% CI, 86%-93%) and 97% (95% CI, 94%-99%), respectively. The highest proportion of false positives was associated with S. pneumoniae followed by S. agalactiae, and the highest proportion of false negatives was for herpes simplex viruses 1 and 2, enteroviruses, and C. neoformans/gattii. Despite promising potential, the ME panel cannot yet replace traditional testing methods for ME diagnosis, and knowledge of limitations is essential for utilization.56,58 It may be particularly helpful in hospitals with high CNS infection prevalence (eg, pediatric and neonatal patients).

GI Infection Cultures

Acute gastroenteritis is a leading cause of morbidity and mortality and responsible for an estimated 47.8 million episodes annually in the United States.60,61 Gastroenteritis is characterized by acute onset of diarrhea with or without vomiting and caused by a wide variety of bacteria, viruses, and parasites as well as other noninfectious cases. Identification of an infectious agent is critical for patient care and infection prevention practices; however, the etiologic pathogen goes unidentified in approximately 80% of cases.60,62,63

Conventional methods of identification (eg, antigen testing, microscopic examinations, and culture) are time-consuming, expensive, and have limited sensitivity.64 Multiplex PCR-based GI panels, such as the FilmArray, have emerged as a more rapid and accurate diagnostic tool to diagnose gastroenteritis, although clinical outcomes data are limited. The BioFire FilmArray GI panel combines 22 enteric pathogens into a single cartridge-based test with a turnaround time of less than 2 hours. Assay performance was assessed and demonstrated 100% and 94.5% or higher sensitivity for 12 of 22 and 7 of 22 targets, respectively, and 97.1% or higher specificity for all targets.65

Although symptoms are often self-limiting, some patients may benefit from antimicrobials and experience delays in therapy due to lengthy testing methods. Hospitalization and further testing such as colonoscopy or abdominal ultrasonography may be required in patients with multiple comorbidities or severe illness pending test results, leading to unnecessary patient isolation and more extensive infection prevention practices. Beal et al evaluated the clinical and economic impact of the FilmArray GI panel compared with historical controls using traditional stool culture testing methodology.66 The positivity rate of the GI panel was 32.8% compared with 6.7% for the historical controls. The GI panel resulted in faster results reported in the electronic health record (8.94 vs 54.75 hours), less additional stool tests ordered overall (0.58 vs 3.02 additional tests; P=0.0001), fewer antibiotic days per patient (1.73 [95% CI, 1.41-2.04] and 2.12 [95% CI, 1.892.35] days per patient; P=0.06), fewer imaging studies (0.18 vs 0.39 imaging studies per patient; P=0.0002), shorter LOS (5.2±3.2 vs 5.6±3.4 days; P=0.14), and a cost savings of approximately $294 per patient.

A similar rate of positivity was observed in another study comparing the FilmArray GI panel with historical stool culture controls (29.2% vs 4.1%, respectively).67 Clinical outcomes were also improved with the GI panel; patients were less likely to undergo endoscopy (8.4% vs 9.6%; P=0.008) or abdominal radiology (29.4% vs 31%; P=0.002) and less likely to receive antimicrobials (36.2% vs 40.9%; P<0.001).67

The prevalence of GI coinfection in the United States is not well known compared with developing countries; however, the FilmArray GI panel commonly detects coinfection in up to 32.9%.59-61,65-67 This may be because the PCR is not able to differentiate between asymptomatic colonization and infection.

Conclusion

The development and implementation of RDTs have significantly augmented ASPs and improved clinical outcomes for patients with suspected or confirmed infections. When combined with stewardship initiatives, RDTs improve the timeliness and effectiveness of antimicrobial optimization. Although outcomes data are most substantive for BSIs, RTIs, and CNS infections, GI panels are offering advances for patients suffering from these conditions. Awareness of the benefits they may provide, along with a critical assessment of institutional needs, can optimize patient care while minimizing harm associated with inappropriate antimicrobial utilization.

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About the author

Sarah M. Wieczorkiewicz, PharmD,

FIDSA, BCPS, BCIDP, is an infectious diseases clinical specialist in Chicago, Illinois, and has 15 years of clinical experience.