This is part one of a 2-part article. Rapid blood diagnostics implementation will be covered in Part 2.
Bacterial and fungal bloodstream infections are significant causes of morbidity, mortality, and health care-associated costs. Furthermore, it has been found that insufficient initial antimicrobial therapy for patients in septic shock is associated with a five-fold increase in mortality.1 To mitigate the high risk for mortality associated with inadequate initial antimicrobial therapy for sepsis, the Surviving Sepsis Campaign guidelines provide a strong recommendation for the use of “empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage)”.2 Unfortunately, some patients may remain on unnecessarily broad-spectrum, costly antibiotics until pathogen identification and antimicrobial susceptibilities are known.
Traditional positive blood culture workflow includes an initial Gram stain to detect pathogen morphology, followed by genus and species identification, and then determination of antibiotic susceptibilities. In total, results from these steps are usually available 2 to 3 days after an initial positive Gram stain result. In contrast, rapid blood culture diagnostic assays can minimize the time from positive blood culture to organism identification (a range of 1 to 5 hours), and in some instances, enable antibiotic susceptibilities to be available within 7 hours. This substantial reduction in time needed to produce useful patient information should allow providers to make more timely and meaningful clinical interventions. Accordingly, shorter time to optimal antimicrobial treatment can lead to improved outcomes, reduced patient care costs and hospital lengths of stay (LOS), fewer adverse drug events, and reduced antibiotic resistance rates.3-5
Available Rapid Blood Culture Diagnostic Platforms
Various rapid blood culture diagnostic platforms are currently available on the market, with more in the development pipeline. These diagnostic tools differ in many ways:
TABLES 1 and 2 compare the currently available, FDA-approved testing platforms in the United States. Of note, while all of the currently available platforms detect the most commonly encountered pathogens, they have limited abilities to identify fastidious or anaerobic organisms. With this in mind, the ideal rapid blood culture diagnostic assay would have a high sensitivity and specificity for pathogen identification and AST results, and a large pathogen library, as well as require minimal hands-on time, afford rapid TAT, and remain cost efficient overall.
Verigene BC-GN and BC-GP Panels6-8
The Verigene (Luminex Corporation, Austin, TX, USA) system employs DNA microarray and nanoparticle technology for pathogen and genetic resistance marker identification. It utilizes two different cartridges for gram-positive (BC-GP) and gram-negative (BC-GN) pathogens. The BC-GP panel can identify 12 FDA-approved gram-positive pathogens and 3 resistance gene markers, while the BC-GN panel can identify 8 FDA-approved gram-negative pathogens (see TABLE 2). Clinical studies have demonstrated an overall sensitivity of 93-100% and 86-94% for the BC-GP and BC-GN panels, respectively. Similar to other multiplex polymerase chain reaction (PCR)-based testing applications, polymicrobial blood cultures can be a challenge for both Verigene BC-GP and BC-GN panels.
BioFire FilmArray BCID9-10
The BioFire (bioMérieux, Marcy-l’Étoile, France) FilmArray BCID panel utilizes nested, multiplex PCR technology for pathogen and resistance gene detection. The same limitation of multiplex PCRs and polymicrobial infections can been seen with this assay. The BCID panel houses both its gram-positive and gram-negative PCRs in one comprehensive cassette. The BCID panel offers a robust pathogen library in a single test cartridge—including 8 gram positives, 11 gram negatives, and 5 Candida species (see TABLE 2). This platform has been shown to have a 95% sensitivity and 100% specificity for pathogens identifiable from the assay. BioFire is currently developing their second-generation platform called BCID2, which is expected to include an expanded pathogen and resistance gene identification library.
T2Biosystems T2Candida and T2Bacteria11-12
Magnetic resonance technology is utilized by T2Biosystems (Lexington, MA, USA) assays to identify microorganisms and biomarkers direct from whole blood without the need for positive blood samples. This nanodiagnostic technology has a small lower limit for detection; therefore, these platforms should be highly sensitive to the presence of detectable pathogens from its libraries. The company’s first product, the T2Candida panel, is FDA-approved to detect the presence of 5 of the most common Candida species (see TABLE 2). T2Candida’s performance was evaluated in a multicenter clinical trial and demonstrated an overall 91% sensitivity and 99% specificity.11 Another platform available from T2Biosystems, T2Bacteria, utilizes the same technology to identify 5 of the most common bacterial pathogens. This panel demonstrates a per-patient sensitivity of 90% and specificity ranging from 90-96% (varying based on if probable bloodstream infections are included in the analysis). This platform has a limited pathogen library, does not detect resistance gene markers, has a slower TAT, and does not perform AST.
Accelerate Diagnostics Accelerate Pheno13-15
Newest on the market, Accelerate Pheno was developed by Accelerate Diagnostics (Tucson, AZ, USA) and is currently the only FDA-approved rapid assay that can perform both pathogen identification and AST with minimal inhibitory concentrations (MICs). The test is performed on a positive blood culture and has a TAT for pathogen identification of 1.5 to 2 hours and AST within an additional 5 hours (overall TAT of approximately 7 hours). Clinical trials have demonstrated its sensitivity to be similar to other rapid diagnostic assays, as well as high specificity and categorical agreement with standard of care testing methods for pathogen identification and AST. The Accelerate Pheno library for pathogen identification contains 6 gram positives (including 2 at the genus level), 8 gram negatives (including 4 at the genus level), and 2 Candida species.
Of note, AST is unable to be performed when Streptococcus and yeast pathogens are detected. Accelerate Pheno does not detect resistance genes for gram-negative bacteria; therefore, end-users must be able to interpret the antibiotic MICs reported for patterns of extended-spectrum beta-lactamase (ESBL)- and carbapenem-resistant Enterobacteriaceae (CRE)-producing pathogens. The antibiotics reported in the EMR based on Accelerate Pheno’s AST can be customized based on an institution’s formulary and antimicrobial stewardship program (ASP) preferences.
Pitching Rapid Diagnostic Technology to the C-Suite
With a variety of available rapid diagnostic platforms to choose from, ASPs can support the microbiology department in making the case for bringing a specific technology into an institution. Some considerations to evaluate include:
The ASP team can emphasize the positive impact these rapid diagnostic platforms could have on antimicrobial prescribing and duration of therapy. The laboratory also can emphasize how this new technology is expected to lead to process improvements and increased efficiency. Due to the number of available platforms, it is essential to explain why a particular product is preferable over others according to a specific lab’s needs.
A hospital’s administration will likely need the technology’s cost to be justified in terms of ROI; thus, doing so should include details on how the technology can help optimize patient care and potentially reduce patient LOS, readmissions, mortality, and attendant hospital costs. If there are federal reimbursements for quality measures that are impacted (eg, sepsis bundles), then it will be helpful to indicate the benefit of this technology on those metrics. Be sure to highlight the patient population(s) that would benefit, current supporting medical literature, and whether other similar institutions have implemented related technology. Finally, demonstrating cost-effective analyses will help support the need for a rapid diagnostic platform.
At our institution, Tampa General Hospital (TGH), we held multiple meetings with microbiology laboratory and hospital administration representatives, and discussed our due diligence on the number of local institutions that had adopted the proposed rapid diagnostic platform, as well as published outcomes in the available medical literature supporting the benefits of this technology. Our hospital administrators decided to track metrics related to sepsis and LOS, and under the supervision of our laboratory director and hospital administration, we have shown improvement in both metrics.
Ripal Jariwala, BS, PharmD, BCIDP, AAHIVP, is co-chair of the antimicrobial subcommittee at Tampa General Hospital (TGH) in Tampa, Florida.
Nicholas Piccicacco, PharmD, BCIDP, AAHIVP, is co-chair of the TGH antimicrobial subcommittee.
Kristen Zeitler, BS, PharmD, BCPS, is co-chair of the TGH antimicrobial subcommittee.
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