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 return on investment (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 institutions similar to your institution have implemented related technology. Finally, budget is always a consideration, so 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.
The Roles of Antimicrobial Stewardship and Microbiology
It is essential for the ASP team to work closely with microbiology personnel during the integration of rapid diagnostic platforms and help end users interpret information with appropriate clinical context. The ASP team also should develop a good understanding of microbiology workflow, ascertain how results should ideally appear to the end user, and provide constructive feedback to the microbiology department before and after implementation. Additional points of consideration include whether results will be available to the clinician in real time or if specimens will be batched. ASP and microbiology team members should regularly discuss the overall timeline, as well as information technology (IT) requirements when building this process into the EMR.
Our institution’s ASP team met with microbiology to discuss pre- and post-implementation plans for the diagnostic platform (see the SIDEBAR). Pre-implementation, we decided that a microbiology technician would contact nursing via telephone with a positive blood culture result at the time the panel identified a pathogen. We also decided to use the platform on all blood cultures, as opposed to a specific type of organism (eg, only gram-negative pathogens). Microbiology made a commitment to use this technology 24/7 to ensure real-time data could be made available to clinicians around the clock. We made additional group decisions on which antibiotics should and should not be reported, as well as susceptibility reporting. In addition, we disseminated this information to our Antimicrobial Subcommittee members, who forwarded the information to their colleagues. The organisms identified on the panel were discussed, as well as those organisms that did not have susceptibility data available through the technology.
Post-implementation, the ASP team met again with microbiology to discuss result reporting. We developed a standardized statement for positive blood cultures when the platform did not identify an organism from the panel. We also worked to adjust verbiage related to cefoxitin screening and S. aureus results. The ASP now provides ongoing feedback to the microbiology department and periodically meets as a group to discuss other ideas for optimization of this rapid diagnostic platform at our institution.
Communication of Results with Medical Staff
Rapid diagnostic technology integration within a hospital and/or across a health system cannot be successful without clear communication among the health care team. Although the diagnostic results are reported out in the EMR by the microbiology staff, there are important roles that other clinical team members can assume. When blood culture results are available and communicated by microbiology, the nurse receiving this information maintains a vital role in relaying it to the appropriate clinical provider in the event modifications in antimicrobial therapy are warranted. If nursing is not included in this communication pathway at your institution, this responsibility may be assigned to the microbiology technician who ran the testing. Depending on the institution, this communication may be verbal, electronic, or via the EMR; no matter which method is used, swift communication facilitates timely changes to antimicrobial therapy.
In addition to these team members, pharmacy staff also can play an important role in communicating subsequent updates in blood culture results and recommending escalation or de-escalation of drug therapy. As medication experts, pharmacists are uniquely positioned to make drug therapy recommendations to providers as culture results are updated, especially if results are reported from the microbiology lab in real time. Identified opportunities for de-escalation of antimicrobials minimizes selection pressure, and reduces both acquired drug-resistance and the risk for C. difficile infection. Timely interventions for antimicrobial escalation can help ensure a patient is on effective antimicrobials that will improve clinical outcomes.
At TGH, we received support from pharmacy administration to utilize a real-time blood culture report, which was eventually built as an alert into our information system’s patient scoring build and incorporated into pharmacy workflow. If the medical team does not review the blood culture updates in a timely manner, it is critical to promptly contact them, especially if escalation or de-escalation opportunities exist. Our ASP team created a guide on how to interpret blood culture results and what antimicrobial recommendation(s) should be provided based on our institutional formulary. This pharmacy-based activity at TGH is targeted on patients who do not already have an infectious diseases (ID) provider following their case and providing antimicrobial recommendations.
Rapid diagnostic technology platforms continue to offer more advanced capabilities; this is particularly true for blood culture specimens. ASPs and microbiology departments are uniquely positioned to evaluate available options when determining which platform may best fit the needs of their institution. Clear and direct communication with hospital administrators is crucial when making the case in favor of these technologies, as the expense may overshadow the known clinical benefit in some cases.
Once integrated into the institution’s workflow, timely communication of results to the provider is necessary in order to evaluate for escalation or de-escalation of therapy. Teamwork and communication across the health care provider spectrum is essential for benefits to be seen with rapid diagnostic blood culture platforms and improvements in patient clinical outcomes.
Ripal Jariwala, BS, PharmD, BCIDP, AAHIVP, is co-chair of the Tampa General Hospital (TGH) antimicrobial subcommittee. She received her BS in chemistry from the Georgia Institute of Technology in 2003 and her Doctor of Pharmacy degree from the University of Tennessee in 2008.
Nicholas Piccicacco, PharmD, BCIDP, AAHIVP, co-chair of the TGH antimicrobial subcommittee, received his Doctor of Pharmacy degree from the University of Florida in 2014. He then went on to complete a pharmacy practice residency at TGH and an Infectious Diseases specialty residency at Morton Plant Hospital – BayCare Health System in Clearwater, Florida.
Kristen Zeitler, BS, PharmD, BCPS, co-chair of the TGH antimicrobial subcommittee, received a BS in chemistry from Fairfield University in Connecticut in 2007, followed by a Doctor of Pharmacy from the University at Buffalo in 2011. Upon completion of a pharmacy practice residency and an infectious diseases specialty residency at the Hospital of the University of Pennsylvania in Philadelphia, Kristen joined TGH in 2013.
Case Study of TGH’s Implementation Experience
In November 2018, Tampa General Hospital went live with a rapid diagnostic testing platform. Prior to this, our institution did not utilize any rapid diagnostic technology on positive blood cultures. Thus, the decision-making, integration, and rollout process of this technology required an integrated team effort.
Rolling out the program required multiple meetings among hospital administration, microbiology, and ASP. We needed to decide on a technology platform, determine the best workflow process in microbiology when positive blood cultures were identified, and make decisions related to reporting of antimicrobial susceptibilities on pathogens included in the instrument’s panels. The ASP team also collaborated with microbiology in order to tailor the reporting of susceptibilities to match the hospital’s medication formulary.
As highlighted in the article, the unit-based pharmacists are integrated at our institution to receive real-time alerts when blood culture pathogen identification or drug susceptibility results are updated in the EMR. This occurs for patients who do not have an ID physician involved in their care. This alert for pharmacists is built into an Antimicrobial Stewardship section of patient scoring in the information system (see FIGURE 1), notifying them that updates require their review. A score of 10 for pathogen identification, as well as drug susceptibility, is reported in order to highlight the significance of this result (see FIGURE 2).
Since implementation of the platform, our institution has shown an impressive decrease in the time to pathogen identification and susceptibility reporting. Our internal data showed a reduction in the time to pathogen identification of 30.5 hours and a decrease in time to susceptibility results of 37 hours. Once data was available for clinicians, we also saw swift de-escalation was taken for most patients. In an early review of 138 positive blood cultures prior to involvement by the unit-based pharmacists (excluding coagulase negative Staphylococcus spp. isolates, as those were routinely considered contaminants), we identified the median time to targeted antimicrobial therapy as 14.6 hours during the week and 20.8 hours on the weekends. We also saw similar times to targeted therapy between ID providers and non-ID providers, likely demonstrating interventions from the ASP team early on and the confidence providers have with our team.
We continue to expand upon our experience with the rapid diagnostic testing platform, educating our providers and pharmacy staff on its utility and innovative technology so that its rapid results are able to aid in clinical decision-making for our patients.
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