Strengthening antimicrobial defenses with novel diagnostic stewardship approaches
The symbiotic relationship between antimicrobial stewardship and diagnostic technology is becoming more evident.
The desire to uncover three truths — the presence of infection, definitive pathogen, and antimicrobial therapy options — has fueled the development and use of novel diagnostic tests. Early and accurate diagnosis of an infection can improve treatment efficacy, avoid long-term complications, prevent spread and lessen misuse of antimicrobial therapy while reducing cost. As a result, the term “diagnostic stewardship” has emerged in the literature.
Diagnostic stewardship is a coordinated effort of ensuring appropriate tests, at the right time, for each patient to optimize antimicrobial therapy. One goal of diagnostic stewardship is to alter prescribing practices before antimicrobials are prescribed, targeting interventions during preanalytic, analytic and postanalytic phases.
Newer diagnostic tests come with their own set of limitations, including cost considerations and negative consequences, such as diagnostic errors and overuse. The diagnostic stewardship landscape is one that remains largely untouched, leaving room for innovative approaches. Bloodstream infections (BSIs), which are associated with significant morbidity and mortality, have been most extensively studied when implementing rapid diagnostic tests and provide a solid platform to explore diagnostic stewardship interventions impacting each phase.
Preanalytical phase interventions focus on when the test is being ordered and/or collected. Direct-from-blood assays, such as T2 Biosystems, and next-generation sequencing, like Karius, are diagnostic avenues to achieve early effective treatment for BSIs. Diagnostic stewardship is more challenging with direct-from-blood assays because the responsibility of appropriate ordering rests with the clinician. Diagnostic algorithms and inclusion of computerized order entry (CPOE) decision support can be used to direct test ordering appropriateness while limiting redundant tests. Collaborative development of diagnostic algorithms or use criteria may tease out clinical situations where these tests have maximum benefit. An example is requiring negative culture and PCR data before next-generation sequencing is ordered. Preauthorization by infectious disease providers or antimicrobial stewardship programs (ASPs) is another method for assessing diagnostic tests not meeting prespecified criteria. CPOE may curb less cost-effective test ordering and redundancy (eg, single-plex vs. multiplex PCR tests). Significantly more literature is needed to investigate the outcomes of patients with suspected BSIs when these tests are used coupled with ASP intervention.
Molecular rapid diagnostic tests (RDTs) have proven to have strong performance standards with high sensitivity and specificity, transforming the management of BSIs. PCR-based (eg, BioFire FilmArray and GenMark ePlex) or nanoparticle technology (eg, Luminex Verigene) yield earlier organism identification in comparison to traditional culture. These molecular RDTs have been shown to decrease time to effective therapy, hospital length of stay and mortality when associated with antimicrobial stewardship interventions.
Avdic and colleagues examined outcomes with and without ASP intervention after implementation of the Verigene gram-positive panel. Both Verigene with ASP and Verigene alone reduced the time to optimal therapy, which indicates that ASP intervention may be reduced once clinicians become comfortable in assessing data from molecular RDTs to make appropriate therapy revisions. However, Pliakos and colleagues showed molecular RDTs in coordination with ASPs had an 80% chance of being cost-effective, whereas molecular RDTs without an ASP had only a 41.1% chance.
The selection of the right test for the right patient at the right time does not affect clinical care unless the result is reported at the right time.
Although some of the molecular RDTs include genotypic testing, the advent of rapid phenotypic testing may advance the management of BSIs even further. The Accelerate Pheno system yields pathogen identification, minimum inhibitory concentrations (MICs) and susceptibility information in roughly 7 hours after a positive blood culture. The obvious benefit of providing identification and susceptibility data is not without implementation challenges.
The hurdles commonly encountered are laboratory workflows, especially in labs not staffed 24/7, willingness and awareness of clinicians to respond much quicker to available microbiological data and uncertainty surrounding long-term economic impact. One hospital in Spain codeveloped an efficient communication flow from the Accelerate Pheno system to clinical departments around the clock. This same hospital incorporated the Accelerate Pheno system as part of its sepsis bundle. Antimicrobial therapy was modified in 48% of the sepsis cases at receipt of Accelerate Pheno results, signifying greater ability to maximize antimicrobial pharmacokinetics and pharmacodynamics with known MICs. A retrospective study estimated that more than 50% of patients would have warranted antimicrobial therapy adjustments with Monte Carlo simulations given the availability of Accelerate Pheno results in concert with ASP intervention. More studies are needed to ensure this type of technology improves patient outcomes and justifies added consumable reagent costs.
In conclusion, rapid molecular diagnostic tests are revolutionizing the ability to uncover the three truths. Current diagnostic technology can identify potential pathogens and generate genotypic or phenotypic data for treatments. The persistent challenge of definitively ruling out an infection with a diagnostic test may never go away. The mutualistic relationship between diagnostic stewardship and antimicrobial stewardship is a prime opportunity for collaboration between clinicians, infectious disease providers and pharmacists, microbiologists and infection preventionists to develop system-centered approaches as new diagnostic tests are approved. As antimicrobial resistance mechanisms become more complex, the potential impact of novel diagnostic tests on antimicrobial stewardship and patient outcomes is promising. While weighing the benefits and risks of each test, a delicate balance must be struck between what is feasible and what is clinically important.
- Avdic E, et al. J Antimicrob Chemother. 2017;doi:10.1093/jac/dkx267.
- Fong, K, et al. The changing antimicrobial landscape: Rapid diagnostic testing and biomarkers affecting stewardship. https://www.idse.net/Review-Articles/Article/03-20/The-Changing-Antimicrobial-Landscape/58033. Accessed September 16, 2020.
- Graf EH, et al. Curr Infect Dis Rep. 2020;doi:10.1007/s11908-020-0714-5.
- Humphries R, et al. J Antimicrob Chemother. 2019;doi:10.1093/jac/dky534.
- Madden GR, et al. Infect Control Hosp Epidemiol. 2018;doi:10.1017/ice.2017.278.
- Messacar K, et al. J Clin Microbiol. 2017;doi:10.1128/JCM.02264-16.
- Morgan DJ, et al. JAMA. 2017;doi:10.1001/jama.2017.8531.
- Morjaria S, et al. J Mol Diagn. 2020;doi:10.1016/j.jmoldx.2020.06.012.
- Pliakos EE, et al. Clin Microbiol Re-. 2018;doi:10.1128/CMR.00095-17.
- Sofjan AK, et al. Ann Pharmacother. 2018;doi:10.1177/1060028018765486.
- Timbrook T, et al. The current state of antibiotic stewardship and rapid diagnostic testing. https://www.idse.net/Review-Articles/Article/06-19/The-Current-State-of-Antibiotic-Stewardshipand-Rapid-Diagnostic-Testing/55119. Accessed September 16, 2020.
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- Jennifer Ross, PharmD, BCIDP, is an infectious diseases clinical pharmacist at M Health Fairview – University of Minnesota Medical Center. Ross can be reached at email@example.com.