Molecular rapid diagnostic testing for bloodstream infections have the potential to improve patient care. Here, the lead author on a recent systematic review and meta-analysis provides insights on the topic.
Interview With: Tristan Timbrook, Pharm.D., MBA, BCPS
Interview By: Timothy P. Gauthier, Pharm.D., BCPS-AQ ID
When a patient is suspected to have an infection, many times a specimen (e.g., blood, urine, cerebral spinal fluid) is taken and sent to the microbiology laboratory for testing and analysis. In recent years new methods for testing called molecular rapid diagnostic tests have become available. These test allow the lab personnel to more rapidly identify which organism may be present as well as if the organism is antibiotic-resistant.
More rapid availability of information for providers translates to potential for optimizing care delivered to patients. In turn, many thought leaders identify these tests as a key tools in the fight against infectious pathogens.
Current literature supporting the use of molecular rapid diagnostic tests in clinical practice is encouraging, but there is still much to learn.
Recently, Timbrook et al undertook an important project aimed at assessing existing literature focused on molecular rapid diagnostic tests for bloodstream infections. Their work entitled The Effect of Molecular Rapid Diagnostic Testing on Clinical Outcomes in Bloodstream Infections: A Systematic Review and Meta-analysis is published ahead of print as of November 2016 within the premiere infectious diseases journal Clinical Infectious Diseases.
Given the importance of this topic and their work, I reached out to and requested an interview. Dr. Timbrook was kind enough to accept and the following five questions were posed. It is intended that readers will obtain a greater understanding of this topic through review of these responses.
1. What prompted you to review molecular rapid diagnostic tests for bloodstream infection?
During pharmacy residency training my institution adopted molecular rapid diagnostic testing (mRDT) for bloodstream infections (BSIs). While our antimicrobial stewardship program already had a clinical pathway for BSIs and monitored BSIs before mRDT, the introduction of mRDT had a profound impact on patient care, which I witnessed firsthand.
Then three things happened. First, when I came to do my fellowship training I found that the practice site had not yet adopted the technology. Second, when the new antimicrobial stewardship guidelines were released this year, they classified the use of mRDT for BSIs as a weak recommendation. Third, when discussing mRDT with other clinicians at my fellowship practice site, I found many were not convinced of the benefits, as some studies failed to show clinical benefits such as decreases in mortality risk.
Therefore, I set out to determine what the literature reflected overall on the potential clinical benefits of mRDT for BSIs.
2. Did you find any of the results from your project to be of particular note?
Before beginning the study, I performed a quick narrative review to evaluate differences in study definitions and endpoints. While similar definitions of time to effective therapy, length of stay, and mortality could be surmised, it was surprising that time to optimal therapy or de-escalation definitions varied so considerably within the literature. The latter appears to still be an evolving concept [Weiss et al., Clin Microbio Infect. 2015].
In addition, it was surprising that while antimicrobial stewardship goals of improved patient outcomes (i.e. mortality) and reduced cost have been explored, to the best of my knowledge safety outcomes (i.e. acute kidney injury) and resistance have not been explored.
An area of interest was to see if the benefit of mRDT was present in not only Gram positive infections but also Gram negative infections, as the latter had been specifically excluded from testing in one of the studies included in our meta-analysis. In this excluded study the authors noted in their methods a lack of benefit in Gram negative infections.
Anecdotally, I have heard of other sites doing similar things. In agreement with my major assumptions, the data from our meta-analysis reflects that mRDT is important in both Gram negative and Gram positive BSIs for reducing mortality risk.
In addition, we were surprised to find that heterogeneity in time to effective therapy was driven by a vancomycin-resistant Enterococci (VRE) study.
Pooling that study with VRE data from other studies and finding that mRDT was particularly associated with decreased time to effective therapy in VRE was an unexpected, yet intuitive finding.
This made sense as your average BSI patient is not started on antibiotics that cover VRE in most practice settings.
3. What advice you have for people interested in implementing rapid diagnostic tests for bloodstream infections at their practice site?
There are multitude of considerations when implementing mRDT for BSIs.
First, even before implementation, optimizations in practices related to both microbiology and pharmacy can improve patient care for bloodstream infections. A recently published article [Banerjee et al., Clin Infect Dis. 2016] described the potential improvements that laboratories can pursue related to pre-analytical, analytical, post-analytical processes for blood cultures.
Additionally, an important component of time to effective therapy relates to the pharmacy preparation and distribution of the medication, a feature not addressed in mRDT literature. This can be particularly problematic with restricted and/or not ward stocked antibiotics as suggested in a study [Powell et al., J Antimicrob Chemother 2015], which reflected 30% of first doses of antibiotics were omitted when restricted and not ward stocked.
While these types of process improvements don’t get as much attention as the new mRDT technologies, they are no less important in evaluating when striving to improve patient outcomes in BSIs.
For the actual implementation of mRDT, it is essential that the planning is interdisciplinary, involving both antimicrobial stewardship and microbiology.
The interdisciplinary team should evaluate at least one year of their institution’s previous BSIs to determine the organism epidemiology and resistance patterns along with empiric prescribing patterns in the institution. This will help with the both decisions on technology choice and clinical pathway development. During implementation, the stewardship team should educate providers on use of the results with the pathway.
Finally, to ensure the correct and timely use of mRDT results, the antimicrobial stewardship team should actively monitor the results and initiate escalations and de-escalations of therapy accordingly.
4. If rapid diagnostic tests are able to reduce time to appropriate antibiotic therapy, reduce length of stay and reduce mortality, would it be fair to use their presence as a quality marker for antimicrobial stewardship programs?
While not all rapid diagnostics have been shown to yield clinical benefits, the data is fairly clear for BSIs. However, the presence of mRDT for BSIs must be accompanied by a clinical pathway, clinician education during implementation, and routine monitoring by the ASP to make sure the information is acted upon in a clinically relevant timeframe.
5. Which areas in this field require the most attention for future study?
There are several areas of opportunity for future study.
Primarily, there is a sparsity of data in community hospitals. Those facilities are very different than academic medical centers where the majority of the studies originate. Thus, community hospitals may require different implementation strategies.
For instance, microbiology may utilize a centralized offsite lab and limited resources for antimicrobial stewardship program monitoring of BSIs may be present. The clinical impact of variations in time coverage of the latter are also unclear in academic medical centers (i.e. 24hrs/7days versus 9:00 AM to 5:00 PM only).
In our meta-analyses, we attempted to examine if real-time antimicrobial stewardship program monitoring was associated with decreased risk of mortality, however with the limited number of studies, it was difficult to conclude if there truly was a lack of association. Additionally, as mentioned earlier, outcomes related to adverse effects and resistance seem to have not been explored.
In the near future, FDA-approved rapid phenotypic testing for BSIs will be available. This offers considerable opportunities for study as many different scenarios could be evaluated related to drug selection or early pharmacokinetic/pharmacodynamic optimization opportunities such as utilization of extended or continuous infusion beta-lactams for isolates with increased minimum inhibitory concentrations.
Finally, establishing the benefit of other non-BSI mRDT in improving clinical outcomes is important. While the new technologies are exciting and having prompt information is comforting to the treating clinicians, the utility of a test is in its ability to measurably improve patient care, and therefore these data are needed.
About Dr. Timbrook, the interviewee
Tristan Timbrook, Pharm.D., MBA, BCPS is a Post-Doctoral Outcomes Pharmacy Fellow in Antimicrobial Stewardship at the Providence VA Medical Center (Providence, RI).
Dr. Timbrook obtained his PharmD and MBA at Sullivan University (Louisville, KY). He then completed his PGY-1 Pharmacy Practice Residency and PGY-2 Infectious Diseases Pharmacy Residency at Medical University of South Carolina (Charleston, SC).
His primary interests include integrations of rapid diagnostics and antimicrobial stewardship, comparative effectiveness research, and medical informatics with particular interest given to clinical decision support systems.
You can find him on Twitter @TimbrookTT
I would like to express my utmost appreciation to Dr. Timbrook for taking time out of his busy schedule to participate in this interview and help share this important perspective.
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