Rapid molecular diagnostics contribute to improved patient outcomes
by Jimm Chengary, MBA
Although sepsis is a serious and potentially fatal medical condition that is estimated to affect more than 30 million people globally each year, public recognition and understanding of the condition is generally very limited. Sepsis is particularly challenging to diagnose and treat, which is one reason that it is also one of the leading causes of death in hospitals.1
Sepsis is a devastating, systemwide immune response to an infection that rapidly becomes life-threatening. Mortality rates associated with sepsis rise 7.6% with each hour that optimal treatment is delayed.2 The condition is often associated with infections of the gut, lungs, skin, and urinary tract; the infections are typically bacterial, but they may also be fungal, protozoan, or viral.
When administered early against an infection that is bacterial, the standard antibiotic treatment can be effective. Unfortunately, treatment delays and antibiotic resistance complicate medicine’s ability to reverse the damage caused by sepsis.
Best practices for treating sepsis—outlined in international guidelines for the management of severe sepsis and septic shock—include giving the patient broad-spectrum antibiotics and treatment for hypotension within the first 3 hours of the onset of symptoms (Figure 1).3,4
Ideally, the guidelines state, such treatments should only be given after tests have been performed to confirm the diagnosis of sepsis. Using traditional culture-based methods, however, it can take 2 to 4 days to identify the pathogen and generate clinically actionable information about drug-resistance markers.
Another challenge in dealing with sepsis is that it is increasingly associated with antibiotic resistance. Consequently, treatment selection must also take into account the susceptibility profile of the causative pathogen.
Sepsis also contributes to the global spread of antibiotic resistance, as patients whose positive blood cultures were caused by contaminants or other confounding factors are still likely to receive unnecessary broad-spectrum antibiotics.
Healthcare teams would greatly benefit from receiving more and earlier information about potential sepsis cases. Recent studies offer mounting evidence that rapid molecular diagnostics can provide such information in a clinically relevant time frame. Such tests can be used to follow-up positive blood cultures, generating species identification and antibiotic resistance results within only a couple of hours. Such a short turnaround time enables healthcare providers to select treatments based on clinical evidence, reducing the unnecessary use of antibiotics, and allowing patients who need treatment to get the most targeted therapy for their specific infection profile.
The Sepsis Situation
There is nothing straightforward about sepsis. Even the underlying biological response to infection is complex and uncontrolled. In the United States, sepsis is the costliest cause of hospitalization and the leading reason for readmission.5
In addition to selecting the right treatment, healthcare providers dealing with possibly septic patients have to deliver treatment quickly. The pressure of beating the clock can all too easily lead to the use of broad, nonspecific antibiotics, or to the unnecessary use of antibiotics for people who are not experiencing sepsis from a bacterial pathogen at all.
Because of the time crunch, significant effort has gone into training relevant healthcare professionals to improve recognition of the signs of sepsis. These include an unusually high or low temperature, low blood pressure, confusion or excessive sleepiness, shortness of breath, and a high heart rate. Nevertheless, recognition of patients who may be septic only makes a difference when combined with the ability to diagnose and treat the condition.
In some cases, the dire need to halt the progression of sepsis has led healthcare providers to focus on ruling it out; in other words, healthcare providers begin with a diagnosis of sepsis when the symptoms fit in order to get patients started on medication as quickly as possible. The previously mentioned clinical guidelines—commonly referred to as the ‘3-hour bundle,’ due to their requirement to deliver care within 3 hours—have been tested in a multisite study which showed that treatment within this window led to significantly lower death rates for septic patients.6 In some cases, the addition of electronic alerts that use software-based analysis of health records and patient vital signs has improved detection rates of sepsis.7
While the goal of rapid intervention is laudable, an unfortunate consequence of assuming a sepsis diagnosis is that many patients who do not have the condition are treated with heavy-duty antibiotics that promote the development of antibiotic resistance. Positive diagnostic tests are still needed to tailor treatment for each patient. Blood culture bottles can deliver positive results quickly, but using culture-based testing to then determine the pathogen species and antibiotic susceptibility profile can take days—far too long to have a meaningful impact on patient care.
For faster results, many hospital teams have turned to rapid molecular diagnostics, which have evolved over the years to cover drug susceptibility testing in addition to detecting the source of an infection (Figure 2). These are utilized when the initial blood culture bottle shows a positive result. In about 2 hours, these tests can produce a genus- and species-level identification, as well as results indicating genetic markers of antibiotic resistance. Multiplex molecular tests include many pathogens in a single panel, avoiding the much longer time frame required for serial testing of individual pathogens. Importantly, these tests can also identify common contaminants that are known to trigger a positive blood culture result; this allows providers to recommend against unnecessary antibiotic treatments.
The push to improve the diagnosis of sepsis comes, in part, from stakeholders tasked with reducing the unnecessary use of antibiotics. Often organized as antimicrobial stewardship teams (ASTs), these programs have formed as a response to the growing antibiotic resistance crisis. They have made it their mission to evaluate and adopt practices that can reduce antibiotic use, limit the spread of drug-resistant pathogen strains, and deliver more-targeted treatments to patients whose infections are marked by some element of antimicrobial resistance. Because sepsis is such a major concern in healthcare facilities, it is a strategic focus for AST members.
ASTs typically consist of professionals from different areas within a hospital or other healthcare facility (Figure 3). The participation of hospital leadership is critical to their success; these programs require budgets and other resources to achieve their goals. Other members are often clinical lab managers, pharmacists, and physicians. The idea is to assemble a team capable of establishing a comprehensive view of the patient population, treatment selection trends, and drug-resistance metrics within the hospital.
While it may seem that ASTs would focus entirely on the use of antibiotic or antiviral therapies, they actually have a much broader mandate (Figure 4).8 These teams play an essential role in implementing optimal isolation protocols and diagnostic tests, developing algorithms for therapy deescalation, and considering patient screening policies that can go further than standard clinical guidelines.
When it comes to sepsis—and many other conditions associated with infectious diseases—a number of ASTs have homed in on rapid molecular diagnostics. Conventional testing methods take far too long to prevent the overuse of antimicrobials; patients are typically treated with broad-spectrum antibiotics based solely on empiric observations.
With rapid molecular diagnostics, clinical lab teams can generate accurate, reliable results in just a few hours. In some cases, that’s fast enough to postpone treatment selection until the necessary information is available; in other cases, speedy results allow healthcare providers to confidently deescalate treatment for patients whose conditions don’t call for broad-spectrum antibiotics (Figures 5a, 5b).
For the best results with this approach, clinical lab members often work collaboratively with pharmacists. The clinical lab staff is responsible for developing the most robust, rapid workflows to run the molecular diagnostics, generating results as soon as possible. That information—which should include species-level pathogen identification as well as a profile of its drug resistance markers—would be immediately turned over to a pharmacist in addition to the patient’s physician to streamline the selection and delivery of treatment for the potentially septic patient.
A number of healthcare teams have now evaluated and implemented rapid molecular diagnostics for sepsis, and many have published results from their experiences. These reports consistently demonstrate that rapid tests allow for the successful reduction of unnecessary antibiotics and for deescalation of therapy when appropriate. Typically, early interventions based on rapid molecular diagnostics are also associated with shorter hospital stays and lower overall healthcare costs.9–11 Further, the implementation of rapid molecular testing for bloodstream infections such as sepsis has been shown to reduce the duration of hospital stays, overall healthcare costs, and readmission rates (Figure 6).12
One example of this approach comes from clinicians at the Children’s Hospital Los Angeles and the University of Southern California, who published results from a 5-year analysis of a rapid molecular test for Gram-positive bacteria. The test, which was used for more than 1,600 samples during that time, also covers common markers of antibiotic resistance, and was designed for use with blood culture bottles that had returned positive results.
The study had several aims, including determining whether rapid molecular diagnostic testing delivered results that were concordant with those from conventional culture-based tests. Researchers found that there was 99.8% positive agreement in genus-level results and 94.3% agreement at the species level from both types of tests.9 When it came to antibiotic resistance markers, the tests had a 100% concordance rate for methicillin-
resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, and vancomycin-resistant Enterococcus faecium.
In their report of these results, the investigators wrote that the rapid molecular diagnostic test “demonstrated excellent performance, and clinicians can confidently deescalate antimicrobial therapy in the absence of mecA and vanA/B gene[s].” They added that their results indicate the “suitability and dependability” of tests designed to detect genotypic resistance instead of phenotypic resistance.
Several other studies support and expand on these findings. For instance, a multisite study performed by Scripps Health, San Diego, determined that a rapid molecular diagnostic for Gram-negative bacteria in blood cultures contributed significantly to AST efforts.10 The study spanned more than 1,000 patients, half of which were diagnosed using conventional methods, and the other half using the rapid molecular test. Results clearly showed that the use of targeted antibiotics increased, and the use of antipseudomonal antibiotics decreased, for patients diagnosed using the rapid test compared to those diagnosed using conventional tests. Rapidly diagnosed patients also spent less time in the intensive care unit.
In a similar study from the Cleveland Clinic, researchers discovered that healthcare providers were able to select the optimal antimicrobial treatment or stop giving ineffective therapies almost 16 hours earlier with rapid molecular testing than they could with conventional testing.11 Patients who were tested using rapid diagnostics were released 20% sooner, on average, than those who were diagnosed using conventional methods.
Rapid molecular diagnostics are becoming established as a key component of antimicrobial stewardship efforts, and their particular importance in sepsis cases is evident. The pressure to deliver treatment quickly for potentially septic patients is enormous—as it should be for a health condition with a mortality rate that ticks higher with every passing hour.
But we have learned the hard way that giving antibiotics in the absence of reliable information about the causal pathogen and its resistance profile poses a huge threat of contributing to the growth of antibiotic resistance. Going forward, clinical lab teams can help their hospitals reduce the unnecessary use of antibiotics and get patients with sepsis on more-targeted treatments faster by adopting rapid molecular diagnostics.
Jimm Chengary, MBA, is the product manager for the blood culture portfolio at Luminex. For further information, contact CLP chief editor Steve Halasey via [email protected].
- Sepsis [online]. Geneva: World Health Organization, 2018. Available at: www.who.int/news-room/fact-sheets/detail/sepsis. Accessed July 28, 2019.
- Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589–1596; doi: 10.1097/01.ccm.0000217961.75225.e9.
- Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock, 2016. Intensive Care Med. 2017;43(3):304–377; doi: 10.1007/s00134-017-4683-6.
- About antimicrobial resistance [online]. Atlanta: Centers for Disease Control and Prevention, 2018. Available at: www.cdc.gov/drugresistance/about.html. Accessed July 9, 2019.
- Torio CM, Moore BJ. National inpatient hospital costs: the most expensive conditions by payer, 2013. Healthcare Cost and Utilization Project, Statistical Brief 204 [online]. Rockville, Md: Agency for Healthcare Research and Quality, 2016. Available at: www.hcup-us.ahrq.gov/reports/statbriefs/sb204-Most-Expensive-Hospital-Conditions.jsp. Accessed July 28, 2019.
- Leisman DE, Doerfler ME, Ward MF, et al. Survival benefit and cost savings from compliance with a simplified 3-hour sepsis bundle in a series of prospective, multisite, observational cohorts. Crit Care Med. 2017;45(3):395–406; doi: 10.1097/ccm.0000000000002184.
- Nguyen SQ, Mwakalindile E, Booth JS, et al. Automated electronic medical record sepsis detection in the emergency department. PeerJ. 2014;2:e343; doi: 10.7717/peerj.343.
- Lawrence KL, Kollef MH. Antimicrobial stewardship in the intensive care unit: advances and obstacles. Am J Respir Crit Care Med. 2009;179(6):434-438; doi: 10.1164/rccm.200809-1394cp.
- Vareechon C, Mestas J, Polanco CM, Bard JD. A 5-year study of the performance of the Verigene Gram-positive blood culture panel in a pediatric hospital. Eur J Clin Microbiol Infect Dis. 2018;37(11):2091–2096; doi: 10.1007/s10096-018-3343-2.
- Box MJ, Lee JM, Ortiz CD, et al. Rapid identification of Gram-negative bacteremia and impact on anti-pseudomonal antibiotic consumption in combination with antibiotic stewardship at a community-based hospital system. J Am Coll Clin Pharm. 2019;2(1):26-31; doi: 10.1002/jac5.1013.
- Wojewoda CM, Sercia L, Navas M, et al. Evaluation of the Verigene Gram-positive blood culture nucleic acid test for rapid detection of bacteria and resistance determinants. J Clin Microbiol. 2013;51(7)2072–2076; doi: 10.1128/jcm.00831-13.
- Sinha M, Jupe J, Mack H, Coleman TP, Lawrence SM, Fraley SI. Emerging technologies for molecular diagnosis of sepsis. Clin Microbiol Rev. 2018;31(2):e00089-17; doi: 10.1128/CMR.00089-17.