BY: PATRICK R. MURRAY, PHD
Patrick R. Murray, PhD, is worldwide director, Scientific Affairs, BD Diagnositcs – Diagnostic Systems, Franklin Lakes, NJ. Murray formerly served as chief of the Microbiology Service and senior scientist at the 
National Institutes of Health (NIH) Clinical Center, where he oversaw the clinical and research programs in microbiology and postdoctoral training of PhD and MD microbiology and infectious disease fellows. He received the NIH Clinical Center Director’s Award for Patient Care and the NIH Director’s Award for Clinical Research. Prior to NIH, Murray served as a professor and head of Clinical Microbiology at the University of Maryland Medical Center and as professor in the Department of Medicine & Pathology at Washington University in Saint Louis. He received his PhD in microbiology at the University of California, Los Angeles, and conducted postgraduate training in clinical microbiology at the Mayo Clinic in Rochester, Minn.
CLP: Let’s start with the basics. Can you describe the key issues laboratories and clinicians face when diagnosing sepsis?
Patrick R. Murray, PhD: Because sepsis is characterized by a systemic inflammatory response to an infection, its progression is largely determined by the laboratory’s ability to rapidly and accurately identify the causative organism, and provide guidance for the selection of appropriate antimicrobial treatment.
There are a number of factors that make each of these steps challenging. When sepsis is suspected, patients require immediate treatment with antimicrobials; however, administering such treatment early poses a tremendous challenge to pathogen identification, as antimicrobials could artificially sterilize the patient’s blood culture. Also at risk of jeopardizing the blood culture is the volume of blood collected. It is recommended that a minimum of two blood cultures with significant blood volume are collected within 30 minutes of sepsis presentation and prior to antibiotic administration; however, this is rarely the case given the urgency to begin treating the potential infection. Additionally, phlebotomists and nurses are often challenged to collect the recommended amount of blood for each culture.
Once blood cultures are drawn, there can also be significant delays to getting the bottles transported to the laboratory and placed in the appropriate instrument to begin incubation, which again prevents a prompt diagnosis. Following an initial diagnosis, clinicians also face the challenges of selecting the most effective, least toxic empiric antibiotic therapy and adjusting of this therapy once an organism is recovered in the blood culture. Not only does this require that the right person receives the results as soon as they become available, but also that the informed clinician correctly utilizes the diagnostic information to select the best treatment for the patient.
CLP: Clearly there are a lot of diagnostic challenges. Which would you prioritize?
Murray: Since selecting the best therapy largely determines patient outcome, rapidly providing information that can guide treatment decisions should be the priority. This would involve developing techniques to reduce the time to obtain actionable results; that is, reduce the time to obtain a positive culture, identify the organism, and obtain antimicrobial susceptibility results.
It will also be important to continue to refine the diagnostic process to ensure critical information consistently and reliably reaches the appropriate clinical decision-makers. Correcting the process at the broadest level will feed into an improved diagnostic system overall, as the other challenges I discussed are addressed at a technological level.
CLP: What are the most promising solutions to attack these problems?
Murray: The supplementation of blood culture media with proprietary formulations of antibiotic-binding resin beads have led to more positive blood cultures and earlier detection, even following antimicrobial administration.
Additionally, the MALDI mass spectrometry technique has proven very promising at providing a faster, accurate means of identifying organisms compared to other conventional systems, leading to improved empiric antimicrobial therapy. These media improvements and technical solutions have made notable advances to address both problems of speed and accuracy.
CLP: Are you aware of any progress in the STOP Sepsis Collaborative, a campaign undertaken by a consortium of 55 hospitals in the New York region to aggressively identify sepsis for early treatment?
Murray: The STOP Sepsis Collaborative is an initiative designed to implement standardized protocols for sepsis recognition and treatment. With the current momentum in conversation around critical issues related to sepsis diagnosis, the initiative has potential to generate meaningful discussions around best practices for the diagnosis of sepsis and the latest clinical and technological developments in this area.
CLP: What are diagnostic companies such as BD doing to improve outcomes?
Murray: At BD, we have been focusing our efforts on multiple dimensions of the diagnostic process. Our primary goals are to improve both conventional approaches to blood culture collection and organism identification, as well as advance antimicrobial susceptibility testing. From a product standpoint, developments such as the BD BACTEC™ Blood Culture System for the rapid and sensitive detection of bloodstream infections are addressing several of these goals in combination.The system includes blood culture media with the previously mentioned antimicrobial-neutralizing resin beads, which have demonstrated notable pathogen recovery. Additionally, the BD BACTEC FX Blood Culture System also allows for remote placement of blood culture instruments in high-volume areas of the hospital, such as the emergency department and intensive care unit, thus eliminating delays in transporting blood culture bottles to the laboratory and associated delays in detection of positive cultures.
In addition, BD has extensive experience in microbiology and is currently working with Bruker Daltonics, which has experience in mass spectrometry, to produce integrated systems that decrease the time for organism identification and antimicrobial susceptibility test results. There is also a broad effort to standardize the diagnosis process, as there is still room to reduce technical errors and speed time to results.
Ultimately, BD and other diagnostic companies are trying to improve the efficiency of the whole diagnosis process through product design, standardization, and advanced technology.
CLP: Beyond faster detection, what other implications would improved diagnostic techniques provide?
Murray: Achieving faster time to detection is a catalyst to achieving the other half of the equation: actionable results that can guide patient management. With sepsis, the nature of the condition not only requires that the pathogen be identified quickly, but also that such information is used to determine the appropriate treatment for the patient. Given the large variety of both causative agents and treatment options, there are countless combinations to achieving patient care, and it is crucial that each patient receives the right one. As we improve speed of diagnosis, we are also managing to improve accuracy by quickly collecting key information that can be put into action to improve patient outcome.
Additionally, as we continue to increase the efficiencies of diagnostic techniques, it stands to reason that these efficiencies will be seen at the broader hospital and health care system levels as well. Between 2000 and 2008, the number of US hospital admissions for sepsis more than doubled, and in the United States alone, more than $17 billion a year is spent managing severe sepsis patients. This tremendous burden on our health care system could be lessened with improved diagnostic techniques that yield downstream results of shorter hospital stays, targeted treatments, and lower costs of care.
CLP: What steps can health care providers take to improve sepsis diagnosis and management?
Murray: First, the work to improve sepsis diagnosis and management is under way, and many hospitals and health care systems are already examining their current practices and putting new practices into place with this specific goal in mind. Since sepsis diagnosis is largely dependent on positive blood cultures, a key step providers can take moving forward is optimizing the blood culture collection process, such that specimens are in the best condition possible for analysis. This means ensuring an adequate amount of blood is cultured in both aerobic and anaerobic bottles, and that appropriate media are used for specimens collected from patients on antimicrobial therapy.
Integration and communication are also essential. The implementation of new, advanced diagnostics will require procedural shifts across the process so that reductions in time to diagnosis are properly leveraged and the opportunity exists culturally to make faster, more accurate treatment decisions in real-time using the output of advanced blood culture systems.
For more information, contact Editor Judy O’Rourke, [email protected]
