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Rapid Blood Culture Testing in the Age of Antimicrobial Stewardship

Molecular technologies enable timely optimization of treatment for septic patients

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In addition to conferring a mortality rate 8 times higher than average hospitalizations, sepsis maintains the dubious distinction of being the most expensive cause of hospitalization in the United States, with costs of care totaling over $15 billion per year.1 In a healthcare environment increasingly focused on costs, the prevention and treatment of this condition, triggered by an infection in a patient's bloodstream, has understandably received considerable attention. However, with the rise of hospital-acquired infections and new antibiotic-resistant bacteria, the incidence of sepsis has more than doubled in the past 20 years.1

The Dilemma
The high mortality and soaring costs associated with the treatment of sepsis are due, in large part, to a fundamental diagnostic limitation: physicians do not know what kind of infection they are treating until 2-3 days after diagnosis. Once bacterial growth is detected in a blood culture bottle, physicians must empirically treat a patient for up to 72 hours while they wait for conventional biochemical methods to identify the causative bacterium and determine whether or not it is resistant to common antibiotics. These empiric treatment regimens usually include strong broad-spectrum antibiotics like vancomycin, which most patients do not need. In fact, upwards of 40% of positive blood cultures are caused by contamination and do not represent actual bloodstream infections.2 The overuse of these drugs has contributed to increased rates of antibiotic resistance3 and a dwindling list of treatments available to fight new resistant infections.

Furthermore, in many cases, these broad-spectrum antibiotics are not as effective as other more targeted treatment options. While vancomycin is often an appropriate treatment for infections caused by methicillin-resistant Staphylococcus aureus (MRSA), for other organisms, like methicillin-sensitive S. aureus (MSSA) and other non-resistant streptococci and enterococci, penicillin derivatives or other beta lactams are not only a more responsible choice, but are associated with better patient outcomes than vancomycin.4 Unfortunately, these treatment decisions must be guided by a reliable characterization of the bacteria causing the infection - information that conventional microbiology cannot provide until days after bacterial growth is detected.


First-Generation Solutions
In an effort to close this gap, laboratories have employed a host of novel methods to provide clinicians with additional information in a timely fashion. Direct biochemical methods like the tube coagulase test can differentiate S. aureus from likely contaminants the same day a blood culture bottle goes positive. Similarly, fluorescent in situ hybridization (FISH) methods can identify S. aureus and several other organisms directly from positive blood culture bottles. However, neither of these methods can determine whether or not these organisms are resistant to common antibiotics.

Real-time PCR methods have been employed to amplify gene segments associated with particular antibiotic-resistant bacteria, such as MRSA, directly from positive blood culture bottles. Other assays use immunochromatography and rely on overnight growth from plated cultures to identify proteins associated with antibiotic resistance. Modifications to standard culture techniques, including chromogenic culture media and Kirby-Bauer disk diffusion, can also help identify antibiotic resistance after overnight growth.

The Benefit
While these methods increase laboratory costs and can involve disruptive workflows, there is often a substantial return on investment, even when only limited identification or resistance information is produced. In addition to supporting the responsible use of antibiotics, the clinical and financial benefits realized from early optimization of treatment are significant. Rapid differentiation of MRSA from MSSA from blood cultures has been associated with a reduced length of stay of 6.2 days and a cost savings of over $21,000 per patient.5 Differentiation of enterococci and streptococci in blood cultures has been estimated to reduce ICU mortality in these patients by more than 45%.6 Even the unnecessary treatment associated with contaminated cultures comes at a significant cost, with estimates ranging up to $8,750 per patient.7

Still, widespread use of rapid testing methods has yet to materialize. Complicated workflows, slow turnaround times, or the need for highly trained staff or specialized facilities have prevented most institutions from implementing truly impactful strategies for decreasing blood culture turnaround times.

Next-Generation Technologies

New direct molecular microarray technologies, such as Nanosphere's FDA-cleared Verigene BC-GP Test for gram-positive blood cultures, have made rapid testing more accessible to laboratories of all sizes. The Verigene test consolidates the type of results produced by multiple earlier efforts into a single automated test that simultaneously provides identification for a broad range of bacteria and antibiotic resistance determinants. Early studies have shown good correlation with conventional methods,5 but as importantly, the test can be run without disrupting the normal workflow of a microbiology lab. Tests require less than 5 minutes of hands-on time to perform, and single-use test cartridges include onboard internal controls, so patient samples can be run on-demand without the need to batch runs.

Advances in chemistry and automation have enabled the consolidation of rapid blood culture testing methods into multiplexed molecular platforms that are accessible to laboratories of all sizes. In the age of antimicrobial stewardship, optimizing antibiotic therapy as quickly as possible for the sickest patients in our hospitals - and discontinuing treatment for those who don't need it - will be an increasingly important effort in combatting sepsis, the misuse of antibiotics, and the rising costs of healthcare.

Zack Crowther is product manager, Nanosphere, Northbrook, Ill.

References

1. Elixhauser, A. (Agency for Healthcare Research and Quality), Friedman, B. (Agency for Healthcare Research and Quality) and Stranges, E. (Thomson Reuters). Septicemia in U.S. Hospitals, 2009. HCUP Statistical Brief #122. October 2011. Agency for Healthcare Research and Quality, Rockville, MD. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb122.pdf
2. Weinstein MP, Towns ML, Quartey SM, et al. The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults. Clin Infect Dis. 1997;24(4):584-602.
3. Kullar R, Davis SL, Levine DP, Rybak MJ. Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets. Clin Infect Dis. 2011;52(8):975-981.
4. Kim SH, Kim KH, Kim HB, et al. Outcome of vancomycin treatment in patients with methicillin-susceptible Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2008;52(1):192-197.
5. Bauer KA, West JE, Balada-Llasat JM, Pancholi P, Stevenson KB, Goff DA. An antimicrobial stewardship program's impact with rapid polymerase chain reaction methicillin-resistant Staphylococcus aureus/S. aureus blood culture test in patients with S. aureus bacteremia. Clin Infect Dis. 2010;51(9):1074-1080.
6. Gamage DC, Olson DP, Stickell LH, et al. Significant decreases in mortality and hospital costs after laboratory testing with PNA FISH. Poster D-1302b. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011); September 2011; Chicago, Illinois, USA.
7. Zwang O, Albert R. Analysis of strategies to improve cost effectiveness of blood cultures. J Hosp Med. 2006;1:272-276.



     

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