Timely Identification for Informed Patient Care in Infectious … · 2019-02-08 · 3 Timely Identification for Informed Patient Care in Infectious Diseases: Bloodstream Infections

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Timely Identification for Informed Patient Care in Infectious Diseases: Bloodstream Infections CME / ABIM MOC / ACCENT

www.medscape.org/cmetv/acute-gastroenteritis

Timely Identification for Informed Patient Care in Infectious DiseasesBloodstream Infections

CME / ABIM MOC / ACCENT

Supported by an independent educational grant from BioFire Diagnostics, LLC.

Presented through a collaboration between The American Association for Clinical Chemistry (AACC) and Medscape Education.



Target AudienceThis activity is intended for physicians who practice in the areas of infectious diseases, critical care, pediatrics, hospital medicine, and emergency medicine, as well as laboratory and point-of-care-testing professionals.

Goal The goal of this activity is to increase awareness of the benefits and limitations of new and emerging diagnostic tests for bloodstream infections.

Learning ObjectivesUpon completion of this activity, participants will:

• Have increased knowledge regarding the• Key distinguishing characteristics among laboratory methods for the diagnosis of bloodstream infection

• Have greater competence related to• The clinical implications of rapid molecular diagnostics for bloodstream infection

• Demonstrate greater confidence in their ability to• Identify key attributes of molecular diagnostic tests in the diagnosis of bloodstream infection

Credits AvailablePhysicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ABIM Diplomates - maximum of 0.25 ABIM MOC points Laboratory and Point-of-Care Testing Professionals - maximum of 0.25 ACCENT® credit hours

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For Physicians Medscape, LLC designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

For Laboratory and Point-of-Care Testing Professionals The American Association for Clinical Chemistry (AACC) will designate this activity for a maximum of 0.25 ACCENT® credit hours.

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This article is a CME / ABIM MOC / ACCENT certified activity.To earn credit for this activity visit:

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Medscape, LLC staff have disclosed that they have no relevant financial relationships.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 0.25 MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Aggregate participant data will be shared with commercial supporters of this activity.

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Follow these steps to earn CME/CE credit*:

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Disclosures

Faculty

Ritu Banerjee, MD, PhDAssociate ProfessorMedical DirectorPediatric Antimicrobial Stewardship ProgramVanderbilt University Medical CenterNashville, Tennessee

Disclosure: Ritu Banerjee, MD, PhD, has disclosed the following relevant financial relationships: Received grants for clinical research from: Axcellerate Pharma; BioFire; bioMérieux; Roche

Editors

Susan L. Smith, MN, PhD Lead Scientific Director, Medscape, LLCDisclosure: Susan L. Smith, MN, PhD, has disclosed no relevant financial relationships.

CME Reviewer

Nafeez Zawahir, MDCME Clinical Director, Medscape, LLCDisclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.



Taryn Brill: Hello, and welcome to the fourth and final episode of Diagnosis TV: Timely Identification for Informed Patient Care in Infectious Diseases: Bloodstream Infections. I’m Taryn Brill. Before we begin, please take a moment to answer the pre-assessment questions.

Ms Brill: Sepsis, an immune-mediated response to a bloodstream infection, is a medical emergency. It is a leading cause of death in both adults and infants in the United States.[1] Early identification and appropriate immediate management, including administration of antibiotics in the initial hours after development of sepsis improves outcomes.[2]



In fact, the Surviving Sepsis Campaign recently recommended a 1-hour bundle for immediate initiation of resuscitation and management of patients presenting with sepsis or septic shock. Obtaining blood for measuring lactate and blood cultures, administration of fluids and antibiotics, and initiation of vasopressor therapy if indicated, are all begun immediately.[2] Because signs and symptoms of sepsis are similar, regardless of the infectious cause, it is recommended that empiric broad-spectrum intravenous with one or more antibiotics be given to cover all likely pathogens until the offending pathogen can be identified and its antibiotic susceptibility determined.[2]

To better understand the role of rapid diagnostic methods for identification of pathogens in patients with sepsis, we visited Dr Ritu Banerjee, Associate Professor of Pediatrics and Director of the Vanderbilt Vaccine Research Program at Vanderbilt University School of Medicine, in Nashville, Tennessee.

I opened our discussion with a question about how recent advances in rapid microbial identification might improve providers’ ability to optimize antimicrobial therapy in patients with sepsis.

Ritu Banerjee, MD, PhD: The conventional method of determining the etiology of sepsis begins with obtaining a blood culture. Once a blood culture turns positive, which means it shows organism growth, the microbiology laboratory looks at the organism under a microscope after performing a Gram stain. The Gram stain result is available within a few minutes, but it does not give the provider specific details about the type of organism or the drug susceptibility profile of the organism. This information is necessary for initiating targeted antibiotic therapy.



Once a blood specimen tests positive (positive Gram stain), the specimen must be tested further to identify organism species and susceptibility, which takes 2 to 3 days using conventional methods. During this time, patients with possible sepsis usually receive broad-spectrum antibiotics, which may be too much or too little. That is, the pathogen may not be susceptible to the empiric antibiotic, putting patients at significant risk of morbidity and mortality. Alternatively, the pathogen might be quite susceptible to the empiric antibiotic and the therapy is thus, overly broad and more than the patient needs, putting the patient at risk for antibiotic-related toxicities and leading to the emergence of resistant bacteria.



Panel-based molecular diagnostic assays are now available for direct testing of positive blood culture bottles that can identify the species of organisms and detect some antibiotic resistance genes within about 1 to 3 hours of a positive Gram stain result, allowing both earlier administration of targeted antimicrobial therapy and earlier de-escalation of broad-spectrum therapy.[3-8]

Ms Brill: Dr Banerjee mentioned that multiplex molecular diagnostic assays can both identify key pathogens and detect common genes for antibiotic resistance. I asked her to elaborate on how the detection of resistance markers translates clinically to antibiotic susceptibility in patients with bloodstream infections.



Dr Banerjee: For many gram-positive bacteria, the presence or absence of resistance genes using a multiplex molecular panel translates well to phenotypic drug susceptibility. In contrast, in Gram-negative bacteria, the correlation between the detection of resistance genes and the susceptibility of an isolate to a given class of antibiotics is not as straightforward because Gram-negative organisms have a wide array of resistance mechanisms compared with Gram-positive organisms. It is impossible to put all the different resistance genes found in Gram-negative organisms on a single multiplex molecular panel.

Ms Brill: The ability to detect selected antibiotic resistance genes is an important feature of multiplex molecular panels. Although, as Dr Banerjee said, the usefulness of this information in terms of antibiotic prescribing decisions may vary depending on whether the organism is Gram positive or Gram negative. I asked Dr Banerjee to help clarify this concept with case study examples.

Dr Banerjee: A typical case would be a patient with a comorbidity that requires a central intravenous catheter. The patient presents to the emergency department with a high fever. Suspecting a bloodstream infection, the emergency department physician draws blood for culture from both the central line and a peripheral vein. The patient is then prescribed empiric broad-spectrum, combination antibiotic therapy, such as vancomycin and cefepime, to cover both Gram-positive and Gram-negative bacteria. After about 24 hours, the blood culture result is reported as positive for growth of bacteria.

If we use a multiplex, panel-based molecular diagnostic assay, in many cases we are able to identify the pathogen within 1 to 3 hours, depending on the test panel used. Let’s say the pathogen is Staphylococcus aureus, a Gram-positive organism that is a common cause of sepsis.



A multiplex molecular panel that detects the presence or absence of the methicillin-resistance gene mecA, reports that this patient’s isolate is mecA-negative. So, it is a methicillin-susceptible strain or methicillin-susceptible Staphylococcus aureus (MSSA). So, within 1 to 3 hours after a positive blood culture bottle test result, we know that the patient has an MSSA bloodstream infection. The provider can then target antimicrobial therapy accordingly. Cefepime, which targets Gram-negative bacteria can be stopped, and vancomycin, which was started empirically to target methicillin-resistant organisms, can be changed to nafcillin or some other narrow-spectrum antibiotic that is not as nephrotoxic as vancomycin, and is highly effective against this type of bacteria.



In other words, the rapid identification of MSSA using multiplex molecular technology allows us to de-escalate broad-spectrum, combination, multiple antibiotic therapy to a narrow-spectrum, single agent with high efficacy within a few hours of a positive culture result. This is in contrast to 24 to 48 hours after a positive blood culture result, using conventional diagnostic techniques.

Ms Brill: I asked Dr Banerjee if she could provide us with an example of another case that illustrates how the more complicated resistance mechanisms associated with Gram-negative bacteria impact the choice of antimicrobial therapy.

Dr Banerjee: There is a child in our hospital who has cancer and who has contracted a bloodstream infection. Empiric broad-spectrum antibiotic therapy was initiated, and blood for culture was sent to the laboratory. About 24 hours later, after the culture showed positivity for infection, a multiplex molecular panel test[9] rapidly detected Escherichia coli, a very common Gram-negative pathogen that causes sepsis.



The panel also detected the presence of the CTX-M gene, which codes for a β-lactamase and therefore, resistance to many β-lactam antibiotics.[10] In this case, detection of the CTX-M gene was useful because it told me that a cephalosporin or penicillin would not be effective therapy. So, as a result of this information, I switched the child’s antibiotic therapy to a carbapenem, specifically meropenem, which is effective against extended-spectrum β-lactamase (ESBL)-producing E coli. However, I still did not have information as to whether this isolate was susceptible to other classes of antibiotics used to treat Gram-negative infections, such as fluoroquinolones. The many different genes that may provide fluoroquinolone resistance are not present on the multiplex panel. So, as this patient’s condition improved and I wanted to de-escalate therapy, I still had to wait 2 or 3 days for standard methods of susceptibility testing before I had the necessary information to select the most appropriate antibiotic.

Ms Brill: In Dr Banerjee’s case example, her institution used a multiplex molecular panel to identify isolates and detect antibiotic resistance. I asked Dr Banerjee if she could briefly describe the key features of the different types of rapid diagnostic technologies available today.

Dr Banerjee: Multiplex polymerase chain reaction (PCR)-based molecular blood culture panels for detection of bloodstream infections test for the presence of common pathogens, including Gram-positive and Gram-negative bacteria, and yeast, as well as select antibiotic resistance markers.



Advantages of multiplex molecular panels include ease of use, accuracy, the capacity to test for multiple pathogens at the same time, and the ability to both identify pathogens and detect select resistance genes from a positive culture within about 1 to 3 hours. The available test platforms differ somewhat in the specific pathogens and resistance genes they can identify, the time to test completion, and the procedures required for analyzing the culture.[11] Rapid blood culture diagnostic tests are add-on tests performed in addition to conventional testing and therefore, can increase the complexity of laboratory testing and the cost of patient care.

Another widely used rapid detection method is matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS).[12] MALDI-TOF MS can identify an organism by using mass spectrometry to measure its unique proteomic signature.



Unlike a multiplex molecular panel, MALDI-TOF MS is approved by the United States Food and Drug Administration (FDA) for use only from subculture plates vs culture bottles. Once a colony forms on a plate, it takes MALDI-TOF MS only a few minutes to identify pathogens. This device also has an extensive library of species, far more than multiplex molecular panels. However, MALDI-TOF MS cannot determine bacterial resistance to antibiotics. Another drawback is its large size and high cost, although once the initial investment is made, testing individual isolates is inexpensive.

Another recently approved rapid detection device is the T2 Magnetic Resonance (T2MR) system, which uses magnetic resonance to identify select species of bacteria and Candida for blood cultures.



Unlike the multiplex molecular panels and MALDI-TOF MS, the T2MR method can identify microorganisms directly from a whole blood sample without waiting for organism growth in a blood culture bottle.[13] The time required to identify an organism from a whole blood sample is 3 to 5 hours, which is the fastest overall detection method available. However, the T2MR panel includes fewer bacterial species than the multiplex molecular panels and it does not detect genes for antibiotic resistance.



And, a recently approved platform using fluorescence in situ hybridization (FISH) technology identifies select bacteria and Candida species from a positive blood culture bottle within 90 minutes. The system is also able to measure phenotypic susceptibilities of the isolate to a variety of antibiotics within 7 hours.[14] The disadvantages of this system are high cost, a complicated instrument, and inability to identify all organisms that grow in blood cultures.

Ms Brill: As Dr Banerjee has explained, the availability of rapid diagnostic systems for identifying bloodstream pathogens and detecting antibiotic resistance enables a provider to more quickly and appropriately escalate or de-escalate antibiotic therapy to target a specific bloodstream infection. I wondered how this improved diagnostic capability translated into actual improvements in patient outcomes, such as morbidity, mortality, and hospital costs.

Dr Banerjee: Most of the clinical evaluations of rapid blood culture diagnostics have focused on test performance -- how quickly and accurately the test method can identify pathogens and determine antibiotic susceptibility. There have been relatively little data on whether more rapid blood culture diagnostics have impacted patient outcomes. In fact, observational studies on the impact of rapid blood culture diagnostics on clinical and cost-related outcomes have shown mixed results. While some studies have shown that the use of blood culture diagnostic tests lowered mortality, decreased hospital length of stay, and reduced healthcare costs,[15,16] other studies have not confirmed these benefits compared with conventional blood culture and susceptibility testing.[17]



What we do know is that the clinical impact of rapid blood culture diagnostic tests depends on a variety of factors related to the specific healthcare institution, including antimicrobial prescribing practices, the implementation of antibiotic stewardship programs,[18] patient populations, and local rates of pathogen resistance.[17]



A randomized, controlled trial of the evaluation of blood cultures using a multiplex molecular panel, published by myself and my colleagues in 2015, showed that faster identification and resistance characterization of pathogens resulted in more judicious antibiotic use compared with conventional testing when test results were delivered with guidelines on diagnostic interpretation and antimicrobial use.[19] We also found that the combination of rapid molecular blood culture testing with active antimicrobial stewardship audit and feedback to providers, further enhanced the rate of effective antimicrobial de-escalation.[19] At many institutions now, stewardship programs review all positive blood cultures, to ensure rapid antibiotic de-escalation as needed, when results of molecular blood culture diagnostics are available.

I want to end with a few comments on how rapid molecular diagnostics tests equip providers to be good stewards of antibiotics. Once pathogen identification and susceptibilities are established, empiric antimicrobial therapy can be narrowed.



Getting patients on the most narrow-spectrum, effective antibiotic therapy as quickly as possible improves outcomes and safety, and reduces unnecessary broad-spectrum antibiotic use that in turn, preserves our shrinking antibiotic armamentarium.

Ms Brill: This brings us to the close of episode 4 and the Diagnosis TV program. We hope you found it to be informative and helpful to your practice. Whether we are talking about meningitis, acute gastroenteritis, acute respiratory tract infections, or sepsis, the advent of rapid blood culture diagnostic tests is helping to address one of the greatest challenges in the treatment of infectious diseases - the rapid and precise targeting of specific pathogens with the most effective and safest antimicrobial regimens available.



Abbreviations

AS = antimicrobial stewardshipAST = antimicrobial susceptibility testingBCB = blood culture bottleBCID = blood culture identificationCSF = cerebrospinal fluid ESBL = extended-spectrum β-lactamaseFDA = United States Food and Drug AdministrationFISH = fluorescence in situ hybridizationID = identificationMALDI-TOF MS = matrix-assisted laser desorption ionization-time of flight mass spectrometryMSSA = methicillin-susceptible Staphylococcus aureusPCR = polymerase chain reactionPNA-FISH = fluorescence in situ hybridization using peptide nucleic acid probesrmPCR = rapid multiplex polymerase chain reactionT2MR = T2 Magnetic Resonance

References

1. Kochanek KD, Xu J, Murphy SL, et al. Deaths: preliminary data for 2009. National Vital Statistics Reports. 2011;59.2. Levy M, Evans LE, Rhodes A. The Surviving Sepsis Campaign bundle: 2018 update. Crit Care Med. 2018;46:997-1000.3. Altun O, Almuhayawi M, Ullberg M, et al. Clinical evaluation of the FilmArray blood culture identification panel in

identification of bacteria and yeasts from positive blood culture bottles. J Clin Microbiol. 2013;51:4130-4136.4. Wojewoda C, 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;51:2072-2076.5. Hill JT, Tran KD, Barton KL, et al. Evaluation of the Nanosphere Verigene BC-GN assay for direct identification of gram-

negative bacilli and antibiotic resistance markers from positive blood cultures and potential impact for more rapid antibiotic interventions. J Clin Microbiol. 2014;52:3805-3807.

6. Stender H, Williams B, Coull J. PNA fluorescent in situ hybridization (FISH) for rapid microbiology and cytogenetic analysis. Methods Mol Biol. 2014;1050:167-178.

7. Deck MK, Anderson ES, Buckner RJ, et al. Multicenter evaluation of the Staphylococcus QuickFISH method for simultaneous identification of Staphylococcus aureus and coagulase-negative staphylococci directly from blood culture bottles in less than 30 minutes. J Clin Microbiol. 2012;50:1994-1998.

8. Stevenson LG, Drake SK, Murray PR. Rapid identification of bacteria in positive blood culture broths by matrix-assisted laser desorption ionization-time of flight mass spectrometry. J Clin Microbiol. 2010;48:444-447.

9. Ray ST, Drew RJ, Hardiman F, et al. Rapid identification of microorganisms by FilmArray blood culture identification panel improves clinical management in children. Pediatr Infect Dis. 2016;35:3134-138.

10. Cantón R, González-Alba J, Galán JC. CTX-M enzymes: origin and diffusion. Front Microbiol. 2012;3:1-18.11. Ramanan P, Bryson AL, Binnicker MJ, et al. Syndromic panel-based testing in clinical microbiology. Clin Microbiol Rev.

2018;31:1-28.12. Verroken A, Defourny L, le Polain de Waroux O, et al. Clinical impact of MALTI-TOF MS identification and rapid

susceptibility testing on adequate antimicrobial treatment in sepsis with positive blood cultures. PLOS One. 2016;26:1-15.13. Bazzi AM, Rabaan AA, El Edaily Z, et al. Comparison among four proposed direct blood culture microbial methods using

MALDI-TOF MS. J Infect Pub Health. 2017;10:308-315.



14. Pancholi P, Carroll KC, Buchan BW, et al. Multicenter evaluation of the Accelerate PhenoTest BC Kit for rapid identification and susceptibility testing using morphokinetic cellular analysis. J Clin Microbiol. 2018;56:1-21.

15. Beekman SE, Diekema DJ, Chapin KC, et al. Effects of rapid detection of bloodstream infections on length of hospitalization and hospital charges. J Clin Microbiol. 2003;41:3119-3125.

16. Vessenmeyer AF, Olson JA, Hersch AL, et al. A retrospective study of the impact of rapid diagnostic testing on time to pathogen identification and antibiotic use for children with positive blood cultures. 2016;5:555-570.

17. Banerjee R, Ozenci V, Patel R. Individualized approaches are needed for optimized blood cultures. Clin Infect Dis. 2016;63:1332-1339.

18. Buss BA, Baures TJ, Yoo M, et al. Impact of multiplex PCR assay for bloodstream infections with and without antimicrobial stewardship intervention at a cancer hospital. Open Forum Infect Dis. 2018;5:ofy258.

19. Banerjee R, Teng CB, Cunningham SA, et al. Randomized trial of rapid multiplex polymerase chain reaction-based blood culture identification and susceptibility testing. Clin Infect Dis. 2015;61:1071-1080.

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Timely Identification for Informed Patient Care in Infectious … · 2019-02-08 · 3 Timely Identification for Informed Patient Care in Infectious Diseases: Bloodstream Infections