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    1. Disease

    Rapid diagnostics are the critical link to improving sepsis care and addressing AMR

    Feb. 23, 2022
    Image by Dr_Microbe @ Bigstock photos
    Bigstock Sepsis Bacteria In Blood D 269249659 62140140d380f

    Sepsis is a life-threatening organ dysfunction, which is caused by the dysregulated host response to infection.1 It is a spectrum that starts from bacteremia, the presence of viable bacteria in the bloodstream, which might progress to sepsis that, in addition to bacteremia, includes organ dysfunction.2 The final stage may lead to septic shock, a condition where the patient exhibits poor blood hypoperfusion, despite adequate intravascular fluid resuscitation.2 Sepsis causes the death of nearly 270,000 Americans annually3 and claims more lives each year than the top three cancers combined (lung, colorectal, breast).4 The extended time from symptom presentation to appropriate therapy remains a major contributor to poor patient outcomes and the proliferation of antimicrobial resistance (AMR). 5 For every hour of delay in time to appropriate therapy, survival decreases by 7.6% during septic shock.5

    Intersection of COVID-19 and sepsis

    Since late 2019, the global COVID-19 pandemic6 has significantly added to the burden of sepsis.7 Individuals who are hospitalized with COVID-19 have shown to be more prone to secondary bacterial and fungal infections.7 These secondary bacterial and fungal infections are likely to occur in a significant portion of critically ill hospitalized patients with COVID-19.7 Hospitalized COVID-19 patients are at a 22% increased risk of developing sepsis and 113% more likely to experience septic shock when compared to hospitalized influenza patients, and the overall inpatient mortality incidence was also found to be much higher when compared to those hospitalized influenza patients (15.8% vs. 4.1%).8

    Unnecessary treatment for bacterial and fungal infections is common in patients with COVID-19.9 As a result, the overuse of antibiotics incurred during the pandemic may have long term ramifications for increased antimicrobial resistance.9 The clinical conditions of sepsis and COVID-19 may lead to irrational and prolonged antibiotic use, which may lead to the development of anti-microbial resistance (AMR),9 whereby microbiological pathogens become resistant to the common antimicrobial agents, necessitating the use of the newer and more expensive drugs.10

    Infec Diag

    The global threat of antimicrobial resistance (AMR)

    According to the World Health Organization (WHO), “the persistent failure to develop, manufacture, and distribute effective new antibiotics is further fueling the impact of antimicrobial resistance (AMR)11 and threatens our ability to successfully treat bacterial infections.”11, 12 Every year, 700,000 people die of AMR, and if no action is taken, the death toll because of AMR could rise to as many as 10 million, annually by 205012 and cause a 3.8% reduction in annual gross domestic product (GDP).12 This global threat has created room for innovation in the terrain of rapid diagnostic tests to combat the development and spread of drug resistance bacteria. There is a federal challenge/competition, with a prize of $20 million, a joint effort between the National Institutes of Health and the Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response (ASPR) to address the issue of AMR.13

    The challenge calls for new, innovative, and novel laboratory diagnostic tests that identify and characterize antibiotic-resistant bacteria, to reduce the unnecessary use of antibiotics, a major cause of antibiotic resistance.13 It is important to note that diagnostic tests play an important role in the prevention and inappropriate use of antibiotics because they assist in the selection of the most effective therapy, thereby reducing the risk for antibiotic resistance.14

    Laboratory diagnoses of sepsis causing pathogens

    The gold standard for the detection of sepsis-causing pathogens is a blood culture (BC),15 which requires a higher blood volume for testing, up to 30 ml with multiple culture sets.15 This has been in use since the inception of early microbiological diagnosis and has served patients with sepsis well, but there are issues that include the delayed resulting of specimens of up to 3 days, cross contamination, and the impact of prior antibiotics use on the likelihood of pathogen detection that could further impact the management of the patient.15

    There are numerous other tests, apart from BC, which are non-specific such as the complete blood count (CBC) that identifies an increase in the white blood cells (WBC), signifying an infection, and a reduction of the WBC may also indicate the individual is at risk of developing an infection.16 The elevated lactate level is another non-specific method of managing sepsis patients, though lactate levels may also be elevated in other situations such as intense exercise or heart failure.16, 17

    Another non-specific test is the C-reactive protein (CRP) that the body produces when there is an inflammation, and several other conditions can cause inflammation, including infections.16, 17 Procalcitonin (PCT) is a protein in blood that rises if there is a bacterial infection, but it does not identify the specific bacterial pathogen. Other tests are Prothrombin time and partial thromboplastin time (PT and PTT), platelet count, and d-dimer.16, 17

    Rapid diagnostic test (RDT)

    The ideal rapid diagnostic test (RDT) would potentially have advantages that include rapid and reliable results, low detection limits, high-throughput testing, and specific organism detection directly from a clinical specimen.18 There are numerous U.S. Food and Drug Administration (FDA) approved molecular diagnostic tests for detecting sepsis causing pathogens,18 some are culture independent tests such as the magnetic resonance (T2MR), metagenomic shotgun sequencing methods, and nucleic acid amplification platforms. There are also the culture dependent platforms or post-culture, meaning it relies on the BC result before it can be tested on such a diagnostic platform such as MALDI-TOF MS, Real-time multiplex PCR, and in situ hybridization.18 Culture is the standard for pathogen detection, but in recent times, culture independent diagnostic tests are increasingly used due to their advantages such as rapid detection of organisms, which is critical to clinical decision making.19

    The newer rapid diagnostic tests (RDT) could shorten the time to the detection of pathogens, and this could potentially lead to faster initiation of appropriate and targeted therapy,19, 20, 21 shortening the time of unnecessarydrugs,19 thereby, reducing the time of exposure to ineffective medicine. This may reduce the chances of developing AMR.19, 20, 21 All these could have an impact on the rate of mortality, length of stay (LOS) in the hospital, and a reduction in cost of both drugs and bed occupancy per patient.19, 20, 21

    Aparna Ahuja, MD, PGDip Hosp Mgment, DCH&FW, IFCAP, Chief Medical Officer at T2 Biosystems

    Temitayo Famoroti, MD, MPH, MMed, Senior Medical Affairs Specialist, T2 Biosystems

    Muhsen Alkurdi, BSMG, ICBB, Medical Affairs Manager at T2 Biosystems

    References

    1. World Health Organization (WHO). Sepsis. https://www.who.int/news-room/fact-sheets/detail/sepsis. Published Aug. 26, 2020. Accessed February 2, 2022.
    2. Forrester J. Introduction to Bacteremia, Sepsis, and Septic Shock — Infections — Merck Manuals Consumer Version. https://www.merckmanuals.com/home/infections/bacteremia-sepsis-and-septic-shock/introduction-to-bacteremia-sepsis-and-septic-shock. Updated September 2021. Accessed February 2, 2022.
    3. Centers for Disease Control and Prevention Sepsis. https://www.cdc.gov/sepsis/what-is-sepsis.html. Reviewed Aug. 17, 2021. Accessed February 2, 2022.
    4. Centers for Disease Control and Prevention. An Update on Cancer Deaths in the United States. https://www.cdc.gov/cancer/dcpc/research/update-on-cancer-deaths/index.htm. Reviewed February 23, 2021. Accessed February 2, 2022.
    5. Kumar A, 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 Jun;34(6):1589-96. doi: 10.1097/01.CCM.0000217961.75225.E9.
    6. Centers for Disease Control and Prevention. Basics of COVID-19. https://www.cdc.gov/coronavirus/2019-ncov/your-health/about-covid-19/basics-covid-19.html.Published November 17, 2021. Accessed February 2, 2022.
    7. Zhang G et al. Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China. J Clin Virol. 2020; 127:104364. doi: 10.1016/j.jcv.2020.104364.
    8. Little DR, et al. Sepsis mortality rates are higher in patients hospitalized for covid-19 than for influenza. Epic Health Research Network. https://ehrn.org/articles/sepsis-and-mortality-rates-are-higher-in-patients-hospitalized-for-covid-19-than-for-influenza. Published November 19, 2020. Accessed February 2, 2022.
    9. Langford BJ, So M, Raybardhan S. et al. Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect. 2020 Dec; 26(12): 1622–1629.. doi: 10.1016/j.cmi.2020.07.016.
    10. World Health Organization (WHO). Antimicrobial Resistance. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance. Published Nov.17, 2021. Accessed February 2, 2022.
    11. World Health Organization (WHO). Global shortage of innovative antibiotics fuels emergence and spread of drug-resistance. https://www.who.int/news/item/15-04-2021-global-shortage-of-innovative-antibiotics-fuels-emergence-and-spread-of-drug-resistance. Published Apr. 15, 2021. Accessed February 2, 2022.
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    13. National Institute of Health (NIH). Antimicrobial Resistance Diagnostic Challenge. https://dpcpsi.nih.gov/AMRChallenge. Reviewed Aug. 5, 2020. Accessed date February 2, 2022.
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    15. Lamy B, Dargère S, Arendrup MC, et al. How to optimize the use of blood cultures for the diagnosis of bloodstream infections? A state-of-the art. Front Microbiol. 2016 May 12;7:697. doi: 10.3389/fmicb.2016.00697.
    16. Sepsis Alliance. Testing for sepsis. https://www.sepsis.org/sepsis-basics/testing-for-sepsis/. Updated Jan. 26, 2022. Accessed February 2, 2022.
    17. Fan SL, Miller NS, Lee J, et al. Diagnosing sepsis–The role of laboratory medicine. Clinica chimica acta. 2016. 460: 203-210. doi: 10.1016/j.cca.2016.07.002.
    18. Eubank TA, Long SW, Perez KK. Role of rapid diagnostics in diagnosis and management of patients with sepsis. J Infect Dis. 2020. 222(Supplement_2): S103-S109. doi: 10.1093/infdis/jiaa263.
    19. Langley G, Besser J, Iwamoto M, et al. Effect of culture-independent diagnostic tests on future emerging infections program surveillance. Emerg Infect Dis. 2015. 21(9): 1582-8. doi: 10.3201/eid2109.150570.
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    21. Giannella M, Pankey GA, Pascale R, et al. Antimicrobial and resource utilization with T2 magnetic resonance for rapid diagnosis of bloodstream infections: Systematic Review with Meta-analysis of Controlled Studies. Expert Rev Med Devices. 2021 May;18(5):473-482. doi: 10.1080/17434440.2021.1919508.