Diagnostics are key to preventing and controlling this growing global threat
By Jean B. Patel, PhD D(ABMM)
There was a time when antimicrobial-resistant infections occurred only in healthcare settings. Now, although resistant pathogens do appear in communities as well as in hospitals and other healthcare facilities, it is rare for a community-associated infection to be hard-to-treat or nearly untreatable.
Unfortunately, these infections are all-too common in healthcare settings. Nearly all pathogens that top the Centers for Diseases Control’s list of antibiotic resistant (AR) threats as well as the World Health Organization’s list of antimicrobial resistance priority pathogens are frequent causes of healthcare-associated infections (HAIs).1,2
Most new types of antimicrobial resistant pathogens are first identified as the cause of HAIs. At first, a healthcare facility may identify a single case and then sporadic cases. Left unchecked, these cases progress to outbreaks and then endemic transmission of the AR pathogen. According to CDC point prevalence study, at any given time, about 1 in 25 inpatients—hospitalized for reasons including cancer, heart disease, or covid-19—have an infection related to hospital care.3 For patients like these, infection with a drug-resistant pathogen is too often a life-threatening event. Preventing HAIs is possible, but it is important to get ahead of the curve. A robust prevention program depends upon fast and accurate detection of resistant pathogens, an ongoing site-specific surveillance program that tracks infection trends, dedicated infection prevention staff, and organizational buy-in to make infection prevention a priority. For additional details, see the CDC’s Healthcare Infection Control Practices Advisory Committee (HICPACC) recommendations for HAI prevention.4
An HAI is generally defined as an infection with onset greater than 48 hours after admission to a healthcare facility. In additional to bacterial, HAIs can also be fungal, especially Candida spp., and viral, such as norovirus and those that cause hepatitis. This article focuses on drug-resistant infections caused by bacteria and Candida spp.—these are the infections that have the biggest impact on patients and healthcare systems.
CDC identifies five pathogens as “urgent threats,” four of which commonly cause HAIs: Clostridioides (Clostridium) difficile, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Acinetobacter, and Candida auris. Each of these pathogens is listed as urgent for several reasons including high-infection rates, few treatment options, increased mortality for serious infections, and the ability to share resistance with other bacteria because the mechanism is on a mobile genetic element (that is, a plasmid). Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common HAI pathogens, but this one is considered a serious, not urgent, AR threat because more drugs are still available to treat MRSA infections than to treat infections caused by gram-negative bacteria.
Role of Laboratory Testing
General infection control practices are essential for preventing HAIs, but when rates of infection increase, more focused interventions may be required.5,6 The laboratory plays a critical role here. Lab data are used to identify infection trends, to identify new types of resistant pathogens, and to identify patients colonized with HAI pathogens who might be a source of transmission. Perhaps the most consequential function is detecting new resistance. For example, when KPC-mediated carbapenem-resistant Enterobacteriaceae (CRE) first emerged in the United States, cases were missed and outbreaks were not recognized because some of the most common antimicrobial susceptibility testing (AST) systems demonstrated poor performance for detecting KPC-mediated resistance.7,8
Sometimes laboratory testing is accurate, but the significance of new resistance is not recognized. After CRE emerged in the United States, CDC recommended that all hospitals review their lab records for previous cases.7 Often hospitals found previous cases that were correctly detected in the laboratory, but no infection control concern was recognized. The Clinical and Laboratory Standards Institute (CLSI) subcommittee for AST addressed this issue by publishing a table that recommends specific actions based upon specific resistance findings in the laboratory (Appendix A of CLSI M100).9 Recommendations include when to confirm results, when to contact infection control, and when to alert the local public health authority. An important function of the CDC AR lab network is to confirm and characterize isolates with new or rare types of resistance.10 National public health authorities may decide that a new type of resistance warrants communication to the World Health Organization, which will share this information with AR points of contact in member countries.
Laboratory tests to identify patients with resistant pathogens are commonly called active surveillance testing. These tests are used to make infection control decisions either for the patient or for a larger population. The patient-centric decision is usually whether the person needs to be placed in contact precautions. In cases of MRSA nasal colonization testing, the decision may also include whether to decolonize the nasal passages with a drug like mupirocin or retapamulin. Population-based decisions might range from cohorting patients during an outbreak to implementing intra-facility communication and infection control measures to prevent regional transmission. CDC recommends active surveillance testing for CRE as a primary intervention strategy, although it is recognized that this may be more important in some settings than others. See CDC’s CRE Prevention Toolkit for specific recommendations.11
CRE active surveillance testing is so important for prevention that CDC placed this testing in the AR Lab Network to support infection control efforts by healthcare facilities. Candida auris active surveillance testing is also recommended whenever cases are identified in hospitals. Currently, there are no commercial assays, but testing is available in the CDC AR Lab Network. Active surveillance testing for MRSA is often used when enhanced infection control measures are needed.6 Many hospitals have implemented universal decolonization strategies for patients at risk of MRSA infection and implement MRSA-specific testing when infections rates are increasing despite these efforts. Multidrug resistant organism (MDRO)-specific surveillance testing to guide infection control decisions has proven effective when tests are readily available and results are timely. The challenge is that there are few FDA-approved tests, and, for most labs, these tests are not performed daily, which means maintaining proficiency is challenging and costly.
Molecular typing of HAI pathogens can be used to characterize transmission dynamics during an outbreak or to identify a point source for transmission. Pulse field gel electrophoresis (PFGE) or next generation sequencing are the technologies most commonly used for molecular typing. PFGE linked 39 cases of CRE infections from one hospital to a single duodenoscope.12 This and similar investigations ultimately led to new recommendations for sterilizing these devices. Molecular typing is uncommonly performed in hospital microbiology labs, but this testing is available in reference labs and public health labs including those that are part of the CDC AR Lab Network.
In the future, microbiome analysis may enable clinicians to predict HAIs before they occur. The human microbiome is the collection of health bacteria that colonize our gastrointestinal (GI) tract, respiratory tract, and skin. These healthy bacteria are may be our best defense against a range of diverse health issues including heart disease, diabetes, and weight gain. A diverse microbiome may also be a patient’s best defense against HAIs.
Several studies have demonstrated that HAIs are preceded by a disruption of the gastrointestinal microbiome and a shift in the population of GI bacteria from diverse species to the predominance of a pathogen.13 Furthermore, the HAI causative agent is the same pathogen (that is, clonal relationship) to the pathogen that predominates in the GI microbiome. This makes intuitive sense. We know that patients may be admitted to the hospital already colonized with a MDRO or acquire MDRO colonization during their stay. We also know that MDRO colonization is a risk factor for infection and that prolonged exposure to antibiotics disrupts the normal microbiome and allows for MDRO overgrowth. All of this adds up—but what do we do with the information?
If we had diagnostic tools to assess a patient’s microbiome status (diverse population or predominance of a pathogen) and then to characterize the pathogen, a clinician would have enough information to treat a HAI at early onset. Better yet, imagine if a clinician could be armed with therapeutic interventions to restore a disrupted microbiome, thus inhibiting MDRO overgrowth and preventing HAIs. This approach could be an important new strategy to defeat HAI, but a lot of work needs to happen first. Several technologies could be applicable for microbiome diagnostics, and these range greatly in test complexity and cost. It is good to have options, but commercial product development will not occur in earnest until a clinical need is established. Studies are needed to evaluate the clinical impact of microbiome analysis to treat or prevent HAIs.
As the science of HAI prevention progresses, keeping up with and implementing existing tools is necessary to minimize the clinical impact of infections. It is easy to find these tools. Guidance for infection control practice are available from CDC/HICPAC (www.cdc.gov/hicpac/), Association for Professionals in Infection Control and Epidemiology (www.apic.org), and Society for Healthcare Epidemiology of America (www.shea-online.org). Surveillance tools for reporting and benchmarking infection rates can be found in the CDC National Healthcare Safety Network (www.cdc.gov/nhsn/) and laboratory guidance for diagnostic testing can be found in CLSI documents (www.CLSI.org) and CDC’s website (www.cdc.gov/hai/).
Implementation is harder. As stated earlier, this takes organizational commitment and resources. We know prevention works. This was a primary message of CDC’s 2019 AR Threats Report update. For the first time, trend charts for several AR threat pathogens had a downward slope. Great news, but any loss in focus could reverse these trends, and there is always a new challenge on the horizon. We have more work to do.l
Jean B. Patel, PhD, D(ABMM), is principal scientist, scientific affairs at Beckman Coulter Diagnostics who works within Beckman Coulter Microbiology to support innovation and assay implementation. Previously, she served nearly 17 years on the antibiotic resistance coordination and strategy unit at the Centers for Disease Control and Prevention. During her tenure there, she led the implementation of the Antibiotic Resistance Laboratory Network and the CDC and FDA Antibiotic Resistance Isolate Bank. Patel has served as chair and vice chair of the Clinical and Laboratory Standards Institute (CSLI) Subcommittee for Antimicrobial Susceptibility Testing and has been a member of the Trans-Atlantic Task Force on Antimicrobial Resistance. She also works with the World Health Organization to develop technical guidance for detecting resistance and strengthening global surveillance of antimicrobial resistance.
1. Antibiotic Resistance Coordination and Strategy Unit. Antibiotic Resistance Threats in the United States. Atlanta: U.S. Centers for Disease Control and Prevention; 2019. Available at https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf. Accessed October 7, 2020.
2. World Health Organization. Prioritization of Pathogens to Guide Discovery, Research and Development of New Antibiotics for Drug-Resistant Bacterial Infections, including Tuberculosis. Geneva: World Health Organization; 2017. Available at https://www.who.int/medicines/areas/rational_use/PPLreport_2017_09_19.pdf?ua=1. Accessed October 7, 2020.
3. Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health care–associated infections. N Engl J Med. 2014;370:1198–1208. doi: 10.1056/NEJMoa1306801.
4. Healthcare Infection Control Practices Advisory Committee. U.S. Centers for Disease Control and Prevention. https://www.cdc.gov/hicpac/index.html. Accessed October 7, 2020.
5. Core Infection Prevention and Control Practices for Safe Healthcare Delivery in All Settings—Recommendations of the Healthcare Infection Control Practices Advisory Committee. Atlanta: U.S. Centers for Disease Control and Prevention; updated March 15, 2017. https://www.cdc.gov/hicpac/pdf/core-practices.pdf. Accessed October 7, 2020.
6. Siegel JD, Rhinehart E, Jackson M, Chiarella L, Healthcare Infection Control Practices Advisory Committee. Management of Multidrug-Resistant Organisms in Healthcare Settings (2006). Atlanta: U.S. Centers for Disease Control and Prevention; updated February 15, 2017. https://www.cdc.gov/infectioncontrol/pdf/guidelines/mdro-guidelines.pdf. Accessed October 7, 2020.
7. Centers for Disease Control and Prevention. Guidance for control of infections with carbapenem-resistant or carbapenemase-producing Enterobacteriaceae in acute care facilities. MMWR Morb Mortal Wkly Rep. 2009;58: 256–260.
8. Anderson KF, Lonsway DR, Rasheed JK, et al. Evaluation of methods to identify the Klebsiella pneumoniae carbapenemase in Enterobacteriaceae. J Clin Microbiol. 2007;45(8):2723–2725. doi: 10.1128/JCM.00015-07.
9. Clinical and Laboratory Standard Institute. Performance Standards for Antimicrobial Susceptibility Testing. 29th ed. Wayne, PA: Clinical and Laboratory Standard Institute; 2019.
10. Antibiotic/Antimicrobial Resistance. U.S. Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/laboratories.html. Accessed October 7, 2020.
11. National Center for Emerging and Zoonotic Infectious Diseases. Facility Guidance for Control of Carbapenem-resistant Enterobacteriaceae (CRE): November 2015 Update—CRE Toolkit. Atlanta: U.S. Centers for Disease Control and Prevention; 2015. Available at https://www.cdc.gov/hai/pdfs/cre/CRE-guidance-508.pdf. Accessed October 7, 2020.
12. Epstein L, Hunter JC, Arwady MA, et al. New Delhi metallo-β-lactamase-producing carbapenem-resistant Escherichia coli associated with exposure to duodenoscopes. JAMA. 2014;312(14):1447–1455. doi: 10.1001/jama.2014.12720.
13. Freedberg DE, Zhou MJ, Cohen ME, et al. Pathogen colonization of the gastrointestinal microbiome at intensive care unit admission and risk for subsequent death or infection. Intensive Care Med. 2018; 44(8):1203–1211. doi: 10.1007/s00134-018-5268-8.
Featured image: Figure 1. Medical illustration of Clostridioides difficile bacteria, formerly known as Clostridium difficile, from the CDC publication Antibiotic Resistance Threats in the United States, 2019. Medical Illustrator Jennifer Oosthuizen, courtesy CDC.