By Jane Guttendorf, DNP, CRNP, ACNP-BC, CCRN

Assistant Professor, Acute & Tertiary Care, University of Pittsburgh, School of Nursing

Dr. Guttendorf reports no financial relationships relevant to this field of study.

What is Antimicrobial Stewardship?

In 2012, antimicrobial stewardship (AMS) was defined in a policy statement by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS) as “coordinated interventions designed to improve and measure the appropriate use of antimicrobial agents by promoting the selection of the optimal antimicrobial drug regimen including dosing, duration of therapy, and route of administration.”1 Dyar et al expanded this definition to focus on the importance of responsible antimicrobial use by all healthcare providers: “A coherent set of actions which promote using antimicrobials responsibly.”2 This better defines the outcome standards and processes of stewardship that hospitals should strive to meet. The concept and subsequent operationalization of AMS has been developing over several decades, but gained particular support over the last several years, in part due to The Joint Commission’s new AMS standard instituted in 2017, mandating that all hospitals, acute care access centers, and nursing care centers establish an evidence-based AMS program.3 The primary objectives of AMS are to improve clinical outcomes related to antimicrobial treatments, minimize toxicities, reduce costs, and, most importantly, reduce antimicrobial resistance.1 This review will discuss some of the key principles and practices related to successful AMS programs, particularly as they relate to critical care.

Impact of the Problem

The Centers for Disease Control and Prevention (CDC) reported that in U.S. acute care hospitals, about 30% of prescribed antibiotics are either unnecessary or inappropriate.4 Additionally, the CDC estimates that more than 2.8 million antibiotic-resistant infections occur in the United States each year, resulting in more than 35,000 deaths.5 Combating antibiotic resistance is one of the most important objectives of AMS, and global efforts are underway, spearheaded by the CDC, the World Health Organization, the European Centre for Disease Prevention and Control (ECDC), and multiple professional organizations to actively address the problem of the growing number of antimicrobial-resistant organisms.5-7 The issue of multidrug-resistant organisms is particularly germane in critical care, since immunocompromised patients often present with severe illness, sepsis, and multisystem organ dysfunction, requiring prompt recognition and broad empiric therapies that may place them at risk for complications of antimicrobial therapies and limited choices for effective antibiotics.

What are the Guidelines?

The CDC has encouraged all U.S. hospitals to adopt AMS and provided guidelines for implementation with the publication of the Core Elements of Hospital Antibiotic Stewardship Programs: 2019 (an update of the original Core Elements published in 2014).4 The Centers for Medicare and Medicaid Services (CMS) has mandated AMS for hospitals as a condition for receiving national funding.4

The CDC Core Elements consist of seven primary components to be included as part of any AMS program. Since 2014, when these were implemented for acute care hospitals, they have been evaluated through the National Healthcare Safety Network’s (NHSN) Patient Safety Component Annual Hospital Survey and reported through the CDC. Staff in hospitals complete annual surveys regarding incorporation of each of the core elements. The percentage of acute care hospitals responding to the NHSN annual survey meeting all seven core elements improved from 41% in 2014 to 85% in 2018.8 (See Table 1 for the seven Core Elements of Antibiotic Stewardship Programs and the percentage of hospitals incorporating each component in the 2018 NHSN annual survey, http://bit.ly/2FRLHJ8.)8

The joint policy statement (SHEA, IDSA, PIDS) on AMS from 2012 strongly recommends that all hospitals adopt AMS programs and details minimum requirements: 1) multidisciplinary interprofessional teams, including at least a pharmacist, a physician, a clinical microbiologist, and an infection control preventionist; 2) an antimicrobial formulary with recommended drugs to avoid overlaps in coverage; 3) institutional guidelines for management of common infections; 4) additional interventions to improve the appropriate use of antibiotics (tailoring multidrug regimens to avoid redundancy in coverage, treating only positive cultures, instituting appropriately broad empiric coverage, and tailoring as soon as culture results become available); 5) hospital processes to measure and benchmark antimicrobial use; and 6) the creation of regularly updated institution-specific antibiograms.1

The Healthcare Infection Control Practices Advisory Committee (HICPAC), a federal advisory group that provides guidance to the CDC and the Department of Health and Human Services (HHS), has published similar guidelines for antibiotic stewardship based on the CDC Core Elements.9 HICPAC also recommends principles of diagnostic testing (rapid diagnostic tests, biomarkers, and molecular testing when appropriate) and principles of treatment, including early source control for infection, empiric broad-spectrum antibiotics appropriate for the severity of infection, optimal dosing based on pharmacokinetics/pharmacodynamics, the shortest effective duration of therapy, and early de-escalation of therapy based on available cultures.9

The IDSA and SHEA published a guideline (2016) for implementing an antibiotic stewardship program, based on the best available evidence.10 The guideline recommends that an infectious disease physician with additional training in stewardship lead the AMS program. The guideline recommends particular interventions for success in antimicrobial stewardship. Two of the common interventions are preauthorization of antibiotics at the time of order entry (requiring providers to get approval before ordering), and prospective audit and feedback (PAF), which allows the provider to order the antibiotic, but AMS team engagement may follow at a later date. Pros and cons of each intervention are delineated, and have been studied. Preauthorization has the advantages of limiting exposure to unnecessary antibiotics and optimizing empiric choices with a review of prior cultures and antibiotic use, but it may result in a delay in initiating therapy and is labor-intensive for the AMS team. Prospective audit allows the provider more freedom in ordering and can be less labor-intensive for the AMS team. It allows for AMS involvement in review and de-escalation of antibiotics and teaching opportunities for clinicians. Disadvantages of PAF include providers’ reluctance to make changes to antibiotics if the patient is noted to be improving, and delays in achieving desired outcomes of reducing overall antimicrobial use. The mechanism of providing feedback to clinicians also is important. The guidelines strongly recommend preauthorization and/or PAF as important strategies over no intervention. Hospitals should decide the most effective and feasible strategy based on available resources.10

Implementing facility-specific clinical practice guidelines for specific infections is a weak recommendation. There is a strong recommendation to implement interventions to reduce exposure to antibiotics associated with a high risk of developing Clostridioides difficile infection (formerly known as Clostridium difficile).10 Current common practices, such as antibiotic time-outs to review cultures and appropriate tailoring/de-escalation of antibiotics and applying stop orders, are listed as weak recommendations with low-quality evidence.10 The guidelines recommend against antibiotic cycling as a stewardship strategy.10 Overall, a number of important strategies and interventions remain understudied.

Antimicrobial Stewardship: What Works?

Since the IDSA/SHEA guideline for implementation of Antibiotic Stewardship Programs published in 2016,10 two systematic reviews have been published evaluating AMS programs and other specific interventions.11,12 Shutz et al reviewed 145 studies, evaluating 14 AMS objectives for four specific outcomes in adult inpatients: clinical outcomes, adverse events, costs, and bacterial resistance.11 Overall data were available for only nine of the 14 objectives, six of which had significant outcomes. Prescribing empiric therapy via guidelines was associated with a 35% relative risk reduction in mortality (relative risk [RR], 0.65; 95% confidence interval [CI], 0.54-0.80, P < 0.0001), and de-escalation in therapy was associated with a 56% relative risk reduction in mortality (RR, 0.44; 95% CI, 0.30-0.66, P < 0.0001). Additional improvements in outcome were noted with switching from intravenous (IV) to oral treatment, therapeutic drug monitoring (reduction in nephrotoxicity RR, 0.50; 95% CI, 0.29-0.88, P = 0.02), use of a restricted formulary of antibiotics, and bedside consultation, particularly for Staphylococcus aureus bacteremia (reduction in mortality RR, 0.34; 95% CI, 0.15-0.75, P = 0.008).11 Davey et al reported a Cochrane Review of 221 studies of antibiotic prescribing practices for hospital inpatients, bundling interventions into restriction and enablement.12 The duration of antibiotic treatment decreased significantly by 1.95 days (95% CI, 2.22 -1.67). The risk of death was the same in both the intervention and control groups (11%). With AMS interventions, the length of stay was reduced by 1.12 days (95% CI, 0.7 -1.54 days). Both enablement and restriction were independently associated with increased antibiotic policy compliance.12

Campion and Scully specifically reviewed the literature evaluating optimization and de-escalation of antibiotics in the intensive care unit (ICU).13 Beneficial strategies identified for the ICU include employing empiric guidelines for antibiotic use, collecting appropriate specimens and using molecular diagnostics, optimizing antibiotic dosing, and reducing the total therapy duration. Empiric antibiotic therapy in sepsis should be directed at the suspected location of infection and known risk factors, such as immunosuppression and prior antibiotic exposure, not solely on providing gram-positive, gram-negative, Pseudomonas, and methicillin-resistant Staphylococcus aureus (MRSA) coverage. Prior IV antibiotic use, poor functional status, and comorbid conditions may increase the risks of multidrug-resistant organisms. Dual gram-negative coverage (the use of two agents with different mechanisms of action) for empiric coverage of infection, particularly in patients at risk for resistant organisms or reduced susceptibility, may be a useful strategy in critically ill patients, particularly when the susceptibility pattern for antipseudomonal beta-lactam antibiotics is < 90%. A beta-lactam plus aminoglycoside may provide better empiric coverage over beta-lactam alone or beta-lactam plus fluoroquinolone.13

Biomarkers, molecular diagnostics, and procalcitonin are tools to help clinicians in antibiotic prescribing and de-escalation. Molecular diagnostics analyze the nucleic acids of organisms for identification and for common mechanisms of resistance, providing results much more rapidly than conventional testing.13-15 Earlier identification of a specific organism limits the time on empiric therapy and facilitates earlier tailoring of antibiotics to the specific organism. Identification of resistance patterns can facilitate earlier escalation of therapy to more appropriate antibiotics. Molecular tests can be applied to many types of culture samples (blood, urine, sputum, stool), but are more costly than traditional culture. The use of procalcitonin levels, which rise in the setting of bacterial infection, can facilitate the tapering of antibiotics, but is not recommended to be used as a marker to initiate antibiotic therapy.16 Other optimization strategies include the use of pharmacokinetics and pharmacodynamics to adjust drug dosing in critically ill patients who may have increased volume of distribution and in those with rapidly changing renal function, and the use of extended duration of infusion for beta-lactam antibiotics to improve efficacy.13

AMS in the ICU requires a multi-professional approach, aggressive management of critically ill patients, appropriate empiric therapy, and willingness to de-escalate therapy when appropriate culture data support it. New diagnostic tools using molecular diagnostics to identify causative organisms and resistance mechanisms can facilitate earlier and more appropriate tailoring to specific therapy. A comprehensive AMS approach can help improve antimicrobial utilization, reduce broad-spectrum antimicrobial use, reduce colonization with multidrug-resistant organisms, and reduce costs.16 AMS is the responsibility of everyone involved in the care of critically ill and hospitalized patients. Education of prescribers is important, particularly regarding the benefits of AMS; early and specific culturing of sites; appropriate empiric therapy; early tailoring of antibiotics to specific culture data; the conduction of an “antibiotic time-out” at 48 to 72 hours after antibiotic initiation to actively review culture results and patient progress and determine de-escalation; intravenous to oral route adjustment; and discussion of definitive duration of therapy. Preauthorization and PAF are effective tools, particularly when coupled with face-to-face feedback to the prescribing clinician. Additional research is required to specifically address the most effective tools for successful AMS.

REFERENCES

  1. Society for Healthcare Epidemiology of America, Infectious Diseases Society of America, Pediatric Infectious Diseases Society. Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol 2012;33:322-327.
  2. Dyar OJ, Huttner B, Schouten J, et al. What is antimicrobial stewardship? Clin Microbiol Infect 2017;23:793-798.
  3. Joint Commission on Hospital Accreditation. APPROVED: New antimicrobial stewardship standard. Jt Comm Perspect 2016;36:1-8.
  4. Centers for Disease Control and Prevention. Core elements of hospital antibiotic stewardship programs. US Department of Health and Human Services, CDC; 2019. Available at: https://www.cdc.gov/antibiotic-use/core-elements/hospital.html. Accessed Jan. 8, 2020.
  5. Centers for Disease Control and Prevention. Antibiotic Resistance & Patient Safety Portal (AR&PSP). Antibiotic resistance, use & stewardship. Available at: https://arpsp.cdc.gov/profile/antibiotic. Accessed Jan. 8, 2020.
  6. World Health Organization. Antimicrobial resistance. Available at: https://www.who.int/antimicrobial-resistance/en/. Accessed Jan. 8, 2020.
  7. European Centre for Disease Prevention and Control. Available at: https://bit.ly/2QP4ISJ. Accessed Jan. 8, 2020.
  8. Centers for Disease Control and Prevention. Antibiotic Resistance & Patient Safety Portal – Stewardship. Hospital antibiotic stewardship. Available at: https://arpsp.cdc.gov/profile/stewardship. Accessed Jan. 8, 2020.
  9. Healthcare Infection Control Practices Advisory Committee. Antibiotic stewardship statement for antibiotic guidelines — Recommendations of the HICPAC. 2016. Available at: https://www.cdc.gov/hicpac/recommendations/antibiotic-stewardship-statement.html. Accessed Jan. 8, 2020.
  10. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis 2016;62:e51-e77.
  11. Schuts EC, Hulscher MEJL, Mouton JW, et al. Current evidence on hospital antimicrobial stewardship objectives: A systematic review and meta-analysis. Lancet Infect Dis 2016;16:847-856.
  12. Davey P, Marwick CA, Scott CL, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev 2017;2:CD003543.
  13. Campion M, Scully G. Antibiotic use in the intensive care unit: Optimization and de-escalation. J Intensive Care Med 2018;33:647-655.
  14. Wenzler E, Wong JR, Goff DA, et al. Controversies in antimicrobial stewardship: Focus on new rapid diagnostic technologies and antimicrobials. Antibiotics 2016;5:6.
  15. Sullivan KV. Advances in diagnostic testing that impact infection prevention and antimicrobial stewardship programs. Curr Infect Dis Rep 2019;21:20.
  16. Timsit JF, Bassetti M, Cremer O, et al. Rationalizing antimicrobial therapy in the ICU: A narrative review. Intensive Care Med 2019;45:172-189.