All Together Now Part 1: Cohesive Antimicrobial Stewardship

Nov. 15, 2021

This article was originally published April 9, 2019 and has been updated by the author.

Antimicrobial stewardship,  also known as the structured act of promoting appropriate antimicrobial use, continues to evolve and play an essential role in public health worldwide. Today, antimicrobial stewardship is recognized as a global One Health initiative that brings together experts from human and animal medicine, healthcare and research to promote appropriate use of antimicrobials. Additionally, stewardship aims include the development of diagnostic tests and optimization of their use, vaccine development and infection prevention. Although antimicrobial stewardship has become widely accepted, the methods, language and metrics used to measure performance are riddled with variability. Without a common stewardship language, we may fail to reach global goals. How can we ensure that the goals and language of stewardship are aligned and met?

Antibiotic Stewardship from a Historical Perspective 

How did “antibiotic stewardship,” a term with 1016 entries in Pubmed in 2018, enter the clinical microbiology and infection control vocabulary? The first article to use the term in relation to antibiotic use was written by 2 American scientists and published in 1996. In 1997, the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA) began using the term in their guidelines for keeping hospitals free of drug-resistant organisms. The term slowly gained popularity in the literature until 2011, when the numbers of PubMed citations containing antimicrobial stewardship soared.

Pubmed citations on antimicrobial or antibiotic stewardship over the past 20 years.
Pubmed citations on antimicrobial or antibiotic stewardship over the past 20 years.

Once guidelines for best practices were available, many hospitals all over the world began building stewardship teams. High quality, meaningful research that demonstrated the positive effects of interventions that limited inappropriate antibiotic use began to emerge. Years of good research have shown that when unnecessary antibiotics are avoided and appropriate antibiotics are selected and dosed correctly, patient outcomes improve. We know that putting less unnecessary selective pressure on microorganisms reduces or slows the development of antibiotic resistance. Many organizations around the globe have implemented stewardship practices and demonstrated other benefits, including reduced costs, length of stay in the hospital and improper antimicrobial use. These are all meaningful steps in the battle against drug resistance. 

In 2015, the CDC released a national action plan to reduce antibiotic resistance. This plan was supported by $160 million in new investments provided by Congress to continue to meet national goals. These included slowing the emergence of resistant bacteria, developing new therapeutics and improving international collaboration and capacities for antibiotic resistance prevention. 

The first item on the list of outcomes the CDC hopes to achieve from this initiative is to improve antimicrobial stewardship in hospitals. This is a wonderful goal - a goal that seems reasonable and attainable - so what’s the challenge here? Well, antimicrobial stewardship seems to mean something different to everyone. Everything from the size of the stewardship team to the way interventions are delivered varies greatly between institutions. Despite the progress that has been made, the practice of antimicrobial stewardship is still about as scattered as the stars in the sky.
An example of the variety of stewardship interventions that have been performed since 2008.
An example of the variety of stewardship interventions that have been performed since 2008.

How COVID-19 Has Impacted Stewardship 

It is no surprise that amidst the death and destruction SARS-CoV-2 has inflicted across the globe, stewardship programs and associated activities have also been significantly impacted. Early reports of pandemic-era stewardship metrics are concerning, demonstrating that even though the prevalence of bacterial infection in COVID-19 patients is low, approximately 75% of patients diagnosed with COVID-19 receive antibiotics. It is important to note that the COVID-19 pandemic has overwhelmed healthcare systems across the world and diverted resources from stewardship services to what are perceived to be more immediate threats. Additionally, many systems are faced with personnel and medication shortages, which compound the challenges associated with maintaining and successfully executing stewardship activities during the pandemic and beyond.

However, it is not all bad news for the future of stewardship programs. A recent study from the United Kingdom described several positive impacts the pandemic has had on stewardship programs. These include an emphasis on diagnostic stewardship and appropriate interpretation of a wide variety of tests to accurately assess clinical disease, as well as the use of technology that can be harnessed in the future to bring stewardship efforts to a variety of settings in real-time.

The larger problem we face now, in addition to personnel shortages, is lack of consistency or cohesion. It has been said that "teamwork makes the dream work," and solving the drug resistance issue will push our teamwork abilities to the limit. Below are some areas that could use fine-tuning.

Antibiotic Resistance Remains Poorly Defined 

The actual definition of drug resistance is well understood and used practically everywhere. If an organism is not killed by an acceptable level of antibiotic in the laboratory, then it is considered to be non-susceptible (resistant). However, in order to tackle the enormous task of tracking resistance over time, we need to attempt to standardize the way resistance is thought about in various settings and, at the very least, make sure it is well-defined in the literature. For example, resistance may be defined by genotypic (detection of a resistance gene or product) or phenotypic (antimicrobial susceptibility testing), and the interpretation may vary depending on the diagnostic tools or guidelines used.

Testing Volume in the Microbiology Lab 

Many researchers have applied stewardship interventions in their facilities and analyzed the proportion of susceptible isolates from culture samples, both immediately before and after the intervention. While this might suggest whether an intervention was successful or not, these studies rarely record how many total samples were collected for microbiological testing during these intervention periods. Without knowing that value, only the number of isolates that underwent susceptibility testing is certain. Why does this matter? Knowing the total number of specimens collected during intervention periods would provide an understanding of increases in volumes, changes in testing procedures or differences between wards within a facility. It is important to note that not everything that grows in culture in the microbiology laboratory undergoes susceptibility testing, and knowing testing volume helps interpret what the burden of resistant organisms really is.

Here's a good example: if we looked at the proportion of carbapenem-resistant Pseudomonas aeruginosa isolates reported from tracheal aspirate specimens in the microbiology lab during a 5 year period to see if that value had increased or decreased, we would only be looking at data for the tracheal aspirate culture isolates that happened to be selected for susceptibility testing (and the decision to perform susceptibility testing on isolates from these specimens varies greatly among laboratories). Because only a small, biased selection of the true population is sampled, these data won't capture behavioral changes in the broader collection of these specimens. Using this example, what does resistance in a given facility really mean, without a better idea of what the diagnostic stewardship side of things looks like?
 Examination of the percentage of susceptible isolates using isolate number only.
Examination of the percentage of susceptible isolates using isolate number only.

Variation in Specimen Type 

Some studies attempt to describe the change in resistance over time but fail to discuss the types of specimens tested or the hospital units they were collected from, while others clearly define the specimen types that were tested, as well as whether the patient was in the ICU or not. Knowing the location of a patient with a resistant organism can be important, as behaviors and training of staff differ greatly between wards within the hospital. Additional complications arise because laboratories are using different versions of susceptibility testing protocols and interpretations of results (CLSI, FDA and EUCAST), as well as different instrumentation and commercial methods for susceptibility testing. It is impossible to ask every laboratory to do things in the same way, so it is imperative that the methods used are well-defined in the literature.

Differences in Technique 

Lastly, while some studies define resistance as lack of susceptibility to a drug based on a minimum inhibitory concentration (MIC) determined in the laboratory, others define it based on resistance genes (determined by molecular testing). The relationship between traditional methods of testing MICs and molecular methods are rarely discussed together when evaluating clinical outcomes and effectiveness of stewardship programs.
Antibiotic resistance determined by genetic resistance mechanism
Antibiotic resistance determined by genetic resistance mechanism

Antibiotic Stewardship Programs Need a Common Language  

It is imperative that we standardize stewardship terms and continue building a common vocabulary within the field. While the effect of stewardship on decreasing costs and antibiotic usage has been well documented, the effect of stewardship on resistance over time has not been. Part of the reason this relationship seems challenging to define is because provider behavior varies so greatly between hospital units, and organisms and resistance patterns differ between specimen types. Without cohesion in the literature and consistent interpretation, it’s difficult to get a grasp on how to measure resistance over time in any meaningful way. The first step to correcting this is to ensure that all elements of resistance are well-defined and that the incidence of antibiotic resistant organisms is thoroughly described for different settings (inpatient, outpatient, transplant, etc.).
Metrics to consider that can help standardize stewardship-focused research and quality improvement initiatives include:
  • How specimens are collected.
  • When patients are cultured.
  • How extensively cultures are worked up and organisms are fully identified.
  • How infection is defined as nosocomial (an infection that originates within the hospital or clinical setting). 
Future work on standardizing these factors in research studies will be essential to understanding how rates of resistance are changing in each facility and across the world.

In the Lab: Antimicrobial Susceptibility Testing Breakpoint Update Requirements

Antimicrobial susceptibility testing (AST) is one of the most important functions of the clinical microbiology lab and a core element of antimicrobial stewardship programs. However, there are significant challenges related to consistency between labs and the way results are interpreted and reported to clinicians. The challenges associated with this practice are multi-faceted and involve accrediting and regulatory agencies like the College of American Pathologists (CAP) and the Food and Drug Administration (FDA), as well as in vitro diagnostics companies and clinical microbiology labs. Companies that manufacture AST systems must use antimicrobial breakpoints (an accepted concentration of drug at which an organism can be treated) published by the FDA, meaning they cannot use the breakpoints updated and released by The Clinical and Laboratory Standards Institute (CLSI) until the FDA gives the ‘okay’ to do so.  Once a breakpoint has been recognized by the FDA, the manufacturer must submit test performance data to the Center for Radiological Health (CDRH) to obtain approval to use the new breakpoints with their AST system. Not only does this process take time, but manufacturers may not make updating breakpoints a priority.

The result of this series of events is inconsistency of MIC reporting across labs and use of old CLSI breakpoints that may no longer be clinically useful or relevant. This can have a direct impact on both stewardship efforts and patient care. Labs that don’t want to wait for FDA acknowledgement of a new breakpoint or manufacturer upgrades can perform internal validations on their systems in order to start using the new breakpoints in-house. However, these validations are complex and time consuming and may pose a challenge to some labs.

What’s Next for Antimicrobial Stewardship? 

Current stewardship research has focused on topics such as diagnostic stewardship, the use of machine learning for a variety of purposes, including improving AMR diagnostics and expanding the pathway for antibiotic development, and finally the role of health professionals such as nurses and clinical laboratory scientists in stewardship efforts and interventions.

There is an incredible amount of work to be done. While a strong foundation has been set, we need to continue to develop innovative ways to unify the world of antimicrobial and diagnostic stewardship. While the development of new therapeutics is essential, it will mean nothing if we have not changed our behavior. Here are some wise words by Helen Keller which readily apply to antibiotic stewardship efforts:

"Alone we can do so little; together we can do so much."

Author: Andrea Prinzi, Ph.D., MPH, SM(ASCP)

Andrea Prinzi, Ph.D., MPH, SM(ASCP)
Andrea Prinzi, Ph.D., MPH, SM(ASCP) is a field medical director of U.S. medical affairs and works to bridge the gap between clinical diagnostics and clinical practice.