Antibiotic De-Escalation: Is This the Right Outcome Measure?

The 21st century ushered in a new way of thinking about antimicrobial prescribing. Clinicians pivoted from a mentality of “start low and go slow” to “go big and go home.” This was due, in part, to the literature demonstrating worsened outcomes with delays in therapy for treating severe infections. Empiric use of broad-spectrum antimicrobials became commonplace, accompanied by a promise to tailor antimicrobials “later,” according to microbiology results.¹ Antibiotic ‘de-escalation’ (to tailor, narrow, streamline, or optimize empiric therapy) was quickly adopted to mitigate broad-spectrum antimicrobial consumption.

Antibiotic de-escalation remains an essential antimicrobial stewardship (AMS) strategy, particularly in the critical care setting where extended-spectrum agents are utilized more frequently. It is recommended by international guidelines^2,3 and is commonly used as a benchmark to measure the effectiveness of stewardship interventions including rapid diagnostic tests.^4-6

De-escalation is an appealing strategy for AMS programs as it is a seemingly easier approach than targeting empiric therapy selection. At the time of de-escalation, clinicians often have more clarity in the clinical picture and microbiology test results to help guide decision-making. However, routinely conducting de-escalation is a time-intensive and resource-heavy activity with minimal adoption or acceptance in some settings.^4,7

In the setting of increasing rates of antimicrobial resistance (AMR) and the continued need for value-based healthcare, AMS programs are under a great deal of pressure to demonstrate the impact of interventions on clinical outcomes. There are limited resources to perform AMS activities, and burnout continues to be a significant challenge among AMS program leaders.⁸ Given these considerations, should antimicrobial de-escalation be a standard outcome measure for evaluating the effectiveness of AMS programs? While de-escalation of unwarranted antimicrobial therapy is paramount to curtailing unnecessary exposure, this article will discuss the shortcomings of antimicrobial de-escalation and challenge whether it is an optimal measure for AMS interventions.

What are we Measuring?

While antimicrobial de-escalation is considered a cornerstone of AMS programs, there is no consensus definition.^9-11 In a systematic review of antimicrobial de-escalation in the intensive care setting the reviewers found varied definitions amongst the 14 included studies. It was generally described as a narrowing or streamlining of antimicrobial spectrum; however, only 4 studies provided a ranking of antimicrobial spectra. Additionally, the reviewers found there was a wide range in time (2-5 days) when de-escalation was performed after initiation of the empiric regimen and only four studies included discontinuation of therapy in their definition.⁹ There is ongoing work to provide guardrails on what should and should not be considered de-escalation^9-11 and studies utilizing spectrum scores to increase capture of antimicrobial changes.^5,12

Even with better definitions, there is a need to account for situations when narrowing therapy is not warranted. If de-escalation does not occur because the selected empiric regimen is appropriately narrow, this is the consummate example of ideal antimicrobial use.

Strictly evaluating de-escalation does not capture this AMS win. Another insufficiency, when solely measuring de-escalation rates, is the inability to capture the level of spectrum change and the time at which this change occurs in relation to the total duration of therapy. Consider the following 3 scenarios 1) changing meropenem to oxacillin on treatment day 1 of 14 for methicillin-susceptible Staphylococcus aureus uncomplicated bacteremia or 2) discontinuing cefepime and vancomycin on day 3 of therapy for suspected ventilator-associated pneumonia with negative cultures, and 3) narrowing from piperacillin/tazobactam to ceftriaxone on day 2 and then to amoxicillin/clavulanate on day 4 of a seven-day treatment course for pan-susceptible E coli bacteremia. All 3 scenarios are considered de-escalation, but they likely have varying degrees of effect on clinical outcomes (eg, risk of C difficile infection, MDRO acquisition, length of stay, etc).

Effect on Clinical Outcomes and Risk of Developing Drug Resistance

Given the nebulous definition of antimicrobial de-escalation throughout the literature, it is no surprise that a Cochrane review published in 2013 found insufficient evidence to recommend for or against de-escalation in adults with sepsis.¹³ A subsequent review and meta-analysis, published in 2016, evaluated the safety and impact of de-escalation in adults with microbiologically documented infections (pneumonia, bacteremia, or severe sepsis). In this review, the observational studies suggested a lowered mortality benefit that the RCTs did not substantiate.⁴ The preponderance of evidence suggests that antibiotic de-escalation is safe (ie, no difference in mortality) compared to continuing empiric therapy.^4,7,9-11,14

Despite the outwardly logical notion and long-held belief that streamlining empiric therapy reduces the emergence of resistance, this has not been well documented, and the available evidence is contradictory.^4,7,11,14-17

Risk of MDRO acquisition likely varies based on the selected empiric and definitive drug regimen, the number of antimicrobial changes, exposure to different antimicrobial classes, total duration of therapy, the patient’s baseline microbiota, as well as local epidemiology making risk determination a challenge. However, it should be considered that sequential exposure to two or more antimicrobials is not necessarily better than receipt of one broad-spectrum agent for short courses of therapy.¹⁰

A study evaluating the impact of antimicrobial exposure demonstrated that the number of unique antibiotic classes was associated with increased 90-day readmission with severe sepsis or septic shock. Compared to patients without antimicrobial exposure, those who received one class of antibiotic had slightly increased odds of developing septic shock. In contrast, patients who received therapy from 4 or more classes of antibiotics had more than twice the odds of developing severe sepsis.¹⁸ Measuring rates of de-escalation does not consider the number of antimicrobial modifications and total exposure for a particular patient which may influence the emergence of resistance.

The ongoing uncertainty regarding the proposed clinical benefits of de-escalation has undoubtedly contributed to its lukewarm adoption in some settings.^4,10 Compounding this is another key issue with many AMS metrics: the behavioral and cultural factors influencing antimicrobial prescribing. If the behavioral component of AMS is not addressed or accounted for it will limit the ability to assess the true impact of any intervention on antimicrobial utilization and downstream clinical outcomes.¹⁹

Beyond AMS Program Performance

The impact of selecting appropriate AMS metrics extends beyond quantifying program performance. Rapid diagnostics have been identified as a tool to aid AMS programs in optimizing antimicrobial therapy.³ Despite the limitations of de-escalation as an outcome measure, evaluations of rapid diagnostic technologies continue to target de-escalation as a primary outcome measure.⁶ In the value-based care environment, diagnostic testing is under significant scrutiny to show clinical value. The thoughtful implementation and appropriate measurement of effectiveness is imperative for the future of rapid diagnostics in their ability to demonstrate clinical utility.²⁰

What’s Next? Is There a Better Way to Measure AMS Success?

One potential strategy to better understand the impact of de-escalation is to focus the scope on a specific patient population and/or disease state with set antimicrobial regimens. The SIMPLIFY study group released a preprint that took this approach. They evaluated de-escalation in bacteremia due to Enterobacterales for patients receiving empiric antipseudomonal β-lactams. They found de-escalation was non-inferior in clinical effectiveness and safety compared to continuing initial therapy.²¹

Realizing and moving beyond the limitations of anti-biotic de-escalation, we should ask, is there a more meaningful outcome to fully appreciate AMS interventions? The Antibacterial Resistance Leadership Group ARLG has done much work developing tools and methods to improve the evaluation of intervention benefits and harms. Specifically, the Desirability and Outcome Ranking (DOOR) a “patient-centric benefit-risk evaluation” model was created to aid in designing, analyzing, and interpreting clinical research.²²

Further expanding on this, the Desirability of Outcome Ranking Management of Antimicrobial Therapy (DOOR-MAT) model was developed to address the complexities of antimicrobial selection in the face of resistance and quantify the desirability of one therapy relative to another. DOOR MAT accounts for the necessary use of broad-spectrum agents where de-escalation cannot be performed and can be tailored to address various clinical settings with distinct priorities. The DOOR MAT framework has been utilized to compare rapid diagnostic platforms and the desirability of theoretical antimicrobial decisions based on their results.²³

Lastly, would AMS efforts be better directed at optimizing empiric therapy? A recent publication calls into question the need for extended-spectrum empiric regimens outside of septic shock or bacterial meningitis. Proposing a more relaxed time window to initiate appropriate empiric antimicrobials allowing for a more thorough workup and inclusion of biomarkers and rapid diagnostic test results to guide selection. In the era of rapid diagnostics, is it reasonable to initiate targeted antimicrobial therapy in select populations?²⁴

Final Thoughts

The lack of continuity in its definition and discernment between degrees of spectrum modification has complicated the evaluation of antimicrobial de-escalation and the determination of its clinical utility. The impact of antimicrobial modifications on the emergence of resistance and downstream clinical outcomes requires further study. Awareness of limited AMS resources in conjunction with a focus on comprehensive and meaningful outcome measures should be considered to better inform AMS practice.

References

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