What’s in your antimicrobial stewardship toolbox?

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Picture of Lauren Igneri
Lauren Igneri
Critical care pharmacist and proud Rutgers University graduate. Enjoys rock climbing, cycling, travel, and lively discussions on the finer points of pharmacokinetics and critical care over a beer with friends.

The Pre-brief

  • Procalcitonin (PCT) is a precursor hormone of calcitonin that is undetectable in healthy states but is upregulated by cytokines released in response to bacterial infections.
    • Serum levels rise rapidly in response to systemic inflammatory insults within 6-12 hours, and peak levels correlate to the intensity of the stimulus.
    • Levels decline rapidly with a resolution of inflammation.
    • PCT has a half-life of 25 to 30 hours.
  • PCT was approved by the FDA in 2005 as a diagnostic aid for sepsis with serial levels being used to assess sepsis progression and 28-day mortality risk.
    • However, PCT properties lend themselves to being potentially useful for antimicrobial stewardship (AMS) including therapy initiation and/or cessation decisions.
  • Limitations of procalcitonin:
    • False positives may be seen from other major stressors causing systemic inflammation including severe trauma, circulatory shock, surgery, burns, inhalation injury, and pancreatitis. 
    • False negatives may be seen in patients with contained or localized infections including mediastinitis, empyema, or abscesses, or if PCT is drawn too early in the course of infection.

Procalcitonin as a tool for antimicrobial stewardship

Numerous randomized studies have examined whether PCT-based algorithms can assist clinicians in deciding whether to start or stop antimicrobial therapy, without adversely impacting patients through delayed antimicrobial therapy or inadequate treatment courses. Serum levels peak within 6 to 12 hours of initial infection and decrease by half for each day the infection is controlled by appropriate antimicrobial therapy. 

Efficacy has primarily been demonstrated in 2 clinical scenarios: adult patients with suspected respiratory infections and critically ill adults with any type of suspected infection. Improving antibiotic use in these scenarios carries the potential for important clinical benefit since respiratory infections are the most common indication for antibiotics in hospitalized patients, and antibiotic use is most prevalent in the ICU.

The MOSES study was a blinded, prospective multicenter observational clinical trial that evaluated the prognostic accuracy of a lack in PCT decrease >80% from baseline to day 4. PCT samples were collected within 12 hours after diagnosis of severe sepsis or septic shock and daily for 5 days. 28-day all-cause mortality was two-fold higher in patients who did not have a decrease in PCT by >80% from baseline to day 4 compared to those who did have >80% reduction (20% vs. 10.4%, respectively). The inability to decrease PCT by at least 80% was determined to be a significant independent predictor of mortality in sepsis and may be important to aid in prognostication. 

Initiation of antimicrobial therapy

In a large retrospective, propensity score-matched multivariable analysis of the Premier Healthcare Database, patients with 1-2 PCT evaluations on day 1 of ICU admission (n=33,569) were shown to have decreased total LOS (11.5 vs. 12.7, p<0.001), lower hospital costs ($30,454 vs. $33,213, p<0.001), and significantly less total antibiotic exposure (16.2 vs. 16.9 days, p=0.006) compared to a non-PCT propensity-matched cohort (n=98,543). While the mechanisms for improved healthcare utilization are not directly apparent from a database review, earlier recognition of sepsis may allow for the initiation of appropriate management protocols. Early use of appropriate antibiotics, source control, and fluid/vasopressor administration would be expected to lead to patient improvement, reduced LOS, and decreased healthcare expenditures. 

PCT has been criticized as a sepsis recognition tool since there is the potential for false-negative results depending on the timing of serum level measurement in relation to the onset of sepsis or septic shock (e.g. drawn <6 hours from onset). Therefore, PCT should not replace traditional sepsis diagnostic strategies or delay initiation of sepsis pathways when clinical suspicion is high despite a low PCT measurement. Instead, PCT may be most useful if measured serially (e.g. every 2 days) and used as a strategy to augment the clinician’s assessment of response to therapy. 

Cessation of antimicrobial therapy

The following table summarizes findings from recent systematic reviews and meta-analyses seeking to determine the impact of PCT guidance on the cessation of antimicrobial therapy.

Overall, serial evaluation of PCT in patients with sepsis is associated with a significantly reduced 30-day mortality and may allow for a 1-3 day shorter duration of antimicrobial therapy with no apparent compromise in clinical outcomes. Proposed interpretation of PCT is summarized in the figure:

The Debrief

  • PCT is upregulated within 6-12 hours of the onset of bacterial infections and levels decline rapidly with a resolution of inflammation.
  • Serial PCT evaluation in patients with sepsis is associated with a significantly reduced 30-day mortality and duration of antimicrobial therapy.
  • Measure PCT at baseline and daily. Consider early antimicrobial discontinuation if the patient is clinically stable, >80% reduction in PCT from baseline and the absolute PCT <0.5-1 mcg/L.
    • Consider broadening therapy if unable to achieve goals by day 4.
  • Interpret PCT cautiously in the setting of renal failure, pancreatitis, severe cardiogenic shock, or trauma

References:

  1. Balk RA, Kadri SS, Cao Z, et al. Effect of Procalcitonin Testing on Health-care Utilization and Costs in Critically Ill Patients in the United States. CHEST. 2017; 151:23-33.
  2. Schuetz P, Birkhahn R, Sherwin R, et al. Serial procalcitonin predicts mortality in severe sepsis patients: results from the multicenter procalcitonin monitoring sepsis (MOSES) study. Crit Care Med. 2017;45:781-9.
  3. Lam SW, Bauer SR, Fowler R, Duggal A. Systematic review and meta-analysis of procalcitonin-guidance versus usual care for antimicrobial management in critically ill patients: focus on subgroups based on antibiotic initiation, cessation, or mixed strategies. Crit Care Med. 2018; 46:684-90.
  4. Iankova I, Thompson-Leduc P, Kirson NY, et al. Efficacy and safety of procalcitonin guidance in patients with suspected or confirmed sepsis: a systematic review and meta-analysis. Crit Care Med. 2018; 46:691-8.

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