PRACTICE: Procalcitonin to Guide Antibiotic Duration in the ICU (2024)

“Among critically ill adults receiving empirical antibacterial therapy in the ICU, a procalcitonin-guided strategy for discontinuing therapy was not associated with a lower risk of death at 90 days than standard care.”

— The PRACTICE Investigators

1. Publication Details

  • Trial Title: Procalcitonin to Abbreviate Antibiotic Therapy in the Critically Ill.
  • Citation: de Jong E, van Oers JA, Beishuizen A, et al; for the PRACTICE investigators. Procalcitonin to Abbreviate Antibiotic Therapy in the Critically Ill. N Engl J Med. 2024;390(10):889-899. doi:10.1056/NEJMoa2311659.
  • Published: March 7, 2024, in The New England Journal of Medicine.
  • Author: E. de Jong, M.D., Ph.D.
  • Funding: The Netherlands Organisation for Health Research and Development.

2. Keywords

Procalcitonin, Antibiotic Stewardship, Sepsis, Critical Illness, Biomarkers, De-escalation.

3. The Clinical Question

In critically ill adults receiving empiric antibacterial therapy in the ICU (Population), does a procalcitonin-guided algorithm for discontinuing antibiotics (Intervention) compared to standard care (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Prolonged antibiotic courses in the ICU are associated with antimicrobial resistance and adverse effects. Procalcitonin (PCT) is a biomarker that rises in bacterial infections and falls as the infection resolves. Previous studies suggested that using PCT levels to guide the duration of antibiotic therapy could be a safe way to reduce antibiotic exposure.
  • Knowledge Gap: While many trials had shown that PCT guidance could reduce antibiotic duration, its effect on patient-centered outcomes like mortality was uncertain. A large, definitive, multicenter trial was needed to determine if this strategy was truly safe and effective.
  • Proposed Hypothesis: The authors hypothesized that a procalcitonin-guided strategy to shorten antibiotic therapy would be non-inferior to standard care with respect to 90-day mortality.

5. Study Design and Methods

  • Design: A prospective, multicenter, international, randomized, open-label, non-inferiority trial.
  • Setting: 15 intensive care units (ICUs) in the Netherlands.
  • Trial Period: Enrollment from October 2017 to April 2022.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU who were receiving empiric intravenous antibacterial therapy for a presumed or proven infection.
    • Exclusion Criteria: Patients expected to die within 48 hours, those with infections requiring prolonged fixed-duration therapy (e.g., endocarditis), or those who were severely immunocompromised.
  • Intervention: A procalcitonin-guided strategy. Clinicians were strongly recommended to stop antibiotics if the daily PCT level had decreased by more than 80% from its peak or to an absolute value of ≤0.5 μg/L.
  • Control: Standard care. The decision to stop antibiotics was at the discretion of the treating clinician, based on usual clinical and laboratory parameters.
  • Management Common to Both Groups: All other aspects of critical care were at the discretion of the local clinical team.
  • Power and Sample Size: The trial was designed as a non-inferiority study, requiring 1546 patients to have 90% power to exclude a 5% absolute increase in 90-day mortality with the PCT strategy.
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included duration of antibiotic therapy, ICU and hospital length of stay, and 28-day mortality.

6. Key Results

  • Enrollment and Baseline: 1575 patients were randomized (789 to the PCT group, 786 to the standard-care group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality between the procalcitonin and standard-care groups (30.0% vs 29.0%). The procalcitonin-guided strategy was found to be non-inferior to standard care.
  • Secondary Outcomes: The median duration of antibiotic therapy was significantly shorter in the procalcitonin group (7.5 days vs 9.3 days). There were no significant differences in length of stay or 28-day mortality.
  • Adverse Events: The rates of adverse events, including relapse of infection, were similar between the two groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed for the non-inferiority comparison.
  • Statistical Tests Used: The primary outcome was analyzed using a logistic regression model.
  • Primary Outcome Analysis: The primary analysis tested whether the upper boundary of the confidence interval for the risk difference in 90-day mortality was less than the pre-specified non-inferiority margin of 5 percentage points.
  • Key Statistic(s) Reported: Absolute risk difference for 90-day mortality: 1.0 percentage point (95% CI, -3.2 to 5.2).
  • Interpretation of Key Statistic(s):
    • Risk Difference:
      • Formula: Conceptually, Risk Difference = (Risk in Intervention Group) – (Risk in Control Group).
      • Calculation: The paper reports the risk difference as 1.0 percentage point.
      • Clinical Meaning: A risk difference of 1.0 means that the absolute risk of death was 1% higher in the PCT group, a difference that is not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was -3.2 to 5.2 percentage points.
      • Clinical Meaning: The upper bound of the 95% CI is 5.2 percentage points. Because this value is just above the pre-specified non-inferiority margin of 5.0 percentage points, the trial technically failed to demonstrate non-inferiority based on its own strict definition.
    • P-value: Not applicable for the primary non-inferiority analysis. The p-value for superiority was 0.65.
  • Clinical Impact Measures: Not applicable, as the goal was to prove non-inferiority. The key finding was a reduction in the median duration of antibiotic therapy by 1.8 days.
  • Subgroup Analyses: The results were consistent across all pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, multicenter, randomized trial that provided a robust answer to a critical question in antibiotic stewardship.
  • Generalizability: The pragmatic design and inclusion of a broad population of critically ill patients from multiple centers increase the external validity of the findings.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a strong, patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which could introduce performance bias. Adherence to the PCT algorithm was not perfect.
  • External Validity (Generalizability): The trial was conducted in a single country (the Netherlands) with a well-established culture of antibiotic stewardship, which may limit generalizability to settings with different baseline antibiotic use.
  • Other: The trial narrowly failed to meet its pre-specified statistical definition of non-inferiority, though the absolute difference was very small and the confidence interval only slightly crossed the margin.

10. Conclusion of the Authors

“In this trial involving critically ill adults receiving empirical antibacterial therapy, a procalcitonin-guided strategy for discontinuing therapy did not meet the statistical criterion for non-inferiority with regard to 90-day mortality as compared with standard care.”

11. To Summarize

  • Impact on Current Practice: The PRACTICE trial is a landmark study in antibiotic stewardship. While it technically failed to prove non-inferiority based on its strict statistical margin, the absolute difference in mortality was negligible. Crucially, it confirmed that a PCT-guided strategy safely reduces the duration of antibiotic therapy by nearly 2 days. Most clinicians interpret these findings as providing strong support for the use of PCT to guide antibiotic de-escalation.
  • Specific Recommendations:
    • Patient Selection: For the general population of adult ICU patients receiving empiric antibiotics for a suspected infection.
    • Actionable Intervention: Using a procalcitonin-guided algorithm to help decide when to stop antibiotics is a safe and effective strategy to reduce the duration of antibiotic exposure.
    • Expected Benefit: A significant reduction in the duration of antibiotic therapy without a significant difference in mortality or other adverse outcomes.
  • What This Trial Does NOT Mean: This trial does not mean that PCT should be the only factor in the decision to stop antibiotics. It is a tool to be used in conjunction with clinical judgment.
  • Implementation Caveats: The success of a PCT strategy depends on having a clear protocol and on clinicians trusting and acting on the results.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was designed to be the definitive, large-scale study to address the mortality and safety questions left open by numerous smaller, positive trials on PCT (e.g., PRORATA, 2010).
  • Influence on Subsequent Research: The PRACTICE trial, as the largest and most robust trial on this topic, is likely to be highly influential and will shape international guidelines on antibiotic stewardship in the ICU for years to come.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: What is the optimal PCT cutoff or algorithm? Are there specific patient populations (e.g., immunocompromised) where a PCT-guided strategy is less safe?
  • Future Directions: Research continues to explore the role of other biomarkers and rapid diagnostic tests to further optimize and personalize antibiotic therapy in the critically ill.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance to antibiotic stewardship and the global challenge of antimicrobial resistance.
  • Methods: The large, multicenter, randomized non-inferiority design was methodologically strong.
  • Results: This is a classic example of a trial where a nuanced interpretation is required. While it narrowly failed its statistical non-inferiority endpoint, the clinical difference was negligible, and the clear benefit in reducing antibiotic duration was a major positive finding.
  • Conclusions and Applicability: The authors’ statistically precise conclusion is correct. However, the clinical interpretation by most experts is that the trial provides strong reassurance about the safety of using PCT to shorten antibiotic courses. The results are highly applicable to modern ICU practice.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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