🧭 REBEL Rundown
📌 Key Points
- 🧪 Trending PCT continues to remain an unreliable indicator for cessation of antibiotics
- 📉 Researchers recommended stopping Abx earlier in PCT group vs others
- 📊 CRP guidance did not meet non-inferiority
- ☠️PCT strategy may have stopped antibiotics 1 day earlier but mortality was higher
- 👀 Reaffirms looking at overall clinical picture and patient, not just treating numbers
📝 Introduction
Antibiotic stewardship entails delivering the most appropriate antimicrobial therapy for the most appropriate duration of time to help provide the best outcome for patients with sepsis. An unnecessarily extended course of antibiotics leads to adverse effects, greater cost, medication utilization and most importantly antimicrobial resistance. However, too short of a course could lead to failure to treat and clinical deterioration. The optimal duration of antibiotics in sepsis remains uncertain and several biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT) have been studied to help clinicians reduce overtreatment and preserve antibiotic effectiveness. The authors of this 3-group multicenter randomized control trial sought to investigate whether biomarker-guided protocols could safely assist in the decision to discontinue antibiotics.
🧾 Paper
Dark P. et al ADAPT-Sepsis Collaborators. Biomarker-Guided Antibiotic Duration for Hospitalized Patients With Suspected Sepsis: The ADAPT-Sepsis Randomized Clinical Trial. JAMA. 2025 Feb 25 PMID: 39652885
PREVIOUSLY COVERED ON REBEL EM:
⚙️ What They Did
📈 Results
- Total of 16109 patients were screened for eligibility
- Of these 2761 patients were enrolled in the study with 1 being removed due to erroneous randomization
- 127 patients completely withdrew from the study prior to 28 days
💥 Critical Results
- Compared with standard care, there was a significant reduction in the total duration of antibiotic treatment from randomization to 28 days for the PCT-guided protocol
- The PCT-guided strategy had a 1.5% increase in mortality when compared to the other two arms. Although not statistically significant, this is very clinically significant and concerning
- There was no difference between the standard care and daily CRP guided protocol
- There was also a significant reduction in the duration of antibiotics for the initial sepsis period for biomarker protocols compared to standard care
💪 Strengths
- Large sample size: Enhances statistical power and precision of estimates that attempts to answer a clinically relevant question related to trending biomarkers, specifically, procalcitonin
- Multicenter RCT: Performed across a wide variety of intensive care units (ie. academic vs community) which also serves to increase external validity
- Followed CONSORT Guidelines and Trial Registered with The UK’s Clinical Study Registry: ISRCTN47473244: Promotes transparency and accountability.
- Protocol published in advance: Reduces risk of bias through prespecified analysis plans.
- Broad inclusion criteria: Supports generalizability across a wide spectrum of patients with sepsis and accounted for multiple presumed sites of infection
- Computer generated randomization: stratified by sepsis severity, recruitment site and recent surgery
- Solid concealment process: Strong protocol that reduces the risk unblinding
- Sufficiently sick: The patient population was representative of the sepsis population as a whole (ie. High SOFA, APACHE and Septic Shock in 50% of the sample)
- Well-balanced groups after randomization: Baseline characteristics were similar, reducing confounding and enhancing internal validity.
- Intervention variability: Standard of care was compared to an intervention that included two biomarkers as opposed to one
- Minimal loss to follow-up: Ensures data completeness and reliability of results
⚠️ Limitations
- Limited generalizability: Results only applicable to ICU patients in one country with socialized medicine
- Patient population: Severely immunocompromised patients excluded
- Primary outcome issues: Primary outcome is not patient oriented but rather process-oriented and they technically had two primary outcomes (i.e. 28-day all cause mortality)
- High number of excluded patients: 8046 septic patients were excluded for already having received IV antibiotic treatment for greater than 24 hours
- Unintended delay: Possible that while awaiting stop-advice, treating clinicians may have waited too long in stopping antibiotics
- Protocol contamination: There may have been contamination because treatment protocols and standard care was carried out in a single shared environment
- Physician discretion allowed: Clinicians in the standard care were allowed to monitor CRP outside of trial protocol so unclear how this may have impacted results
- Omission of details: Antibiotic resistance at specific hospitals and the variability was never mentioned in the study nor how it may have impacted the decision to discontinue antibiotics
🗣️ Discussion
- Treating clinicians receiving “daily recommendations” in and of itself is limiting because the research team may not be looking at the entire clinical picture vs just the biomarkers in sepsis and how that impacts the duration of antibiotics
- We should be treating patients based on their whole clinical picture and not just any one particular lab or imaging test
- Primary outcome is the wrong kind of POO. Instead of it being a patient-oriented outcome (ie. Mortality and quality of life), it’s a PROCESS-oriented outcome like ICU/Hospital length of stay or in this case: time on/off antibiotics in sepsis
- “Strong stop advice”
- Researchers gave this advice more commonly and earlier for the PCT-protocol compared with the CRP protocol. Not sure what this exactly means, stop means stop so unclear how/why advice to stop was presented as “stronger”. The authors attempt to justify this by stating that PCT concentrations are known to increase earlier and normalize more rapidly than CRP in response to treatment.
- The above could have skewed the resulted and overestimated the benefit of a PCT guided protocol as there was significant reduction in total duration of antibiotics in this group when compared with standard care
- The time period of 28-days in and of itself can be a major limitation when addressing the population of patients with very extended hospital stays. For example, the results of cant be applied to heart failure and mechanical circulatory support patients who sometimes have a long hospital stay and need multiple courses of antibiotics
- The time period begs to ask the question of whether a 28-day mortality enough of a time period vs something longer like 90-day mortality
- The reduction in antibiotic use for sepsis provides a significant cost and labor savings and more importantly a reduction in development of antimicrobial resistance.
- The authors however fail to mention anything else related to resistance, such as how the antibiograms at each of the enrollment sites may have impacted antibiotic choice, dose or duration.
- It’s important to note that the 2021 Surviving Sepsis Guidelines provides a weak recommendation for using procalcitonin in conjunction with clinical evaluation to guide discontinuation of antibiotics
- Lastly, the combination of a higher mortality in the PCT-guided group with a large non-inferiority margin raises concern for more deaths (although not statistically significant) and the premature stopping of antibiotics (by 1 day) even though patients may have still been infected
📘 Author's Conclusion
“Care guided by measurement of PCT reduces antibiotic duration safely compared with standard care, but CRP does not. All-cause mortality for CRP was inconclusive.”
💬 Our Conclusion
The methodology of this multicenter, single country randomized control trial has too many flaws to be incorporated into everyday clinical practice. The primary outcome was process and not patient-oriented. More importantly, the PCT-guided strategy had a higher mortality rate and a large non-inferiority margin meaning antibiotics may have been stopped one day earlier but it also led to more deaths
🚨 Clinical Bottom Line
In this multicenter, single country randomized control trial, procalcitonin was not a reliable indicator to guide the cessation of antibiotics in adult patients with sepsis. While not statistically significant, the trending of procalcitonin led to 5% more deaths when compared to the other groups all for the sake of saving one day of antibiotics. This like any other biomarker should be cautiously interpreted alongside clinical judgement in treating patients over numbers.
🔄 REBEL Recap
📚 References
- Dark P. et al. ADAPT-Sepsis Collaborators.
Biomarker-Guided Antibiotic Duration for Hospitalized Patients With Suspected Sepsis: The ADAPT-Sepsis Randomized Clinical Trial.
JAMA. 2025 Feb 25
PMID: 39652885 Evans L, Rhodes A, Alhazzani W, et al.
Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021.
Crit Care Med. 2021;49(11):e1063–e1143.
PMID: 34605781
Post Peer Reviewed By: Anand Swaminathan, MD (Twitter/X: @EMSwami), and Marco Propersi, DO (X: @Marco_Propersi)
👤 Co Editor-In-Chief
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