By Jake Scott, MD
Synopsis: In this multicenter, intervention-concealed, randomized clinical trial of 2,760 critically ill patients hospitalized with sepsis, the use of a daily procalcitonin-guided protocol resulted in shorter antibiotic duration as compared with standard care, without a significant difference in 28-day all-cause mortality. There was no significant difference in antibiotic duration between patients managed with a daily C-reactive protein-guided protocol and standard care, and the difference in all-cause mortality between these two groups was inconclusive.
Source: Dark P, Hossain A, McAuley DF, et al. Biomarker-guided antibiotic duration for hospitalized patients with suspected sepsis: The ADAPT-Sepsis randomized clinical trial. JAMA. 2024;Dec. 9. doi: 10.1001/jama.2024.26458. [Online ahead of print].
ADAPT-Sepsis was an intervention-concealed, randomized clinical trial (RCT) that was conducted to assess whether the use of daily protocols based on procalcitonin (PCT) or C-reactive protein (CRP) led to a safe reduction in the duration of antibiotic therapy for critically ill patients hospitalized with suspected sepsis as compared with standard care.1 The trial was investigator-initiated and conducted at 41 National Health Service (NHS) intensive care units (ICUs) in the United Kingdom between January 2018 and June 2024. Adult patients were enrolled in the trial if they were admitted to an ICU for suspected sepsis and if intravenous (IV) antibiotics had been initiated within 24 hours and expected to be continued for at least 72 hours. Patients were excluded if they required more than 21 days of antibiotic therapy, were severely immunocompromised (e.g., had neutropenia), were expected to receive interleukin-6 (IL-6) receptor inhibitors (e.g., tocilizumab or sarilumab) during their hospitalization, or if sepsis treatments were expected to be discontinued within 24 hours because of futility. Patients were randomly assigned in a 1:1:1 ratio to standard care, PCT, or CRP groups. Group assignment was concealed from patients, clinical teams, and research staff.
Biomarker testing was conducted within 24 hours of initiating IV antibiotics and biomarker levels were monitored daily until antibiotics were discontinued or the patient died or withdrew from the trial. For the PCT group, the protocol “strongly” supported the discontinuation of antibiotics if the PCT was less than 0.25 mcg/L, supported the discontinuation of antibiotics if the PCT fell by at least 80% from baseline or was between 0.25 mcg/L and 0.50 mcg/L, and supported standard care if the PCT did not meet the previously mentioned criteria. For the CRP group, the protocol “strongly” supported the discontinuation of antibiotics if the CRP was less than 25 mg/L, supported the discontinuation of antibiotics if the CRP fell by at least 50% from baseline, and supported standard care if the CRP did not meet the previously mentioned criteria. The primary clinical effectiveness outcome was the total duration of antibiotics in number of days and the primary safety outcome was 28-day all-cause mortality. Several secondary outcomes also were evaluated.
Of 16,109 patients screened for eligibility, 2,761 (17.1%) were enrolled in the study. Baseline characteristics and demographics of patients were similar among the three groups. The overall mean age was 60 years and 60% were males. The majority of patients were enrolled in the emergency department and admitted to the medical ICU. Respiratory tract infections accounted for approximately half of the presumed causes of sepsis. A causative microorganism was identified in slightly less than half of patients. Roughly half of patients had sepsis and the other half had septic shock.
Strong advice to discontinue antibiotics was more common and triggered earlier in the PCT-protocol group than in the CRP-protocol group. The duration of antibiotic treatment from randomization to 28 days was significantly shorter in the PCT-guided group than in the standard care group (mean total duration, 9.8 [standard deviation (SD), 7.2] days for the PCT group and 10.7 [SD, 7.6] days for the standard care group, mean difference 0.88 days; 95% confidence interval [CI], 0.19 to 1.58; P = 0.01). Regarding the primary effectiveness outcome, no difference was observed between standard care and the daily CRP-guided protocol (mean total duration, 10.6 [SD, 7.7] days for the CRP group, mean difference, 0.09 days; 95% CI, -0.60 to 0.79; P = 0.79). Results were similar in the adjusted analyses, including accounting for patients who died within the 28-day study period. There were no differences in secondary outcomes, with the exception of a significant reduction in the duration of antibiotics for the initial sepsis period for both the PCT and CRP groups as compared with the standard care group. With respect to the primary safety outcome, the 28-day all-cause mortality for the daily PCT-guided protocol was noninferior to standard care (mortality, 19.4% [170 of 878] for standard care, 20.9% [184 of 879] for PCT; absolute difference, 1.57; 95% CI, -2.18 to 5.32; P = 0.02). The difference in 28-day all-cause mortality for the daily CRP-guided protocol was inconclusive in terms of noninferiority (mortality, 19.4% [170 of 878] for standard care, 21.1% [184 of 874] for CRP; absolute difference, 1.69; 95% CI, -2.07 to 5.45; P = 0.03). There were no differences in 90-day all-cause mortality between the three groups.
Commentary
The optimized duration of antibiotic therapy is fundamental for the sake of maximizing clinical effectiveness while minimizing untoward consequences of excessive exposure to antibiotics, including adverse effects, Clostridioides difficile colitis, and the promotion of antibiotic-resistant organisms. The ADAPT-Sepsis trial provides further evidence that the use of a PCT- but not CRP-guided protocol can safely lead to earlier discontinuation of antibiotic therapy in critically ill patients with sepsis compared to standard care. PCT has been extensively evaluated for this purpose, and several RCTs have demonstrated that in certain settings a systematic use of PCT may play an important role in the safe de-escalation of antibiotic treatment.2 PCT levels are normally less than 0.1 mcg/L in healthy individuals. Invasive bacterial infections can lead to an increase in serum PCT levels within two to six hours due to the release of PCT from tissues in response to bacterial endotoxins and inflammatory cytokines.3,4 With appropriate treatment, PCT levels typically peak within 24 hours and then decline by roughly 50% per day.5 CRP is a less specific marker of inflammation that tends to increase in response to stimuli more slowly than PCT (12-24 hours) and also tends to peak later than PCT (two to three days after exposure to stimuli).6,7 These differences may at least partly explain why PCT has been consistently shown to be a more useful adjunctive tool for antibiotic stewardship than CRP. While multiple RCTs have shown PCT guidance to be associated with a safe and effective reduction in antibiotic duration for hospitalized patients, CRP-based studies have failed to show a significant effect.2
In conclusion, ADAPT-Sepsis was a large, well-designed, multicenter trial that adds to the growing body of evidence in support of PCT-guided antibiotic stewardship protocols as safe and effective interventions to optimize the duration of antibiotic therapy.
Jake Scott, MD, is Associate Clinical Professor of Medicine, Stanford University.
References
1. Dark P, Hossain A, McAuley DF, et al. Biomarker-guided antibiotic duration for hospitalized patients with suspected sepsis: The ADAPT-Sepsis randomized clinical trial. JAMA. 2024;Dec. 9. doi: 10.1001/jama.2024.26458. [Online ahead of print].
2. Scott J, Deresinski S. Use of biomarkers to individualize antimicrobial therapy duration: A narrative review. Clin Microbiol Infect. 2023;29(2):160-164.
3. Wiedermann FJ, Kaneider N, Egger P, et al. Migration of human monocytes in response to procalcitonin. Crit Care Med. 2002;30(5):1112-1117.
4. Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: Clinical utility and limitations. Crit Care Med. 2008;36(3):941-952.
5. Charles PE, Tinel C, Barbar S, et al. Procalcitonin kinetics within the first days of sepsis: Relationship with the appropriateness of antibiotic therapy and the outcome. Crit Care. 2009;13(2):R38.
6. Markanday A. Acute phase reactants in infections: Evidence-based review and a guide for clinicians. Open Forum Infect Dis. 2015;2(3):ofv098.
7. Simon L, Gauvin F, Amre DK, et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: A systematic review and meta-analysis. Clin Infect Dis. 2004;39(2):206-217.
In this multicenter, intervention-concealed, randomized clinical trial of 2,760 critically ill patients hospitalized with sepsis, the use of a daily procalcitonin-guided protocol resulted in shorter antibiotic duration as compared with standard care, without a significant difference in 28-day all-cause mortality. There was no significant difference in antibiotic duration between patients managed with a daily C-reactive protein-guided protocol and standard care, and the difference in all-cause mortality between these two groups was inconclusive.
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