Providing timely and appropriate antimicrobial therapy is essentially an international care standard meant to provide optimal outcomes for patients with sepsis. The best duration of antibiotic therapy for sepsis is unknown and decisions to stop treatment are guided by clinician assessment of patient progress and biomarkers in serum such as serum C-reactive protein (CRP) and procalcitonin (PCT).
Optimizing antibiotic duration helps avoid overtreatment, limit unnecessary side effects, and prolong the effectiveness of an antibiotic because it reduces resistance. Very good evidence from biomarkers-guided withdrawal, specifically with PCT, may yield a safe reduction in the duration of antibiotics but clinical trial evidence has been considered as low in quality leading to weak recommendations for routine adoption of PCT-based decisions for sepsis management, and no guidance consensus has been reached regarding CRP.
So, do critically ill adult patients who are admitted on suspicion of sepsis have a PCT or CRP-based protocol for intravenous antibiotics safe reduction in treatment duration compared to standard care? This question was answered by research published in JAMA Network.
A multi-center 3-group intervention-concealed randomized clinical trial was conducted to ascertain whether treatment protocols for monitoring CRP or PCT safely resulted in a reduction in the duration of antibiotic therapy for critically ill hospitalised adults with suspected sepsis. The primary outcome of the study was to measure clinical efficacy concerning the reduction in antibiotic duration (noninferiority) but at the same time provide a measure of safety concerning: 28-day all-cause mortality as a noninferiority criterion.
From January 1, 2018, to June 5, 2024, 918 patients were assigned to the daily PCT-guided protocol, 924 to the daily CRP-guided protocol, and 918 were assigned to standard care.
The daily protocol of PCT-guided therapy in a multi-center randomized trial involving 2,760 patients reduced total antibiotic duration and showed noninferiority regarding all-cause mortality compared with standard care. There was no difference in total antibiotic duration between the standard care and daily CRP-guided protocol, and CRP was inconclusive regarding all-cause mortality.
Among the randomized patients (mean age 60.2 years [standard deviation (SD) 15.4]; 60.3% male), those assigned to the daily PCT-guided protocol experienced a significant reduction in antibiotic duration from randomization to 28 days compared with standard care (mean duration: 10.7 days [SD 7.6] for standard care vs. 9.8 days [SD 7.2] for PCT; mean difference: 0.88 days; 95% confidence interval (CI), 0.19–1.58; P = 0.01). Regarding all-cause mortality within 28 days, the daily PCT-guided protocol was non-inferior to standard care, with a noninferiority margin of 5.4% (19.4% [170/878] for standard care vs. 20.9% [184/879] for PCT; absolute difference: 1.57; 95% CI, −2.18 to 5.32; P = 0.02).
No significant difference in antibiotic duration was observed between standard care and the daily CRP-guided protocol (mean duration: 10.6 days [SD 7.7] for CRP; mean difference: 0.09 days; 95% CI, −0.60 to 0.79; P = 0.79). For all-cause mortality, the daily CRP-guided protocol yielded inconclusive results compared with standard care (21.1% [184/874] for CRP; absolute difference: 1.69; 95% CI, −2.07 to 5.45; P = 0.03).
The primary outcomes were the total duration of antibiotics (effectiveness) and all-cause mortality (safety) to 28 days. Secondary outcomes included critical care unit data and hospital stay data. Ninety-day all-cause mortality was also collected.
In adults being critically ill and hospitalized infected with sepsis, significant total safe reductions in antibiotic days are obtained by using daily PCT-I protocolized treatment compared with standard care. A daily CRP-I protocol does not provide for total differences in antibiotic days.
Reference: 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. doi:10.1001/jama.2024.26458
