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Randomized Controlled Trial
. 2025 Feb 25;333(8):682-693.
doi: 10.1001/jama.2024.26458.

Biomarker-Guided Antibiotic Duration for Hospitalized Patients With Suspected Sepsis: The ADAPT-Sepsis Randomized Clinical Trial

Paul Dark  1 , Anower Hossain  2 , Daniel F McAuley  3   4 , David Brealey  5 , Gordon Carlson  6 , Jonathan C Clayton  7 , Timothy W Felton  8 , Belinder K Ghuman  2 , Anthony C Gordon  9 , Thomas P Hellyer  10   11 , Nazir I Lone  12 , Uzma Manazar  2 , Gillian Richards  2 , Iain J McCullagh  10 , Ronan McMullan  3   4 , James J McNamee  4 , Hannah C McNeil  2 , Paul R Mouncey  13 , Micheal J Naisbitt  14 , Robert J Parker  15 , Ruth L Poole  16 , Anthony J Rostron  11   17 , Mervyn Singer  18 , Matt D Stevenson  19 , Tim S Walsh  12 , Ingeborg D Welters  20 , Tony Whitehouse  21 , Simon Whiteley  22 , Peter Wilson  23 , Keith K Young  2 , Gavin D Perkins  2 , Ranjit Lall  2 ; ADAPT-Sepsis Collaborators
Collaborators, Affiliations
Randomized Controlled Trial

Biomarker-Guided Antibiotic Duration for Hospitalized Patients With Suspected Sepsis: The ADAPT-Sepsis Randomized Clinical Trial

Paul Dark et al. JAMA. .

Abstract

Importance: For hospitalized critically ill adults with suspected sepsis, procalcitonin (PCT) and C-reactive protein (CRP) monitoring protocols can guide the duration of antibiotic therapy, but the evidence of the effect and safety of these protocols remains uncertain.

Objective: To determine whether decisions based on assessment of CRP or PCT safely results in a reduction in the duration of antibiotic therapy.

Design, setting, and participants: A multicenter, intervention-concealed randomized clinical trial, involving 2760 adults (≥18 years), in 41 UK National Health Service (NHS) intensive care units, requiring critical care within 24 hours of initiating intravenous antibiotics for suspected sepsis and likely to continue antibiotics for at least 72 hours.

Intervention: 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 assigned to standard care.

Main outcomes and measures: The primary outcomes were 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.

Results: Among the randomized patients (mean age 60.2 [SD, 15.4] years; 60.3% males), there was a significant reduction in antibiotic duration from randomization to 28 days for those in the daily PCT-guided protocol compared with standard care (mean duration, 10.7 [SD, 7.6] days for standard care and 9.8 [SD, 7.2] days for PCT; mean difference, 0.88 days; 95% CI, 0.19 to 1.58, P = .01). For all-cause mortality up to 28 days, the daily PCT-guided protocol was noninferior to standard care, where the noninferiority margin was set at 5.4% (19.4% [170 of 878] of patients receiving standard care; 20.9% [184 of 879], PCT; absolute difference, 1.57; 95% CI, -2.18 to 5.32; P = .02). No difference was found in antibiotic duration for standard care vs daily CRP-guided protocol (mean duration, 10.6 [7.7] days for CRP; mean difference, 0.09; 95% CI, -0.60 to 0.79; P = .79). For all-cause mortality, the daily CRP-guided protocol was inconclusive compared with standard care (21.1% [184 of 874] for CRP; absolute difference, 1.69; 95% CI, -2.07 to 5.45; P = .03).

Conclusions and relevance: 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.

Trial registration: isrctn.org Identifier: ISRCTN47473244.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Dark reported receiving grants from Roche Diagnostics and Abbott via the National Institute of Health and Care Research (NIHR)–agreed contract for biomarker research assay set-up and maintenance in supporting NHS hospitals for which assays are not routinely available, from an NIHR senior investigator award and the NIHR deputy medical director outside the submitted work; and nonfinancial support from Thermo Fisher Scientific via an NIHR memorandum of understanding to assist with knowledge to identify and set up research sites during the conduct of the study. Dr McAuley reported receiving grants from the NIHR Health Technology Assessment (HTA) program during the conduct of the study; consulting fees from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Eli Lilly, Aptarion, Aviceda, and Direct Biologics; research grants from Vir Biotechnology Inc, Wellcome Trust, Innovate UK, Medical Research Council (MRC), Northern Ireland Health Social Care; serving on the advisory board of Direct Biologics and on a data monitoring and ethics committee for Vir Biotechnology; having patent US8962032 issued to Queen’s University, Belfast; and serving as the codirector of research for the Intensive Care Society and NIHR/MRC Efficacy and Mechanisms Evaluation. Dr Brealey reported receiving personal fees from David Andrew Brealey for conducting educational sessions for bioMerieux outside the submitted work. Dr Gordon reported receiving consulting fees from Beckman Coulter and AstraZeneca paid to his institution outside the submitted work. Dr Lone reported receiving grants from NIHR during the conduct of the study and serving as director of research for the UK Intensive Care Society, chair of the Scottish Intensive Care Society audit group, Public Health Scotland. Dr McCullagh reported receiving grants from the NIHR during the conduct of the study. Dr McMullan reported receiving grants from the NIHR HTA program during the conduct of the study. Dr Mouncey reported receiving grants from the NIHR HTA program during the conduct of the study. Dr Poole reported receiving grants from the Intensive Care Society and from the Welsh government outside the submitted work. Dr Singer reported receiving grants from the NIHR during the conduct of the study and from Gentian; honoraria from Biotest, Matisse, Volition, AOP Pharma, Aptarion, and Deltex Medical; personal fees from deePull, Sanofi, BioMerieux, Safeguard Biosystems, and Roche Diagnostics; and nonfinancial support from the International Sepsis Forum outside the submitted work. Dr Stevenson reported receiving grants from the NIHR during the conduct of the study. Dr Walsh reported receiving grants from the NIHR HTA program during the conduct of the study. Dr Welters reported receiving grants from the NIHR and the European Union outside the submitted work. Dr Whitehouse reported receiving grants from the NIHR Efficacy and Mechanism Evaluation Project (EME-14/150/85) and personal fees from AOP Orphan outside the submitted work. Dr Perkins reported receiving grants from the NIHR during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Recruitment, Randomization and Follow-Up in the ADAPT-Sepsis Trial
aNo data were collected for this patient. bEleven patients withdrew completely from the trial by day 28 and requested removal of their data. In addition, data were missing and unobtainable from 54 patients. CRP indicates C-reactive protein; IV, intravenous; and PCT, procalcitonin.
Figure 2.
Figure 2.. Indicative Maps of Patient Care Pathways
Trial patients were drawn at random (100 per group) and shown to indicate their care pathways from randomization to day 28 in each group. When antibiotics were stopped and protocol advice ended, the patient entered the follow-up phase or was discharged from the hospital. Any antibiotics administered during the follow-up phase are shown by black X’s. Patients in each panel are ordered by length of total antibiotics from randomization to day 28.
Figure 3.
Figure 3.. Kaplan-Meier Curves for Probability of Antibiotic Duration and Mortality to 28 Days
The medians of the total antibiotic treatment duration up to 28 days for each of the 3 groups are 7.8 (IQR, 4.5-13.6) days for the daily procalcitonin (PCT)–guided protocol, 8.9 (IQR, 4.5-14.9) days for the daily C-reactive protein (CRP)–guided protocol, and 9.0 (IQR, 4.7-14.6) days for standard care.
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