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Cited by 114Sepsis Diagnosis and TreatmentAntibiotics Pharmacokinetics and EfficacyAntibiotic Use and Resistance

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

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Dark, Paul, Hossain, Anower, McAuley, Daniel F., Brealey, David, Carlson, Gordon, Clayton, Jonathan C., Felton, Timothy W., Ghuman, Belinder K. +539 more·2025·JAMA
DOI 10.1001/jama.2024.26458PMC PMC11862976
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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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  • Biomarker-guided strategies, randomized trials of bloodstream infection duration, and recent meta-analyses have shown that less antibiotic exposure can be appropriate in selected patients when clinical stability and source control are present.

    “Biomarker-guided strategies, randomized trials of bloodstream infection duration, and recent meta-analyses have shown that less antibiotic exposure can be appropriate in selected patients when clinical stability and source control are present (24–29).”

    From Day-4 antipseudomonal and anti-MRSA de-escalation was not associated with higher mortality in critically ill patients with sepsis (2026) · cites this paper as [25]

    The Discussion reports that daily procalcitonin-guided discontinuation safely reduced total antibiotic duration in critically ill adults with suspected sepsis, supporting the biomarker-guided part of the sentence. It also says CRP guidance did not reduce total duration, and the passages do not establish clinical stability and source control as conditions for the finding. The bloodstream-infection trials and meta-analyses are not findings of this trial. (LLM, conf=0.84)

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  1. ICH C. E9 (R1) Addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials. 2019. Proceedings of the international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf

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Dark, P., Hossain, A., McAuley, D. F., Brealey, D., Carlson, G., Clayton, J. C., Felton, T. W., Ghuman, B. K., Gordon, A. C., Hellyer, T. P., Lone, N. I., Manazar, U., Richards, G., McCullagh, I. J., McMullan, R., McNamee, J. J., McNeil, H. C., Mouncey, P. R., Naisbitt, M. J., Parker, R. J., Poole, R. L., Rostron, A. J., Singer, M., Stevenson, M. D., Walsh, T. S., Welters, I. D., Whitehouse, T., Whiteley, S., Wilson, P., Young, K. K., Perkins, G. D., Lall, R., Collaborators, A.-S., Bion, J., MacGowan, A., McCrone, P., O'Kane, M., Attwood, B., Sturmey, G., Prentice, J., Yu, L.-M., Clutton-Brock, T., Young, D., Simpspm, J., Marshall, K., Gates, S., White, J., Mistry, D., Regan, S., McGowan, N., Kaur, D., Ji, C., Nevels, N., Welters, I. D., Williams, K., Shaw, D., Waugh, V., Patrick-Heselton, J., Paisley, C., Phillips, S., Johnson, E., Fernandez Roman, J., Lopez Martinez, M., Mahiya, A., Watkin, D., Thomas, Z., Davison, A., Farina, S., Norris, M., Manes, S., Yuan, J.-X., Colfar, J., Lythgoe, C., Almafreji, I., Bailey, L., Parker, R., Turner-Bone, I., Wilding, L., Lloyd, M., Murrant, H., Smith, L., Morton, B., Middleton, D., Mccaig, W., Hughes, A., Fuller, L., Kay, D., Barber, S., Parez, J., Lee, S., Doonan, R., Swindells, L., Pendlebury, J., Holden, J., Hadfeild, J., Naisbitt, J., Caxton, A., Parkin, E., Horner, D., sukumaian, A., Gyamerah, B., Dunombe, A., Taylor, D. C., Habeichi, D. 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J., Williams, A., Connor, S., Allock, R., Halsall, L., McMullen, S., Rajasekar, J., Purvis, S., Garg, I., Jagannathan, V., Corr, H., Stefaniak, M., Sinclair, S., Wilson, C., Brealey, D., MacCallum, N., Hass, I., Bercades, G., Smyth, D., Martir, G., Reyes, A., Zapata Martinez, M. 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Affiliations
  • University of Manchester (GB)
  • Warwick Medical School, Clinical Trials Unit, University of Warwick, Coventry, United Kingdom
  • Queen's University Belfast (GB)
  • Northern Care Alliance NHS Foundation Trust (GB)
  • Department of Clinical Biochemistry, Lancashire Teaching Hospitals NHS Foundation Trust, Sharoe Green Lane, Fulwood, Preston Lancashire, United Kingdom
  • Respiratory Academic Group, Division of Immunology, Immunity to Infection and Respiratory Medicine, University of Manchester, Wythenshawe Hospital, Manchester, United Kingdom
  • University of Warwick (GB)
  • Imperial College London (GB)
  • Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
  • Anaesthesia, Critical Care and Pain Medicine, Usher Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh Royal Infirmary, Edinburgh, United Kingdom
  • Newcastle upon Tyne Hospitals NHS Foundation Trust, United Kingdom
  • Royal Victoria Hospital Belfast, Belfast, United Kingdom
  • Intensive Care National Audit & Research Centre (GB)
  • Salford Royal Hospital (GB)
  • Liverpool University NHS Foundation Trust, Aintree University Hospital, Liverpool, United Kingdom
  • Cardiff and Vale University Health Board (GB)
  • University of Newcastle, Newcastle Upon Tyne, United Kingdom
  • University College London (GB)
  • University of Sheffield (GB)
  • University College London Hospitals NHS Foundation Trust (GB)
  • for the ADAPT-Sepsis Collaborators
Corresponding author
Dark, Paul
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2025-02-25
Volume
333
Issue
8
Pages
682
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2024.26458
PMC
PMC11862976
OpenAlex
W4405172006
Cited by
114
References
16
Citations by year
2026: 73 · 2025: 40 · 2024: 1
FWCI
34.58
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • JAMA (publishedVersion)
  • PubMed Central (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (publishedVersion)
  • UCL Discovery (University College London) (acceptedVersion)
  • Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
  • Research Explorer (The University of Manchester) (acceptedVersion, cc-by)
  • Research Portal (Queen's University Belfast) (acceptedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
  • Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
  • Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Antibiotic Use and Resistance
Keywords
procalcitonin, C-reactive protein, antibiotic duration, critically ill adults, intensive care, all-cause mortality, length of hospital stay, non-inferiority, sepsis severity, sepsis severity score
MeSH terms
Procalcitonin, Duration of Therapy, Adult, Aged, Anti-Bacterial Agents, C-Reactive Protein, Female, Humans, Intensive Care Units, Length of Stay, Male, Middle Aged, Time Factors, Biomarkers, Critical Illness, Treatment Outcome, Sepsis, Administration, Intravenous

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