Effect of C-Reactive Protein–Guided Antibiotic Treatment Duration, 7-Day Treatment, or 14-Day Treatment on 30-Day Clinical Failure Rate in Patients With Uncomplicated Gram-Negative Bacteremia: A Randomized Clinical Trial
Open accessAbstract
Importance: Antibiotic overuse drives antibiotic resistance. Gram-negative bacteremia is a common infection that results in substantial antibiotic use. Objective: To compare the clinical effectiveness of C-reactive protein (CRP)-guided, 7-day, and 14-day antibiotic durations 30, 60, and 90 days after treatment initiation. Design, Setting, and Participants: Multicenter, noninferiority, point-of-care randomized clinical trial including adults hospitalized with gram-negative bacteremia conducted in 3 Swiss tertiary care hospitals between April 2017 and May 2019, with follow-up until August 2019. Patients and physicians were blinded between randomization and antibiotic discontinuation. Adults (aged ≥18 years) were eligible for randomization on day 5 (±1 d) of microbiologically efficacious therapy for fermenting, gram-negative bacteria in blood culture(s) if they were afebrile for 24 hours without evidence for complicated infection (eg, abscess) or severe immunosuppression. Intervention: Randomization in a 1:1:1 ratio to an individualized CRP-guided antibiotic treatment duration (discontinuation once CRP declined by 75% from peak; n = 170), fixed 7-day treatment duration (n = 169), or fixed 14-day treatment duration (n = 165). Main Outcomes and Measures: The primary outcome was the clinical failure rate at day 30, defined as the presence of at least 1 of the following, with a non-inferiority margin of 10%: recurrent bacteremia, local suppurative complication, distant complication (growth of the same organism causing the initial bacteremia), restarting gram-negative-directed antibiotic therapy due to clinical worsening suspected to be due to the initial organism, or death due to any cause. Secondary outcomes included the clinical failure rate on day 90 of follow-up. Results: Among 504 patients randomized (median [interquartile range] age, 79 [68-86] years; 306 of 503 [61%] were women), 493 (98%) completed 30-day follow-up and 448 (89%) completed 90-day follow-up. Median antibiotic duration in the CRP group was 7 (interquartile range, 6-10; range, 5-28) days; 34 of the 164 patients (21%) who completed the 30-day follow-up had protocol violations related to treatment assignment. The primary outcome occurred in 4 of 164 (2.4%) patients in the CRP group, 11 of 166 (6.6%) in the 7-day group, and 9 of 163 (5.5%) in the 14-day group (difference in CRP vs 14-day group, -3.1% [1-sided 97.5% CI, -∞ to 1.1]; P < .001; difference in 7-day vs 14-day group, 1.1% [1-sided 97.5% CI, -∞ to 6.3]; P < .001). By day 90, clinical failure occurred in 10 of 143 patients (7.0%) in the CRP group, 16 of 151 (10.6%) in the 7-day group, and 16 of 153 (10.5%) in the 14-day group. Conclusions and Relevance: Among adults with uncomplicated gram-negative bacteremia, 30-day rates of clinical failure for CRP-guided antibiotic treatment duration and fixed 7-day treatment were noninferior to fixed 14-day treatment. However, interpretation is limited by the large noninferiority margin compared with the low observed event rate, as well as low adherence and wide range of treatment durations in the CRP-guided group. Trial Registration: ClinicalTrials.gov Identifier: NCT03101072.
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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 [28]
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- Authors
- von Dach, E., Albrich, W. C., Brunel, A.-S., Prendki, V., Cuvelier, C., Flury, D., Gayet-Ageron, A., Huttner, B., Kohler, P., Lemmenmeier, E., McCallin, S., Rossel, A., Harbarth, S., Kaiser, L., Bochud, P.-Y., & Huttner, A.
- Affiliations
- Faculty of Medicine, Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland
- Kantonsspital St. Gallen (CH)
- Centre Hospitalier Universitaire Vaudois (CH)
- University Hospital of Geneva (CH)
- Faculty of Medicine, Clinical Research Center, Geneva University Hospitals, Geneva, Switzerland
- Corresponding author
- Huttner, Angela
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2020-06-02
- Volume
- 323
- Issue
- 21
- Pages
- 2160
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC7267846
- OpenAlex
- W3032265239
- Cited by
- 259
- References
- 19
- Citations by year
- 2026: 25 · 2025: 57 · 2024: 42 · 2023: 49 · 2022: 50 · 2021: 29 · 2020: 7
- FWCI
- 20.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Tel Aviv University
- Technion-Israel Institute of Technology
- Topics
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Antibiotic Use and Resistance
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
- Keywords
- gram-negative bacteremia, antibiotic duration, recurrent bacteremia, antibiotic overuse, antibiotic resistance, non-inferiority, hospitalized adults, sepsis, non-fermenting Gram-negative bacilli
- MeSH terms
- Duration of Therapy, Aged, Aged, 80 and over, Algorithms, Anti-Bacterial Agents, C-Reactive Protein, Drug Administration Schedule, Female, Gram-Negative Bacteria, Humans, Male, Microbial Sensitivity Tests, Middle Aged, Recurrence, Regression Analysis, Multivariate Analysis, Bacteremia, Gram-Negative Bacterial Infections, Treatment Failure, Intention to Treat Analysis
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