Key Points
Question
In patients with bacteremia, is a high day 7 procalcitonin (PCT) level associated with increased risk of adverse outcomes if treated with 7 vs 14 days of antibiotics?
Findings
In this cohort study of 125 patients with bacteremia, antibiotic duration beyond 7 days was not associated with improved outcomes in patients with a residually high PCT level.
Meaning
These findings suggest a 7-day course of antibiotics is sufficient for patients with uncomplicated bacteremia independent of serum PCT level.
Abstract
Importance
The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) trial showed that 7 days of antibiotics was noninferior to 14 days among patients with bacteremia. However, it is unknown whether patients with high serum procalcitonin (PCT) level at day 7 of therapy would benefit from a prolonged treatment course.
Objective
To investigate whether an elevated serum PCT level at day 7 of bacteremia was associated with increased mortality among patients treated with 7 vs 14 days of antibiotics.
Design, Setting, and Participants
This cohort study was a planned secondary analysis of the BALANCE trial from 2014 to 2023, a multicenter randomized clinical trial where serum was collected on day 7 of bacteremia and patients were followed up for 90 days after study enrollment. Serum samples were collected from patients 7 days after initiation of antibiotics; PCT levels were later quantified by an antibody-based assay and therefore were not available to clinicians. Data were analyzed from January to June 2025.
Intervention
Patients were randomized to receive either 7 or 14 days of antibiotics. Antibiotic selection, dosing, and route were at the discretion of the treating team.
Main Outcomes and Measures
The primary outcome was defined as death from any cause within 90 days of the positive index blood culture result. Secondary outcomes included death by any cause while admitted to the ICU, death by any cause while admitted to the hospital, number of days alive and not admitted to the ICU within 28 days of the index positive blood culture, number of days alive and not admitted to hospital within 28 days of the index positive blood culture, and the duration of mechanical ventilation.
Results
A total of 125 patients (median age 63, [IQR, 58-79] years; 80 [64.0%] male) were included in this study. Sixty-five participants (52%) had low PCT levels (<250 pg/mL) and 60 (48%) had high PCT levels (≥250 pg/mL) on day 7. The high PCT group was older, had more comorbidities, and had a higher prevalence of community-acquired bacteremia. Ninety-day mortality was higher in the high vs low PCT group: 21.6% (13 of 60) vs 6.2% (4 of 65) (absolute risk difference [ARD] 15.5%; 95% CI, 3.6%-27.5%). Among patients with high PCT level, 90-day mortality was not different among participants with 7 vs 14 days of antbiotics (ARD, −21.9%; 95% CI, −41.8 to −2.1).
Conclusions and relevance
In this cohort study, elevated PCT level on day 7 was associated with increased 90-day mortality. However, prolonging antibiotics beyond 7 days was not associated with improved mortality in patients with a residually high PCT level. Seven days of antibiotics appears sufficient for most patients with bloodstream infections independent of day 7 serum PCT level.
This cohort study reports a secondary analysis of the BALANCE randomized clinical trial assessing whether procalcitonin levels are associated with survival among patients receiving 7 vs 14 days of antibiotics for bloodstream infections.
Introduction
Bloodstream infections (BSIs) arise from various sources and are a substantial cause of hospitalization, intensive care unit (ICU) admission, and mortality worldwide.1 Timely and appropriate antibiotic therapy is critical for improving outcomes. However, prolonged antibiotic courses can potentially increase the risk of adverse effects such as Clostridioides difficile infection, antimicrobial resistance, and added health care costs.2,3 The BALANCE (Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness) multicenter randomized clinical trial (RCT) demonstrated that a 7-day course was noninferior to a 14-day course with respect to 90-day mortality for most BSIs.4
While BALANCE was a trial of fixed durations of antibiotic treatment for BSIs, other studies have explored the utility of serum biomarkers to personalize antibiotic treatment durations.5,6 Procalcitonin (PCT) has emerged as a clinically relevant biomarker for assessing illness severity in bacteremia.7,8 Under normal conditions, PCT is primarily produced by parafollicular C cells of the thyroid where it serves as a precursor to calcitonin.9 In bacterial infections, PCT is produced by leukocytes in the lungs, liver, intestines, and kidneys.10,11 In contrast, during viral infection, interferon gamma secretion suppresses its production.12 As such, PCT has been proposed as a bacterial infection-specific biomarker.
Several studies have examined whether reduced serum PCT levels can safely guide antibiotic discontinuation in patients with BSI or sepsis.13,14,15,16 The 2010 Procalcitonin to Reduce Patients' Exposure to Antibiotics in Intensive Care Units (PRORATA) trial randomized nonsurgical ICU patients with sepsis to PCT-guided therapy vs standard care. While the PCT-guided group had noninferior 30-day and 60-day mortality and reduced antibiotic exposure, adherence to PCT-based recommendations was modest (49%).13 The 2024 Biomarker-Guided Duration of Antibiotic Treatment in Hospitalised Patients With Suspected Sepsis (ADAPT-Sepsis) trial compared PCT-guided treatment, C-reactive protein-guided treatment, and standard care. PCT-guided therapy led to a reduction in antibiotic duration of approximately 1 day, whereas C-reactive protein-guided therapy did not. The overall median treatment durations in all arms exceeded the 7-day regimen used in BALANCE.14
Within the BALANCE trial of fixed antibiotic treatment durations, a subset of patients had serum PCT levels measured after 7 days of antibiotics; these results were not reported to the clinical team. In this planned secondary analysis of the BALANCE RCT, we investigated whether CT level on day 7 was associated with 90-day mortality in patients with BSIs, and whether a high PCT level on day 7 was associated with differential mortality among patients treated with 7 vs 14 days of antibiotics.
Methods
Study Design
The cohort study received ethical approval by Clinical Trials Ontario (project identifier: 0796). Informed consent from patients or their substitute decision makers was obtained before enrollment. BALANCE-PCT was a planned secondary analysis of the initial BALANCE trial from 2014 to 2023, a multicenter, open-label, randomized, clinical noninferiority trial comparing 7-day vs 14-day courses of antibiotic treatment for patients hospitalized with BSIs.4 Data were analyzed from January to June 2025. Twelve Canadian centers from the BALANCE study were part of BALANCE-PCT and prospectively collected serum samples at day 7 of treatment. This study was completed in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.
Serum PCT Measurement
Blood samples were collected from consenting participants at day 7 of antibiotic treatment and centrifuged for serum separation. Serum samples were stored at −20 °C. The Luminex multiplex platform (Luminex MagPix machine; Luminex), with PCT kits and reagents from R&D Systems (R&D Systems) were used to quantify serum PCT concentrations according to the manufacturer’s instructions. Luminex data were collected using xPONENT version 4.2 software (Luminex). Clinicians and study investigators were blinded to PCT results until after the study conclusion.
Outcome Measurements
The primary outcome was defined as death from any cause within 90 days of the positive index blood culture result. Secondary outcomes included death by any cause while admitted to the ICU, death by any cause while admitted to the hospital, number of days alive and not admitted to the ICU within 28 days of the index positive blood culture, number of days alive and not admitted to hospital within 28 days of the index positive blood culture, and the duration of mechanical ventilation. Primary and secondary outcomes were available for all study participants. Protocol deviations from the 7-day or 14-day treatment were monitored including early discontinuation (more than 2 days earlier than assigned duration) or prolongation (more than 2 days longer than assigned duration). Sensitivity analysis was performed using a day-7 PCT level cut-off of 500 pg/mL.
Statistical Analysis
Statistical analyses were conducted in R, version 4.5.1 (R Project for Statistical Computing). The Fisher exact test was used for categorical variables and Mann-Whitney-U test for continuous variables. Primary and secondary outcome analyses were conducted by calculating the absolute risk difference (ARD) with its 95% CI. Based on previous studies,9 a serum PCT level of 250 pg/mL was used as a cut-off to define high (≥250 pg/mL) vs low (<250 pg/mL) levels. The intention-to-treat approach was used for the analysis comparing the 7-day vs 14-day treatment course.
The primary outcome analysis investigated the risk difference in 90-day mortality between patients with low vs high PCT level on day 7. Furthermore, among patients with a day 7 serum PCT greater than 250 pg/mL, 90-day mortality risk was compared among individuals randomized to 7-day vs 14-day antibiotic duration. Secondary outcome analyses compared death in the ICU, death in the hospital, number of ICU-free days by day 28 of the index positive culture, number of hospital-free days by day 28 of the index positive culture, antibiotic-free days by day 28 of the index positive culture, and adherence to the treatment duration assignment between patients with a low vs high PCT level on day 7. Statistical significance was set at P < .05.
Results
Study Participant Characteristics
Day 7 serum PCT level was measured in 125 participants from the BALANCE trial. There were 80 males (64%) and 45 females (36%), median age was 63 (IQR, 58–79) years, 120 (96%) were enrolled while in the ICU, and 40 (32%) participants were mechanically ventilated at time of study enrollment.
A total of 65 (52%) of the planned secondary analysis participants had low serum PCT levels and 60 (48%) high serum PCT levels (eFigure in Supplement 1). Among participants with a high serum PCT level, the median level was 818 (IQR, 467-1638) pg/mL. Compared with the group with low PCT level on day 7, the group with high PCT level on day 7 had a greater median day 0 sequential organ failure assessment (SOFA) score (high PCT level: 9.5 [IQR, 6–13]; low PCT level: 6 [IQR, 4–9]; P < .001), a greater proportion with diabetes (high PCT level: 9 of 60 [15%]; low PCT level: 1 of 65 [1.5%]; P = .007), and more participants who were dialysis-dependent (high PCT level: 6 of 60 [10%]; low PCT level: 0 of 65 [0%]; P = .01). Community-acquired bacteremia was also more frequent in the high PCT level group (45 of 60 [75%]) than the low PCT level group (33 of 65 [51%]) (P = .02). There were no significant differences between groups regarding sex, age, site of admission at time of enrollment, requirement for mechanical ventilation at baseline, source of bacteremia, or pathogens isolated (Table 1). Study participant and infection characteristics of BALANCE-PCT participants by BALANCE randomization arm are reported in the eTable in Supplement 1.
Table 1. Patient, Infection, and Pathogen Characteristics at Baseline Stratified by PCT Level on Day 7.
| Characteristic | No. (%) | P value | |
|---|---|---|---|
| PCT Level <250 pg/mL (n = 65) | PCT Level ≥250 pg/mL (n = 60) | ||
| Patient characteristics | |||
| Sex | |||
| Female | 25 (38.5) | 20 (33.3) | .68 |
| Male | 40 (61.5) | 40 (66.7) | |
| Age, median (IQR), y | 60 (46-71) | 66 (54-75) | .50 |
| SOFA score on day 0, median (IQR)a | 6 (4-9) | 9.5 (6-13) | <.001 |
| Enrollment location | |||
| ICU | 62 (95.4) | 58 (96.7) | .99 |
| Ward | 3 (4.6) | 2 (3.3) | .99 |
| Baseline rate of mechanical ventilation | 19 (29.2) | 21 (35) | .65 |
| Comorbidity | |||
| Diabetes | 1 (1.5) | 9 (15) | .007 |
| Solid organ cancer | 4 (6.2) | 7 (11.7) | .35 |
| Obesity | 11 (16.9) | 14 (23.3) | .50 |
| Arrhythmia | 9 (13.8) | 8 (13.3) | .99 |
| Corticosteroid use/immunosuppressionb | 2 (3.1) | 0 | .49 |
| Chronic obstructive pulmonary disease | 10 (15.4) | 10 (16.7) | .99 |
| Kidney insufficiency | 3 (4.6) | 9 (15.0) | .07 |
| Coronary artery disease | 4 (6.2) | 5 (8.3) | .74 |
| Congestive heart failure | 4 (6.2) | 6 (10.0) | .52 |
| Liver disease | 7 (10.8) | 6 (10.0) | .99 |
| Peripheral vascular disease | 3 (4.6) | 5 (8.3) | .48 |
| Dialysis dependency | 0 | 6 (10.0) | .01 |
| Leukemia or lymphoma | 0 | 1 (1.7) | .48 |
| Clinical frailty scale score, median (IQR) | 3 (2-4) | 3 (2-5) | |
| Any source control procedure | 28 (43.1) | 29 (48.3) | .68 |
| Infection characteristics | |||
| Acquisition of bacteremia | |||
| Community-onset | 33 (50.8) | 45 (75.0) | .02 |
| Hospital ward–acquired | 9 (13.8) | 6 (10.0) | |
| Hospital ICU–acquired | 23 (35.4) | 9 (15.0) | |
| Source of bacteremia | |||
| Urinary tract | 17 (26.2) | 17 (28) | .85 |
| Intra-abdominal/hepatobiliary | 11 (16.9) | 14 (23) | |
| Lung | 12 (18.5) | 13 (22) | |
| Vascular catheter related | 9 (13.8) | 4 (7) | |
| Skin and/or soft tissue | 3 (4.6) | 2 (3) | |
| Other | 1 (1.5) | 1 (2) | |
| Undefined/unknown | 12 (18.5) | 9 (15) | |
| Most commonly isolated pathogens in blood culturesc | |||
| Escherichia coli | 15 (23.1) | 24 (40) | .06 |
| Klebsiella spp | 14 (21.5) | 8 (13.3) | .33 |
| Enterococcus spp | 6 (9.2) | 7 (11.7) | .88 |
| Streptococcus pneumoniae | 2 (3) | 7 (11.7) | .09 |
| Enterobacter spp | 8 (12.3) | 1 (1.7) | .03 |
| Coagulase-negative Staphylococci | 5 (7.7) | 1 (1.7) | .21 |
| Pseudomonas spp | 4 (6.2) | 2 (3.3) | .68 |
| Proteus spp | 3 (4.6) | 2 (3.3) | .99 |
| Streptococcus agalactiae | 1 (1.5) | 1 (1.7) | .99 |
| Streptococcus pyogenes | 0 | 1 (1.7) | .48 |
| Type of organism | |||
| Monomicrobial, gram negative | 42 (64.6) | 36 (60.0) | .24 |
| Monomicrobial, gram positive | 11 (16.9) | 18 (30.0) | |
| Polymicrobial | 12 (18.5) | 6 (10.0) | |
Abbreviations: ICU, intensive care unit; PCT, procalcitonin; SOFA, sequential organ failure assessment.
Scores on the SOFA range from 0 to 24, with higher scores indicating more severe organ failure.
Immunosuppression included chemotherapy and prednisone or equivalent glucocorticoid use of more than 15 mg per day.
High PCT Level on Day 7 and Risk of 90-Day Mortality
Primary outcome results were available for the entire planned secondary analysis cohort. Death within 90 days of the positive index blood culture occurred in 4 participants with a low PCT level on day 7 (6.2%) and 13 participants with a high PCT level on day 7 (21.6%) (ARD, 15.5%; 95% CI, 3.6%-27.5%) (Table 2). A sensitivity analysis was performed with a PCT cut-off of 500 pg/mL. There were 82 participants with a PCT level equal or lower to the cut-off and 43 participants with a PCT level higher than this cut-off. Ninety-day mortality was more common among participants with a PCT level greater than 500 pg/mL (11 of 43 [25.6%]) vs a PCT level less than 500 pg/mL (6 of 82 [7.3%]) (ARD, 18.3%; 95% CI, 4.0%-32.6%). Patients receiving dialysis are known to have higher levels of circulating PCT, which was seen in the current study as well. As such, we performed a sensitivity analysis excluding patients receiving dialysis. Among study participants without kidney failure, a day 7 serum PCT level greater than 250 pg/mL was associated with an increased risk of 90-day mortality (ARD, 16.1%; 95% CI, 3.6%-29.2%).
Table 2. Outcomes of Primary and Secondary End Points Stratified by PCT Level on Day 7.
| End point | No. (%) | Difference (95% CI)a | |
|---|---|---|---|
| PCT Level <250 pg/mL (n = 65) | PCT Level ≥250 pg/mL (n = 60) | ||
| Primary | |||
| 90-d mortality | 4 (6.2) | 13 (22) | −15.5 (−27.5 to −3.6) |
| Secondary | |||
| Death in ICU | 2/62 (3.2) | 2/58 (3.5) | −0.2 (−6.7 to 6.2) |
| Death in hospital | 2 (3.1) | 13 (21.7) | −18.6 (−29.8 to −7.4) |
| ICU-free days by day 28, median (IQR) | 19 (12 to 23) | 18 (3 to 23) | 1.7 (−1.4 to 2.1) |
| Hospital-free days by day 28, median (IQR) | 5 (0 to 15) | 0 (0 to 15) | −1.2 (−0.3 to 1.4) |
| Antibiotic-free days by day 28, median (IQR) | 14 (9 to 20) | 12 (0 to 16) | 2.2 (−0.2 to 6.8) |
| Adherence to treatment duration assignment | |||
| Shorter than defined stop date | 3/65 (4.6) | 1/60 (1.7) | 2.9 (−3.1 to 9) |
| Longer than defined stop date | 14/65 (21.5) | 18/60 (30.0) | −8.5 (−23.8 to 6.8) |
Abbreviations: ICU, intensive care unit; PCT, procalcitonin.
Differences are expressed in percentage points as absolute risk differences or, for variables shown as medians, as median differences.
High PCT Level on Day 7 and Length of Antibiotic Course
Among the 60 participants with a high day 7 serum PCT level, 29 participants were in the 7-day treatment group and 33 participants were in the 14-day treatment group. A prolonged course of antimicrobial therapy was not associated with a reduced risk of 90-day mortality among participants with 7 vs 14 days of antibiotics (7 days: 3 of 29 [10.3%]; 14 days: 10 of 31 [32.3%]; ARD, −21.9%; 95% CI, −41.8 to −2.1) (Table 3). In the sensitivity analysis where a high day 7 serum PCT level was defined as greater than 500 pg/mL, there was no difference in 90-day mortality among participants receiving 7 days vs 14 days of antibiotics (ARD, −5.1%; 95% CI, −19.8% to 44.7%).
Table 3. Outcomes of Primary and Secondary End Points for Participants With PCT Level on Day 7 Greater Than 250 pg/mL Stratified by 7-Day or 14-Day Antibiotic Course.
| Outcome | Antibiotic course length, No. (%) | Difference | ||
|---|---|---|---|---|
| 7 d (n = 29) | 14 d (n = 33) | Absolute risk (95% C) | Median (IQR) | |
| 90-d mortality | 3 (10.3) | 10 (32.3) | −21.9 (−41.8 to −2.1) | NA |
| Death in ICU | 1/27 (3.7) | 1/31 (3.2) | 0.5 (−8.5 to 9.2) | NA |
| Death in hospital | 3 (10.3) | 7 (22.6) | −1.9 (−20.8 to 19.8) | NA |
| ICU-free days by day 28 | 20 (9 to 23) | 15 (0 to 22) | NA | 5.5 (−1.3 to 11.3) |
| Hospital-free days by day 28 | 7 (0 to 16) | 0 (0 to 15) | NA | 7.4 (−0.2 to 14.2) |
| Length of mechanical ventilation, d | 8 (6 to 16) | 9 (4 to 13) | NA | −1.6 (−5.8 to 3.8) |
Abbreviations: ICU, intensive care unit; NA, not applicable; PCT, procalcitonin.
Secondary Outcomes
Study participants with a low serum PCT level were less likely to die in hospital (ARD, −18.6%; 95% CI, −29.8 to −7.4). Death in ICU, ICU-free days by day 28, hospital-free days by day 28, antibiotic-free days by day 28, and physician adherence to assigned treatment duration were not significantly different between the high and low PCT level groups (Table 2). In the high PCT level subgroup, there was no difference in secondary outcomes between participants randomized to the 7-day vs 14-day treatment groups (Table 3).
Discussion
In this planned secondary analysis of the BALANCE trial, participants with an elevated day 7 serum PCT level were more likely to die within 90 days but did not receive any incremental mortality benefit from randomization to prolonged antibiotic treatment. In this study, we observed that patients with diabetes, higher baseline SOFA scores, and community-acquired bloodstream infections were more likely to have elevated serum PCT levels on day 7. This finding is consistent with a meta-analysis of 26 RCTs evaluating PCT-guided antibiotic duration in BSI, which reported that PCT levels were associated with illness severity.17 We also noted that while patients with elevated PCT level on day 7 had a higher risk of 90-day all-cause mortality, randomization to a longer course of antibiotics was not associated with improved outcomes in this group. Taken together, these observations suggest that circulating PCT may not directly reflect the burden of bacterial infection itself, but rather the intensity of the host’s inflammatory response. This is consistent with the known pathophysiology of PCT induction via host inflammatory pattern-recognition receptor ligation via bacterial antigen. This distinction is important as systemic inflammation, shaped by host factors such as immune dysregulation or comorbidities, may drive PCT elevations independently of bacterial antigen load, limiting its utility as a standalone guide for determining antibiotic duration.18
Numerous studies have investigated PCT-guided strategies to tailor antibiotic duration in patients with bacteremia.13,14,17,19 Among them, the PRORATA trial is notable for demonstrating the largest reduction in antibiotic use, achieving a mean decrease of 2.7 days in critically ill patients with sepsis.13 However, despite the use of biomarker-guided protocols, the median antibiotic duration for patients with BSI in PRORATA remained 11.6 days, longer than the 7-day fixed duration demonstrated to be safe in BALANCE. These findings support the notion that a standardized 7-day course may safely reduce antibiotic exposure in bacteremia without reliance on serial PCT measurements, offering a clinically effective alternative to biomarker-based approaches. Using a standardized fixed course of antibiotics may help support stewardship programs to safely reduce unnecessary antibiotic use without requiring biomarker measurement, thereby simplifying practice and reducing costs.
The 2024 ADAPT-Sepsis trial evaluated PCT-guided strategies to inform antibiotic discontinuation in patients with sepsis.14 The trial used a tiered stopping algorithm, using PCT level less than 500 pg/mL as a suggested threshold and PCT level less than 250 pg/mL as a strong recommendation to stop antibiotics. The intervention led to a 0.88-day reduction in total antibiotic duration compared with usual care. However, the PCT algorithm often triggered a strong stop suggestion at a median of just 3.5 days after the index positive blood culture, based on reaching the less than 250 pg/mL threshold. This finding raises the possibility of whether patients with bloodstream infections could be safely managed with even shorter durations of antibiotic therapy.
Limitations
We acknowledge certain limitations to this study. First, serum was only collected in a small subset of BALANCE patients from selected sites. Given this, our secondary analysis has limited statistical power. Furthermore, most included sites were high-income countries, and therefore these results may not be generalizable to other countries. This planned secondary analysis only collected serum at day 7 of study enrollment; thus we were not able to assess relative changes in serum PCT level. Additionally, the BALANCE trial excluded patients with Staphylococcus aureus and Staphylococcus lugdenensis BSIs, so these findings will not be generalizable to patients with infections involving these pathogens.
Conclusions
In this planned secondary analysis of the initial BALANCE trial of 125 patients, a high day 7 serum PCT level was associated with an increased risk of 90-day all-cause mortality. However, patients with a high day 7 serum PCT level did not benefit from a prolonged course of antibiotic therapy. This latter finding suggests that a fixed treatment duration of 7 days is a safe course, independent of serum PCT levels for most patients. PCT measurement is not required, for most patients, to motivate discontinuation of antibiotic treatment at 7 days, but perhaps future studies could investigate whether this biomarker could contribute to identifying patients that could benefit from even shorter courses of antibiotics.
eFigure. Distribution of Procalcitonin (PCT) Concentration in Plasma at Day 7 of BALANCE trial
eTable. Patient, Infection and Pathogen Characteristics at Baseline Among Participants With High Day 7 PCT Stratified Based on Randomization to 7-Day vs 14-Day of Antibiotics
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eFigure. Distribution of Procalcitonin (PCT) Concentration in Plasma at Day 7 of BALANCE trial
eTable. Patient, Infection and Pathogen Characteristics at Baseline Among Participants With High Day 7 PCT Stratified Based on Randomization to 7-Day vs 14-Day of Antibiotics
Data Sharing Statement
