Abstract
Background:
The utility of procalcitonin testing in the pediatric intensive care unit (PICU) is not known. We sought to determine the impact of a procalcitonin-guided antibiotic treatment algorithm implemented with antibiotic stewardship (AS) guidance vs. usual care on antibiotic use in critically ill children.
Methods:
Single center, pragmatic, randomized prospective clinical trial of critically ill children admitted to an ICU setting and started on intravenous antibiotics from February 15, 2018 to April 11, 2019.
Patients were assigned on a monthly basis to either the procalcitonin or usual care arm. The procalcitonin arm had procalcitonin testing on hospital days 0, 1, 2 and 4 and stewardship assistance with algorithm result interpretation. Both arms had routine AS audit and feedback.
The primary outcome was median antibiotic days of therapy per patient in the first 14-days after enrollment.
Results:
Among 270 patients, 137 were in the procalcitonin arm and 133 in the usual care arm. Antibiotic days of therapy (DOT) were not significantly different between the procalcitonin arm (6.6, IQR 3.1, 10.9) and the usual care arm (7.6, IQR 3, 11.8), (p = 0.37). More AS recommendations were made in the procalcitonin vs. control arm (54 vs. 37, p=0.03). Adherence with algorithm-based antibiotic recommendations was high in the procalcitonin arm (70%).
Conclusions:
We found no difference in antibiotic DOT between study arms. This trial was underpowered but demonstrates feasibility of using a procalcitonin-guided antibiotic treatment algorithm with AS audit and feedback in the PICU.
Keywords: Procalcitonin, Pediatric, Antibiotics, Antibiotic Stewardship, Pediatric Intensive Care
Introduction
Procalcitonin (PCT), a biomarker that can predict bacterial infections, has been best studied in critically ill patients with pneumonia and sepsis.1-6 Studies have demonstrated that PCT-guided algorithms for antibiotic cessation result in significantly shorter antibiotic courses, with no increase in adverse clinical outcomes in the treatment of adults with pneumonia and sepsis, in children with pneumonia, and in neonates with sepsis.1-9 However, a limitation of many of these trials is that a high proportion of providers (up to 64%) chose not to follow algorithm guidance for subjects randomized to the PCT-guided arm.1,2,4,10 A recently published retrospective analysis of PCT use in the pediatric ICU (PICU) without accompanying algorithm guidance or stewardship intervention found no change in antibiotic use before or after introduction of PCT testing.11
Thus, although PCT appears to be a useful guide for safe antibiotic de-escalation in the adult ICU, the ideal method for implementing the test and integrating it into pediatric critical care is unclear. Notably, none of the prior clinical trials evaluated integration of PCT testing into antimicrobial stewardship audit and feedback activities. For these reasons, we conducted a pragmatic clinical trial to assess whether a PCT-guided antibiotic treatment algorithm with the addition of antimicrobial stewardship guidance for result interpretation would decrease antibiotic use as compared to usual care. Additionally, we evaluated the impact of the algorithm on antimicrobial stewardship recommendation volume and acceptance.
Materials and Methods
Study Participants
Any patient older than 7 days admitted to the medical/surgical or cardiac PICU at Vanderbilt Children’s Hospital in Nashville, TN, USA between February 15, 2018 and April 11, 2019 was eligible for inclusion if they had been started on antibiotics within one calendar day of enrollment. Patients were ineligible if they had received intravenous (IV) antibiotics for any indication other than surgical prophylaxis within the prior 7 days, had a history of primary or secondary immune deficiency (including history of malignancy, bone marrow transplant or solid organ transplant), were neonates <34 weeks’ gestation, or were receiving antibiotics for an infection requiring prolonged antibiotic therapy, such as endocarditis, mediastinitis or osteomyelitis. Short-term corticosteroid use was not considered a secondary immune deficiency and patients receiving steroids were eligible for study inclusion. The PICU census was screened daily for patients with new antibiotic initiation. Participants were eligible to participate in the study more than once provided that at least 7 days had passed since completing their prior antibiotic course. The study followed the Consolidated Standards of Reporting Trials (CONSORT) guideline.12 All enrolled patients who met inclusion criteria for the entirety of the study period were included in the modified intention-to-treat (mITT) population. We also included a modified per-protocol population, restricted to patients in the PCT arm who had at least 1 PCT level drawn.
The study was approved by the Vanderbilt University Institutional Review Board and written informed parental consent and child assent (where appropriate) were obtained prior to study enrollment. Participants were then assigned on a monthly basis to either the PCT-testing arm or the usual care arm (see Figure, Supplemental Digital Content 1). The first trial month was randomly chosen to be a usual care month. Treatment assignments then alternated each month between PCT testing and usual care for a total of 14 months. Block randomization by month was chosen in an effort to reduce contamination between arms, as PCT was not orderable during usual care months. If a patient’s PICU stay bridged the end of an enrollment period, they did not cross over into the new group. If a patient were hospitalized for a prolonged period and re-enrolled in the study, their new treatment group was assigned based on their new enrollment month.
Study Intervention
Patients in the usual care arm received provider-directed laboratory testing and therapy and baseline antimicrobial stewardship. Antimicrobial stewardship in the usual care arm consisted of audit and in-person feedback (i.e. handshake stewardship)13 from 9am-5pm Monday - Friday. Midway through the study, the protocol was modified to enable PCT testing at enrollment for subjects in the usual care arm in order to compare baseline PCT levels between arms for post hoc analysis. Usual care PCT samples were processed and stored frozen until study completion, at which time PCT testing was performed but not reported in the medical record.
Patients in the PCT arm received PCT testing on days 0, 1, 2 and 4 after enrollment. PCT results were reported in the medical record within 3 hours of sample collection. Throughout the duration of the study, PCT was only orderable through the research study and was not otherwise available for clinical use at our institution. The patient’s bedside nurse was responsible for obtaining the PCT sample, and they were aware that the sample was for a research study. An antimicrobial stewardship provider followed up on all PCT test results and offered PICU providers guidance about interpretation based on the algorithm, 24 hours/day, 7 days per week. De-escalation of antibiotics (defined as stopping one or more antibiotics, narrowing spectrum of antibiotic coverage or converting from intravenous to oral antibiotics) was recommended if the PCT level fell by 80% or more of the peak PCT level, or when the PCT level was less than 0.5 μg/L. Continuation or escalation (broadening spectrum) of antibiotics was recommended if the PCT level was greater than or equal to 0.5 μg/L or increased as compared to previous peak PCT level (see figure, Supplemental Digital Content 2, Procalcitonin-based Treatment Algorithm). Serum samples for PCT testing were collected in gel separator tubes and PCT testing was performed using Roche Elecsys® BRAHMS PCT reagent on a cobas e411 immunoassay analyzer, with an analytic range of 0.06 to 100 μg/L.
The decision to adhere to the PCT algorithm or stewardship recommendation was at the discretion of the PICU provider. Prior to study initiation, the antimicrobial stewardship team performed targeted education to PICU providers (attending physicians, fellows, and nurse practitioners) about the potential benefits and limitations of PCT use. The PCT-based algorithm was disseminated to PICU providers and displayed in PICU workrooms. If an antibiotic stewardship recommendation was not followed, study personnel queried the treating clinician regarding the reason for nonadherence.
Study Outcomes
The primary outcome was antibiotic days of therapy (DOT) per patient in the first 14 days following randomization. Days of therapy (DOT) per patient was defined as the sum of individual intravenous and oral antibiotics received on each calendar day (i.e. if a patient was on 2 antibiotics for 3 days each, their antibiotic DOT would be 6 days).
Secondary outcomes included length of antibiotic therapy (LOT) per patient in the first 14 days following randomization (defined as the time from enrollment to the time that the intravenous or oral antibiotic order was stopped; i.e. if a patient was on 2 antibiotics for 3 days each, their antibiotic LOT would be 3 days). DOT per patient of broad-spectrum antibiotic therapy (defined as vancomycin, daptomycin, amikacin, ceftazidime, cefepime, piperacillin/tazobactam, aztreonam, or carbapenems) in the first 14 days following randomization and median time from randomization to first antibiotic modification (escalation or de-escalation) in the first 14 days following randomization.
Clinical outcomes included 30-day mortality, length of ICU stay, and overall hospital stay within 30-days post randomization. Additional clinical and post hoc exploratory outcomes are listed in the Supplemental Digital Content 3 (Methods).
Statistical Analysis
We estimated that a sample size of at least 128 patients per arm would provide at least 90% power to detect a difference in antibiotic use of at least 1 day between study arms, with a two-sided Type 1 error rate of 0.05, assuming a median LOT of 3 days of antibiotics (IQR 2 to 5 days) in the usual care arm, based on retrospective review of median antibiotic LOT among patients admitted to the PICU in the year prior to study initiation.
We analyzed all data according to a mITT principle and compared the median antibiotic DOT per patient between arms using a Wilcoxon rank sum test. For all other analyses, Wilcoxon rank sum test was used to compare continuous variables and Pearson’s chi-squared test was used to compare categorical variables. We used a Kaplan-Meier estimate to evaluate time to antibiotic change within 14 days of enrollment. In a modified per-protocol analysis, we evaluated the primary outcome restricted to patients in the PCT arm who had at least 1 PCT level drawn.
We performed a post-hoc analysis using a multivariable ordinal logistic regression model to assess the association between randomization arm and the overall antibiotic DOT per patient, adjusting for the following variables at the time of enrollment: sex, recent surgical procedure, antibiotic indication of possible sepsis, fever, vasopressor support and need for mechanical ventilation. We relied on treating provider documentation in the electronic medical record to determine indication for antibiotics. If this was not clear from documentation, then the antimicrobial stewardship team discussed indication with the treating team. We also used a Cox proportional hazards model adjusting for location of enrollment (medical/surgical vs. cardiac PICU) and study day to evaluate the hazard ratio for time to cessation of antibiotics within 4-days of enrollment.
Statistical analyses were conducted using R version 3.5.2 (Boston, MA) and Stata/IC version 15.1 for Mac (College Station, TX). P-values <0.05 were considered statistically significant.
Results
Patients
Among 528 eligible participants, 271 provided consent and underwent randomization; 1 patient underwent a heart transplant on day 3 of study protocol and was excluded from further analysis, leaving a mITT analysis cohort of 270 patients (137 in the PCT arm and 133 in the usual care arm) (see Figure, Supplemental Digital Content 1). Patients who did not consent to study inclusion were younger than those who did consent (median age 9 months [interquartile range, IQR, 6, 66] vs. 23.2 months [IQR 5.7, 104.7] (see Table, Supplemental Digital Content 4, Characteristics of Patients Who Did Not Provide Consent). Although there were more male patients in the PCT arm than the usual care arm (58% vs. 45%, p=0.03), other baseline characteristics were similar between arms (see Table, Supplemental Digital Content 5). In the PCT arm, all 4 PCT levels were drawn in 52 (38%) patients, at least one PCT level was drawn in 122 (89%) patients and 0 PCT levels were drawn in 15 (11%) patients (see table, Supplemental Digital Content 6. Count of Procalcitonin Measurements and Duration of Antibiotic Therapy among Patients in Procalcitonin-Arm (n=137). The majority of the patients (223, 82.6%) were admitted to the medical/surgical PICU (see Table, Supplemental Digital Content 5).
Impact on Antibiotic Use
Median antibiotic DOT per patient in the first 14-days after enrollment was similar between the PCT and usual care arms in the mITT analysis (6.6 days [IQR 3.1, 10.9] and 7.6 days [IQR 3.0, 11.8]) (p = 0.37) (Table 1). Median antibiotic LOT per patient in the first 14-days after enrollment was also similar between the PCT and usual care arms in the mITT analysis (5.92 days [IQR 1.59, 9.51] and 6.91 days [IQR 1.6, 10.5]) (p=0.29). Results were also similar in the modified per protocol analysis. There was additionally no difference in median IV antibiotic DOT per patient, the number of patients on any antibiotic for greater than 72 hours, and the number of patients on broad-spectrum antibiotics for longer than 72 hours between arms (Table 1). Time to first antibiotic escalation or de-escalation did not differ between the arms (see Figure, Supplemental Digital Content 7, Kaplan-Meier Plot for Probability of Antibiotic Change from Enrollment to Day 14, in the Modified Intention-to-treat Population). Likelihood of having antibiotics stopped within 4-days of enrollment was also similar between arms (Cox proportional hazard ratio [95% CI] 1.18 [0.8, 1.72], p=0.4). There was additionally no difference in antibiotic use in subgroup analyses (Table 1).
Table 1.
Antibiotic Use and Clinical Outcomes by Study Arm
| Procalcitonin (n=137) |
Usual Care (n=133) |
p -value |
|
|---|---|---|---|
| Antibiotic days of therapy (DOT) (median, IQR) | |||
| Intravenous (IV) and oral antibiotic DOT | 6.62 (3.07,10.93) | 7.63 (3.01, 11.84) | 0.37 |
| IV antibiotic DOT | 3.43 (1.54, 6.1) | 2.73 (1.16, 6.82) | 0.45 |
| Broad-spectrum DOTa | 0.09 (0, 2.60) | 0 (0, 1.75) | 0.13 |
| Antibiotic length of therapy (LOT) (median, IQR_) | 5.92 (1.59, 9.51) | 6.91 (1.6, 10.5) | 0.29 |
| Antibiotic LOT > 72 hours (n, %) | |||
| Any antibiotic | 84 (61.31) | 86 (64.66) | 0.57 |
| IV antibiotics | 51 (37.23) | 43 (32.33) | 0.4 |
| Broad-spectrum antibiotics | 21 (15.33) | 17 (12.78) | 0.55 |
| Patients on 2 or more antibiotics at timepoint (n, %) | |||
| 24 h after enrollment | 71 (51.82) | 58 (43.61) | 0.18 |
| 48 h after enrollment | 41 (29.93) | 30 (22.56) | 0.17 |
| 72 h after enrollment | 25 (18.25) | 21 (15.79) | 0.59 |
| 96 h after enrollment | 12 (8.76) | 9 (6.77) | 0.54 |
| Patients with antibiotics escalated (n, %) | 3 (2.19) | 5 (3.76) | 0.45 |
| Patients with antibiotics de-escalated (n, %) | 56 (40.88) | 62 (45.26) | 0.34 |
| Antibiotic DOT among subgroups (median, IQR) (n) | |||
| Antibiotics initiated for possible sepsisb | 5.48 (2.02, 11.24) (64) | 6.74 (2.21, 11.28) (51) | 0.95 |
| Final diagnosis of pneumonia | 8.34 (5.90, 11.26) (41) | 9.28 (7.58, 13.63) (44) | 0.08 |
| Initial PCT level <0.5 μg/L | 4.05 (1.8, 7.94) (44) | 6.97 (2.39, 9.98) (26) | 0.27 |
| Initial PCT level ≥0.5 μg/L | 7.86 (5.02, 13.79) (67) | 9.54 (4.46, 14.5) (36) | 0.26 |
| No comorbidities | 5.35 (1.65, 10.72) (49) | 4.5 (2.03, 9.56) (40) | 0.98 |
| Subjects admitted to the medical / surgical PICU | 6.66 (2.1, 10.76) (112) | 7.63 (2.59, 12.5) (111) | 0.18 |
| Clinical outcomes | |||
| Hospital length of stay (days) (median, IQR) | 6 (4, 14) | 7 (3, 12) | 0.38 |
| ICU length of stay (days) (median, IQR) | 2 (1, 6) | 2 (1, 5) | 0.49 |
| Death within 30 days of enrollment (n, %) | 3 (2.19) | 4 (3.01) | 0.67 |
| Antibiotic complication (n, %)c | 2 (1.46) | 3 (2.26) | 0.63 |
| Infection with a multi-drug resistant organism (n, %)d | 2 (1.46) | 1 (0.75) | 0.61 |
| Hospital re-admission within 30 days (n, %) | 14 (10.21) | 11 (8.27) | 0.69 |
Broad-spectrum antibiotics were defined as vancomycin, daptomycin, amikacin, ceftazidime, cefepime, piperacillin/tazobactam, aztreonam, or carbapenems
Possible sepsis was defined as clinician concern for sepsis due to hypotension, hypoxemia, persistent tachycardia or poor extremity perfusion
Antibiotic complication was defined as rash, neutropenia, thrombocytopenia, acute kidney injury or hepatotoxicity attributed to antibiotic use
Multi-drug resistant organism was defined as methicillin-resistant S. aureus, vancomycin-resistant Enterococcus, 3rd generation cephalosporin non-susceptible Enterobacteriaceae, multi-drug resistant Pseudomonas aeruginosa, or Candida species obtained from otherwise sterile sites
Results of the post-hoc ordinal logistic regression analysis are shown in Table 2. After adjusting for the following covariates at the time of enrollment: fever, need for vasopressor support, mechanical ventilation, sex, recent surgical procedure and antibiotic indication of sepsis, study arm was not significantly associated with longer DOT per patient. Variables that were significantly associated with longer antibiotic DOT included fever on day of enrollment (odds ratio [OR] 1.8 [95% CI 1.17, 2.77], p = 0.007) and need for vasopressor support at enrollment (OR 2.32 [95% CI 1.28, 4.2], p=0.006). Antibiotic indication of possible sepsis was significantly associated with a shorter antibiotic DOT (OR 0.54 [95% CI 0.33, 0.87], p = 0.011).
Table 2.
Ordinal Logistic Regression to Assess Association between Randomization Group and Intravenous or Oral Antibiotic Days of Therapy per Patient
| Odds Ratio (95% Confidence Interval) | p-value | |
|---|---|---|
| Fever on day of enrollment | 1.8 (1.17, 2.77) | 0.01 |
| Vasopressor support on day of enrollment | 2.32 (1.28, 4.2) | 0.01 |
| Need for mechanical ventilation on day of enrollment | 0.67 (0.43, 1.07) | 0.10 |
| Usual Care arm | 1.18 (0.77, 1.81) | 0.45 |
| Female sex | 1.07 (0.7, 1.64) | 0.75 |
| Surgical procedure within 2 weeks of enrollment | 0.85 (0.49, 1.48) | 0.57 |
| Antibiotic indication - possible sepsis | 0.54 (0.33, 0.87) | 0.01 |
Model included randomization arm, sex, surgical procedure within 2 weeks prior to enrollment, antibiotic indication of possible sepsis, and presence of fever, vasopressor support or mechanical ventilation at enrollment
Although we did not power the study to assess clinical outcomes, there were no statistically significant differences in clinical outcomes between the arms (Table 1).
Impact on Antimicrobial Stewardship
A total of 54 stewardship recommendations to modify antibiotic therapy were made for 53 (39%) patients in the PCT arm and 37 recommendations for 35 (26%) patients in the usual care arm (p=0.03, Table 3). Stewardship recommendations were made to 14 of the 18 total PICU physicians during the study period (see Table, Supplemental Digital Content 8, Attending Physician Adherence with Stewardship Recommendations). The proportion of recommendations for antibiotic de-escalation was higher in the PCT arm than the usual care arm. There were 51 of 54 (94%) recommendations in the PCT arm vs. 27 of 37 (73%) recommendations in the usual care arm (p = 0.002) (Table 3). Among the subgroup of patients with initial PCT levels <0.5 μg/L, significantly more stewardship recommendations were made within 48-hours of enrollment. In the PCT arm there were 22 recommendations among 44 patients (63.6%) vs. 14 recommendations among 26 patients (19.2%) in the usual care arm (p <0.001) (see Table, Supplemental Digital Content 9, Number of Stewardship Recommendations among Patient Subgroups). When comparing patients with PCT < 0.5 μg/L to those with PCT level ≥ 0.5 μg/L at enrollment, total DOT, broad-spectrum DOT and IV DOT were significantly shorter in the low PCT group compared to the high PCT group (see Table, Supplemental Digital Content 10, Antibiotic Use by Procalcitonin Level at Enrollment among Subjects in Both Study Arms, Regardless of Randomization Arm).
Table 3.
Antimicrobial Stewardship Recommendations by Treatment Arm
| Procalcitonin (n=54) |
Usual Care (n=37) |
p-value | |
|---|---|---|---|
| Number of stewardship recommendations (n, %) | |||
| De-escalate therapya | 51 (94.44) | 27 (72.97) | <0.01 |
| Stop one or more antibiotics | 35 (64.81) | 13 (35.14) | <0.01 |
| Narrow spectrum of therapy | 14 (25.93) | 14 (37.84) | 0.18 |
| Escalate therapy | 1 (1.85) | 3 (8.11) | 0.14 |
| Optimize dose | 2 (3.7) | 5 (13.51) | 0.08 |
| Consult infectious diseases service | 0 | 1 (2.7) | 0.22 |
| De-label beta-lactam allergy | 0 | 1 (2.7) | 0.22 |
| Number of stewardship recommendations accepted (n, %) | 37 (68.52) | 25 (67.57) | 0.87 |
| Reason recommendation was not accepted | |||
| Provider discretionb | 14 (25.93) | 5 (13.51) | 0.04 |
| Patient medication allergies | 1 (1.85) | 0 | 0.03 |
| Waiting for culture results | 1 (1.85) | 2 (5.41) | 0.54 |
| Unknown | 1 (1.85) | 4 (10.81) | 0.31 |
Antibiotic de-escalation was defined as stopping one or more antibiotics, narrowing spectrum of antibiotic coverage or converting from intravenous to oral antibiotics.
Provider discretion was defined as provider either did not believe the PCT result could reliably predict bacterial infection or considered a patient too sick to de-escalate antibiotic therapy.
Results were similar for the modified per-protocol analysis and the mITT analysis.
Discussion
This pragmatic clinical trial among children admitted to the PICU demonstrated feasibility of using a PCT-guided antibiotic treatment algorithm with stewardship guidance in critically ill children. However, procalcitonin testing implemented with stewardship guidance had no statistically significant impact on antibiotic duration between study arms.
Several possible reasons could explain why we observed no difference in antibiotic use between the study arms. Antibiotic DOT in the usual care arm was shorter than those reported in many adult ICU studies1,2,4,15,16 possibly due to use of shorter antibiotic courses in recent years, and/or a robust antibiotic stewardship program in our hospital. Although PCT led to more stewardship recommendations, there remained very high uptake of recommendations in both treatment groups. There may also have been carryover effects from the PCT months to the usual care months, leading clinicians to shorten antibiotic duration in the usual care arm more than they would have prior to the study. Additionally, there was greater variation in antibiotic LOT across participants compared to the retrospective data we used for our power calculation, which led our study to be underpowered. Using a Wilcoxon rank sum test, we re-calculated a power analysis using the actual antibiotic length of therapy we observed in our study, which indicated that we would have needed 762 participants per group to be able to detect a true difference of 1 day between groups with 80% power. Although not significant, there was also an imbalance between study arms, with the PCT arm having a higher proportion of patients with fever, requiring vasopressor support at enrollment, and requiring mechanical ventilation, potentially contributing to longer treatment durations in the PCT arm.
Notably, our study was the first to use antimicrobial stewardship guidance, provided through in-person feedback, to aid with PCT result interpretation, which led to high (70%) adherence to the PCT algorithm. This is higher than algorithm adherence observed in previous studies among adult ICU patients, which ranged from 44-50%.1,2,14 The usual care arm also had high (71%) acceptance rates of antibiotic stewardship recommendations. The PCT arm had more antibiotic stewardship recommendations compared to the usual care arm, highlighting that objective laboratory evidence can facilitate stewardship recommendations.
Significantly more stewardship recommendations were made within 48-hours of enrollment in the PCT arm (63.6%) than the usual care arm (19.2%) among patients with an initial PCT level <0.5 μg/L, and rates of recommendation adherence were similar for both groups. When evaluating only those patients with low PCT levels on enrollment, there was a clinically significant 2.9-day reduction in therapy for patients in the PCT arm compared to the usual care arm. These findings were similar to the OASIS II Study in which investigators found the biggest impact among a subgroup of patients with low biomarker levels at onset of systemic inflammatory response syndrome (SIRS).17 In many of our subgroup analyses, including patients with pneumonia and possible sepsis, we found shorter DOT in the PCT vs. usual care arm, but these were not statistically significant differences, likely due to small sample sizes.
Our study had several limitations. Only 50% of eligible patients provided consent, and only 38% of patients in the PCT arm had all 4 PCT levels drawn according to study protocol. The low percent of patients with PCT levels drawn according to study protocol hinders our ability to draw meaningful conclusions about impact of PCT on antibiotic use in the PICU, but also reflects real-world ordering of PCT levels where providers rarely follow scripted protocols. One possible reason that protocol adherence was so low is that clinical nursing staff responsible for the PCT draws were aware that the order was for a research study and not for clinical care and thus may have chosen not to obtain the lab. Because PCT was not clinically available at our institution at the time of the study, the first PCT level was drawn after informed consent was obtained, which often happened 24 hours after antibiotic initiation, so we were unable to evaluate the impact of the PCT algorithm on antibiotic initiation rates. Also, because PCT was not available for routine clinical care at our medical center, providers were not familiar with test performance characteristics, and results may not be generalizable to other institutions where PCT is routinely used. Antibiotic stewardship guidance was available for the PCT arm 24 hours/day, 7 days per week, but stewardship guidance was only available for patients in the usual care arm from 9 AM – 5 PM Monday through Friday, which is a potential source of observer bias.
Despite these limitations, our results inform how a program could operationalize PCT into their workflow, if desired. Clinicians should consider difficulty in obtaining multiple serial blood draws in children, and timing of PCT testing (prior to or after antibiotic initiation) during pragmatic implementation. Lack of provider familiarity with PCT testing may have reduced adherence to the testing and treatment algorithm, suggesting that intensive clinician education prior to implementation of a new test is essential. Algorithm adherence was high with antibiotic stewardship guidance, highlighting the importance of incorporating stewardship into test implementation strategies. Antibiotic use described in the usual care arm of this study can be used to guide power calculations of future interventional studies. Future trials should factor in the lower than expected consent rate in the PICU and should involve qualitative research investigating reasons for provider adherence or non-adherence to PCT-guided treatment algorithms.
Conclusions
In conclusion, we found no difference in antibiotic DOT with PCT implementation combined with antimicrobial stewardship guidance. While this study was underpowered to detect statistically significant differences in antibiotic exposure between the arms, it demonstrates that implementing a PCT testing and treatment algorithm combined with antimicrobial stewardship guidance is feasible and can increase stewardship recommendations for antibiotic de-escalation.
Supplementary Material
Supplemental Digital Content 1. Screening and Randomization Abbreviations: PCT = procalcitonin [figure]
Supplemental Digital Content 2. Procalcitonin-based Treatment Algorithm [figure]
Supplemental Digital Content 3. Further describes Study Design and Study Outcomes, including additional clinical outcomes and post-hoc exploratory outcomes. [text]
Supplemental Digital Content 4. Characteristics of Patients Who Did Not Provide Consent [table]
Supplemental Digital Content 5. Baseline Characteristics by Study Arm [table]
Supplemental Digital Content 6. Count of Procalcitonin Measurements and Duration of Antibiotic Therapy among Patients in Procalcitonin-Arm (n=137) [table]
Supplemental Digital Content 7. Kaplan-Meier Plot for Probability of Antibiotic Change from Enrollment to Day 14, in the Modified Intention-to-treat Population [figure]
Supplemental Digital Content 8. Attending Physician Adherence with Stewardship Recommendations [table]
Supplemental Digital Content 9. Number of Stewardship Recommendations among Patient Subgroups [table]
Supplemental Digital Content 10. Antibiotic Use by Procalcitonin Level at Enrollment [table]
Acknowledgments
The authors thank Dr. Kathryn Edwards and Dr. Wesley Self for their critical review and input during article preparation, and Dr. Andras Szeles for assistance with enrollment of participants.
Sources of Support: This work was supported by an investigator-initiated research agreement through Roche and by the National Institute of Allergy and Infectious Diseases Childhood Infection Research Program (ChIRP), National Institute of Health. This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Drs. Katz and Banerjee report receiving grants from bioMérieux and Roche. We are grateful to Roche for providing PCT test kits and reagents. The company was not involved in study design, conduct, data analysis, manuscript preparation or publication.
Footnotes
Trial Registration: ClinicalTrials.gov identifier: NCT03440918
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Associated Data
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Supplementary Materials
Supplemental Digital Content 1. Screening and Randomization Abbreviations: PCT = procalcitonin [figure]
Supplemental Digital Content 2. Procalcitonin-based Treatment Algorithm [figure]
Supplemental Digital Content 3. Further describes Study Design and Study Outcomes, including additional clinical outcomes and post-hoc exploratory outcomes. [text]
Supplemental Digital Content 4. Characteristics of Patients Who Did Not Provide Consent [table]
Supplemental Digital Content 5. Baseline Characteristics by Study Arm [table]
Supplemental Digital Content 6. Count of Procalcitonin Measurements and Duration of Antibiotic Therapy among Patients in Procalcitonin-Arm (n=137) [table]
Supplemental Digital Content 7. Kaplan-Meier Plot for Probability of Antibiotic Change from Enrollment to Day 14, in the Modified Intention-to-treat Population [figure]
Supplemental Digital Content 8. Attending Physician Adherence with Stewardship Recommendations [table]
Supplemental Digital Content 9. Number of Stewardship Recommendations among Patient Subgroups [table]
Supplemental Digital Content 10. Antibiotic Use by Procalcitonin Level at Enrollment [table]