Prospective, Randomized Controlled Trial to Evaluate the Impact of a Procalcitonin Testing and Treatment Algorithm on Antibiotic Use and Outcomes in the Pediatric Intensive Care Unit
Phase: NA
Conditions: Sepsis, Procalcitonin, Antimicrobial Stewardship
Sponsor: Vanderbilt University Medical Center

 
 
Protocol Version # 9: 
 
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Prospective, Randomized Controlled Trial to 
Evaluate the Impact of a Procalcitonin Testing 
and Treatment Algorithm on Antibiotic Use and 
Outcomes in the Pediatric Intensive Care Unit 
 
 
Ritu Banerjee, MD, PhD, Associate Professor 
Division of Infectious Diseases 
D-7235 Medical Center North 
1161 21st Avenue South 
Nashville, TN 37232-2250 
 
Sub-Investigator: Sophie Katz, MD, Clinical Fellow 
Department of Pediatrics 
Division of Infectious Diseases 
Vanderbilt University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table of Contents: 

 
 
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Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 Statistical Considerations 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 
 
Appendices 
Appendix A Figure 1 – Procalcitonin-Guided Algorithm 
Appendix B   References 

 
 
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1.0 
Background 
 
The timely use of effective antibiotics can markedly reduce the morbidity and mortality 
associated with bacterial infections, particularly in the intensive care unit (ICU).  However, 
in this setting, much antibiotic use is empiric, and administered to patients with non-
bacterial or non-infectious causes of inflammation that do not respond to antibiotics. This 
widespread empiric use of antibiotics drives the emergence of multi-drug resistant 
organisms and antibiotic-associated adverse events, such as C. difficile infections.  De-
escalation of broad-spectrum empiric antibiotics for ICU patients without proven bacterial 
infections can reduce unnecessary antibiotic use, slow the development of antibiotic 
resistance, and reduce complications associated with antibiotic therapy.  Thus, antibiotic 
de-escalation is an important goal of antimicrobial stewardship programs. Specific tests 
and pathways to predict which patients have bacterial infections and those that would 
benefit from antibiotic therapy would accelerate de-escalation and greatly facilitate 
antimicrobial stewardship efforts. 
 
Procalcitonin (PCT) has been investigated as a biomarker for critically ill adult patients 
with bacterial infection, particularly pneumonia and sepsis.  Following bacteria-induced 
activation of monocytes and adherence of monocytes to endothelial surfaces, procalcitonin 
is expressed and secreted. PCT levels have been shown to rise rapidly and remain elevated 
during ongoing bacterial infections, and PCT levels are more specific for bacterial 
infections than CRP or total white blood cell count.  PCT rises approximately 4 hours after 
bacterial exposure, peaks between 12-24 hours, and has a half-life of 24 hours once the 
infectious stimulus is removed.   
 
2.0 
Rationale and Specific Aims 
 
In many adult trials investigating PCT-guided algorithms for antibiotic cessation (refer to 
section 3.0), a high proportion of providers (up to 50%) chose not to follow algorithm 
guidance for subjects randomized to the PCT-guided group.  Thus, although PCT appears 
to be a useful guide for safe antibiotic de-escalation in the ICU, the ideal method for 
implementing the test and integrating it into clinical care in order to maximize its impact 
in the pediatric population is unclear.  Notably, none of the prior trials evaluated PCT-
associated outcomes in critically ill children nor integrated PCT testing into antimicrobial 
stewardship activities. 
 
PCT will be available for routine clinical care across all hospitals at VUMC in July 2017. To 
better understand the role of PCT in patient management, we will complete a pilot study 
prior to routine use of PCT in clinical care in the pediatric ICU.  We propose the evaluation 
of a PCT testing and treatment algorithm on patient outcomes in the pediatric ICU, a 
setting in which PCT-guided antibiotic de-escalation has not been previously studied.  
 
The proposed project will evaluate whether a procalcitonin (PCT) testing and treatment 
algorithm, implemented through daily antimicrobial stewardship audit and feedback, can 
promote early and safe antibiotic de-escalation in the pediatric ICU.  We will conduct a 
pragmatic, prospective randomized controlled trial comparing antimicrobial use and 
outcomes among children admitted to the ICU who receive either: 1) Routine laboratory 
testing and treatment with antimicrobial stewardship review (control), or 2) PCT testing 

 
 
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and treatment with antimicrobial stewardship review (intervention).  In both arms, 
baseline daily review of antimicrobial management by the stewardship team will occur.  In 
the intervention arm, the stewardship provider (S.K.) also will recommend PCT testing 
and antibiotic modifications using a PCT-based treatment algorithm (Fig 1). This research 
is not to determine if PCT is a good test; this has already been established and evaluated 
as part of the FDA approval process. This pragmatic outcomes trial is evaluating if use of 
the PCT, implemented together with antimicrobial stewardship program oversight, 
improves the quality of care we can provide for children at VCH.  We hypothesize that 
patients in the intervention arm will have shorter duration of antibiotic therapy and similar 
outcomes, as compared to patients in the control arm. 
 
Specific Aims 
1. Compare antimicrobial utilization among children in the ICU who 
receive standard-of-care testing plus stewardship vs. PCT-based 
treatment plus stewardship. We will compare days of antibiotic therapy 
in the first 14 days following randomization between the study arms.  We 
will test the hypothesis that duration of antibiotic therapy will be 2 days 
shorter in the group with PCT-guided management vs. the group with 
standard of care testing and treatment. 
2. Compare clinical outcomes and safety among children in the ICU 
who receive standard-of-care testing plus stewardship vs. PCT-
based treatment plus stewardship.  We will compare mortality, length 
of stay, recurrence of infection, and antibiotic-associated adverse events 
(rash, myelosuppression, renal impairment, hepatotoxicity, C. difficile 
infection) between the study arms.  We will test the hypothesis that 
outcomes and safety will be comparable between the study arms. 
 
3.0 
Animal Studies and Previous Human Studies 
 
Multiple 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 pneumonia in adults and children, and in adults with sepsis.  
Based on these studies, the US FDA has recently expanded PCT indications to include its 
use to guide antibiotic management in adult patients with respiratory tract infections 
and/or sepsis.  Baer et al (PLoS One, 2013) demonstrated that antibiotic courses could be 
safely and significantly shortened for pediatric patients with pneumonia from 6.3 days to 
4.5 days under PCT guidance. Levels were measured on presentation and at days 3 and 
5 of therapy with strict adherence to PCT level guidelines: discontinuation of antibiotics 
was encouraged upon clinical stabilization and when PCT values fell below 0.25 μg/L or, 
for patients with initial PCT values > 10 μg/L, when levels decreased below 90% of the 
initial value.  In a recently published randomized, controlled, multi-center trial of 1575 
adult ICU patients, de Jong et. al (Lancet Infectious Diseases, 2016) demonstrated that 
PCT-guided antibiotic treatment, with antibiotic de-escalation when PCT level fell to 80% 
of its peak value or to 0.5 μg/L or lower, could safely and significantly shorten antibiotic 

 
 
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duration from 7 days in the standard of care group to only 5 days in the PCT-guided group, 
without a significant difference in mortality rates. 
 
4.0 
Inclusion/Exclusion Criteria 
Eligible subjects will be identified on admission to an intensive care setting by monitoring 
daily ICU census in EPIC.   
 
Subjects will be enrolled if they:   
• 
Are prescribed or administered antibiotics in the hospital within 1 calendar day of 
enrollment.   
• 
Are admitted to the pediatric ICU (units 5A or 5C) 
• 
Have parents or legal guardians who provide informed consent, or provide consent 
themselves if 18 years of age or older 
• 
Provide assent if >7 years of age 
 
Subjects will be excluded if they meet any of the following criteria:   
• 
Are not prescribed antibiotics in the hospital 
• 
Receive intravenous antibiotics within 7 days prior to identification for study 
enrollment 
• 
Primary or secondary immune deficiency 
• 
History of malignancy, bone marrow transplant or solid organ transplant 
• 
A diagnosis of cystic fibrosis 
• 
Neonates < 34 weeks gestation 
• 
Patients receiving treatment for endocarditis, osteomyelitis, meningitis, 
mediastinitis, or other invasive infection, for which long durations of antibiotics are 
needed. 
• 
Do not provide informed consent/assent 
 
5.0 
Enrollment/Randomization 
 
The study will begin after PCT becomes available at VUMC, and after IRB approval. 
Enrollment will occur over 16 months..  Eligible subjects will be identified on admission 
to an intensive care setting by monitoring daily ICU census and a clinical pharmacy 
surveillance platform (Sentri7).  Investigators will obtain consent (for all subjects) and 
assent (for subjects >7 years of age) by discussing the study with the patient and 
guardian in a private room, using the IRB-approved consent and assent forms. Privacy 
will be assured, Subjects will be permitted 24 hours to make a decision to participate. 
Investigators will assure that subjects comprehend the nature of the study by asking 
questions to assess their understanding of study objectives and procedures, and the 
risks and benefits of participation. All steps will be taken to avoid coercion. Subjects will 
be assured that if they decline to participate, they will continue to receive standard of 
care treatment in the PICU. Investigators will complete a combined consent-
authorization document. 
 
Enrolled subjects will receive either: 1) Standard of care testing and treatment with 
antimicrobial stewardship review (control), or 2) PCT testing and treatment with 
antimicrobial stewardship review (intervention).  
 

 
 
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6.0 
Study Procedures 
 
Study Design 
The proposed study is a prospective randomized controlled trial among children 
admitted to the ICU setting at Vanderbilt Children’s Hospital (VCH).  Enrolled subjects 
will receive one of two management strategies:  1) Standard of care with antimicrobial 
stewardship review (control), or 2) PCT testing and treatment with antimicrobial 
stewardship review (intervention). All subjects in both arms will have baseline audit of 
antimicrobial orders with feedback to providers by the antimicrobial stewardship team.  
For subjects in the intervention arm, the stewardship team will additionally recommend 
PCT testing and treatment per algorithm (Fig 1). PCT will be used in conjunction with 
clinical status and exam, and results of radiographic and laboratory studies, to make 
medical decisions about antibiotic therapy. The PCT will never be used as the sole basis 
for making decisions to modify or stop antibiotic therapy.  The antibiotic stewardship 
clinicians will review all enrolled subjects (in control and intervention arms) and provide 
recommendations regarding antimicrobial therapy. 
The ultimate decision to obtain PCT testing and/or adhere to the PCT algorithm or 
stewardship recommendations will be at the discretion of the ICU attending physician.  
Preliminary discussions with ICU faculty have revealed that they are highly supportive of 
the proposed study, and would be willing to adhere to the study protocol. 
 
Implementation of Antimicrobial Stewardship Directed PCT Testing and 
Treatment Algorithm 
The antimicrobial stewardship team currently performs daily prospective audit and 
feedback for all patients admitted to VCH who receive antibiotics, providing in-person 
recommendations regarding antimicrobial modifications to providers as needed.  This will 
continue in the standard of care arm.  Current standard of care includes obtaining blood 
cultures, with or without CRP or other laboratory studies, and administering one or more 
broad spectrum antibiotics such as cefepime, piperacillin-tazobactam, and vancomycin for 
a minimum of 48 hours. 
Prior to study initiation, the antimicrobial stewardship team will perform targeted 
education to ICU providers (attending physicians, residents and nurse practitioners) on 
the benefits and limitations of PCT use.  A PCT-based algorithm to guide clinician decisions 
about antibiotic escalation or de-escalation will be disseminated to ICU providers (Fig. 1), 
displayed in ICU workrooms, and available on the intranet.  PCT levels will be measured 
daily for the initial 3 days following randomization and then at day 5 post-randomization. 
Subjects in the intervention group will have a stewardship provider (S.K.) review their 
records daily and make in person rounds in the ICU to strongly encourage provider 
adherence to the PCT testing and algorithm-based management.  De-escalation of 
antibiotics will be recommended if the PCT level falls by 80% or more of the peak PCT 
level, or when the PCT level is less than or equal to 0.25 µg/L (Fig. 1). Continuation or 
escalation of antibiotics will be recommended if PCT level is greater than or equal to 0.5 
µg/L, or increased as compared to previous peak PCT level.  These levels are comparable 
to those used in previously cited studies. 
 
Laboratory Analysis 
The Roche Procalcitonin test is a diagnostic test that is FDA approved for use in adults 
and has been approved by the VUMC laboratory formulary committee. It will be available 

 
 
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for routine clinical use across the medical center, including in children at VCH in the near 
future.  Although the Roche PCT test is not approved for use in children, the same test 
manufactured by Biomerieux does not have an age restriction on its FDA approval. This 
study is not intended to support approval of the test in children, nor promote non-
approved indications. In this study we will use the Roche PCT test in an off-label 
population (children), but it will be used within the scope of clinical practice at Vanderbilt, 
following VUMC-approved guidance. A group of ICU, ED, and ID physicians and the 
chemistry lab director were involved in developing the strategy for reporting PCT results 
in the VUMC electronic medical record. The planned test reporting comments and PCT 
threshold interpretations are more conservative than used in some studies (Fig. 1) and 
are shown below:    
 
Procalcitonin can help differentiate viral from bacterial respiratory infection.  
Procalcitonin may be used to guide antibiotic de-escalation in sepsis (when compared to 
admission level): 
 
PCT < 0.1 ng/ml 
Bacterial infection very unlikely 
  
PCT 0.1 to  0.25 ng/ml 
Bacterial infection unlikely 
  
PCT 0.25 to 0.5 ng/ml 
Bacterial infection possible 
  
PCT > 0.5 ng/ml 
Increased probability of bacterial infection, encourage antibiotic therapy 
 
Serum PCT levels will be determined daily per VCH Laboratory protocol, using the Elecsys 
BRAHMS PCT test. The required blood volume is 0.5 - 1 mL and the estimated turn-
around-time for the test is 3 hours or less.  We will apply for a waiver of consent for the 
first blood sample, so that patients admitted to the ICU who are started on IV antibiotics 
will have leftover blood that is obtained during routine clinical care stored in a study 
refrigerator until study consent is obtained. For subjects enrolled in the intervention arm, 
PCT levels will be monitored at study enrollment, every 24 hours for the initial 2 days 
following randomization, and then at day 5 post-randomization. Whenever possible, 
leftover serum, from clinically collected specimens, will be used for PCT testing. For 
subjects in both arms, CRP, white blood cell count, and other relevant laboratory tests 
that are obtained for routine clinical care will be abstracted from the medical record. 
 
Study Outcomes 
The primary outcome is days of antibiotic therapy in the first 14 days following 
randomization.  Secondary outcomes are duration of broad-spectrum antibiotic therapy 
(defined 
as 
vancomycin, 
daptomycin, 
amikacin, 
ceftazidime, 
cefepime, 
piperacillin/tazobactam, aztreonam, carbapenems), time from randomization to first 
appropriate antibiotic modification (escalation or de-escalation), 30-day mortality, re-
initiation of antibiotics for a bacterial infection within 30-days of antibiotic discontinuation, 
length of ICU stay, length of overall hospital stay, ventilator days, rates of antibiotic-

 
 
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associated complications (i.e. rash, neutropenia, thrombocytopenia, acute kidney injury 
[defined as increase in serum creatinine > 0.3 mg per dL or > 1.5-fold from baseline, or 
urine output < 0.5 mL per kg per hour for more than six hours], hepatotoxicity [defined 
as > 2-fold increase in alanine aminotransferase, ALT, or conjugated bilirubin], or C. 
difficile infection), infection with multi-drug resistant organisms (defined as methicillin-
resistant S. aureus, vancomycin-resistant Enterococcus, 3rd generation cephalosporin non-
susceptible Enterobacteriaceae, multi-drug resistant Pseudomonas aeruginosa [resistant 
to aminoglycosides, cephalosporins, floroquinolones and carbepenems], carbepenem-
resistant Acinetobacter, and Candida spp obtained from otherwise sterile sites [i.e. blood 
or urine cultures]), cost of antibiotics from hospital billing data, and adherence to the PCT-
guided algorithm.  
 
Study Timeline 
The VUMC clinical laboratory PCT validation is complete. This protocol has been approved 
by the VUMC IRB.  Provider education, and PCT clinical algorithm development is 
complete.  We estimate that we will attain the target sample size within 16 months. Data 
analysis and abstract and manuscript preparation will be completed in the year after the 
study closes. 
 
7.0 
Risks 
 
Risks include those associated with routine blood draws – pain, redness, soreness, 
bruising, or infection may occur at the needle stick site. Rarely some people faint.  We 
plan to offer EMLA cream to subjects prior to blood draws.  A maximum of 4 blood 
draws will be obtained for procalcitonin testing in patients randomized to the 
intervention arm. Whenever possible, for PCT testing, we will use leftover blood from 
routine laboratory testing performed as part of ICU care. 
Because PCT has not been well studied for making antibiotic modification 
decisions in children, there may be the risk of premature cessation of antibiotics. 
However, to prevent this from happening, all decisions to stop or continue antibiotic 
therapy will be made by the ICU attending physician, based on clinical judgement and 
standard of care studies such as bacterial cultures, WBC,CRP, and radiographic 
evaluations 
The decision to start antibiotic treatment will in no way be affected by the study. 
In all subjects antibiotics will be started based on clinical suspicion of infection or 
microbiologic evidence of infection. This decision is at the discretion of the treating 
intensive care physician. Similarly, the decision to obtain PCT testing and/or adhere to 
the PCT algorithm or stewardship recommendations will be at the discretion of the ICU 
attending physician. 
All subjects in both arms will have baseline audit of antimicrobial orders with 
feedback to providers by the antimicrobial stewardship team. For subjects in the 
intervention arm, the stewardship team will additionally recommend PCT testing and 
treatment, with recommendations to initiate or expand antibiotic use at PCT levels > 0.5 
ug/L and to stop antibiotics when PCT levels decrease by >80% from peak 
concentration or to an absolute value < 0.25 ug/L.   
Multiple studies to date have demonstrated that procalcitonin-guided antibiotic 
de-escalation algorithms are as safe as standard of care management in the adult ICU 
setting.  As such, we do not anticipate increased risk of infection relapse rates or 

 
 
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increase in 30-day mortality between groups. These parameters will be monitored 
throughout the study and adverse events will be recorded and reported as detailed 
below. 
 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
 
Clinical adverse events will be monitored and recorded throughout the study. Serious 
adverse events include death, or other life-threatening complications like 
hemorrhage.Adverse drug/device events include if the PCT test result leads to 
premature cessation or de-escalation of antibiotics and causes harm to the patient, as 
determined by the PI or treating providers.  Serious adverse device events include if PCT 
test results lead to premature antibiotic cessation, resulting in death, as determined by 
the PI or treating providers. All adverse events, adverse drug events, serious adverse 
events, and serious adverse drug events will be recorded by the study team in the 
RedCap data collection form and reported in an expedited manner to Roche, the VUMC 
IRB (in accordance with the Vanderbilt IRB Procedure III.L.1 – v.17.  ) and the FDA as 
required.   
 
 
9.0 
Study Withdrawal/Discontinuation 
 
Subjects can withdraw from the study at any time. 
 
10.0 Statistical Considerations 
 
Based on data from studies evaluating PCT use among adult ICU patients, we estimate 
that median consumption of antibiotics will be 2.0 days less in the PCT group as 
compared to the control group.7, 18 Assuming normal distribution, and a standard 
deviation of 6 days, a sample size of 125 patients per arm will provide at least 80% 
power to detect a difference in antibiotic duration of at least 2.0 days between study 
arms.  These calculations are based on a chi-squared test with a two-sided Type 1 error 
rate of 0.05.  Per clinical pharmacy data, the average duration of an antibiotic course 
per patient in VCH ICUs is 4 days, thus a difference of 2.0 days would be clinically 
significant. 
 
11.0 Privacy/Confidentiality Issues 
 
Data and specimens will be coded and protected according to institutional policies and 
protocol.  Blood samples will be run on the day that they are obtained, and will only be 
stored afterwards according to routine laboratory protocol.  Any blood that is obtained 
with routine clinical care on admission to the pediatric ICU but not used for the study 
will be discarded in an appropriate biohazard container within 24 hours of when it was 
drawn.  Drs. Katz and Banerjee will maintain a password-protected master key with 
protected health information, and each patient case/medical record will have a unique 
identifier code and the master key will be the only link between the clinical records and 
the corresponding laboratory data. In addition, recorded patient identifiers (MRN, name, 
DOB) will be kept with the master key only. All other clinical data will be recorded in a 

 
 
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designated electronic data abstraction spreadsheet, which will be password-protected 
and separate from the patient identifiers and the key. 
 
 Vanderbilt, Dr Banerjee and her staff will comply with any and all laws regarding the 
privacy of protected health information.   
 
12.0 Follow-up and Record Retention 
The projected duration of the study is from the time of IRB approval through June 30, 
2019.  
Data will be stored in a password-protected RedCap database. Paper copies of 
the data will be kept to the absolute minimum. Only the PI and co-investigators will 
have access to the master patient key and patient identifiers during the study collection 
period. After the collection period, only the PI will maintain the master patient key for 
future study that may require linking clinical laboratory values with clinical data. The key 
will be maintained in the PI's office in the Section of Infectious Diseases at VUMC on a 
single password-protected hospital computer. Any paper copies or data on paper will be 
stored in a locked filing cabinet in the PI's office. Paper copies will be destroyed at the 
earliest possible time by being discarded in the hospital HIPAA-approved receptacles for 
PHI to be shredded according to hospital policy.  
The PI, co-investigators and laboratory personnel will be appropriately trained to 
maintain the confidentiality and protection of PHI according to the study design and 
hospital practice.     
 
Appendix A:  Figure 1 – Procalcitonin-Guided Algorithm 
If blood sample taken for calculation of procalcitonin concentration at early stage of episode, 
obtain a second procalcitonin concentration 6–12 h later
Guidelines for continuing or stopping of antibiotics
Guidelines for starting of antibiotics*
Concentration
<0·25 µg/L
Antibiotics strongly 
discouraged
Concentration ≥0·25 
and <0·5 µg/L
Antibiotics discouraged
Concentration ≥0·5 
and <1 µg/L
Antibiotics encouraged
Concentration ≥1 µg/L
Antibiotics strongly 
encouraged
Concentration
<0·25 µg/L
Stopping of antibiotics
strongly encouraged
Stopping of antibiotics
encouraged
Decrease by ≥80% from 
peak concentration, 
or concentration 
≥0·25 and <0·5 µg/L
Continuing of antibiotics
encouraged
Decrease by <80% from
peak concentration, 
and concentration 
≥0·5 µg/L
Changing of antibiotics
strongly encouraged
Increase of concentration 
compared with peak 
concentration and  
concentration ≥0·5 µg/L

 
 
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Reference:  Bouadma L et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care 
units (PRORATA trial): a multicenter randomized controlled trial. Lancet 2010; 375: 463-74 
Appendix B:  References 
1. Rangel-Frausto MS et al.  The natural history of the systemic inflammatory 
response syndrome (SIRS). JAMA 1995; 273(2): 117-23. 
 
2. Centers for Disease Control and Prevention (CDC). Antibiotic resistance 
threats in the United States, 2013. Atlanta: CDC, 2013. Available at: 
http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-
2013-508.pdf. 
 
3. Bignardi GE. Risk factors for Clostridium difficile infection. J of Hosp Inf 
1998; 40(1): 1-15. 
 
4. Dellit TH et al. Infectious Diseases Society of America and the Society for 
Healthcare Epidemiology of America guidelines for developing an 
institutional program to enhance antimicrobial stewardship. Clin Infect Dis 
2007; 44: 159-77. 
 
5. Bouadma L et al. Use of procalcitonin to reduce patients’ exposure to 
antibiotics in intensive care units (PRORATA trial): a multicenter randomized 
controlled trial. Lancet 2010; 375: 463-74. 
 
6. Downes KJ et al. A pragmatic biomarker-driven algorhithm to guide 
antibiotic use in the pediatric intensive care unit: The optimizing antibiotic 
strategies in sepsis (OASIS) study. J Pediatr Infect Dis Soc 2016. [Epub 
ahead of print]. 
 
7. de Jong E et al. Efficacy and safety of procalcitonin guidance in reducing 
the duration of antibiotic treatment in critically ill patients: a randomized, 
controlled, open-label trial. Lancet Infect Dis 2016; 16(7): 819-27. 
 
8. Soni NJ et al. Procalcitonin-guided antibiotic therapy: A systematic review 
and meta-analysis. J Hosp Med 2013; 8(9): 530-40. 
 
9. Milcent K et al. Use of procalcitonin assays to predict serious bacterial 
infection in young febrile infants. JAMA Pediatr 2016; 170(1): 62-9. 
 
10. Linscheid P et al. Expression and secretion of procalcitonin and calcitonin 
gene-related peptide by adherent monocytes and by macrophage-activated 
adipocytes. Crit Care Med 2004; 32(8): 1715-21. 
 
11. Dandona P et al. Procalcitonin increase after endotoxin injection in normal 
subjects. J Endocrinol Metab 1994; 79(6): 1605-8. 
 
12. Brunkhorst FM, Heinz U and Forycki ZF. Kinetics of procalcitinon in 
iatrogenic sepsis. Intensive Care Med 1998; 24(8): 888-9. 
 
13. Stoltz D et al. Procalcitonin for reduced antibiotic exposure in ventilator-
associated pneumonia: a randomized study. Eur Respir J 2009; 34: 1364-
75. 
 

 
 
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14. Nobre V et al. Use of procalcitonin to shorten antibiotic treatment duration 
in septic patients: a randomized trial. Am J Respir Crit Care Med 2008; 177: 
498-505. 
 
15. Hochreiter M. et al. Procalcitonin to guide duration of antibiotic therapy in 
intensive care patients: a randomized prospective controlled trial. Crit Care 
2009; 13: R83 
 
16. Hohn A et al. Procalcitonin-guided algorithm to reduce length of antibiotic 
therapy in patients with severe sepsis and septic shock. BMC Infect Dis 
2013; 13(158): 1-9. 
 
17. Esposito S et al. Procalcitonin measurements for guiding antibiotic 
treatment in pediatric pneumonia.  Respir Med 2011; 105(12): 1939-45. 
 
18. Baer G et al. Procalcitonin guidance to reduce antibiotic treatment of lower 
respiratory tract infection in children and adolescents (ProPAED): a 
randomized controlled trial.  
PLoS One 2013; 8(8): 1-10. 
 
19. Becker KL, Snider R and Nylen ES. Procalcitonin assay in systemic 
inflammation, infection and sepsis: Clinical utility and limitations. Crit Care 
Med 2008; 36(3): 941-52. 
 
20. Stockmann C et al. Procalcitonin accurately identifies hospitalized children 
with low risk of bacterial community-acquired pneumonia. J Ped Infect Dis 
Soc 2017 
 
21. Self W et al. Procalcitonin as an early marker of the need for invasive 
respiratory or vasopressor support in adults with community-acquired 
pneumonia.  Chest 2016; 150(4): 819-28.