Procalcitonin-Guided Antibiotic Therapy

270 Pages·2012·2.1 MB·English

Comparative Effectiveness Review
Number 78
Procalcitonin-Guided
Antibiotic Therapy
Comparative Effectiveness Review
Number 78

Procalcitonin-Guided Antibiotic Therapy

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
540 Gaither Road
Rockville, MD 20850
www.ahrq.gov

Contract No. 290-2007-10058-I

Prepared by:
Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based
Practice Center
Chicago, IL

Investigators:
Nilam J. Soni, M.D.
David J. Samson, M.S.
Jodi L. Galaydick, M.D.
Vikrant Vats, Ph.D.
David L. Pitrak, M.D.
Naomi Aronson, Ph.D.

AHRQ Publication No. 12(13)-EHC124-EF
October 2012
This report is based on research conducted by the Blue Cross and Blue Shield Association
Technology Evaluation Center Evidence-based Practice Center (EPC) under contract to the
Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2007-
10058-I). The findings and conclusions in this document are those of the authors, who are
responsible for its contents; the findings and conclusions do not necessarily represent the views
of AHRQ. Therefore, no statement in this report should be construed as an official position of
AHRQ or of the U.S. Department of Health and Human Services.

The information in this report is intended to help health care decisionmakers—patients and
clinicians, health system leaders, and policymakers, among others—make well-informed
decisions and thereby improve the quality of health care services. This report is not intended to
be a substitute for the application of clinical judgment. Anyone who makes decisions concerning
the provision of clinical care should consider this report in the same way as any medical
reference and in conjunction with all other pertinent information, i.e., in the context of available
resources and circumstances presented by individual patients.

This report may be used, in whole or in part, as the basis for development of clinical practice
guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage
policies. AHRQ or U.S. Department of Health and Human Services endorsement of such
derivative products may not be stated or implied.

This document is in the public domain and may be used and reprinted without special permission
except those copyrighted materials that are clearly noted in the document. Further reproduction
of those copyrighted materials is prohibited without the specific permission of copyright holders.

Persons using assistive technology may not be able to fully access information in this report. For
assistance contact [email protected].

None of the investigators have any affiliations or financial involvement that conflicts with the
material presented in this report.

Suggested citation: Soni NJ, Samson DJ, Galaydick JL, Vats V, Pitrak DL, Aronson N.
Procalcitonin-Guided Antibiotic Therapy. Comparative Effectiveness Review No. 78. (Prepared
by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based
Practice Center under Contract No. 290-2007-10058-I.) AHRQ Publication No. 12(13)-EHC124-
EF. Rockville, MD: Agency for Healthcare Research and Quality. October 2012.
www.effectivehealthcare.ahrq.gov/reports/final.cfm.

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Preface
The Agency for Healthcare Research and Quality (AHRQ) conducts the Effective Health
Care Program as part of its mission to organize knowledge and make it available to inform
decisions about health care. As part of the Medicare Prescription Drug, Improvement, and
Modernization Act of 2003, Congress directed AHRQ to conduct and support research on the
comparative outcomes, clinical effectiveness, and appropriateness of pharmaceuticals, devices,
and health care services to meet the needs of Medicare, Medicaid, and the Children’s Health
Insurance Program (CHIP).
AHRQ has an established network of Evidence-based Practice Centers (EPCs) that produce
Evidence Reports/Technology Assessments to assist public- and private-sector organizations in
their efforts to improve the quality of health care. The EPCs now lend their expertise to the
Effective Health Care Program by conducting comparative effectiveness reviews (CERs) of
medications, devices, and other relevant interventions, including strategies for how these items
and services can best be organized, managed, and delivered.
Systematic reviews are the building blocks underlying evidence-based practice; they focus
attention on the strength and limits of evidence from research studies about the effectiveness and
safety of a clinical intervention. In the context of developing recommendations for practice,
systematic reviews are useful because they define the strengths and limits of the evidence,
clarifying whether assertions about the value of the intervention are based on strong evidence
from clinical studies. For more information about systematic reviews, see
www.effectivehealthcare.ahrq.gov/reference/purpose.cfm.
AHRQ expects that CERs will be helpful to health plans, providers, purchasers, government
programs, and the health care system as a whole. In addition, AHRQ is committed to presenting
information in different formats so that consumers who make decisions about their own and their
family’s health can benefit from the evidence.
Transparency and stakeholder input are essential to the Effective Health Care Program.
Please visit the Web site (www.effectivehealthcare.ahrq.gov) to see draft research questions and
reports or to join an email list to learn about new program products and opportunities for input.
Comparative effectiveness reviews will be updated regularly.
We welcome comments on this CER. They may be sent by mail to the Task Order Officer
named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD
20850, or by email to [email protected].

Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H.
Director Director, Center for Outcomes and Evidence
Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality

Stephanie Chang, M.D., M.P.H. Supriya Janakiraman, M.D., M.P.H.
Director, EPC Program Task Order Officer
Center for Outcomes and Evidence Center for Outcomes and Evidence
Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality

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Acknowledgments
The authors gratefully acknowledge the following individuals for their contributions to this
project: Claudia Bonnell, R.N., M.L.S.; Lisa Garofalo; Mark Grant, M.D., M.P.H.; Steven
Gutman, M.D.; Lisa Sarsany, M.A.; Kathleen Ziegler, Pharm.D.; Elbert Huang, M.D., M.P.H;
Ronald Thisted, Ph.D.; Michael Douglas, M.S.; and Jessica Hoag, B.A.
Technical Expert Panel
R. Phillip Dellinger, M.D. Joshua Metlay, M.D., Ph.D.
Head, Critical Care Medicine Professor of Medicine, Epidemiology, and
Cooper University Hospital Emergency Medicine
Camden, NJ Perelman School of Medicine
University of Pennsylvania
Jesse Hall, M.D. Philadelphia, PA
Section Chief, Pulmonary and Critical Care
Medicine Emanuel Rivers, M.D., M.P.H.
University of Chicago Vice Chair and Director of Research for the
Chicago, IL Department of Emergency Medicine
Henry Ford Hospital
Stephen Kahn, Ph.D. Detroit, MI
Associate Director, Clinical Laboratories
Loyola University Chicago Gregory Schmidt, M.D.
Maywood, IL Director, Critical Care Programs
University of Iowa
Henry Masur, M.D. Iowa City, IA
Chief, Critical Care Medicine
National Institutes of Health
Bethesda, MD
Peer Reviewers
Derek Angus, M.D., M.P.H. Rongwei (Rochelle) Fu, Ph.D.
Professor and Chair, Critical Care Medicine Associate Professor
Professor, Medicine and Health Policy Oregon Health & Science University
and Management Portland, OR
University of Pittsburgh School of Medicine
Pittsburgh, PA

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Procalcitonin-Guided Antibiotic Therapy
Structured Abstract
Objectives. To systematically review comparative studies of the use of procalcitonin in the
clinical management of adult and pediatric patients with suspected local or systemic infection.

Data sources. MEDLINE®, Embase®, the Cochrane Database of Systematic Reviews, National
Institute for Clinical Excellence, the National Guideline Clearinghouse, and the Health
Technology Assessment Programme were searched from January 1, 1990, to December 16,
2011; the MEDLINE, Embase, and Cochrane searches were updated in December 2011. A
search of the gray literature included databases with regulatory information, clinical trial
registries, abstracts and conference papers, grants and federally funded research, and information
from manufacturers.

Review methods. We sought studies that compared procalcitonin-guided versus clinical-criteria-
guided initiation, discontinuation, or change of antibiotic therapy. Outcomes were antibiotic use,
mortality, morbidity, and adverse drug events of antibiotic therapy. Data were abstracted by a
single reviewer and fact-checked by a second reviewer. Study quality was assessed using the
U.S. Preventive Services Task Force framework. A meta-analysis on short-term mortality in
intensive care unit (ICU) patients was performed using a random-effects model. Strength of the
body of evidence was assessed according to the AHRQ Methods Guide.

Results. There were 18 randomized, controlled trials that addressed five patient populations.
Procalcitonin guidance reduces antibiotic use when used to discontinue antibiotics in adult ICU
patients and to initiate or discontinue antibiotics in patients with respiratory tract infections (high
evidence), without increasing morbidity (moderate evidence) and mortality (low evidence). In
contrast, procalcitonin-guided intensification of antibiotics in adult ICU patients increases
morbidity (moderate evidence). There is moderate evidence from a single good quality study that
procalcitonin guidance reduces antibiotic use for suspected early neonatal sepsis, but insufficient
evidence on morbidity and mortality outcomes was found. Evidence is insufficient to draw
conclusions on outcomes of procalcitonin guidance for: (1) fever of unknown source in children
1–36 months of age; and (2) preemptive antibiotics after surgery.
Immunocompromised hosts and other special populations were generally excluded from
procalcitonin guidance studies. Thus, findings from this review should not be extrapolated to
patients with the following conditions: pregnancy; absolute neutropenia; immunocompromised
states; chronic infections, and infections for which prolonged antibiotic therapy is standard of
care (e.g., infective endocarditis).

Conclusions. Procalcitonin guidance reduces antibiotic use when used to discontinue antibiotics
in adult ICU patients and to initiate or discontinue antibiotics in patients with respiratory tract
infections. Populations for future research include immunocompromised patients, patients with
other conditions (e.g., pregnancy, cystic fibrosis), and pediatric patients. Future research should
compare procalcitonin guidance with antibiotic stewardship programs and to implementation of
guidelines. Outcomes of high interest for future research are the consequences of reduction in
antibiotic use for antibiotic resistance and for adverse events of antibiotic therapy.
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Contents
Executive Summary .................................................................................................................ES-1
Introduction ....................................................................................................................................1
Background and Objectives .......................................................................................................1
Key Questions ............................................................................................................................3
Key Question .......................................................................................................................4
Methods ...........................................................................................................................................6
Topic Development and Refinement .........................................................................................6
Analytic Framework ..................................................................................................................6
Literature Search Strategy..........................................................................................................8
Study Selection ..........................................................................................................................8
Search Strategies for Gray Literature ........................................................................................9
Data Extraction and Data Management ...................................................................................10
Data Elements ....................................................................................................................10
Evidence Tables .................................................................................................................11
Individual Study Quality Assessment ......................................................................................11
Definition of Ratings Based on Criteria.............................................................................11
Data Synthesis ..........................................................................................................................12
Assessment of Applicability ....................................................................................................13
Grading the Body of Evidence for Each Key Question ...........................................................13
Peer Review and Public Commentary .....................................................................................13
Results ...........................................................................................................................................15
Literature Search ......................................................................................................................15
Gray Literature Search .............................................................................................................15
Critically Ill/Ventilator-Associated Pneumonia .......................................................................18
Procalcitonin-Guided Antibiotic Discontinuation .............................................................18
Procalcitonin-Guided Antibiotic Intensification ................................................................26
Respiratory Tract Infections ....................................................................................................30
Study Characteristics .........................................................................................................30
Study Quality .....................................................................................................................33
Antibiotic Use ....................................................................................................................35
Mortality ............................................................................................................................35
Morbidity ...........................................................................................................................39
Adverse Events of Antibiotic Therapy ..............................................................................39
GRADE Evidence ..............................................................................................................39
Neonatal Sepsis ........................................................................................................................42
Study Characteristics .........................................................................................................42
Study Quality .....................................................................................................................42
Antibiotic Use ....................................................................................................................44
Mortality ............................................................................................................................44
Morbidity ...........................................................................................................................44
Adverse Events of Antibiotic Therapy ..............................................................................44
GRADE Evidence ..............................................................................................................45
Fever of Unknown Source (Children Ages 1–36 Months) ......................................................45
Study Characteristics .........................................................................................................45
Study Quality .....................................................................................................................45
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Antibiotic Use ....................................................................................................................47
Mortality ............................................................................................................................47
Morbidity ...........................................................................................................................47
Adverse Events of Antibiotic Therapy ..............................................................................47
GRADE Evidence ..............................................................................................................47
Preemptive Postoperative Antibiotic Therapy .........................................................................48
Study Quality .....................................................................................................................48
Antibiotic Use ....................................................................................................................50
Mortality ............................................................................................................................50
Morbidity ...........................................................................................................................50
Adverse Effects of Antibiotic Therapy ..............................................................................50
GRADE Evidence ..............................................................................................................50
Summary and Discussion ............................................................................................................52
Summary of the Main Findings ...............................................................................................52
Intensive Care Unit Patients...............................................................................................52
Respiratory Tract Infection ................................................................................................52
Neonatal Sepsis ..................................................................................................................53
Fever of Unknown Source in Children Ages 1–36 Months ...............................................53
Postoperative Patients at Risk of Infection ........................................................................53
Clinical Context and Applicability of Evidence for Decisionmaking .....................................53
Discussion of Present Findings in Context of Other Systematic Reviews ..............................55
Limitations of Present Review .................................................................................................58
Future Research .......................................................................................................................58
Summary of Weaknesses or Gaps in the Evidence ............................................................58
Summary of Methodological Weaknesses in the Evidence ...............................................61
Abbreviations ...............................................................................................................................63
References .....................................................................................................................................64

Tables
Table A. Summary characteristics of the included studies ....................................................... ES-8
Table B. Summary of outcomes measures, and strength of evidence .................................... ES-10
Table 1. FDA-cleared procalcitonin assays .................................................................................... 2
Table 2. Summary of characteristics for five trials included in the analysis
of procalcitonin-guided antibiotic discontinuation in the
critically ill/ventilator-associated pneumonia patients ............................................................ 19
Table 3. Procalcitonin-guided antibiotic discontinuation in the critically ill/
ventilator-associated pneumonia patients—study quality ...................................................... 21
Table 4. Procalcitonin-guided antibiotic discontinuation in the critically ill/
ventilator-associated pneumonia patients––outcomes related to antibiotic use ..................... 21
Table 5. Procalcitonin-guided antibiotic discontinuation in the critically ill/
ventilator-associated pneumonia patients––mortality............................................................. 23
Table 6. Procalcitonin-guided antibiotic discontinuation in the critically ill/
ventilator-associated pneumonia patients––morbidity ........................................................... 24
Table 7. Procalcitonin-guided antibiotic discontinuation in the critically ill/
ventilator-associated pneumonia patients––GRADE evidence table ..................................... 26
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Table 8. Summary of characteristics for two trials included in the analysis
of procalcitonin-guided antibiotic intensification in the critically ill/
ventilator-associated pneumonia patients ............................................................................... 27
Table 9. Procalcitonin-guided antibiotic intensification in the critically ill/
ventilator-associated pneumonia patients—study quality ...................................................... 28
Table 10. Procalcitonin-guided antibiotic intensification in the critically ill/
ventilator-associated pneumonia patients—outcomes related to antibiotic use ..................... 28
Table 11. Procalcitonin-guided antibiotic intensification in the critically ill/
ventilator-associated pneumonia patients––28-day mortality ................................................ 29
Table 12. Procalcitonin-guided antibiotic intensification in the critically ill/
ventilator-associated pneumonia patients––morbidity ........................................................... 29
Table 13. Summary of characteristics for eight trials included in the analysis
of procalcitonin-guided antibiotic initiation and/or discontinuation
in patients with respiratory tract infections ............................................................................. 31
Table 14. Procalcitonin-guided antibiotic initiation and/or discontinuation in patients
with respiratory tract infections––study quality ..................................................................... 34
Table 15. Procalcitonin-guided antibiotic initiation and/or discontinuation in patients
with respiratory tract infections––outcomes related to antibiotic use .................................... 36
Table 16. Procalcitonin-guided antibiotic initiation and/or discontinuation in patients
with respiratory tract infections––mortality............................................................................ 38
Table 17. Procalcitonin-guided antibiotic initiation and/or discontinuation in patients
with respiratory tract infections—morbidity .......................................................................... 40
Table 18. Procalcitonin-guided antibiotic initiation and/or discontinuation in patients
with respiratory tract infections—GRADE evidence table .................................................... 41
Table 19. Summary of characteristics for one trial included in the analysis
of procalcitonin-guided antibiotic therapy in neonatal sepsis ................................................. 43
Table 20. Procalcitonin-guided antibiotic therapy in neonatal sepsis—study quality .................. 43
Table 21. Procalcitonin-guided antibiotic therapy in neonatal sepsis in the study
by Stocker et al., 2010 (n=121)—outcomes related to antibiotic use ..................................... 44
Table 22. Mortality and morbidity data for early onset neonatal sepsis in the study
by Stocker et al., 2010 (n=121) ............................................................................................... 44
Table 23. Summary of characteristics for one trial included in the analysis
of procalcitonin-guided antibiotic therapy in children (ages 1–36 months)
with fever of unknown source................................................................................................. 45
Table 24. Procalcitonin-guided antibiotic therapy in children (ages 1–36 months)
with fever of unknown source—study quality ........................................................................ 46
Table 25. Procalcitonin-guided antibiotic therapy in children (ages 1–36 months)
with fever of unknown source—outcomes related to antibiotic use
in the study by Manzano et al., 2010 (n=384) ........................................................................ 47
Table 26. Mortality and morbidity data for fever of unknown source in children
ages 1–36 months in the study by Manzano et al., 2010 (n=384) .......................................... 47
Table 27. Summary of characteristics for one trial included in the analysis
of procalcitonin-guided preemptive postoperative antibiotic therapy .................................... 48
Table 28. Procalcitonin-guided preemptive postoperative antibiotic therapy—study quality ..... 49
Table 29. Procalcitonin-guided preemptive postoperative antibiotic therapy—outcomes
related to antibiotic use in the study by Chromik et al., 2005 ................................................ 50
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Table 30. Procalcitonin-guided preemptive postoperative antibiotic therapy—mortality
and morbidity data in the study by Chromik et al., 2005 (n=20) ............................................ 50
Table 31. Summary of systematic reviews ................................................................................... 57

Figures
Figure A. Analytic framework for procalcitonin as a diagnostic indicator for infection
and as an indicator of response to therapy .......................................................................... ES-4
Figure B. PRISMA diagram for identified trials ...................................................................... ES-6
Figure 1. Analytic framework for procalcitonin as a diagnostic indicator for infection
and as an indicator of response to therapy ................................................................................ 7
Figure 2. PRISMA diagram for identified trials ........................................................................... 15
Figure 3. PRISMA diagram for identified gray literature............................................................. 16
Figure 4. Meta-analysis of mean differences, antibiotic duration (days) in critically ill/
ventilator-associated pneumonia patients ............................................................................... 22
Figure 5. Meta-analysis of risk differences, short-term mortality (in-hospital or 28-day)
in critically ill/ventilator-associated pneumonia patients ....................................................... 23
Figure 6. Meta-analysis of mean differences, ICU length of stay (days) in critically ill/
ventilator-associated pneumonia patients ............................................................................... 24
Figure 7. Meta-analysis of mean differences, antibiotic duration (days) in patients with
respiratory tract infections ...................................................................................................... 37
Figure 8. Meta-analysis of risk differences, antibiotic prescription rate in patients with
respiratory tract infections ...................................................................................................... 37
Figure 9. Meta-analysis of risk differences, short-term mortality (≤6 weeks) in patients
with respiratory tract infections .............................................................................................. 38
Figure 10. Meta-analysis of risk differences in ICU admission in patients with
respiratory tract infections ...................................................................................................... 40

Appendixes
Appendix A. Search Strategy
Appendix B. Excluded Studies
Appendix C. Abstraction Tables
Appendix D. Ongoing Procalcitonin Studies in ClinicalTrials.gov
Appendix E. Screening Guide for Title and Abstract
Appendix F. Screening Guide for Full-Text Articles
Appendix G. Data Abstraction Form

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