Clinical Review & Education

JAMA Clinical Evidence Synopsis

Procalcitonin Testing to Guide Antibiotic Therapy

in Acute Upper and Lower Respiratory Tract Infections
Philipp Schuetz, MD, MPH; Yannick Wirz, MD; Beat Mueller, MD

CLINICAL QUESTION Is the use of procalcitonin for guiding antibiotic decisions in patients with
acute upper and lower respiratory tract infections associated with improved clinical
outcomes compared with usual care?

BOTTOM LINE Among patients with varying types and severity of acute respiratory infection,
using procalcitonin to guide decisions about antibiotics is associated with lower rates of
antibiotic exposure, antibiotic-related adverse effects, and mortality.

Introduction
Distinguishing between bacterial and viral respiratory tract infec-
tions is challenging and can result in overuse of antibiotics. Pro-
calcitonin is expressed by human cells in response to bacterial
infections and can be measured in the blood as a marker associ-
ated with bacterial infection.1 In acute upper and lower respira-
tory tract infections, a low procalcitonin level is associated with a
lower likelihood of bacterial infection and may help identify
patients who do not need antibiotics. In patients prescribed anti-
biotics, a decline in procalcitonin levels over time may help guide
decisions about stopping antibiotic therapy, thereby reducing
antibiotic exposure.2
In February 2017, the US Food and Drug Administration (FDA)
approved procalcitonin to guide clinical decisions regarding antibi-
otic use for patients with respiratory tract infections who are hos-
pitalized or treated in the emergency department.3 This JAMA Clini-
cal Evidence Synopsis summarizes a Cochrane review 4 of an
individual patient data meta-analysis that assessed clinical out-
comes associated with procalcitonin testing for patients with acute
upper and lower respiratory tract infections and is an update from
an earlier publication.5
Summary of Findings
Procalcitonin testing was associated with a shorter duration of an-
tibiotic exposure (from a median of 7 days [interquartile range {IQR},
3-11 days] to 5 days [IQR, 0-8 days]), mean shorter duration of
infection (2.4 days [95% CI, 2.15-2.71 days]), and a 25% reduction
in antibiotic-related adverse effects (247/1513 patients with procal-
citonin testing [16.3%] vs 336/1521 controls [22.1%]; Table).
Procalcitonin testing was associated with lower 30-day mor-
tality (286 deaths/3336 patients with procalcitonin testing
[8.6%] vs 336/3372 controls [10.0%]; adjusted odds ratio, 0.83
[95% CI, 0.70-0.99], P = .04). This favorable association was
similar for distinct types of respiratory infections (ie, community-
acquired pneumonia, exacerbation of chronic obstructive pulmo-
nary disease, bronchitis, upper respiratory infections) and across
subgroups by clinical setting (emergency department, medical
ward, intensive care). However, there were too few deaths in pri-
mary care patients to assess the association of procalcitonin test-
ing with mortality in primary care.
Discussion
Among 6708 patients with acute upper and lower respiratory in-
fection in 26 randomized trials from 12 countries, procalcitonin test-
ing for antibiotic guidance was associated with lower rates of anti-
biotic use, fewer antibiotic-related adverse effects, and improved
overall survival.
Limitations
First, study protocol adherence regarding antibiotic stopping rules
varied among the trials (range, 44%-100%). Second, most trials in-
cluded immunocompetent adults with respiratory tract infections.
Thus generalizability to other patient populations, such as immu-
nocompromised patients and patients with other types of infec-
tions such as urinary tract infection, is unclear. Third, mortality in the
primary care setting was too low to reach conclusions regarding
Evidence Profile
No. of studies: 26 randomized clinical trials
Study years: published: 2004-2016; conducted, 2002-2015
Last search date: February 10, 2017
No. of patients: 6708 (men: 3808 [57%]; women: 2900 [43%])
with acute infections of the upper or lower respiratory tract,
which included community-acquired pneumonia (n = 2910),
exacerbation of chronic obstructive pulmonary disease due to
infections (n = 1252), bronchitis (n = 544), ventilator-associated
pneumonia (n = 380), hospital-acquired pneumonia (n = 505),
upper respiratory infection (n = 552)
Race/ethnicity: Not reported
Age: mean, 61 years (range, 19-92 years)
Settings: Primary care, emergency department, medical ward,
medical and surgical intensive care unit
Countries: Australia, Belgium, Brazil, China, Denmark, France,
Germany, Italy, the Netherlands, Serbia, Switzerland, United States
Comparison: Procalcitonin-guided antibiotic management
vs routine clinical care
Primary outcome: 30-day mortality
Secondary outcomes: Antibiotic use, adverse effects from
antibiotics, length of stay

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 Clinical Review & Education JAMA Clinical Evidence Synopsis

Table. Associations of Procalcitonin Testing With Clinical Outcomes and Antibiotic Use
Procalcitonin Group Control Group Between-Group P
(n = 3336) (n = 3372) Difference (95% CI) Adjusted OR (95% CI)a Value
Clinical Outcomes
30-d mortality, No. (%) 286 (8.6) 336 (10.0) 0.83 (0.70 to 0.99) .04
Treatment failure, No. (%)b 768 (23.0) 841 (24.9) 0.90 (0.80 to 1.01) .07
Length of ICU stay, median (IQR), d 8.0 (4.0 to 17.0) 8.0 (4.0 to 17.0) 0.39 (−0.81 to 1.58) .52
Length of hospital stay, median (IQR), d 8.0 (2.0 to 17.0) 8.0 (2.0 to 17.0) −0.19 (−0.96 to 0.58) .63
Antibiotic-related adverse effects, 247/1513 (16.3) 336/1521 (22.1) 0.68 (0.57 to 0.82) .001
No./total (%)
Antibiotic Exposure
Rates for initiation of antibiotics, 2351/3288 (71.5) 2894/3353 (86.3) 0.27 (0.24 to 0.32) .001
No./total (%)
Duration of antibiotics, median (IQR), d 6.0 (4.0 to 10.0) 8.0 (6.0 to 12.0) −1.83 (−2.15 to −1.50) .001
Total exposure of antibiotics, median (IQR), d 5.0 (0 to 8.0) 7.0 (3.0 to 11.0) −2.43 (−2.71 to −2.15) .001
Abbreviations: ICU, intensive care unit; IQR, interquartile range; OR, odds ratio. reporting any symptoms of an ongoing respiratory tract infection (eg, fever,
a
Multivariable hierarchical regression with outcome of interest as dependent cough, dyspnea) at follow-up. For the emergency department setting,
variable, age and type of respiratory tract infection as independent variables, treatment failure was defined as death, ICU hospitalization, rehospitalization
and trial as a random effect. after index hospital discharge, acute respiratory tract infection–associated
b
complications (eg, empyema or acute respiratory distress syndrome), and
For the primary care setting, treatment failure was defined as death,
recurrent or worsening infection within 30 days of follow-up. For the ICU
hospitalization, acute respiratory tract infection–specific complications
setting, treatment failure was defined as death within 30 days of follow-up.
(eg, empyema, meningitis), recurrent or worsening infection, and participants

the association of procalcitonin measurement with mortality in this
population. Fourth, trials used different procalcitonin cutoffs de-
pending on the clinical setting. Specifically, in intensive care trials,
procalcitonin was used to guide stopping of antibiotic treatment
when procalcitonin levels decreased to below 0.5 μg/L or de-
creased by at least 80% of its peak level. In emergency depart-
ment and primary care trials, procalcitonin was mainly used to guide
initiation and stopping of antibiotic therapy at a procalcitonin cut-
off of 0.25 μg/L.2
Comparison of Findings With Current Practice Guidelines
The 2016 Surviving Sepsis Campaign guidelines recommended an-
tibiotic discontinuation within the first few days after start of therapy
in response to clinical improvement, evidence of resolution of in-
fection, or both.6 These guidelines also suggest that measurement
of procalcitonin is appropriate in patients with sepsis and that pro-
calcitonin levels can be used to support discontinuation of empiri-
cal antibiotics in patients who initially appeared to have sepsis, but
subsequently have limited clinical evidence of infection.6 The
meta-analysis4 supports these recommendations for patients with
respiratory infection as the source of sepsis.
Areas in Need of Future Study
Future studies should assess procalcitonin testing in nonrespira-
tory infections such as urinary tract infection or endocarditis, and
in immunocompromised patients. Currently, the procalcitonin test
is only approved by the FDA for use in the hospital or emergency de-
partment and further research is needed in primary care using rapid
turnaround point-of-care procalcitonin tests. When making deci-
sions about antibiotic treatment, clinicians should carefully con-
sider the clinical assessment in each individual patient in addition
to the procalcitonin results.2

ARTICLE INFORMATION
Author Affiliations: Medical University
Department of Medicine, Kantonsspital Aarau,
Aarau, Switzerland (Schuetz, Wirz, Mueller); Faculty
of Medicine, University of Basel, Basel, Switzerland
(Schuetz, Mueller).
serving as consultants for Thermo-Fisher and
bioMérieux; and receiving research support from
Thermo-Fisher and bioMérieux. No other
disclosures were reported.
Submissions: We encourage authors to submit
papers for consideration as a JAMA Clinical
3. US Food and Drug Administration. FDA clears
test to help manage antibiotic treatment for lower
respiratory tract infections and sepsis [press
release]. https://www.fda.gov/NewsEvents
/Newsroom/PressAnnouncements/ucm543160
.htm. Accessed January 25, 2018.

Corresponding Author: Philipp Schuetz, MD, MPH, Evidence Synopsis. Please contact Dr McDermott at 4. Schuetz P, Wirz Y, Sager R, et al. Procalcitonin
University Department of Medicine, Kantonsspital mdm608@northwestern.edu. to initiate or discontinue antibiotics in acute
Aarau, Tellstrasse, CH-5001 Aarau, Switzerland respiratory tract infections. Cochrane Database
(schuetzph@gmail.com). REFERENCES Syst Rev. 2017;10:CD007498.

Section Editor: Mary McGrae McDermott, MD,
Senior Editor.
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest.
Drs Schuetz and Mueller reported receiving support
to attend meetings and fulfill speaking
engagements from Thermo-Fisher and bioMérieux;
1. Sager R, Kutz A, Mueller B, Schuetz P.
Procalcitonin-guided diagnosis and antibiotic
stewardship revisited. BMC Med. 2017;15(1):15.
2. Schuetz P, Chiappa V, Briel M, Greenwald JL.
Procalcitonin algorithms for antibiotic therapy
decisions: a systematic review of randomized
controlled trials and recommendations for clinical
algorithms. Arch Intern Med. 2011;171(15):1322-1331.
5. Schuetz P, Müller B, Christ-Crain M, et al.
Procalcitonin to initiate or discontinue antibiotics
in acute respiratory tract infections. Cochrane
Database Syst Rev. 2012;9(9):CD007498.
6. Rhodes A, Evans LE, Alhazzani W, et al. Surviving
Sepsis Campaign: international guidelines for
management of sepsis and septic shock: 2016.
Intensive Care Med. 2017;43(3):304-377.

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