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Procalcitonin to Guide Antibiotic Decisions—Reply

Article  in  JAMA The Journal of the American Medical Association · July 2018

DOI: 10.1001/jama.2018.6725

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 Letters
Procalcitonin to Guide Antibiotic Decisions
To the Editor In a JAMA Clinical Evidence Synopsis article,
Dr Schuetz and colleagues1 summarized their recent Cochrane
review2 of outcomes associated with procalcitonin-guided an-
tibiotic treatment of patients with acute upper and lower re-
spiratory tract infections vs usual care. The article is confus-
ing in that it does not address why there would be an associated
survival benefit, especially when no such association has been
found for its use to manage patients with sepsis.3
Mortality reduction was not a primary hypothesis and
outcome tested in the assembled trials. It seems counterin-
tuitive that a median of 2 fewer antibiotic days would lead
to a higher survival rate for treatment of patients with respi-
ratory infections. Was the mortality benefit associated with
fewer antibiotic-related serious adverse events (eg, anaphy-
laxis or Clostridium difficile colitis)?
Another recent Cochrane review of procalcitonin manage-
ment of patients with sepsis found no significant mortality
reduction.3 One randomized trial (not sponsored by a phar-
maceutical company) of 1200 critically ill patients, among
whom the most common diagnosis was respiratory tract in-
fection and the primary tested outcome was death, also found
no survival benefit with procalcitonin-guided care.4 How-
ever, procalcitonin use was associated with significantly in-
creased interventions, intensive care unit stay, and rates of me-
chanical ventilation and renal dysfunction. In the reviewed
studies, many patients had respiratory tract conditions for
which no antibiotic benefit has been demonstrated (eg, acute
bronchitis and asthma).
Furthermore, in many of these trials, procalcitonin use
was actively guided by the investigator during care or clini-
cians were made to justify algorithm deviations, whereas
there were no interventions with usual care. When active
clinical guideline–directed care was compared with usual
care of patients with pneumonia, it was also demonstrated
to reduce antibiotic use.5
The US Food and Drug Administration has recently
expanded the indications for procalcitonin use to include
guiding antibiotic decisions for patients with a wide range of
respiratory tract infections in the emergency department,
and although further study of its effectiveness in this set-
ting continues (eg, Procalcitonin Antibiotic Consensus Trial,
ClinicalTrials.gov NCT02130986), physicians should consider
if procalcitonin should be recommended for routine care.
In light of the uncertainties highlighted above, as well as
the direct and associated costs and time involved with pro-
calcitonin measurements, is it prudent to encourage the use
of a test to decide on antibiotic treatment of conditions for
which clinicians should already know no antibiotic benefit ex-
ists or for which better adherence to clinical guidelines with-
out such testing would likely achieve the same result?
David A. Talan, MD
Author Affiliation: Department of Emergency Medicine, David Geffen School
of Medicine at University of California, Los Angeles.
Corresponding Author: David A. Talan, MD, 14445 Olive View Dr, North Annex,
Sylmar, CA 91342 (dtalan@ucla.edu).
406 JAMA July 24/31, 2018 Volume 320, Number 4 (Reprinted)
© 2018 American Medical Association. All rights reserved.
Downloaded From: by a University of Basel User on 08/15/2018
Conflict of Interest Disclosures: The author has completed and submitted the
ICMJE Form for Disclosure of Potential Conflicts of Interest and none were
reported.
1. Schuetz P, Wirz Y, Mueller B. Procalcitonin testing to guide antibiotic therapy
in acute upper and lower respiratory tract infections. JAMA. 2018;319(9):925-926.
doi:10.1001/jama.2018.0852
2. Schuetz P, Wirz Y, Sager R, et al. Procalcitonin to initiate or discontinue
antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev.
2017;10:CD007498.
3. Andriole BN, Andriole RB, Salomão R, Atallah ÁN. Effectiveness and safety of
procalcitonin evaluation for reducing mortality in adults with sepsis, severe
sepsis and septic shock. Cochrane Database Syst Rev. 2017;1:CD010959.
4. Jensen JU, Hein L, Lundgren B, et al; Procalcitonin And Survival Study (PASS)
Group. Procalcitonin-guided interventions against infections to increase early
appropriate antibiotics and improve survival in the intensive care unit:
a randomized trial. Crit Care Med. 2011;39(9):2048-2058. doi:10.1097/CCM
.0b013e31821e8791
5. Uranga A, España PP, Bilbao A, et al. Duration of antibiotic treatment in
community-acquired pneumonia: a multicenter randomized clinical trial. JAMA
Intern Med. 2016;176(9):1257-1265. doi:10.1001/jamainternmed.2016.3633
In Reply We agree with Dr Talan that the physiopathological ex-
planation for the mortality benefit found in our meta-
analysis remains incompletely understood,1 but our findings
are corroborated by data from earlier studies, such as the Stop
Antibiotics on guidance of Procalcitonin Study (SAPS), which
assessed more than 1500 patients with sepsis.2 The Cochrane
analysis mentioned by Talan includes only 10 trials with a total
of 1215 patients, excludes the most recent larger trials,2 is not
based on individual patient data, and includes studies with a
primary end point of either antibiotic escalation or de-
escalation, which differs from our approach of assessing the
utility of procalcitonin algorithms to decrease antibiotic pre-
scription or duration.
Procalcitonin is not only a good diagnostic marker for bac-
terial infections but also has strong prognostic value, particu-
larly when procalcitonin kinetics are used to monitor re-
sponse to treatment.3 Procalcitonin-guided care in patients
with acute respiratory infections benefits clinical practice in
several ways. First, procalcitonin-guided care may improve the
initial diagnostic management of patients, and a lower than
expected procalcitonin level may direct clinicians to look for
alternative explanations of respiratory symptoms.4
Second, nonpneumonic lower respiratory tract infec-
tions such as acute bronchitis are often a clinical diagnosis with-
out conclusive microbiological or other diagnostic findings to
definitively rule out bacterial infections. In such patients, low
procalcitonin results may offer reassurance to clinicians and
allow them to adhere to clinical guidelines with more confi-
dence. Reduction of antibiotic overuse in nonpneumonic re-
spiratory infection, even if only by 2 days, is a worthy goal.
Third, antibiotic stewardship protocols improve out-
comes even in the most critically ill patients, and current sep-
sis guidelines emphasize that lowering antibiotic exposure is an
important goal. The prognostic information derived from pro-
calcitonin kinetics adds to the assessment of patients and in-
fluences decisions to order diagnostic tests or pursue new thera-
peutic strategies as well as site of care and timing of discharge.
The Multicenter Procalcitonin Monitoring Sepsis (MOSES) trial
found procalcitonin kinetics during a 72-hour period to be a
jama.com

strong and independent predictor of mortality in patients from
13 US sites.3 Persistently elevated procalcitonin levels in criti-
cally ill patients may also result in earlier detection of failure of
therapy or the need for further diagnostic investigations.
Fourth, prolonged antibiotic exposure has toxic effects and
increases the risk for secondary complications (eg, Clos-
tridium difficile infection) and rehospitalization. In our analy-
sis, procalcitonin-guided care resulted in significantly lower
risk for antibiotic adverse events and a nonsignificant lower
risk for adverse outcomes (odds ratio, 0.90 [95% CI, 0.80-
1.01]; P = .07).
Optimal use of antibiotic treatment in respiratory infec-
tions is challenging due to the lack of sensitive diagnostics that
can effectively rule out bacterial infection. Physicians and pa-
tients share the goal of achieving symptom relief quickly and of-
ten see antibiotics as the means to this goal.5 However, emerg-
ing bacterial resistance calls for more effective efforts to reduce
the unnecessary and prolonged use of antibiotics in patients with
self-limited, nonbacterial pulmonary illnesses. Convincing trial
data support the use of procalcitonin treatment algorithms as
an evidence-based approach to more individualized and judi-
cious use of antibiotics in respiratory infections and sepsis.6
Philipp Schuetz, MD, MPH
Beat Mueller, MD
Author Affiliations: Department of Medicine, University of Basel, Basel,
Switzerland.
Corresponding Author: Philipp Schuetz, MD, MPH, Department of Medicine,
University of Basel, Kantonsspital Aarau, Tellstrasse, CH-5001 Aarau,
Switzerland (schuetzph@gmail.com).
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 grants to their institution and compensation for
consulting work from Thermofisher and bioMerieux.
1. Schuetz P, Wirz Y, Sager R, et al. Effect of procalcitonin-guided antibiotic
treatment on mortality in acute respiratory infections: a patient level
meta-analysis. Lancet Infect Dis. 2018;18(1):95-107. doi:10.1016/S1473-3099(17)
30592-3
2. de Jong E, van Oers JA, Beishuizen A, et al. Efficacy and safety of
procalcitonin guidance in reducing the duration of antibiotic treatment in
critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis.
2016;16(7):819-827. doi:10.1016/S1473-3099(16)00053-0
3. Schuetz P, Birkhahn R, Sherwin R, et al. Serial procalcitonin predicts mortality
in severe sepsis patients: results from the Multicenter Procalcitonin Monitoring
Sepsis (MOSES) study. Crit Care Med. 2017;45(5):781-789. doi:10.1097/CCM
.0000000000002321
4. Schuetz P, Daniels LB, Kulkarni P, Anker SD, Mueller B. Procalcitonin: a new
biomarker for the cardiologist. Int J Cardiol. 2016;223:390-397. doi:10.1016
/j.ijcard.2016.08.204
5. Wirz Y, Branche A, Wolff M, et al. Management of respiratory infections with
use of procalcitonin: moving toward more personalized antibiotic treatment
decisions. ACS Infect Dis. 2017;3(12):875-879. doi:10.1021/acsinfecdis.7b00199
6. Mitsuma SF, Mansour MK, Dekker JP, et al. Promising new assays and
technologies for the diagnosis and management of infectious diseases. Clin
Infect Dis. 2013;56(7):996-1002. doi:10.1093/cid/cis1014
Contact Precautions to Prevent Pathogen
Transmission
To the Editor Dr Rubin and colleagues1 noted the lack of robust
evidence supporting discontinuation of contact precautions
(CPs) for endemic methicillin-resistant Staphylococcus aureus
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Letters
(MRSA) and vancomycin-resistant Enterococci (VRE). How-
ever, the evidence to support CPs is also weak. As they men-
tioned, the BUGG (Benefits of Universal Glove and Gown) trial
failed to show reduced acquisition of MRSA or VRE in the uni-
versal glove and gown group.2
The authors cited the decrease in MRSA in the past
decade in the United States and in Europe after implementa-
tion of bundled infection-prevention strategies. These strate-
gies included, in addition to CPs, increased use of chlorhexi-
dine bathing, a horizontal infection-prevention intervention.
Furthermore, there has been a shift toward single-patient
hospital rooms, especially in acute care hospitals in the
United States. Such a shift away from shared rooms might
have contributed to decreased MRSA acquisition, although
robust evidence is lacking.3
The burden of CPs goes beyond the cost of gowns and
gloves. Donning and doffing gowns takes valuable and lim-
ited health care worker time; the effect is amplified by the
multiple times a busy team may need to enter and exit
patient rooms.
Inaction is not the only response to the status quo in the
absence of strong evidence. In the case of CPs for MRSA or VRE,
it may be reasonable for each institution to make a choice based
on local hand hygiene, MRSA or VRE rates, use of chlorhexi-
dine bathing, and use of single-occupant patient rooms.
Looking to the future, I agree with the authors that non-
confounded studies large enough to demonstrate a signifi-
cant difference between CP and non-CP strategies to reduce
MRSA or VRE are unlikely to be done; studies looking at sur-
rogate outcomes are more practical.
Amy Beth Kressel, MD, MS
Author Affiliation: Division of Infectious Diseases, Indiana University School of
Medicine, Indianapolis.
Corresponding Author: Amy Beth Kressel, MD, MS, Division of Infectious
Diseases, Indiana University School of Medicine, 545 Barnhill Dr, EH 435,
Indianapolis, IN 46202 (abkresse@iu.edu).
Conflict of Interest Disclosures: The author has completed and submitted the
ICMJE Form for Disclosure of Potential Conflicts of Interest and none were
reported.
1. Rubin MA, Samore MH, Harris AD. The importance of contact precautions for
endemic methicillin-resistant Staphylococcus aureus and vancomycin-resistant
Enterococci. JAMA. 2018;319(9):863-864. doi:10.1001/jama.2017.21122
2. Harris AD, Pineles L, Belton B, et al; Benefits of Universal Glove and Gown
(BUGG) Investigators. Universal glove and gown use and acquisition of
antibiotic-resistant bacteria in the ICU: a randomized trial. JAMA. 2013;310(15):
1571-1580. doi:10.1001/jama.2013.277815
3. Simon M, Maben J, Murrells T, Griffiths P. Is single room hospital
accommodation associated with differences in healthcare-associated infection,
falls, pressure ulcers or medication errors? a natural experiment with
non-equivalent controls. J Health Serv Res Policy. 2016;21(3):147-155. doi:10.1177
/1355819615625700
In Reply Dr Kressel raises several important points in response
to our Viewpoint, which we believe reinforce the major argu-
ments from the article.
First, as Kressel points out and as acknowledged in our
Viewpoint, the evidence to support CPs is not strong. Although
the BUGG trial1 failed to show a difference in the primary com-
posite outcome of acquisition of MRSA or VRE, the secondary
(Reprinted) JAMA July 24/31, 2018 Volume 320, Number 4 407