ORIGINAL CONTRIBUTION

Effect of Procalcitonin-Based Guidelines

vs Standard Guidelines on Antibiotic Use
in Lower Respiratory Tract Infections
The ProHOSP Randomized Controlled Trial
Philipp Schuetz, MD Context In previous smaller trials, a procalcitonin (PCT) algorithm reduced antibi-
Mirjam Christ-Crain, MD otic use in patients with lower respiratory tract infections (LRTIs).
Robert Thomann, MD Objective To examine whether a PCT algorithm can reduce antibiotic exposure with-
Claudine Falconnier, MD out increasing the risk for serious adverse outcomes.

Marcel Wolbers, PhD Design, Setting, and Patients A multicenter, noninferiority, randomized con-
trolled trial in emergency departments of 6 tertiary care hospitals in Switzerland with
Isabelle Widmer, MD an open intervention of 1359 patients with mostly severe LRTIs randomized between
Stefanie Neidert, MD October 2006 and March 2008.
Thomas Fricker, MD Intervention Patients were randomized to administration of antibiotics based on a
PCT algorithm with predefined cutoff ranges for initiating or stopping antibiotics (PCT
Claudine Blum, MD group) or according to standard guidelines (control group). Serum PCT was measured
Ursula Schild, RN locally in each hospital and instructions were Web-based.
Katharina Regez, RN Main Outcome Measures Noninferiority of the composite adverse outcomes of
death, intensive care unit admission, disease-specific complications, or recurrent in-
Ronald Schoenenberger, MD
fection requiring antibiotic treatment within 30 days, with a predefined noninferiority
Christoph Henzen, MD boundary of 7.5%; and antibiotic exposure and adverse effects from antibiotics.
Thomas Bregenzer, MD Results The rate of overall adverse outcomes was similar in the PCT and control groups
Claus Hoess, MD (15.4% [n=103] vs 18.9% [n=130]; difference, −3.5%; 95% CI, −7.6% to 0.4%).
The mean duration of antibiotics exposure in the PCT vs control groups was lower in
Martin Krause, MD all patients (5.7 vs 8.7 days; relative change, −34.8%; 95% CI, −40.3% to −28.7%)
Heiner C. Bucher, MD and in the subgroups of patients with community-acquired pneumonia (n=925, 7.2
vs 10.7 days; −32.4%; 95% CI, −37.6% to −26.9%), exacerbation of chronic
Werner Zimmerli, MD obstructive pulmonary disease (n=228, 2.5 vs 5.1 days; −50.4%; 95% CI, −64.0%
Beat Mueller, MD to −34.0%), and acute bronchitis (n=151, 1.0 vs 2.8 days; −65.0%; 95% CI, −84.7%
for the ProHOSP Study Group to −37.5%). Antibiotic-associated adverse effects were less frequent in the PCT
group (19.8% [n=133] vs 28.1% [n=193]; difference, −8.2%; 95% CI, −12.7% to

U
NNECESSARY ANTIBIOTIC USE −3.7%).
importantly contributes to in- Conclusion In patients with LRTIs, a strategy of PCT guidance compared with stan-
creasing bacterial resistance dard guidelines resulted in similar rates of adverse outcomes, as well as lower rates of
and increases medical costs antibiotic exposure and antibiotic-associated adverse effects.
and the risks of drug-related adverse Trial Registration isrctn.org Identifier: ISRCTN95122877
events.1-3 The most frequent indication JAMA. 2009;302(10):1059-1066 www.jama.com
for antibiotic prescriptions in the north-
western hemisphere is lower respira-
rial community-acquired pneumonia An approach to estimate the probabil-
tory tract infections (LRTIs),which range
(CAP).4 Clinical signs and symptoms, as ity of bacterial origin in LRTI is the mea-
in severity from self-limited acute bron-
well as commonly used laboratory mark- surement of serum procalcitonin (PCT).
chitis to severe acute exacerbation of
ers, are unreliable in distinguishing vi-
chronic obstructive pulmonary disease
ral from bacterial LRTI.5-7 As many as Author Affiliations and Members of the ProHOSP
(COPD), and to life-threatening bacte-
75% of patients with LRTI are treated Study Group are listed at the end of this article.
Corresponding Author: Beat Mueller, MD, Department
with antibiotics, despite the predomi- of Internal Medicine, Kantonsspital Aarau, Tellstrasse, CH-
For editorial comment see p 1115.
nantly viral origin of their infection.8 5001 Aarau, Switzerland (happy.mueller@unibas.ch).

©2009 American Medical Association. All rights reserved. (Reprinted) JAMA, September 9, 2009—Vol 302, No. 10 1059

Downloaded From: https://jamanetwork.com/ by Roxana Munteanu on 03/26/2019

 PROCALCITONIN GUIDANCE AND ANTIBIOTICS IN LOWER RESPIRATORY INFECTIONS

Evidence from clinical trials suggests Patient Population routinely available around the clock
that use of clinical algorithms based on Between October 2006 and March 2008, within 1 hour. The PCT levels were
PCT cutoff ranges leads to important 1825 patients with a primary diagnosis communicated in the PCT group by
reductions in antibiotic use.9-14 However, of LRTI were treated in the EDs of the 6 the Web site to the treating physician
4 of these trials were performed in single participating hospitals. Patients were re- together with a treatment recommen-
academic hospital settings, compared quired to be at least 18 years and admit- dation for antibiotics based on a PCT
PCT-basedalgorithmswithnonstandard- ted from the community or a nursing algorithm validated in previous stud-
ized routine care, and were all insuffi- homewithacuteLRTIoflessthan28days’ ies.9,11,12,14 According to the PCT al-
cientlypoweredtoshowwhetherpatients duration. Inclusion criteria for LRTI were gorithm (eFigure 1, available at http:
treatedwithPCT-basedalgorithmsdonot thepresenceofatleast1respiratorysymp- //www.jama.com), initiation or con-
have higher rates of disease-related com- tom (cough, sputum production, dys- tinuation of antibiotics was strongly dis-
plications. pnea, tachypnea, pleuritic pain), plus at couraged if PCT was less than 0.1 µg/L
We initiated a large multicenter trial least 1 finding during auscultation (rales, and discouraged if levels were 0.25 µg/L
in both academic and nonacademic hos- crepitation), or 1 sign of infection (core or lower. Initiation or continuation of
pitals in Switzerland to compare whether body temperature ⬎38.0°C, shivering, or antibiotics was strongly encouraged if
the use of PCT guidance would be non- leukocyte count ⬎10 000/µL or ⬍4000/ PCT was higher than 0.5 µg/L and en-
inferior in terms of adverse medical out- µL) independent of antibiotic pretreat- couraged if levels were higher than 0.25
comes and to reduce antibiotic expo- ment. CAP was defined as a new infiltrate µg/L. If antibiotics were withheld,
sure in patients with LRTI compared on chest radiograph.16-19 COPD was de- hospitalized patients were clinically re-
with treatment based on established, in- fined by postbronchodilator spirometric evaluated and PCT measurement was
ternationally recognized guidelines. criteria, according to the Global Initia- repeated after 6 to 24 hours.
tive for Chronic Obstructive Lung Dis- All hospitalized patients were clini-
METHODS ease (GOLD) guidelines.16,21 In patients cally reassessed to follow the resolu-
Study Design withaclinicalhistoryofCOPDandsmok- tion of the infection on days 3, 5, and
ProHOSPisaninvestigator-initiated,mul- ing, lung function testing at the time of 7 and at discharge. In patients in the
ticenter, noninferiority, randomized con- inclusionwasnotmandatory.Acutebron- PCT group with increased PCT values
trolledtrial.Detailsofthetrialdesignhave chitis was defined as LRTI in the absence and antibiotic therapy, PCT measure-
already been published.15 We consecu- of an underlying lung disease or focal ments were repeated after 3, 5, and 7
tivelyenrolledpatientswithLRTIpresent- chest signs and infiltrates on chest radio- days and antibiotic treatment was dis-
ing to the emergency departments (EDs) graph, respectively.17 continued using the same cutoff ranges.
of 6 participating tertiary care hospitals Patients were ineligible if they were not In patients with high PCT values on ad-
andrandomizedthepatientstoreceivean- able to give written informed consent be- mission (ie, ⬎10 µg/L), the algorithm
tibiotics based on a PCT algorithm (PCT cause of language restriction or severe de- recommended stopping antibiotics if
group) or according to evidence-based mentia. Exclusion criteria included pa- PCT levels decreased by 80% and we
guidelines (control group). Allocation of tients with active intravenous drug use, strongly recommended stopping anti-
patients was concealed by a study Web severe immunosuppression other than biotics if PCT levels decreased by 90%
site, which provided all study-related in- corticosteroid use, life-threatening medi- of the initial value. In outpatients, the
formation on the treatment of LRTI based cal comorbidities leading to possible im- initiation and duration of antibiotic
onthemostrecentrecommendations.16-19 minent death, patients with hospital- therapy was based on the initial PCT
To enforce both the guidelines and the acquired pneumonia (development of value and patients were reassessed only
PCTalgorithm,thetreatingphysicianhad pneumonia ⱖ48 hours after hospital ad- in case of worsening disease.
to follow Web-based instructions before mission or if they were hospitalized Overruling of the PCT algorithm was
registeringandenteringbaselinedata.Lo- within 14 days before presentation), and possible by prespecified criteria, namely
cal investigators and the medical staff of patients with chronic infection necessi- in patients with immediate need for in-
each hospital were trained in group semi- tating antibiotic treatment. tensive care unit (ICU) admission, with
nars and received handouts to become respiratory or hemodynamic instability,
familiar with the details of the trial, the Study Protocol and Intervention with positive antigen test for Legionella
correct handling of the PCT algorithm, In all patients, PCT was measured using pneumophila, or after consulting with the
current guideline recommendations, and a rapid sensitive assay with a func- study center. In patients with severe CAP
the study Web site. The protocol was ap- tional assay sensitivity of 0.06 µg/L (pneumonia severity index [PSI]22 IV or
provedbyalllocalethicalcommittees,and (Kryptor PCT; Brahms, Hennigsdorf, V) or COPD (GOLD23 IV or III) and PCT
written informed consent was obtained Germany) and an assay time of less than values of less than 0.1 µg/L or 0.25 µg/L
from all participants. This study adhered 20 minutes. The test was performed on- or less, respectively, initial overruling of
to the consolidated standards for the re- site at the central laboratory of each par- thealgorithmwaspossible.Incaseofover-
porting of noninferiority trials.20 ticipating hospital and the results were ruling, a repeated PCT measurement and
1060 JAMA, September 9, 2009—Vol 302, No. 10 (Reprinted) ©2009 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Roxana Munteanu on 03/26/2019

 PROCALCITONIN GUIDANCE AND ANTIBIOTICS IN LOWER RESPIRATORY INFECTIONS

earlydiscontinuationofantibiotictherapy tibiotic treatment, and length of hospital tation by chained equations to impute the
after3,5,or7dayswasstronglysuggested. stay. Outcomes were assessed during the primary end point for patients lost to fol-
Inthecontrolgroup,antibioticusewas hospital stay by unblinded study physi- low-up. Results were aggregated over 10
in accordance with recommendations cians and by structured telephone inter- imputed sets using the Rubin variance
from up-to-date guidelines.16-19 In brief, views at day 30 by blinded medical stu- formula and the imputation was based
antibiotic use was encouraged in CAP for dents. An independent data and safety on the estimated joint distribution of the
5 to 10 days in uncomplicated cases, at monitoring board was established to randomized treatment group, the diag-
least 14 days in L pneumophila CAP, at monitor safety and adverse events dur- nosis, all covariates included in the deri-
least 10 days in necrotizing CAP, and in ing the trial. vation of the PSI score, length of hospi-
the case of empyema or lung abscess, tal stay, and binary indicators for all
where drainage was suggested. In COPD, Statistical Analysis components of the primary end point.
antibiotic therapy was recommended for The primary study hypothesis was that Because in a noninferiority trial an in-
5 to 10 days if the patient had either se- a PCT algorithm is noninferior to the tention-to-treat analysis is not necessar-
vereCOPD(GOLD23 IV)orpurulentspu- treatment with enforced guidelines with ily conservative, the primary analysis was
tum, and at least 1 of the following: in- respect to the overall adverse outcome. repeated on the per-protocol population.
creased dyspnea and increased sputum To estimate the frequency of the pri- In a second step, the primary end point
volume.21 In acute bronchitis, antibiot- mary end point, we used data from pre- was modeled with a logistic regression
ics were strongly discouraged. A short 3- vious intervention trials.11,12,14 Based on model, adjusted for the following covar-
to 5-day course of antibiotics was recom- these data, the risk of disease-specific fail- iates (in addition to the treatment group):
mended only in patients with purulent ure was assumed to be at most 20%. To age, sex, LRTI subgroup, and center. We
sputumandanadditionalriskfactor(⬎75 define noninferiority with regard to the alsotestedforaninteractionbetweentreat-
years and fever, chronic heart failure, primary combined end point, the plan- ment group and center. The adjusted
insulin-dependent diabetes, or serious ning committee agreed on a 7.5% abso- analysis was repeated in patients with
neurological disorder).19 Irrespective of lute difference as the clinically tolerable CAP, with PSI class as an additional co-
patients’ allocation, other laboratory test upper limit (ie, at worst the risk of an variate.Additionally,Kaplan-Meiercurves
results including white blood cell count overall adverse outcome in the PCT of the time to the first adverse outcome
and C-reactive protein, usually routinely group was increased by ⬍7.5%). Based were calculated. Continuous secondary
requested by the treating physician to on this noninferiority boundary, a mini- end points were compared with the Wil-
monitor the resolution of the infection, mal sample size of 1002 patients was de- coxon rank sum test; CIs for the relative
were allowed by the protocol. termined allowing for an overall ad- reduction in antibiotics exposure and
In both groups, the choice of antibi- verse outcome rate in the control group length of hospital stay were based on the
otic regimen was left at the discretion of at most 20% and aiming for a power bootstrap percentile method. For binary
of the treating physician. A switch from of 90%. Instead of a fixed sample size, secondary end points, we calculated CIs
intravenous to oral antibiotics was rec- we predefined a fixed recruitment pe- fortheriskdifference(overallandinLRTI
ommended if patients had stable or im- riod of 18 months with the goal to ran- subgroups), according to the method of
proving vital signs, resolution of the domize all eligible patients from the 6 AgrestiandCaffo,25 andPvaluesusingthe
predominant clinical sign, and if oral participating hospitals during that pe- ␹2 test.
intake was possible.18,19 riod and an extension if less than 1002 All reported CIs were 2-sided 95%
patients had been recruited.15 This pro- intervals, and tests were 2-sided with
End Points spective rule allows for the possibility of a 5% significance level. All analyses
The primary noninferiority end point was a higher number of patients and thus bet- were performed with R version 2.5.1
a composite of overall adverse out- ter power for subgroup analyses, while (R Foundation for Statistical Comput-
comes occurring within 30 days follow- maintaining the integrity of the trial. All ing, Vienna, Austria)26 and STATA ver-
ing the ED admission. It included death secondary end points were superiority sion 9.2 (Stata Corp, College Station,
from any cause, ICU admission for any end points. No interim analyses were Texas). Multiple imputation was per-
reason, disease-specific complications (ie, planned or performed during the trial. formed with the contributed R pack-
persistence or development of pneumo- The primary analysis population is the age mice.27
nia, lung abscess, empyema, and acute full analysis set, which includes all ran-
respiratory distress syndrome), and re- domized patients following an intention- RESULTS
currence of LRTI in need of antibiotics to-treat principle. A confidence interval We randomized a total of 1381 pa-
with or without hospital readmission. (CI) for the difference of the overall ad- tients; 22 patients withdrew informed
Predefined secondary superiority end verse outcome rates was calculated based consent during the trial and were ex-
points were antibiotic exposure, includ- on Cochran statistic using Mantel- cluded from all analyses, resulting in
ing duration of intravenous and oral an- Haenszel weights and stratification by 1359 patients for the intention-to-treat
tibiotic therapy, adverse effects from an- type of LRTI.24 We used multiple impu- analysis (FIGURE 1). Each of the 6 hos-
©2009 American Medical Association. All rights reserved. (Reprinted) JAMA, September 9, 2009—Vol 302, No. 10 1061

Downloaded From: https://jamanetwork.com/ by Roxana Munteanu on 03/26/2019

 PROCALCITONIN GUIDANCE AND ANTIBIOTICS IN LOWER RESPIRATORY INFECTIONS

prescription did not have a higher risk

Figure 1. Flow Diagram of Patients in Trial
of the combined adverse outcome com-
1825 Patients with lower
pared with patients in the control
respiratory tract infection group. The odds ratio (OR) for the com-
assessed for eligibility
bined adverse outcome was 0.76 (95%
237 Excluded (not eligible)
CI, 0.57-1.01) with lower odds in the
PCT group for all patients, and the OR
1588 Screened for the subgroup of patients with CAP
was 0.76 (95% CI, 0.53-1.07). There
207 Excluded
51 Had severe immunosuppression
was no indication of an interaction be-
29 Had concomitant infection tween study group and center (P=.64).
25 Were active drug users
45 Had hospital-acquired pneumonia Kaplan-Meier curves of the time to
45 Had severe comorbidity
12 Other
the first adverse outcome are shown
in eFigure 2 (available at http://www
1381 Randomized .jama.com).

687 Randomized to receive antibiotics 694 Randomized to receive antibiotics Secondary End Points
based on procalcitonin algorithm based on standard guidelines
Prescription rates and overall antibiotic
16 Withdrew informed consent 6 Withdrew informed consent
exposureweresignificantlyreducedinthe
1 Lost to follow-up 0 Lost to follow-up PCT group for the whole population as
34 Died 33 Died
well as in all LRTI subgroups (TABLE 3).
636 Completed 30-d interview 655 Completed 30-d interview The mean duration of antibiotic exposure
was less overall (FIGURE 2). The overall
671 Included in primary analysis 688 Included in primary analysis reduction in the duration of antibiot-
16 Excluded (withdrew informed 6 Excluded (withdrew informed
consent) consent) ics exposure due to PCT guidance
ranged between 25.7% and 38.7% in the
6 study sites, respectively. The reduc-
pitals contributed between 171 and 265 8.6%) and in patients with CAP, exacer- tions in antibiotic prescription rates
patients and in total 180 residents and bation of COPD, and acute bronchitis. were from 87.7% to 75.4% for all
62 senior residents cared for the pa- MorepatientswithCAPwithlow-riskPSI LRTIs, from 99.1% to 90.7% for CAP,
tients at the 6 participating sites. classes I and II were treated as outpatients from 69.9% to 48.7% for exacerbated
The 2 groups of patients were balanced (20.8%) compared with high-risk PSI COPD, and from 50.0% to 23.2% for
with regard to baseline characteristics classes IV to V (2.4%). acute bronchitis. Reductions in the
(TABLE 1). Antibiotic pretreatment was mean duration of intravenous antibi-
present overall in 27% of patients and in Primary End Point otic therapy was from 3.8 to 3.2 days
26%, 29%, and 29% of patients with CAP, A total of 103 patients in the PCT group for all LRTIs (relative change, −17.1%;
exacerbation of COPD, and acute bron- (15.4%) vs 130 patients (18.9%) in the 95% CI, −26.6% to −6.5%; P ⬍ .001),
chitis,respectively.In11%ofpatients,sys- control group reached the primary end from 4.8 to 4.1 days for CAP, from 1.9
temic corticosteroids mainly for severe point of combined adverse outcome to 1.3 days for exacerbated COPD, and
COPDwereprescribed.In68%ofpatients, within 30 days of ED admission. The from 1.0 to 0.6 days for bronchitis.
CAP was diagnosed; 17% had exacerba- 95% CI for the risk difference (−7.6% to Similarly, reductions in the mean du-
tion of COPD, 11% had acute bronchitis, 0.4%) excludes an excess risk in the PCT ration of oral antibiotic therapy was
and 4% had other final non–LRTI diag- group of 7.5% or more satisfying the pre- from 4.9 to 2.5 days for all LRTIs (rela-
noses(otherinfections[n=15],acutecon- defined noninferiority criterion and the tive change, −48.5%; 95% CI, −54.7%
gestive heart failure [n=8], pulmonary same holds true for the analysis on the to −41.5%; P ⬍ .001), from 5.9 to 3.1
embolism [n=7] or tumor [n=7], vascu- per-protocol population (TABLE 2). Both, days for CAP, from 3.2 to 1.3 days for
litis [n=6], other pneumopathy [n=4], the primary end point and mortality were exacerbated COPD, and from 1.8 to 0.4
other conditions [n=8]). More than 50% similar or tended to be lower for the PCT days for bronchitis.
of patients with CAP were in high-risk group for all LRTI subgroups; 95% CIs In the 925 patients with CAP, 72
classes according to the PSI score.22 Over- for the combined adverse outcome rate (7.8%) had growth of microorganisms in
all,102patients(7.5%)weretreatedasout- and mortality exclude excess risks of blood cultures (Streptococcus pneumoniae
patientsandthemedianlengthofstaywas more than 2.5% overall and in the sub- [n=59], Escherichia coli [n=2], Haemo-
8days(interquartilerange,4-12).Therate group of patients with CAP. philus influenzae [n=2], Staphylococcus
of outpatient treatment was similar in the Adjusted analyses confirmed that aureus [n=2], Pseudomonas aeruginosa
PCT and control groups overall (6.4% vs patients with PCT-guided antibiotic [n=1],Streptococcocusspecies[n=6]),and
1062 JAMA, September 9, 2009—Vol 302, No. 10 (Reprinted) ©2009 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Roxana Munteanu on 03/26/2019

 PROCALCITONIN GUIDANCE AND ANTIBIOTICS IN LOWER RESPIRATORY INFECTIONS

25 patients (2.7%) had a positive urine 29.3% in acute bronchitis). In the sub- (from 7.7 to 5.4 days), the prescription
antigentestforLpneumophila.MeanPCT group of patients in both study groups in rate was decreased from 84.4% to 72.9%,
values in patients with CAP with posi- whom the treatment algorithm was not and adverse effects from antibiotics were
tive blood test cultures (15.3 µg/L) were overruled, the mean duration of antibi- decreased by absolute 7.2% (from 26.6%
higher vs patients with CAP without bac- otic courses was still decreased by 29.3% to 19.4%).
terial growth in blood test cultures (3.3
µg/L). In both groups, the mean dura- Table 1. Baseline Characteristics Overall and by Randomization Group a
tion of antibiotic therapy was longer in All PCT Group Control Group
patients with positive blood test cultures, Characteristics (N = 1359) (n = 671) (n = 688)
namely 10.3 vs 7.0 days in the PCT group Demographics
Age, median (IQR), y 73 (59-82) 73 (59-82) 72 (59-82)
and 15.1 vs 10.2 days in the control Male sex, No. (%) 782 (57.5) 402 (59.9) 380 (55.2)
group. Patients with L pneumophila CAP Coexisting illnesses, No. (%)
had higher mean PCT levels (7.5 vs 4.1 Coronary heart disease 282 (20.8) 146 (21.8) 136 (19.8)
µg/L), but were similarly treated in both Cerebrovascular disease 110 (8.1) 54 (8.1) 56 (8.1)
groups (12.5 days in the PCT group and Renal dysfunction 302 (22.2) 156 (23.3) 146 (21.2)
13.0 days in the control group) as rec- COPD 533 (39.2) 265 (39.5) 268 (39.0)
ommended by the overruling criteria. Neoplastic disease 167 (12.3) 69 (10.3) 98 (14.2)
Diabetes 231 (17.0) 118 (17.0) 113 (16.4)
ThePCTgroupshowedanabsolutede-
Clinical history, No. (%)
creaseof8.2%(95%CI,−12.7%to−3.7%) Antibiotics before presentation 362 (26.8) 187 (28.0) 175 (25.8)
in the rate of adverse effects, including Corticosteroids pretreatment 151 (11.4) 76 (11.6) 75 (11.2)
nausea, diarrhea, and rash (from 28.1% Cough 1164 (88.7) 572 (87.9) 592 (89.4)
to19.8%).Thisdecreasewasmostpromi- Sputum production 678 (50.9) 332 (50.1) 346 (51.8)
nent in patients with CAP (from 33.1% Dyspnea 1009 (77.0) 496 (76.2) 513 (77.7)
to 23.5%) (Table 3). The length of hos- Fever 782 (57.9) 374 (55.8) 408 (59.9)
pital stay was similar in both groups for Chills 362 (32.0) 182 (32.1) 180 (32.0)
all patients and in all LRTI subgroups. Clinical findings
Confusion, No. (%) 84 (6.8) 41 (6.7) 43 (7.0)
Respiratory rate, median (IQR), 20 (16-25) 20 (16-26) 20 (16-25)
Adherence With Study Algorithm breaths/min
In the PCT group, PCT measurements Systolic blood pressure, median 134 (120-150) 134 (120-150) 134 (120-150)
(IQR), mm Hg
were taken at 4.3 different points overall
Heart rate, median (IQR), beats/min 93 (80-106) 93 (80-106) 93 (81-106)
(4.3timesinCAP,4.5timesinCOPD,and Body temperature, median (IQR), °C 37.8 (37.0-38.6) 37.8 (37.0-38.7) 37.8 (37.0-38.5)
3.5 times in acute bronchitis). Only 1 out- Rales, No. (%) 832 (64.1) 418 (64.9) 414 (63.3)
patient (n=43) in the PCT group had a Laboratory findings, median (IQR)
PCTreassessmentatday3.In609patients PCT, µg/L 0.24 (0.11-1.36) 0.24 (0.12-1.18) 0.24 (0.11-1.60)
(90.8%)inthePCTgroup,antibioticswere C-reactive protein, mg/L 114 (41-220) 115 (38-212) 114 (41-220)
initiatedandstoppedaccordingtothePCT Leukocyte count, cells/µL 11 400 (8400-15 300) 11 600 (8500-15 400) 11 200 (8400-15 200)

algorithm, including 70 patients (11.5%) Final diagnosis, No. (%)

CAP 925 (68.1) 460 (68.6) 465 (67.6)
in whom the algorithm was overruled Exacerbation of COPD 228 (16.8) 115 (17.1) 113 (16.4)
based on prespecified criteria (high-risk Acute bronchitis 151 (11.1) 69 (10.3) 82 (11.9)
patients [n=22], instability and ICU Other final diagnosis 55 (4.0) 27 (4.0) 28 (4.0)
admission [n=39], pneumonia due to Risk assessment in patients with CAP (n = 925) (n = 460) (n = 465)
L pneumophila [n=9]). In 62 patients PSI points overall, median (IQR) 91 (66-115) 91 (67-117) 91 (66-114)
(9.2%) in the PCT group, the algorithm PSI class, No. (%)
I 90 (9.7) 76 (11.0) 63 (9.3)
was overruled in violation of the criteria
II 173 (18.7) 138 (20.1) 124 (18.4)
basedonthejudgmentofthetreatingphy-
III 189 (20.4) 147 (21.4) 152 (22.7)
sician(9.6%inCAP,10.4%inCOPD,and IV 349 (37.7) 243 (35.3) 252 (37.6)
2.9% in acute bronchitis). The rates of V 124 (13.4) 84 (12.2) 80 (11.9)
overruling for initiation of therapy and Hospitalized patients, No. (%) 1257 (92.5) 628 (93.7) 629 (91.4)
prolonged antibiotic therapy for the dif- Initial prescription of antibiotics b 1060 (84.3) 492 (78.3) 568 (90.3)
ferent conditions were 5.3% and 20.2% Outpatients, No. (%) 102 (7.5) 43 (6.4) 59 (8.6)
for CAP, 5.3% and 15.9% for exacerbated Initial prescription of antibiotics c 49 (48.0) 14 (32.6) 35 (59.3)
COPD, and 7.3% and 21.9% for acute Abbreviations: CAP, community-acquired pneumonia; COPD, chronic obstructive pulmonary disease; IQR, interquartile
range; PCT, procalcitonin; PSI, pneumonia severity index.
bronchitis, respectively. The overruling a See the “Results” section for definition of other final diagnosis. Higher PSI class refers to higher risk for mortality.
b P⬍.01.
rate in the control group was 20.6% c P⬍.001.
(20.2% in CAP, 21.2% in COPD, and
©2009 American Medical Association. All rights reserved. (Reprinted) JAMA, September 9, 2009—Vol 302, No. 10 1063

Downloaded From: https://jamanetwork.com/ by Roxana Munteanu on 03/26/2019

 PROCALCITONIN GUIDANCE AND ANTIBIOTICS IN LOWER RESPIRATORY INFECTIONS

COMMENT
Table 2. Rates of Combined Adverse Outcomes and Mortality by Randomization Group
In this large multicenter trial includ-
No. (%) of Patients
ing patients with LRTI, an algorithm
PCT Control Risk Difference, with PCT cutoff ranges was noninfe-
Group Group % (95% CI)
rior to algorithm-based clinical guide-
All patients (intention-to-treat) a (n = 671) (n = 688)
Overall adverse outcome 103 (15.4) 130 (18.9) −3.5 (−7.6 to 0.4)
lines in terms of adverse outcomes and
Death 34 (5.1) 33 (4.8) 0.3 (−2.1 to 2.5)
was more effective in reducing antibi-
ICU admission 43 (6.4) 60 (8.7) −2.3 (−5.2 to 0.4) otic exposure and associated adverse
Recurrence/rehospitalization 25 (3.7) 45 (6.5) −2.8 (−5.1 to −0.4) effects.
Disease-specific complication 17 (2.5) 14 (2.0) 0.5 (−1.1 to 2.0) Emerging bacterial resistance to mul-
Per-protocol population (n = 633) (n = 650) tiple antimicrobial agents calls for more
Overall adverse outcome 95 (15.0) 123 (18.9) −3.9 (−8.2 to 0.03) efficient efforts to reduce the use of an-
Death 29 (4.6) 31 (4.8) −0.2 (−2.6 to 2.0) timicrobialagentsinself-limitedandnon-
Community-acquired pneumonia (n = 460) (n = 465) bacterial diseases and to shorten the du-
Overall adverse outcome 74 (16.1) 94 (20.2) −4.1 (−9.1 to 0.9)
ration of antibiotic treatment in bacterial
Death 24 (5.2) 26 (5.6) −0.4 (−3.3 to 2.6)
Exacerbation of COPD a (n = 115) (n = 113)
infections.2 Although several strategies
Overall adverse outcome 15 (13.0) 21 (18.6) −5.3 (−14.8 to 4.4)
have been proposed to reduce antibiotic
Death 4 (3.5) 5 (4.4) −0.9 (−6.4 to 4.5) overuse as well as misuse, adherence to
Acute bronchitis (n = 69) (n = 82) guidelines in routine clinical care is
Overall adverse outcome 6 (8.7) 8 (9.8) −1.1 (−10.4 to 8.7) variable,28-30 which was also confirmed in
Death 1 (1.4) 0 1.4 (−2.9 to 6.1) this trial. The overruling rates in this trial
Other diagnoses (n = 27) (n = 28) were lower in the PCT group vs the con-
Overall adverse outcome 8 (29.6) 7 (25.0) 4.6 (−18.7 to 27.5) trol group and should be interpreted in
Death 5 (18.5) 2 (7.1) 11.4 (−7.5 to 28.9) the context of our study population with
Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; PCT,
procalcitonin. a high number of high-risk patients with
a Outcome was missing for 1 patient with exacerbation of COPD. For the calculation of the risk (n and %) in each group,
CAP (PSI class IV and V) and high rate
this patient was treated as being without adverse outcome, but estimates for the risk difference are based on mul-
tiple imputation of the missing outcome. of ICU admissions.
Higher circulating peak levels and pro-
Figure 2. Antibiotic Exposure in Patients Receiving Antibiotic Therapy tracted normalization of PCT levels cor-
All patients (n = 1359) Community-acquired pneumonia (n = 925)
relate with a more severe systemic in-
100 fection, mirroring a slower bacterial
PCT
clearance and a higher virulence of the
Antibiotic Therapy, %
Patients Receiving

80 Control
microorganism.12,31,32 As shown in 2 pre-
60
vious smaller studies12,13 and in this
40 study, patients with bacteremic CAP had
20 markedly increased PCT concentra-
tions resulting in a longer duration of
0
0 1 3 5 7 9 11 >13 0 1 3 5 7 9 11 >13 treatment. Recommendations for micro-
Time After Study Inclusion, d Time After Study Inclusion, d biological testing in LRTI remain con-
No. of patients
PCT 506 484 410 306 207 138 72 46 417 410 359 272 181 126 64 41 troversial. Positive bacterial cultures may
Control 603 589 562 516 420 324 157 100 461 453 444 426 361 292 146 91 have a major effect on the treatment of
a severely ill patient and are important
Exacerbation of COPD (n = 228) Acute bronchitis (n = 151) for epidemiologic studies and surveil-
100 lance of antibiotic susceptibility pat-
Antibiotic Therapy, %

terns. Conversely, the low sensitivity and

Patients Receiving

80
the infrequent positive effect on clinical
60
care argue against the routine use of
40
blood and sputum cultures in all pa-
20 tients with LRTI.33,34
0
In our trial including patients with dif-
0 1 3 5 7 9 11 >13 0 1 3 5 7 9 11 >13 ferent severities of LRTIs, CAP was the
Time After Study Inclusion, d Time After Study Inclusion, d
most important definite diagnosis. Most
No. of patients
PCT 56 47 30 23 16 6 4 2 16 11 9 3 3 1 1 1 patientswerereferredbytheirprimarycare
Control 79 78 67 58 40 20 5 4 41 38 35 19 8 3 0 0 physician, because of the severity of the
PCT indicates procalcitonin; COPD, chronic obstructive pulmonary disease. infection,concomitantimportantcomor-
1064 JAMA, September 9, 2009—Vol 302, No. 10 (Reprinted) ©2009 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Roxana Munteanu on 03/26/2019

 PROCALCITONIN GUIDANCE AND ANTIBIOTICS IN LOWER RESPIRATORY INFECTIONS

bidities,orboth.Thismayexplaintherela- use of this approach in smaller medical mortality rate, which, however, is at
tively high antibiotic exposure in patients clinics and outpatient physician offices. worst2.5%.Physiciansknowingtheywill
in the control group treated according to A recent trial has proven the feasibility, be monitored better adhere to guidelines
current guidelines. In patients with life- efficacy, and safety of a PCT-guided an- resulting in a possibly lower antibiotic
threatening infections such as CAP, the tibiotic stewardship in primary care.9 prescription rate compared with the real-
PCTalgorithmwasexpectedtoreducean- The strengths of our trial are (1) the life setting (Hawthorne effect). The in-
tibiotic exposure by shortening the anti- large cohort of patients with LRTIs of dif- tervention with PCT testing and physi-
bioticcourses.Appropriatedecreaseofthe ferentseverityandclinicalmanifestations cians’ gained experience of reduced
treatment duration is an important aspect representative for patients typically antibiotic treatment may have affected
ofloweringantibiotic-associatedcostsand treated in EDs and hospitals, (2) the rig- antibiotic prescription patterns in the
minimizing selection pressures for resis- orous follow-up, (3) similar Web-based control group (spillover effect). The fi-
tant organisms.33 Conversely, in milder implementation of both algorithms in nal decision to withhold or decrease an-
respiratoryinfections,namelyacutebron- each treatment group, and (4) the par- tibiotic treatment was left to the discre-
chitis and upper respiratory tract infec- tially blinded outcome assessment. Our tion of the attending physician in both
tions in primary care, initiation of anti- studyalsohaslimitations.Compositeend groups. Thus, physicians were not
biotic therapy is markedly decreased up points including mortality as the clini- obliged to always conform to the study
to 75% by PCT guidance.9 Point-of-care cally most important component have protocol in both groups. However, pro-
testing for PCT measurement are becom- drawbacks. The combined adverse out- tocol overruling would result in a “con-
ing available in Europe and in the United come tended to be lower in the PCT servative bias,” potentially underestimat-
States, which enables a more widespread group, but we observed a slightly higher ingthebenefitofaPCT-guidedapproach.

Table 3. Antibiotic Exposure, Adverse Effects, and Length of Hospital Stay

Relative Mean Change or Rate
PCT Group Control Group Difference % (95% CI)
All patients (n = 671) (n = 688)
Antibiotic exposure, mean (median [IQR]), d 5.7 (5 [1-8]) 8.7 (9 [6-11]) −34.8 (−40.3 to −28.7)
Antibiotic prescription rate, No. (%) 506 (75.4) 603 (87.7) −12.2 (−16.3 to −8.1)
Adverse effect rate from antibiotics, No. (%) 133 (19.8) 193 (28.1) −8.2 (−12.7 to −3.7)
Duration in patients with adverse effects, median (IQR), d 3 (1-7) 4 (2-10)
Length of hospital stay, mean (median [IQR]), d 9.4 (8 [4-12]) 9.2 (8 [4-12]) 1.8 (−6.9 to 11.0)
Community-acquired pneumonia (n = 460) (n = 465)
Antibiotic exposure, mean (median [IQR]), d 7.2 (7 [4-10]) 10.7 (10 [8-12]) −32.4 (−37.6 to −26.9)
Antibiotic prescription rate, No. (%) 417 (90.7) 461 (99.1) −8.5 (−11.3 to −5.6)
Adverse effect rate from antibiotics, No. (%) 108 (23.5) 154 (33.1) −9.6 (−15.4 to −3.8)
Duration in patients with adverse effects, median (IQR), d 3 (2-7) 5 (2-10)
Length of hospital stay, mean (median [IQR]), d 10.0 (8 [5-13]) 9.5 (8 [4-12]) 5.3 (−5.1 to 16.8)
Exacerbation of COPD (n = 115) (n = 113)
Antibiotic exposure, mean (median [IQR]), d 2.5 (0 [0-4]) 5.1 (6 [0-8]) −50.4 (−64.0 to −34.0)
Antibiotic prescription rate, No. (%) 56 (48.7) 79 (69.9) −21.2 (−33.2 to −8.5)
Adverse effect rate from antibiotics, No. (%) 14 (12.2) 18 (15.9) −3.8 (−12.8 to 5.4)
Duration in patients with adverse effects, median (IQR), d 1.5 (1-4) 2 (1-3.5)
Length of hospital stay, mean (median [IQR]), d 8.8 (8 [5-11]) 9.2 (8 [5-13]) −4.4 (−19.1 to 12.9)
Acute bronchitis (n = 69) (n = 82)
Antibiotic exposure, mean (median [IQR]), d 1 (0) 2.8 (1 [0-5]) −65.0 (−84.7 to −37.5)
Antibiotic prescription rate, No. (%) 16 (23.2) 41 (50.0) −26.8 (−40.7 to −11.5)
Adverse effect rate from antibiotics, No. (%) 7 (10.1) 11 (13.4) −3.3 (−13.5 to 7.5)
Duration in patients with adverse effects, median (IQR), d 1 (1-2) 1.5 (1-5.8)
Length of hospital stay, mean (median [IQR]), d 5.4 (4 [1-7]) 6.1 (4 [0-9]) −10.3 (−37.1 to 27.0)
Other diagnoses (n = 27) (n = 28)
Antibiotic exposure, mean (median [IQR]), d 4.9 (3 [0-8]) 7.7 (4 [1-11]) −36.1 (−68.3 to 23.2)
Antibiotic prescription rate, No. (%) 63.0 (17) 78.6 (22) −15.6 (−37.9 to 8.7)
Adverse effect rate from antibiotics, No. (%) 4 (14.8) 10 (35.7) −20.9 (−41.5 to 2.6)
Duration in patients with adverse effects, median (IQR), d 5.5 (4.3-6.8) 3.5 (1.0-8.5)
Length of hospital stay, mean (median [IQR]), d 10.9 (9 [6-14]) 13.4 (11 [5-21]) −19.0 (−42.3 to 15.4)
Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; IQR, interquartile range; PCT, procalcitonin.

©2009 American Medical Association. All rights reserved. (Reprinted) JAMA, September 9, 2009—Vol 302, No. 10 1065

Downloaded From: https://jamanetwork.com/ by Roxana Munteanu on 03/26/2019

 PROCALCITONIN GUIDANCE AND ANTIBIOTICS IN LOWER RESPIRATORY INFECTIONS

In conclusion, particularly in coun- Analysis and interpretation of data: Schuetz, Wolbers, Role of the Sponsors: No commercial sponsors had any
Fricker, Schoenenberger, Bregenzer, Bucher, Mueller. role in the design and conduct of the study; in the col-
tries with higher antibiotic prescription Drafting of the manuscript: Schuetz, Wolbers, Mueller. lection, analysis, and interpretation of the data; or in the
rates than Switzerland,34 PCT guidance Critical revision of the manuscript for important in- preparation, review, or approval of the manuscript.
tellectual content: Christ-Crain, Thomann, Falconnier, The ProHOSP Study Group: Rita Bossart, RN, Sabine
will have substantial clinical and public Widmer, Neidert, Fricker, Blum, Schild, Regez, Meier, Pamela Spreiter, Claudia Baehni, Ayesha Chaudri,
health implications to reduce antibiotic Schoenenberger, Henzen, Bregenzer, Hoess, Krause, Fabian Mueller, Jeannine Haeuptle, Roya Zarbosky, Rico
exposure and associated risks of ad- Bucher, Zimmerli. Fiumefreddo, Melanie Wieland, RN, Charly Nus-
Statistical analysis: Schuetz, Wolbers. baumer, MD, Andres Christ, MD, Roland Bingisser, MD,
verse effects and antibiotic resistance. Obtained funding: Christ-Crain, Schoenenberger, Kristian Schneider, RN, Christine Vincenzi, RN, and
Bucher, Zimmerli, Mueller. Michael Kleinknecht, RN, from the University Hospital
Author Affiliations: Department of Internal Medicine, Administrative, technical, or material support: Schuetz, Basel; Brigitte Walz, PhD, and Verena Briner, MD, Kan-
Kantonsspital Aarau, Aarau (Drs Schuetz, Christ-Crain, Schild, Regez. tonsspital Lucerne; Dieter Conen, MD, Andreas Huber,
Bregenzer, and Mueller and Mss Schild and Regez); De- Study supervision: Schoenenberger, Henzen, MD, and Jody Staehelin, MD, Kantonsspital Aarau;
partment of Internal Medicine (Drs Schuetz, Christ-Crain, Bregenzer, Hoess, Krause, Zimmerli, Mueller. Chantal Bruehlhardt, RN, Kantonsspital Liestal; Ruth
Thomann, Falconnier, Blum, and Mueller and Mss Schild Financial Disclosures: Drs Schuetz, Christ-Crain, and Luginbuehl, RN, and Agnes Muehlemann, RN, Buer-
and Regez) and Basel Institute for Clinical Epidemiology Mueller reported receiving support from BRAHMS Inc gerspital Solothurn, Ineke lambinon, and Max Zueger,
and Biostatistics (Drs Schuetz, Wolbers, and Bucher), to attend meetings and fulfilling speaking engage- MD, Kantonsspital Muensterlingen.
University Hospital Basel, Basel; Department of Internal ments. Dr Mueller reported serving as a consultant and Additional Information: eFigures 1 and 2 are avail-
Medicine, Buergerspital, Solothurn (Drs Thomann and receiving research support from BRAHMS Inc. All other able online at http://www.jama.com.
Schoenenberger); Department of Internal Medicine, Kan- authors declared no financial disclosures. Additional Contributions: We thank our data and safety
tonsspital, Liestal (Drs Falconnier and Zimmerli); Depart- Funding/Support: This work was supported in part by monitoringboard,namely,AndreP.Perruchoud,MD(Uni-
ment of Internal Medicine, Kantonsspital, Lucerne (Drs grant SNF 3200BO-116177/1 from the Swiss National versity Hospital Basel), Stephan Harbarth, MD, MS (Uni-
Widmer, Neidert, and Henzen); and Department of In- Science Foundation and contributions from Santésuisse versityofGenevaHospitals),andAndreaAzzola,MD(Hos-
ternal Medicine, Kantonsspital, Muensterlingen (Drs andtheGottfriedandJuliaBangerter-Rhyner-Foundation, pital of Lugano), for continuous supervision of this trial
Fricker, Hoess, and Krause), Switzerland. the University Hospital Basel, the Medical University Clinic and Florian Duerr (University Hospital Basel) for devel-
Author Contributions: Drs Schuetz and Wolbers had Liestal, the Medical Clinic Buergerspital Solothurn, the opment and support of the Web site. We thank all local
full access to all of the data in the study and take re- Cantonal Hospitals Muensterlingen, Aarau, and Lucerne, physicians, the nursing staff, and patients who partici-
sponsibility for the integrity of the data and the ac- respectively, the Swiss Society for Internal Medicine, and pated in this study. We especially thank the staff of the
curacy of the data analysis. the Department of Endocrinology, Diabetology, and Clini- emergency departments, medical clinics, and central labo-
Study concept and design: Schuetz, Christ-Crain, cal Nutrition, University Hospital Basel. BRAHMS Inc, the ratories of the University Hospital Basel, the Cantonal Hos-
Wolbers, Fricker, Hoess, Bucher, Zimmerli, Mueller. major manufacturer of the procalcitonin assay, provided pitals Liestal, Aarau, Luzern, and Muensterlingen, and the
Acquisition of data: Schuetz, Christ-Crain, Thomann, all assay-related material, Kryptor machines if not already “Buergerspital” Solothurn for their assistance, patience,
Falconnier, Widmer, Neidert, Blum, Schild, Regez, Hen- available onsite, and kits and maintenance required for and technical support. None of those listed received any
zen, Krause, Zimmerli, Mueller. 10 000 measurements related to the study. financial compensation for their contributions.

REFERENCES
1. Wenzel RP. The antibiotic pipeline: challenges, costs, acquired pneumonia: a randomized trial. Am J Respir 25. Agresti A, Caffo B. Simple and effective confidence
and values. N Engl J Med. 2004;351(6):523-526. Crit Care Med. 2006;174(1):84-93. intervals for proportions and difference of proportions
2. Whitney CG, Farley MM, Hadler J, et al. Increas- 13. Nobre V, Harbarth S, Graf JD, et al. Use of pro- result from adding two successes and two failures. Ameri-
ing prevalence of multidrug-resistant Streptococcus calcitonin to shorten antibiotic treatment duration in can Statistician. 2000;54(4):280-288.
pneumoniae in the United States. N Engl J Med. 2000; septic patients. Am J Respir Crit Care Med. 2008; 26. R Development Core Team. A language and en-
343(26):1917-1924. 177(5):498-505. vironment for statistical computing. Vienna, Austria:
3. Shehab N, Patel PR, Srinivasan A, Budnitz DS. Emer- 14. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic R Foundation for Statistical Computing; 2008. http:
gency department visits for antibiotic-associated adverse treatment of exacerbations of COPD. Chest. 2007; //www.r-project.org. Accessed August 3, 2009.
events. Clin Infect Dis. 2008;47(6):735-743. 131(1):9-19. 27. van Buuren S, Oudshoorn CGM. Multivariate im-
4. Mizgerd JP. Acute lower respiratory tract infection. 15. Schuetz P, Christ-Crain M, Wolbers M, et al. Pro- putation by chained equations. MICE V1.0 user’s
N Engl J Med. 2008;358(7):716-727. calcitonin guided antibiotic therapy and hospitaliza- manual, TNO Prevention and Health, Leiden, the Neth-
5. Stolz D, Christ-Crain M, Gencay MM, et al. Diag- tion in patients with lower respiratory tract infections. erlands, 2000. http://www.multiple-imputation
nostic value of signs, symptoms and laboratory val- BMC Health Serv Res. 2007;7:102. .com. Accessed August 3, 2009.
ues in lower respiratory tract infection. Swiss Med Wkly. 16. Calverley PM, Walker P. Chronic obstructive pulmo- 28. Menéndez R, Torres A, Zalacain R, et al. Guide-
2006;136(27-28):434-440. nary disease. Lancet. 2003;362(9389):1053-1061. lines for the treatment of community-acquired
6. Müller B, Harbarth S, Stolz D, et al. Diagnostic and 17. Gonzales R, Sande MA. Uncomplicated acute pneumonia. Am J Respir Crit Care Med. 2005;
prognostic accuracy of clinical and laboratory para- bronchitis. Ann Intern Med. 2000;133(12):981-991. 172(6):757-762.
meters in community-acquired pneumonia. BMC In- 18. Niederman MS, Mandell LA, Anzueto A, et al; Ameri- 29. Aujesky D, Fine MJ. Does guideline adherence for
fect Dis. 2007;7:10. can Thoracic Society. Guidelines for the management of empiric antibiotic therapy reduce mortality in com-
7. Wipf JE, Lipsky BA, Hirschmann JV, et al. Diag- adults with community-acquired pneumonia. Am J Respir munity-acquired pneumonia? Am J Respir Crit Care
nosing pneumonia by physical examination. Arch In- Crit Care Med. 2001;163(7):1730-1754. Med. 2005;172(6):655-656.
tern Med. 1999;159(10):1082-1087. 19. Woodhead M, Blasi F, Ewig S, et al. Guidelines 30. Schouten JA, Hulscher ME, Kullberg BJ, et al. Un-
8. Macfarlane J, Lewis SA, Macfarlane R, Holmes W. for the management of adult lower respiratory tract derstanding variation in quality of antibiotic use for
Contemporary use of antibiotics in 1089 adults pre- infections. Eur Respir J. 2005;26(6):1138-1180. community-acquired pneumonia. J Antimicrob
senting with acute lower respiratory tract illness in gen- 20. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Chemother. 2005;56(3):575-582.
eral practice in the U.K. Respir Med. 1997;91(7): Evans SJ; CONSORT Group. Reporting of noninferi- 31. Müller B, Becker KL, Schachinger H, et al. Calci-
427-434. ority and equivalence randomized trials. JAMA. 2006; tonin precursors are reliable markers of sepsis in a medi-
9. Briel M, Schuetz P, Mueller B, et al. Procalcitonin- 295(10):1152-1160. cal intensive care unit. Crit Care Med. 2000;28
guided antibiotic use vs a standard approach for acute 21. Anthonisen NR, Manfreda J, Warren CP, et al. An- (4):977-983.
respiratory tract infections in primary care. Arch In- tibiotic therapy in exacerbations of chronic obstruc- 32. Harbarth S, Holeckova K, Froidevaux C, et al;
tern Med. 2008;168(18):2000-2007. tive pulmonary disease. Ann Intern Med. 1987; Geneva Sepsis Network. Diagnostic value of procal-
10. Briel M, Christ-Crain M, Young J, et al. Procalci- 106(2):196-204. citonin, interleukin-6, and interleukin-8 in critically ill
tonin-guided antibiotic use versus a standard ap- 22. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule patients admitted with suspected sepsis. Am J Respir
proach for acute respiratory tract infections in pri- to identify low-risk patients with community-acquired Crit Care Med. 2001;164(3):396-402.
mary care. BMC Fam Pract. 2005;6:34. pneumonia. N Engl J Med. 1997;336(4):243-250. 33. Scalera NM, File TM Jr. How long should we treat
11. Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. 23. The Global Initiative for Chronic Obstructive Lung community-acquired pneumonia? Curr Opin Infect Dis.
Effect of procalcitonin-guided treatment on antibi- Disease (GOLD), update 2008. http://www.goldcopd 2007;20(2):177-181.
otic use and outcome in lower respiratory tract .com. Accessed August 3, 2009. 34. Filippini M, Masiero G, Moschetti K. Socioeco-
infections. Lancet. 2004;363(9409):600-607. 24. Song JX, Wassell JT. Sample size for K 2⫻2 tables nomic determinants of regional differences in outpa-
12. Christ-Crain M, Stolz D, Bingisser R, et al. Pro- in equivalence studies using Cochran’s statistic. Con- tient antibiotic consumption. Health Policy. 2006;
calcitonin guidance of antibiotic therapy in community- trol Clin Trials. 2003;24(4):378-389. 78(1):77-92.

1066 JAMA, September 9, 2009—Vol 302, No. 10 (Reprinted) ©2009 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Roxana Munteanu on 03/26/2019