0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Effectiveness and Safety of Procalcitonin-Guided Antibiotic Therapy in Lower Respiratory Tract Infections in “Real Life”:  An International, Multicenter Poststudy Survey (ProREAL) FREE

Werner C. Albrich, MD, MSCR; Frank Dusemund, MD; Birgit Bucher; Stefan Meyer; Robert Thomann, MD; Felix Kühn, MD; Stefano Bassetti, MD; Martin Sprenger, MD; Esther Bachli, MD; Thomas Sigrist, MD; Martin Schwietert, MD; Devendra Amin, MD; Pierre Hausfater, MD, PhD; Eric Carre, MD; Jacques Gaillat, MD; Philipp Schuetz, MD, MPH; Katharina Regez, RN; Rita Bossart, RN, PhD; Ursula Schild, RN; Beat Mueller, MD ; for the ProREAL Study Team
[+] Author Affiliations

Author Affiliations: Medical University Department, Kantonsspital Aarau, Aarau, Switzerland (Drs Albrich, Dusemund, Bossart, and Mueller; Mss Bucher, Regez, and Schild; and Mr Meyer); Division of Medicine, Bürgerspital Solothurn, Solothurn, Switzerland (Dr Thomann); Division of Internal Medicine, University Hospital Basel, Basel, Switzerland (Dr Thomann); Division of Medicine, Kantonsspital Olten, Olten, Switzerland (Drs Kühn and Bassetti); Division of Medicine, Spital Uster, Uster, Switzerland (Drs Sprenger and Bachli); Division of Pulmonology, Klinik Barmelweid, Barmelweid, Switzerland (Dr Sigrist); Medical University Department, Kantonsspital Liestal, Liestal, Switzerland (Dr Schwietert); Morton Plant Hospital, Clearwater, Florida (Dr Amin); Emergency Department, Hôpital Pitié-Salpétriêre at Université Pierre of Marie Curie Univ-Paris06, Paris, France (Dr Hausfater); Service des Maladies Infectieuses, Centre Hospitalier de la Région d’Annecy, Annecy, France (Dr Gaillat); and Department of Emergency Medicine, Harvard School of Public Health, Boston, Massachusetts (Dr Schuetz). Dr Carre is in private practice in Baume-les-Dames, France.


Arch Intern Med. 2012;172(9):715-722. doi:10.1001/archinternmed.2012.770.
Text Size: A A A
Published online

Background In controlled studies, procalcitonin (PCT) has safely and effectively reduced antibiotic drug use for lower respiratory tract infections (LRTIs). However, controlled trial data may not reflect real life.

Methods We performed an observational quality surveillance in 14 centers in Switzerland, France, and the United States. Consecutive adults with LRTI presenting to emergency departments or outpatient offices were enrolled and registered on a website, which provided a previously published PCT algorithm for antibiotic guidance. The primary end point was duration of antibiotic therapy within 30 days.

Results Of 1759 patients, 86.4% had a final diagnosis of LRTI (community-acquired pneumonia, 53.7%; acute exacerbation of chronic obstructive pulmonary disease, 17.1%; and bronchitis, 14.4%). Algorithm compliance overall was 68.2%, with differences between diagnoses (bronchitis, 81.0%; AECOPD, 70.1%; and community-acquired pneumonia, 63.7%; P < .001), outpatients (86.1%) and inpatients (65.9%) (P < .001), algorithm-experienced (82.5%) and algorithm-naive (60.1%) centers (P < .001), and countries (Switzerland, 75.8%; France, 73.5%; and the United States, 33.5%; P < .001). After multivariate adjustment, antibiotic therapy duration was significantly shorter if the PCT algorithm was followed compared with when it was overruled (5.9 vs 7.4 days; difference, −1.51 days; 95% CI, −2.04 to −0.98; P < .001). No increase was noted in the risk of the combined adverse outcome end point within 30 days of follow-up when the PCT algorithm was followed regarding withholding antibiotics on hospital admission (adjusted odds ratio, 0.83; 95% CI, 0.44 to 1.55; P = .56) and regarding early cessation of antibiotics (adjusted odds ratio, 0.61; 95% CI, 0.36 to 1.04; P = .07).

Conclusions This study validates previous results from controlled trials in real-life conditions and demonstrates that following a PCT algorithm effectively reduces antibiotic use without increasing the risk of complications. Preexisting differences in antibiotic prescribing affect compliance with antibiotic stewardship efforts.

Trial Registration isrctn.org Identifier: ISRCTN40854211

Figures in this Article

The efficacy, feasibility, and safety of procalcitonin (PCT)-guided antibiotic stewardship in lower respiratory tract infections (LRTIs) and sepsis has been documented in several randomized controlled trials (RCTs).112 Procalcitonin-guided antibiotic stewardship reduced initial antibiotic prescription rates by 40% to 50% in patients with LRTI presenting to the emergency department5 and by 70% to 80% in ambulatory patients presenting to their general physician13 and reduced total antibiotic exposure in community-acquired pneumonia (CAP) by 40% to 50%.4 The main effect was by discouraging antibiotic initiation in bronchitis and acute exacerbation of chronic obstructive pulmonary disease and by shortening antibiotic courses in CAP without increased rates of adverse outcomes.17

Most evidence regarding PCT-guided antibiotic stewardship derives from RCTs, with little data outside of controlled study conditions. Results from RCTs may not unconditionally be generalized because of exclusion criteria or nonenrollment14 and are frequently not adequately implemented in daily practice.

In this context, we previously performed a single-center poststudy surveillance15 to investigate the real-life effectiveness of PCT-guided antibiotic stewardship after completion of the ProHOSP RCT.7 Median duration of antibiotic treatment was significantly shorter in this survey than in the standard of care ProHOSP control group (6 vs 7 days).15 Compliance with the prespecified algorithm was excellent (90%), without differences in adverse outcomes. However, physicians had previous experience with the algorithm, which potentially increased adherence.

To assess whether these results also apply to different health care settings, we investigated the effects of PCT guidance on inpatients and outpatients in hospitals and general physician offices in 3 countries with diverse antibiotic-prescribing cultures.

PARTICIPANTS AND STUDY DESIGN

This prospective, observational, international, multicenter, quality control survey (ProREAL) monitored initiation and duration of antibiotic therapy, adherence to the published PCT algorithm (Figure 1), and outcome of patients with community-acquired LRTI in centers in Switzerland (n = 10), France (n = 3), and the United States (n = 1) between September 12, 2009, and February 28, 2011. Three of the Swiss hospitals had previously participated in the ProHOSP study2,7 and were considered algorithm experienced; all others were considered algorithm naive.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Algorithm for procalcitonin (PCT)-guided antibiotic therapy. This algorithm was available on a password-secured website to all the physicians and study personnel. ARDS indicates acute respiratory distress syndrome; BOOP, bronchiolitis obliterans with organizing pneumonia; CAP, community-acquired pneumonia; COPD GOLD, chronic obstructive pulmonary disease Global Initiative for Chronic Obstructive Lung Disease; CURB-65, confusion, serum urea nitrogen, respiratory rate, blood pressure, and age 65 years or older; HIV, human immunodeficiency virus; ICU, intensive care unit; IMC, intermediate care unit; MOF, multiple organ failure; PSI, Pneumonia Severity Index; SCLC, small-cell lung cancer; SIRS, sepsis inflammatory response syndrome; and TB, tuberculosis.

Measurement of PCT levels was recommended in all patients using highly sensitive immunoassays (Kryptor [BRAHMS AG] or miniVidas [bioMérieux]). Both assays provide similar PCT results.16,17

Diagnostic workup and treatment were left to the discretion of the treating physicians. Consecutive patients with LRTI who were seen at an emergency department or a physician's office were registered by the physician on duty on a password-secured website that displayed the PCT algorithm (Figure 1).3,7 In the US center, study nurses screened hospital admission records and enrolled patients within 24 hours. There were no exclusion criteria. Physicians and study personnel were instructed in initial face-to-face 1-hour seminars. Throughout the study, weekly e-mails were sent to local coordinators that contained current enrollment status, encountered problems, and suggested solutions. If necessary, local coordinators or individual physicians were contacted by e-mail or telephone.

DEFINITIONS

Bronchitis, LRTI, acute exacerbation of chronic obstructive pulmonary disease, and CAP were defined according to guidelines.7 We defined compliance as antibiotic treatment that was initiated and discontinued in accord with the PCT cutoff ranges or, if the PCT levels suggested no antibiotic therapy, with the predefined overruling criteria. Overruling of the algorithm was possible if any of the following criteria were met: admission to the intensive care unit, life-threatening comorbidity, severe immunosuppression, chronic or non–respiratory tract infection requiring antibiotics, complications (abscess and empyema), difficult-to-treat organisms, or high clinical severity scores (Figure 1). Conversely, noncompliance was defined if antibiotic therapy was initiated or not discontinued despite low PCT levels in the absence of these predefined overruling criteria, that is, if the algorithm was overruled based only on clinical judgment.

MONITORING OF PATIENTS

On presentation and during hospitalization, baseline characteristics, comorbidities, clinical severity scores (CURB-65 [confusion, serum urea nitrogen, respiratory rate, blood pressure, and age ≥65 years]18 and the Pneumonia Severity Index [PSI]19), course of PCT levels and antibiotic therapy, length of hospital stay, and complications were prospectively collected and entered by treating physicians or study personnel (US site) on the website. Adverse medical outcomes, including all-cause and LRTI-related hospital mortality, intensive care unit admission, disease-related complications (ie, empyema, acute respiratory distress syndrome, shock, and requirement for a ventilator or vasopressor support), and recurrence, were obtained from hospital records and were documented on the website. Thirty days after enrollment, telephone interviews were performed by study personnel to identify adverse outcomes, including death, recurrence, rehospitalization, requirement for additional or repeated antibiotic therapy, and antibiotic-related adverse effects. Any adverse outcomes and repeated antibiotic courses were confirmed with hospital medical records or with general physicians. Informed consent was obtained from all the patients at the US site but was waived by Swiss and French ethics committees.

END POINTS

The primary end point was the total duration of antibiotic treatment within 30 days. To calculate antibiotic use duration, we divided the number of total doses by the number of daily doses. In case of combination therapy, antibiotic use duration was determined by the duration of the antibiotic that was given longest; doses of different but simultaneously given antibiotics were not summed. Secondary end points were duration of antibiotic therapy at the index presentation, adherence to the PCT algorithm, and adverse medical outcomes in the index hospitalization.

STATISTICAL ANALYSIS

Discrete variables are expressed as number (percentage) and continuous variables as median (interquartile range), unless stated otherwise. Frequency comparison was performed using the χ2 test and 2-group comparisons by the t test. All the regression models were adjusted for potential confounders, including LRTI diagnosis, country, inpatient or outpatient treatment, sex, PSI score, previous experience with the algorithm, multilobar involvement in CAP, and different comorbidities (diabetes mellitus, malignant disease, cerebrovascular disease, congestive heart failure, renal and hepatic disease, chronic lung disease, and peripheral arterial disease). A multivariable generalized linear model was calculated to assess the effect of algorithm compliance and other independent predictors of antibiotic therapy duration. Logistic regression models were performed to investigate the risk of algorithm compliance, with adverse outcomes defined as in-hospital complications (including acute respiratory distress syndrome, empyema, requirement for vasopressors or mechanical ventilation, admission to the intensive care unit, and death), any 30-day complication (any of the in-hospital complications, death within 30 days, recurrence of LRTI, or rehospitalization), or antibiotic adverse effects (including Clostridium difficile –associated diarrhea, nausea, vomiting, rash, allergic reactions, abdominal pain, and candidiasis). For each adverse outcome, 2 multivariable analyses were performed to assess the safety of initially withholding antibiotic therapy based on low PCT levels (≤0.25 ng/mL) and to assess the safety of cessation of antibiotic use after a decrease in the PCT concentration (≤0.25 ng/mL or a ≥80% decrease from maximum). Statistical analyses were performed using commercially available software programs (SAS, version 9.2 [SAS Institute, Inc] and Epi Info 2002 [Centers for Disease Control and Prevention]). All the testing was 2-tailed, and P < .05 was considered statistically significant.

BASELINE CHARACTERISTICS

Of 1810 patients enrolled, 1759 had complete data sets from the index visit (Swiss: 1361; US: 295; and French: 103). Of 1520 patients (86.4%) with a final diagnosis of LRTI, 1425 (93.8%) had sufficient follow-up information at day 30. Patients with CAP who were overruled correctly according to the predefined criteria in the algorithm were sicker than those treated strictly according to PCT values (PSI class: 2.8 vs 2.2; CURB-65 score: 1.5 vs 1.2; P = .002), who, in turn, were sicker than those who were not correctly overruled, that is, “not compliant” with the algorithm (PSI class: 2.2 vs 1.7; CURB-65 score: 1.2 vs 0.8; P < .001). Baseline characteristics were similar to those of patients in the former ProHOSP study7 in the 3 centers participating in both studies except for a higher severity of patients with CAP in the ProHOSP group (Table 1).

Table Graphic Jump LocationTable 1. Baseline Characteristics (Comparison With the ProHOSP Trial)
PRIMARY END POINT

Of 1520 patients with LRTIs, 1208 (79.5%) received at least 1 antibiotic dose. The overall mean duration of antibiotic therapy was 6.9 days (inpatients, 7.3 days; outpatients, 3.5 days; P < .001).

After multivariate adjustment, the predicted mean duration of antibiotic therapy in LRTI was shorter in algorithm-experienced compared with algorithm-naive centers (6.0 vs 6.7 days; absolute difference in days [95% CI], −0.71 [−1.25 to −0.17]; P < .01) and if the PCT algorithm was followed compared with if not (5.9 vs 7.4 days; absolute difference in days [95% CI], −1.51 [−2.04 to −0.98]; P < .001). Other risk factors for longer antibiotic use duration were CAP (vs bronchitis), renal insufficiency, treatment in France (vs Switzerland), in-hospital (vs ambulatory) treatment, and higher PSI classes. More detailed results of the multivariable analysis are displayed in Table 2.

Table Graphic Jump LocationTable 2. Predictors of Antibiotic Therapy Duration From Multivariable Regression

Antibiotic therapy was longer when blood cultures yielded positive results (adjusted regression coefficient, 1.06; 95% CI, 0.13 to 1.99; P = .03) and in patients with positive sputum culture results (adjusted regression coefficient, 2.03; 95% CI, 1.53 to 3.08; P < .001).

Comparing results with those of historic controls, antibiotic therapy duration during ProREAL (6.2 days; 95% CI, 5.8 to 6.7 days) was longer compared with that of the ProHOSP PCT group (5.0 days; 95% CI, 4.4 to 5.6 days; P = .001) but shorter than in the ProHOSP control group (7.9 days; 95% CI, 7.3 to 8.4 days; P < .001) for the 3 centers that participated in both studies (Figure 2).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Antibiotic exposure compared between real-life experience (ProREAL) and a randomized controlled trial (ProHOSP procalcitonin [PCT] group and control group) (for centers participating in both).

SECONDARY END POINTS
Adherence to the PCT Algorithm

During the entire index presentation (ie, clinic visit, emergency department visit, or entire hospitalization), overall algorithm compliance was 68.2%. Antibiotic therapy followed PCT cutoff ranges on initial presentation in 72.4% of patients and predefined overruling criteria in 8.6% (Figure 1), resulting in overall algorithm compliance of 81.0%. The most important overruling reasons were high clinical severity and respiratory or hemodynamic instability. Overruling due to clinical judgment without prespecified reason occurred in 19.0% of patients.

Algorithm compliance was higher in algorithm-experienced than algorithm-naive centers (P < .001), higher in outpatients than in inpatients (P < .001), higher in Switzerland and France than in the US center (P < .001), and highest in bronchitis and influenza (Figure 3).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Algorithm compliance. CAP indicates community-acquired pneumonia; COPD, chronic obstructive pulmonary disease.

Adverse Medical Outcome

In-hospital mortality was 5.2%; 10.5% of patients were admitted to the intensive care unit. Overall, the in-hospital complication rate was 19.3%, 30-day mortality was 7.6%, and the recurrence rate was 6.8%. After controlling for comorbidities and severity of disease, withholding antibiotics at initial presentation in patients with low PCT values (≤0.25 ng/mL) was not associated with in-hospital complications (adjusted odds ratio [OR], 0.63; 95% CI, 0.30 to 1.31; P = .22) or with any complications within 30 days (adjusted OR, 0.83; 95% CI, 0.44 to 1.55; P = .56) but with a reduction in the risk of antibiotic-related adverse events (adjusted OR, 0.23; 95% CI, 0.06 to 0.91; P = .04) in multivariable models (Table 3).

Table Graphic Jump LocationTable 3. Safety of Initial Withholding of Antibiotic Therapy in Patients With Low PCT Values

Early cessation of antibiotic therapy according to PCT levels (if the PCT level decreased to ≤0.25 ng/mL or decreased ≥80% from its maximum) was not associated with risk of in-hospital complications (adjusted OR, 1.10; 95% CI, 0.61 to 1.97; P = .76) or any complication within 30 days (adjusted OR, 0.61; 95% CI, 0.36 to 1.04; P = .07) in multivariable logistic models (Table 4).

Table Graphic Jump LocationTable 4. Safety of Early Discontinuation of Antibiotic Therapy According to PCT Value After a Decrease in the PCT Value

In this first international multicenter poststudy survey of PCT-guided antibiotic therapy for LRTI, the duration of antibiotic therapy was significantly shortened if the algorithm was followed. The mean overall reduction was approximately 20% (from 7.4 to 5.9 days), which is in the range of that (25%) of a randomized trial using a single PCT value at initial presentation.20 A single PCT measurement in the primary care setting was recently shown to safely reduce the antibiotic treatment rate by 41.6%.13

Multivariable analyses controlling for severity of illness and other confounders confirmed that neither withholding antibiotics on hospital admission in patients with low PCT levels nor discontinuation of antibiotic therapy in patients with appropriate decreases in PCT levels was associated with an increased risk of mortality or of developing other adverse events during hospitalization or over 30 days. The risk of antibiotic-associated adverse events was significantly lower if antibiotics were withheld according to the algorithm. This confirms the safety of PCT-guided antibiotic stewardship outside study conditions and is in accordance with all RCTs and meta-analyses, where there was no difference in outcomes despite strict implementation of the algorithm.21,22

In a single-center pilot survey,15 we had detected similar results for the Kantonsspital Aarau, Aarau, Switzerland, with extensive previous PCT algorithm experience, where we reported 7 and 6 days of antibiotic therapy in patients with CAP and LRTIs, respectively, who were treated according to the PCT algorithm. In the single-center and the present multicenter surveys, we recruited patients with severe comorbidities and immunodeficiency who were formerly excluded from the ProHOSP study. This inclusion at least partially explains why, in the present study, the mean (unadjusted) antibiotic therapy duration in the 3 algorithm-experienced centers was 1.2 days longer than that in the ProHOSP intervention group but 1.7 days shorter than that in the ProHOSP control group. In experienced centers, antibiotic treatment duration was similar to that in the previous single-center pilot study and significantly shorter than that in algorithm-naive centers. These results indicate that PCT safely allows individualized and shortened treatment duration also in real-life conditions in different health care settings.

The finding that CAP and in-hospital treatment were predictors of longer antibiotic treatment is plausible since those patients have a higher likelihood of a bacterial etiology than do patients with bronchitis, who more frequently undergo outpatient treatment. Likewise, its association with increasing severity of illness might explain why renal insufficiency was an independent predictor of longer antibiotic treatment. Renal insufficiency does not prolong the half-life of PCT.23 Patients with an identified cause had a longer duration of antibiotic therapy than if no causative agent was identified. The PCT levels have been associated with the presence of bacteremia2426 and bacterial load,26 supporting our observation and the validity of our algorithm.

The second important focus of this survey was to evaluate algorithm adherence outside of stringent study conditions in countries with considerably different antibiotic-prescribing cultures and PCT experience. The observed level of compliance is remarkable, especially considering that initial introductory seminars were short, that only 3 of the 14 participating sites were algorithm-experienced, and that 1 of the 3 countries had limited experience with PCT (the United States). In the previous survey,15 we had achieved overall algorithm compliance of 90% outside of study conditions in a hospital well used to the algorithm. Aujesky et al27 found that 37.4% of patients with low PSI scores were hospitalized mainly for comorbid illnesses, reflecting the difficulty of implementing guidelines into daily clinical practice and limited confidence in clinical scores. Although the PSI algorithm is more complex than the PCT algorithm, resulting in a lower likelihood of being implemented, we assessed PCT compliance not only at presentation but throughout the entire index presentation, that is, hospitalization in inpatients.

Implementation of algorithms is more challenging with increasing severity of illness,9 when physicians might rely on self-perceived levels of experience. This might explain the observation of decreasing compliance from bronchitis to acute exacerbation of chronic obstructive pulmonary disease and CAP. Algorithm compliance was higher in experienced than in naive centers and in Europe than in the United States, probably reflecting a learning curve of the laboratory and the physicians. Therefore, ongoing reinforcement is necessary to increase compliance and the rational use of antibiotics, minimizing antibiotic selection pressure. This also demonstrates the importance of preexisting regional and cultural differences in antibiotic-prescribing habits between Europe and North America,28,29 which influence the success of such interventions. Antibiotic-prescribing patterns reflect multilayer decision making, including sociocultural, health care system, legal, and health belief factors. It, thus, is not surprising that compliance was highest in Switzerland, with the lowest antibiotic consumption and resistance rate.30,31

The strengths of this study are its size as the largest single study of PCT-guided antibiotic therapy and its international web-based design. The inclusion of consecutive patients of all different levels of care and experience without exclusion criteria and the relatively small implementation efforts support its generalizability. Although the study design did not permit a direct control group, comparison with historic controls from an RCT performed at the same locations supports the effectiveness of the algorithm.

A potential limitation is the discrepancy between the number of participating centers in Switzerland (n = 10), France (n = 3), and the United States (n = 1). It is, therefore, difficult to make a general conclusion for all countries based on the findings of this survey. Improved PCT assay availability, preferably as a bedside point-of-care test, and reduced assay costs are prerequisites for widespread implementation.

In conclusion, this real-life effectiveness study complements the excellent efficacy and safety record of PCT-guided antibiotic stewardship from many previous RCTs and extends those beyond the stringent study setting. We demonstrate that good compliance with the PCT algorithm is possible in real-life conditions but has to be reinforced to achieve optimal benefit. Regional and cultural differences in preexisting antibiotic-prescribing habits pose a challenge to its successful implementation that requires particular attention.

Correspondence: Beat Mueller, MD, Medical University Department, Kantonsspital Aarau, Tellstrasse, CH-5001 Aarau, Switzerland (happy.mueller@unibas.ch).

Accepted for Publication: January 2, 2012.

Author Contributions: Dr Albrich had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Albrich, Dusemund, Schuetz, and Mueller. Acquisition of data: Albrich, Dusemund, Bucher, Meyer, Thomann, Kühn, Bassetti, Sprenger, Bachli, Sigrist, Schwietert, Amin, Hausfater, Carre, Regez, Bossart, and Schild. Analysis and interpretation of data: Albrich, Dusemund, Bassetti, Schuetz, and Mueller. Drafting of the manuscript: Albrich and Dusemund. Critical revision of the manuscript for important intellectual content: Albrich, Dusemund, Bucher, Meyer, Thomann, Kühn, Bassetti, Sprenger, Bachli, Sigrist, Schwietert, Amin, Hausfater, Gaillat, Schuetz, Regez, Bossart, Schild, and Mueller. Statistical analysis: Albrich, Dusemund, and Schuetz. Obtained funding: Mueller. Administrative, technical, and material support: Albrich, Dusemund, Kühn, Sprenger, Bachli, Sigrist, Schwietert, Amin, Hausfater, Regez, Bossart, Schild, and Mueller. Study supervision: Albrich, Dusemund, Hausfater, Schuetz, and Mueller.

Financial Disclosure: Drs Albrich, Schuetz, and Mueller have received support from BRAHMS AG to attend meetings and fulfill speaking engagements. Dr Amin has received speaking honoraria from bioMérieux. Drs Albrich and Mueller have received support from bioMérieux to attend meetings. Dr Mueller has served as a consultant to and received research support from BRAHMS AG and bioMérieux.

ProREAL Study Team Members:Kantonsspital Aarau, Aarau, Switzerland: Werner C. Albrich, MD, MSCR; Frank Dusemund, MD; Birgit Bucher; Stefan Meyer; Katharine Regez, RN; Rita Bossart, RN, PhD; Ursula Schild, RN; Beat Mueller, MD; Marcus Batschwaroff, MD; Birsen Arici; Alexander Litke; Ulrich Bürgi, MD; Andreas Huber, MD; Sarosh Irani, MD; and Renate Hunziker. Bürgerspital Solothurn, Solothurn, Switzerland: Robert Thomann, MD. Kantonsspital Olten, Olten, Switzerland: Felix Kühn, MD, and Stefano Bassetti, MD. Spital Uster, Uster, Switzerland: Martin Sprenger, MD, and Ester Bachli, MD. Kreisspital für das Freiamt Muri, Muri, Switzerland: Alexander Spillmann, MD. Spital Menziken, Menziken, Switzerland: Slavka Kraljevic, MD. Kantonsspital Liestal, Liestal, Switzerland: Martin Schwietert, MD, and Werner Zimmerli, MD. Klinik Barmelweid, Barmelweid, Switzerland: Thomas Sigrist, MD, and Martin Frey, MD. Institut für Arbeitsmedizin, Baden, Switzerland: Daniel Rodriguez, MD. Morton Plant Hospital, Clearwater, Florida: Devendra Amin, MD. Harvard School of Public Health, Boston, Massachusetts: Philipp Schuetz, MD, MPH. Hôpital Pitié-Salpétriêre, Paris, France: Piere Hausfater, MD, PhD; Viviane Montout, MD; and Beatrice Madonna-Py, MD. Baume-les-Dames, France: Eric Carre, MD. Centre Hospitalier de la Région d’Annecy, Annecy, France: Jacques Gaillat, MD, and Gaëlle Pillaut, MD.

Funding/Support: bioMérieux provided PCT kits and testing devices and provided a small financial compensation per enrolled patient.

Role of the Sponsor: bioMérieux had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Additional Contributions: Michael Fine, MD, MSc, provided helpful comments and advice. We are grateful to all the patients, physicians, and nursing staff from the centers who participated in this survey.

This article was corrected for errors on May 2, 2014.

Stolz D, Christ-Crain M, Bingisser R,  et al.  Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy.  Chest. 2007;131(1):9-19
PubMed   |  Link to Article
Schuetz P, Christ-Crain M, Wolbers M,  et al; ProHOSP Study Group.  Procalcitonin-guided antibiotic therapy and hospitalization in patients with lower respiratory tract infections: a prospective, multicenter, randomized controlled trial.  BMC Health Serv Res. 2007;7:102
PubMed   |  Link to Article
Christ-Crain M, Stolz D, Bingisser R,  et al.  Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial.  Am J Respir Crit Care Med. 2006;174(1):84-93
PubMed   |  Link to Article
Christ-Crain M, Jaccard-Stolz D, Bingisser R,  et al.  Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial.  Lancet. 2004;363(9409):600-607
PubMed   |  Link to Article
Briel M, Schuetz P, Mueller B,  et al.  Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care.  Arch Intern Med. 2008;168(18):2000-2008
PubMed   |  Link to Article
Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial.  Am J Respir Crit Care Med. 2008;177(5):498-505
PubMed   |  Link to Article
Schuetz P, Christ-Crain M, Thomann R,  et al; ProHOSP Study Group.  Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial.  JAMA. 2009;302(10):1059-1066
PubMed   |  Link to Article
Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease.  Ann Intern Med. 1987;106(2):196-204
PubMed   |  Link to Article
Bouadma L, Luyt CE, Tubach F,  et al.  Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial.  Lancet. 2010;375(9713):463-474
PubMed   |  Link to Article
Stolz D, Smyrnios N, Eggimann P,  et al.  Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study.  Eur Respir J. 2009;34(6):1364-1375
PubMed   |  Link to Article
Hochreiter M, Köhler T, Schweiger AM,  et al.  Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial.  Crit Care. 2009;13(3):R83
PubMed   |  Link to Article
Schuetz P, Christ-Crain M, Müller B. Procalcitonin and other biomarkers to improve assessment and antibiotic stewardship in infections: hope for hype?  Swiss Med Wkly. 2009;139(23-24):318-326
PubMed
Burkhardt O, Ewig S, Haagen U,  et al.  Procalcitonin guidance and reduction of antibiotic use in acute respiratory tract infection.  Eur Respir J. 2010;36(3):601-607
PubMed   |  Link to Article
Juurlink DN, Mamdani MM, Lee DS,  et al.  Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study.  N Engl J Med. 2004;351(6):543-551
PubMed   |  Link to Article
Schuetz P, Batschwaroff M, Dusemund F,  et al.  Effectiveness of a procalcitonin algorithm to guide antibiotic therapy in respiratory tract infections outside of study conditions: a post-study survey.  Eur J Clin Microbiol Infect Dis. 2010;29(3):269-277
PubMed   |  Link to Article
Schuetz P, Christ-Crain M, Huber AR, Müller B. Long-term stability of procalcitonin in frozen samples and comparison of Kryptor and VIDAS automated immunoassays.  Clin Biochem. 2010;43(3):341-344
PubMed   |  Link to Article
Hausfater P, Brochet C, Freund Y, Charles V, Bernard M. Procalcitonin measurement in routine emergency medicine practice: comparison between two immunoassays.  Clin Chem Lab Med. 2010;48(4):501-504
PubMed   |  Link to Article
Lim WS, van der Eerden MM, Laing R,  et al.  Defining community-acquired pneumonia severity on presentation to hospital: an international derivation and validation study.  Thorax. 2003;58(5):377-382
PubMed   |  Link to Article
Fine MJ, Auble TE, Yealy DM,  et al.  A prediction rule to identify low-risk patients with community-acquired pneumonia.  N Engl J Med. 1997;336(4):243-250
PubMed   |  Link to Article
Kristoffersen KB, Søgaard OS, Wejse C,  et al.  Antibiotic treatment interruption of suspected lower respiratory tract infections based on a single procalcitonin measurement at hospital admission: a randomized trial.  Clin Microbiol Infect. 2009;15(5):481-487
PubMed   |  Link to Article
Schuetz P, Albrich W, Christ-Crain M, Chastre J, Mueller B. Procalcitonin for guidance of antibiotic therapy.  Expert Rev Anti Infect Ther. 2010;8(5):575-587
PubMed   |  Link to Article
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
PubMed   |  Link to Article
Meisner M, Schmidt J, Hüttner H, Tschaikowsky K. The natural elimination rate of procalcitonin in patients with normal and impaired renal function.  Intensive Care Med. 2000;26:(suppl 2)  S212-S216
PubMed   |  Link to Article
Müller F, Christ-Crain M, Bregenzer T,  et al; ProHOSP Study Group.  Procalcitonin levels predict bacteremia in patients with community-acquired pneumonia: a prospective cohort trial.  Chest. 2010;138(1):121-129
PubMed   |  Link to Article
Riedel S, Melendez JH, An AT, Rosenbaum JE, Zenilman JM. Procalcitonin as a marker for the detection of bacteremia and sepsis in the emergency department.  Am J Clin Pathol. 2011;135(2):182-189
PubMed   |  Link to Article
van Nieuwkoop C, Bonten TN, van't Wout JW,  et al.  Procalcitonin reflects bacteremia and bacterial load in urosepsis syndrome: a prospective observational study.  Crit Care. 2010;14(6):R206
PubMed   |  Link to Article
Aujesky D, McCausland JB, Whittle J, Obrosky DS, Yealy DM, Fine MJ. Reasons why emergency department providers do not rely on the Pneumonia Severity Index to determine the initial site of treatment for patients with pneumonia.  Clin Infect Dis. 2009;49(10):e100-e108
PubMed   |  Link to Article
Harbarth S, Albrich W, Goldmann DA, Huebner J. Control of multiply-resistant cocci: do international comparisons help?  Lancet Infect Dis. 2001;1(4):251-261
PubMed   |  Link to Article
Harbarth S, Albrich W, Brun-Buisson C. Outpatient antibiotic use and prevalence of antibiotic-resistant pneumococci in France and Germany: a sociocultural perspective.  Emerg Infect Dis. 2002;8(12):1460-1467
PubMed   |  Link to Article
Albrich WC, Monnet DL, Harbarth S. Antibiotic selection pressure and resistance in Streptococcus pneumoniae and Streptococcus pyogenes Emerg Infect Dis. 2004;10(3):514-517
PubMed   |  Link to Article
Filippini M, Masiero G, Moschetti K. Socioeconomic determinants of regional differences in outpatient antibiotic consumption: evidence from Switzerland.  Health Policy. 2006;78(1):77-92
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Algorithm for procalcitonin (PCT)-guided antibiotic therapy. This algorithm was available on a password-secured website to all the physicians and study personnel. ARDS indicates acute respiratory distress syndrome; BOOP, bronchiolitis obliterans with organizing pneumonia; CAP, community-acquired pneumonia; COPD GOLD, chronic obstructive pulmonary disease Global Initiative for Chronic Obstructive Lung Disease; CURB-65, confusion, serum urea nitrogen, respiratory rate, blood pressure, and age 65 years or older; HIV, human immunodeficiency virus; ICU, intensive care unit; IMC, intermediate care unit; MOF, multiple organ failure; PSI, Pneumonia Severity Index; SCLC, small-cell lung cancer; SIRS, sepsis inflammatory response syndrome; and TB, tuberculosis.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Antibiotic exposure compared between real-life experience (ProREAL) and a randomized controlled trial (ProHOSP procalcitonin [PCT] group and control group) (for centers participating in both).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Algorithm compliance. CAP indicates community-acquired pneumonia; COPD, chronic obstructive pulmonary disease.

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics (Comparison With the ProHOSP Trial)
Table Graphic Jump LocationTable 2. Predictors of Antibiotic Therapy Duration From Multivariable Regression
Table Graphic Jump LocationTable 3. Safety of Initial Withholding of Antibiotic Therapy in Patients With Low PCT Values
Table Graphic Jump LocationTable 4. Safety of Early Discontinuation of Antibiotic Therapy According to PCT Value After a Decrease in the PCT Value

References

Stolz D, Christ-Crain M, Bingisser R,  et al.  Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy.  Chest. 2007;131(1):9-19
PubMed   |  Link to Article
Schuetz P, Christ-Crain M, Wolbers M,  et al; ProHOSP Study Group.  Procalcitonin-guided antibiotic therapy and hospitalization in patients with lower respiratory tract infections: a prospective, multicenter, randomized controlled trial.  BMC Health Serv Res. 2007;7:102
PubMed   |  Link to Article
Christ-Crain M, Stolz D, Bingisser R,  et al.  Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial.  Am J Respir Crit Care Med. 2006;174(1):84-93
PubMed   |  Link to Article
Christ-Crain M, Jaccard-Stolz D, Bingisser R,  et al.  Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial.  Lancet. 2004;363(9409):600-607
PubMed   |  Link to Article
Briel M, Schuetz P, Mueller B,  et al.  Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care.  Arch Intern Med. 2008;168(18):2000-2008
PubMed   |  Link to Article
Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial.  Am J Respir Crit Care Med. 2008;177(5):498-505
PubMed   |  Link to Article
Schuetz P, Christ-Crain M, Thomann R,  et al; ProHOSP Study Group.  Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial.  JAMA. 2009;302(10):1059-1066
PubMed   |  Link to Article
Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease.  Ann Intern Med. 1987;106(2):196-204
PubMed   |  Link to Article
Bouadma L, Luyt CE, Tubach F,  et al.  Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial.  Lancet. 2010;375(9713):463-474
PubMed   |  Link to Article
Stolz D, Smyrnios N, Eggimann P,  et al.  Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study.  Eur Respir J. 2009;34(6):1364-1375
PubMed   |  Link to Article
Hochreiter M, Köhler T, Schweiger AM,  et al.  Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial.  Crit Care. 2009;13(3):R83
PubMed   |  Link to Article
Schuetz P, Christ-Crain M, Müller B. Procalcitonin and other biomarkers to improve assessment and antibiotic stewardship in infections: hope for hype?  Swiss Med Wkly. 2009;139(23-24):318-326
PubMed
Burkhardt O, Ewig S, Haagen U,  et al.  Procalcitonin guidance and reduction of antibiotic use in acute respiratory tract infection.  Eur Respir J. 2010;36(3):601-607
PubMed   |  Link to Article
Juurlink DN, Mamdani MM, Lee DS,  et al.  Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study.  N Engl J Med. 2004;351(6):543-551
PubMed   |  Link to Article
Schuetz P, Batschwaroff M, Dusemund F,  et al.  Effectiveness of a procalcitonin algorithm to guide antibiotic therapy in respiratory tract infections outside of study conditions: a post-study survey.  Eur J Clin Microbiol Infect Dis. 2010;29(3):269-277
PubMed   |  Link to Article
Schuetz P, Christ-Crain M, Huber AR, Müller B. Long-term stability of procalcitonin in frozen samples and comparison of Kryptor and VIDAS automated immunoassays.  Clin Biochem. 2010;43(3):341-344
PubMed   |  Link to Article
Hausfater P, Brochet C, Freund Y, Charles V, Bernard M. Procalcitonin measurement in routine emergency medicine practice: comparison between two immunoassays.  Clin Chem Lab Med. 2010;48(4):501-504
PubMed   |  Link to Article
Lim WS, van der Eerden MM, Laing R,  et al.  Defining community-acquired pneumonia severity on presentation to hospital: an international derivation and validation study.  Thorax. 2003;58(5):377-382
PubMed   |  Link to Article
Fine MJ, Auble TE, Yealy DM,  et al.  A prediction rule to identify low-risk patients with community-acquired pneumonia.  N Engl J Med. 1997;336(4):243-250
PubMed   |  Link to Article
Kristoffersen KB, Søgaard OS, Wejse C,  et al.  Antibiotic treatment interruption of suspected lower respiratory tract infections based on a single procalcitonin measurement at hospital admission: a randomized trial.  Clin Microbiol Infect. 2009;15(5):481-487
PubMed   |  Link to Article
Schuetz P, Albrich W, Christ-Crain M, Chastre J, Mueller B. Procalcitonin for guidance of antibiotic therapy.  Expert Rev Anti Infect Ther. 2010;8(5):575-587
PubMed   |  Link to Article
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
PubMed   |  Link to Article
Meisner M, Schmidt J, Hüttner H, Tschaikowsky K. The natural elimination rate of procalcitonin in patients with normal and impaired renal function.  Intensive Care Med. 2000;26:(suppl 2)  S212-S216
PubMed   |  Link to Article
Müller F, Christ-Crain M, Bregenzer T,  et al; ProHOSP Study Group.  Procalcitonin levels predict bacteremia in patients with community-acquired pneumonia: a prospective cohort trial.  Chest. 2010;138(1):121-129
PubMed   |  Link to Article
Riedel S, Melendez JH, An AT, Rosenbaum JE, Zenilman JM. Procalcitonin as a marker for the detection of bacteremia and sepsis in the emergency department.  Am J Clin Pathol. 2011;135(2):182-189
PubMed   |  Link to Article
van Nieuwkoop C, Bonten TN, van't Wout JW,  et al.  Procalcitonin reflects bacteremia and bacterial load in urosepsis syndrome: a prospective observational study.  Crit Care. 2010;14(6):R206
PubMed   |  Link to Article
Aujesky D, McCausland JB, Whittle J, Obrosky DS, Yealy DM, Fine MJ. Reasons why emergency department providers do not rely on the Pneumonia Severity Index to determine the initial site of treatment for patients with pneumonia.  Clin Infect Dis. 2009;49(10):e100-e108
PubMed   |  Link to Article
Harbarth S, Albrich W, Goldmann DA, Huebner J. Control of multiply-resistant cocci: do international comparisons help?  Lancet Infect Dis. 2001;1(4):251-261
PubMed   |  Link to Article
Harbarth S, Albrich W, Brun-Buisson C. Outpatient antibiotic use and prevalence of antibiotic-resistant pneumococci in France and Germany: a sociocultural perspective.  Emerg Infect Dis. 2002;8(12):1460-1467
PubMed   |  Link to Article
Albrich WC, Monnet DL, Harbarth S. Antibiotic selection pressure and resistance in Streptococcus pneumoniae and Streptococcus pyogenes Emerg Infect Dis. 2004;10(3):514-517
PubMed   |  Link to Article
Filippini M, Masiero G, Moschetti K. Socioeconomic determinants of regional differences in outpatient antibiotic consumption: evidence from Switzerland.  Health Policy. 2006;78(1):77-92
PubMed   |  Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 24

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

Users' Guides to the Medical Literature
Clinical Resolution

Users' Guides to the Medical Literature
Clinical Scenario