Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter / Tate, Jillian R.

12 Issues per year


IMPACT FACTOR 2016: 3.432

CiteScore 2016: 2.21

SCImago Journal Rank (SJR) 2016: 1.000
Source Normalized Impact per Paper (SNIP) 2016: 1.112

Online
ISSN
1437-4331
See all formats and pricing
More options …
Volume 56, Issue 1

Issues

Effects of procalcitonin testing on antibiotic use and clinical outcomes in patients with upper respiratory tract infections. An individual patient data meta-analysis

Jonas Odermatt / Natalie Friedli / Alexander Kutz / Matthias Briel
  • Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Heiner C. Bucher
  • Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Mirjam Christ-Crain
  • Division of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Basel, Basel, Switzerland
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Olaf Burkhardt / Tobias Welte / Beat Mueller / Philipp Schuetz
  • Corresponding author
  • University Department of Medicine, Kantonsspital Aarau, Aarau, Switzerland
  • Medical Faculty, University of Basel, Basel, Switzerland
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2017-06-29 | DOI: https://doi.org/10.1515/cclm-2017-0252

Abstract

Background:

Several trials found procalcitonin (PCT) helpful for guiding antibiotic treatment in patients with lower respiratory tract infections and sepsis. We aimed to perform an individual patient data meta-analysis on the effects of PCT guided antibiotic therapy in upper respiratory tract infections (URTI).

Methods:

A comprehensive search of the literature was conducted using PubMed (MEDLINE) and Cochrane Library to identify relevant studies published until September 2016. We reanalysed individual data of adult URTI patients with a clinical diagnosis of URTI. Data of two trials were used based on PRISMA-IPD guidelines. Safety outcomes were (1) treatment failure defined as death, hospitalization, ARI-specific complications, recurrent or worsening infection at 28 days follow-up; and (2) restricted activity within a 14-day follow-up. Secondary endpoints were initiation of antibiotic therapy, and total days of antibiotic exposure.

Results:

In total, 644 patients with a follow up of 28 days had a final diagnosis of URTI and were thus included in this analysis. There was no difference in treatment failure (33.1% vs. 34.0%, OR 1.0, 95% CI 0.7–1.4; p=0.896) and days with restricted activity between groups (8.0 vs. 8.0 days, regression coefficient 0.2 (95% CI –0.4 to 0.9), p=0.465). However, PCT guided antibiotic therapy resulted in lower antibiotic prescription (17.8% vs. 51.0%, OR 0.2, 95% CI 0.1–0.3; p<0.001) and in a 2.4 day (95% CI –2.9 to –1.9; p<0.001) shorter antibiotic exposure compared to control patients.

Conclusions:

PCT guided antibiotic therapy in the primary care setting was associated with reduced antibiotic exposure in URTI patients without compromising outcomes.

This article offers supplementary material which is provided at the end of the article.

Keywords: lower antibiotic exposure; meta-analysis; primary care setting; procalcitonin; procalcitonin guided antibiotic prescription; upper respiratory tract infection

Introduction

Upper respiratory tract infections (URTI) are predominantly of viral origin, sometimes of bacterial and only rarely of other aetiologies. Overall, URTI cause millions of medical consultations and are amongst the most common reason for antibiotic therapy in primary care. To date, there is no validated diagnostic test that allows identifying the viral and/or bacterial microorganism causing the infection with high sensitivity. The diagnostic work-up and treatment decisions are therefore mainly based on ambiguous clinical criteria. As a consequence, despite the mainly viral aetiology, in Europe and the United States (US) over 50% of URTI are treated with antibiotics [1], [2], [3], [4]. While early initiation of antibiotic therapy is – without doubt – highly effective to reduce morbidity caused by bacterial infections [5], [6], overuse of antibiotics in outpatients with viral infections [3], typically URTI, increases antimicrobial resistance and is associated with enormous costs and adverse drug reactions [1], [7]. A safe, rational and effective reduction of antibiotic overuse in the URTI outpatient population is therefore a public health priority.

In addition to repeated educational efforts, circulating markers of inflammation and infection have been found helpful in estimating the risk of bacterial infections and thus the need for antibiotic treatment. Particularly, the biomarker procalcitonin (PCT) – a precursor protein of calcitonin – has been proofed several times to be useful. PCT levels increase to much higher levels in severe bacterial infections, and remain relatively low in viral infections [8], [9]. Furthermore, PCT reveals prognostic information in patients with respiratory infections [10], [11].

Recent randomised-controlled trials (RCTs) have demonstrated that PCT guided clinical decision making for the initiation and discontinuation of antibiotic therapy results in lower antibiotic exposure without negatively affecting outcome [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. Indeed a favourable effect of PCT guided antibiotic therapy has been documented for community-acquired pneumonia [26] and sepsis [27]. Although most trials focused on sepsis and patients with lower respiratory tract infections, two trials also included URTI in the primary care setting. Herein, we assessed safety and efficacy of using PCT guided antibiotic therapy within different URTI subpopulations in primary care by pooling data in an individual patient data meta-analysis.

Materials and methods

Data collection and patients

This analysis includes all patients with URTI from a previous individual patient data meta-analysis [28], where a comprehensive search of the literature was conducted using PubMed (MEDLINE) and Cochrane Library to identify relevant studies. We also performed a search update in September 2016, but no additional studies were retrieved. This report adheres to the PRISMA-IPD Statement [29] and the trial PRISMA flow diagram is presented in the appendix (see Supplemental Figure 1). We focused on two trials involving URTI patients. Both included studies were randomised, multicentre, non-inferiority trials approved by the Local Ethic Committees (University Hospital Basel, Switzerland; Hanover Medical School, Germany). (Trial Registration: isrctn.org, Identifier: ISRCTN73182671; and ClinicalTrials.gov [trial numbers NCT00827060 and NCT00688610]).

Inclusion criteria were age ≥18 years with symptoms of a respiratory tract infection based on a clinical judgement. URTI diagnoses included acute pharyngitis, acute tonsillitis, acute otitis media, acute laryngitis/tracheitis, acute sinusitis and the common cold (Table 1).

Table 1:

Baseline characteristics.

The initial meta-analysis was pre-specified in collaboration with the Cochrane database of systematic reviews [30]. Briefly, the aim of the meta-analysis was to assess the safety and efficacy of a PCT algorithm to guide initiation and duration of antibiotic treatment in patients with acute respiratory tract infections (ARI) assigned to routine PCT measurement or standard of care without PCT measurement. This approach was performed over a large range of patients with varying severities in different clinical settings. Patients with a clinical diagnosis of either upper or lower ARI from 14 randomised or quasi-randomised trials were included. Trials focusing exclusively on paediatric patients or on another purpose than initiation and duration of antibiotic therapy were not eligible. Further details about identifying suitable trials were published previously [30]. No ethical approval was needed for this meta-analysis. Written informed consent was obtained from all participants within the initial trials, including consent to participate in further analyses.

Aim and endpoints

The aim of the current analysis was to study the effect of PCT guidance on adverse clinical outcome (treatment failure, days with restricted activities) and antibiotic consumption. In line with the initial Cochrane meta-analysis protocol [30], the predefined primary combined endpoint was defined as treatment failure at 28 days and number of days with restricted activities within 14 days after randomization. Treatment failure was defined as occurrence of at least one of the following events: death, hospitalization, ARI-specific complications (e.g. empyema for lower ARI, meningitis for upper ARI), recurrent or worsening infection, and patients reporting any symptoms of an ongoing respiratory infection (e.g. fever, cough, dyspnoea) at 28-days follow-up. Restricted activities were defined as number of days within the first 14 days after admission with restricted work or recreation.

Secondary endpoints were initiation of antibiotic therapy, and total days of antibiotic exposure.

In both trials, PCT was measured using a rapid sensitive assay with a functional assay sensitivity of 0.06 μg/L (Kryptor PCT, Brahms, Hennigsdorf, Germany) and an assay time of less than 20 min. We used different a priori defined PCT cut-offs (0.1 μg/L, 0.25 μg/L), which corresponds to cut-offs used in previous antibiotic stewardship trials, and also in practice guidelines on the use of PCT.

Statistical analysis

We used descriptive statistics including median with interquartile range (IQR), mean with standard deviation, and frequencies to describe the study populations, as appropriate. Statistics based on an intention to treat analysis.

For the primary endpoints treatment failure at 28 days and restricted activities at day 14, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression [31], [32]. Apart from the group variable indicating the use of a PCT algorithm we included important prognostic factors such as patient age as additional fixed effects; to account for within-and between-trial variability, we added trial to the model as a random effect. We fitted corresponding linear and logistic regression models for continuous and binary secondary endpoints, respectively.

If subgroups were too small, values were labelled as “not applicable”. Tests were carried out at 5% significance levels. Analyses were performed with STATA 12.1 (Stata Corp., College Station, TX, USA).

Results

Study population

Of 1008 patients included in the initial two trials, 644 patients with a follow-up of 28 days had a final diagnosis of URTI and were thus included in this analysis (see Supplemental Figure 2). Both trials had a non-inferiority design and the outcome assessment was blinded. PCT algorithms were similar in concept and recommended initiation or initiation and continuation of antibiotic therapy based on PCT cut-off levels. However, there are some differences between the two trials: Burkhardt et al. [33] used only a single PCT measurement on admission to guide initiation of antibiotics, while Briel et al. [12] used repeated measurements for guiding initiation and duration of antibiotic treatment. Adherence to algorithms was 85% in the Briel study and 87% in Burkhardt’s study. Both trials had a near-complete follow-up for mortality (99%).

Of 644 patients 228 were included in Switzerland and 416 in Germany. Baseline characteristics were stratified by randomisation arm and trial (Table 1). While there were balanced groups in regard to the randomisation of patients, there were differences comparing between the two trials regarding distribution of URTI subpopulations (common cold, acute sinusitis, acute pharyngitis), PCT blood levels (median and mean) and antibiotic treatment.

Risk of PCT guidance and adverse outcome

For our safety analysis, we focused on days with restricted activities and treatment failure defined as symptoms of ongoing or relapsing infection at 28 days. Table 2 summarises the results in the two groups as well as the effects from logistic regression analysis. Overall, no difference in treatment failure defined as symptoms of ongoing or relapsing infection at 28 days was found between groups (33.1% vs. 34.0%, OR 1.0, 95% CI 0.7–1.4; p=0.896). These results were similar across the different types of URTI (see Supplemental Figure 3), although some subgroups were small with large confidence intervals. Similarly, days with restricted activities did not differ between groups (8 [IQR 5, 13] vs 8 [IQR 5, 14] days, regression coefficient 0.2 days (95% CI –0.4 to 0.9), p=0.465). Again, no difference was found in any of the subgroups (see Supplemental Figure 3).

Table 2:

Adverse events stratified by URTI populations.

Effect of PCT guidance on antibiotic exposure

In the overall URTI population, PCT guidance resulted in lower antibiotic prescription (17.8% vs. 51.0%, OR 0.2, 95% CI, 0.1–0.3; p<0.001) and in a 2.4 day (95% CI –2.9 to –1.9; p<0.001) shorter antibiotic exposure compared to control patients (Table 3). The effects were strong across all URTI diagnoses although not all subgroups showed significant results due to the small sample size. Figure 1 and Supplemental Figure 4 shows the antibiotic exposure in the overall URTI population and in different subgroups based on type of URTI. Again, results suggest a strong effect on antibiotic initiation across the spectrum of URTI.

Table 3:

Antibiotic exposure stratified by URTI populations.

Antibiotic exposure stratified by day and overall in patients with URTI.
Figure 1:

Antibiotic exposure stratified by day and overall in patients with URTI.

Discussion

Key findings of this individual patient data meta-analysis investigating the effects of PCT in URTI patients from two previous randomised trials in regard to antibiotic use and clinical outcomes are twofold: First, PCT guided antibiotic therapy strongly reduced the risk of initiation of antibiotic therapy from 51% to 18% in URTI resulting in a decrease of overall antibiotic exposure of 2.4 days. These effects were observed across the different URTI subgroups including patients with common cold, sinusitis, laryngitis/tracheitis, otitis, tonsillitis and pharyngitis. Second, we did not find any evidence that lower antibiotic exposure by use of PCT guidance would result in adverse clinical outcomes, namely in regard to number of days with restricted activity and treatment failure defined as reported symptoms of ongoing or relapsing infection at 28 days. This approach, thus, appeared to be safe. Again, results were similar in the overall population as well as in URTI subgroups including common cold, acute sinusitis, acute laryngitis/tracheitis, acute otitis media, acute tonsillitis and acute pharyngitis. Although we were able to pool patients from two rather large trials into this analysis, some of the subgroups have small number and future research is needed to study different URTI subpopulations in this regard.

These analyses expand results from previous trials looking at PCT guided antibiotic therapy in different types of infections including lower respiratory tract infections [20], [28], [30], sepsis [27], urinary tract infections [34], among others. Importantly, while PCT was mainly used to monitor patients and decide whether antibiotic treatment can be stopped in more severe infections, the main effect in this primary care patient population was on initial initiation of antibiotics [35]. Reducing antibiotic treatment in primary care is of high relevance as antimicrobial resistance is one of the most urgent problems threatening healthcare systems, causing longer drug adverse events and costs [36]. Therefore, judicious use of antibiotics – mainly in the primary care setting due to its enormous over-prescription – is highly important to preserve their effectiveness [37]. Beside this, economic savings should be considered. A recent large US health system perspective estimated substantial savings associated with PCT protocols when used in patients with acute lower respiratory tract infections across common treatment settings mainly by reducing unnecessary antibiotic utilisation [38].

We recently found low PCT levels to be a strong predictor against treatment failure in patients with respiratory tract infections. This finding may help to “rule out” risk with a high negative predictive value and thus improve site-of-care decisions [39]. The role of prognostication by validated risk scores is endorsed by respiratory infection guidelines mostly in the setting of pneumonia [40]. Yet, these scores are validated only for lower respiratory tract infections but not URTI. Thus, there is a need for additional prognostic markers, which are objectively and rapidly available, as well as responsive to the clinical course. Based on this analysis, PCT is a promising candidate in this regard and helps to identify patients presenting with URTI with no need of antibiotic treatment.

Young et al. found in a meta-analysis of randomised trials that common clinical symptoms cannot reliably identify patients with rhino-sinusitis for whom antibacterial treatment is indicated. Based on the result of this meta-analysis, antibiotics were not justified even if patients report symptoms for longer than 7–10 days. The number needed to treat for antibiotics was high with 15 patients with rhinosinusitis-like complaints [41]. This study shows the low diagnostic accuracy of clinical parameters thus the need for additional markers, such as PCT, to improve management in patients with URTI [42].

In addition to PCT, several studies have investigated the role of C-reactive protein (CRP) in patients with URTI [39], [43], [44]. Similar to our study, CRP was helpful in reducing antibiotic treatment without negative effects in regard to patient outcomes. The study by Cals and colleagues found a combination of communication skills and CRP point-of-care testing to be most effectively because the interaction with the patient may be challenging if antibiotics have been used in this patient for many years to treat URTI [44]. Also, in a multicentre open-label randomised controlled trial in ten primary health-care centres in northern Vietnam, CRP point-of-care testing reduced antibiotic use for non-severe acute respiratory tract infection without compromising patients’ recovery. The advantages of CRP are the lower costs and the availability as a point of care device in primary care. Yet, studies found CRP to be less specific towards bacterial infection and have lower prognostic value compared to PCT [45], [46], [47]. Thus, interventional research comparing these two markers in regard to their potential to direct antibiotic treatment are warranted [37], [48].

For some URTI subgroups, studies have compared PCT vs. CRP. One study compared CRP and PCT in a group A streptococcal acute tonsillitis population with the centor criteria defined as fever, tonsillar exudates, tender anterior cervical andenopathy and absence of cough plus rapid antigen detection test [49]. Both markers, CRP and PCT, were inferior to these criteria when combined with rapid antigen detection testing in regard to both, sensitivity and specify. These results are in line with our findings where the effect of PCT in the group of patients with acute tonsillitis was weak. Importantly, we only had few patients in this subgroup making additional research necessary to understand the effects of PCT testing in tonsillitis patients.

The main strengths of our meta-analysis based on individual patient data are the large number of randomised primary care patients with URTI and the similarity of protocols making the pooling of data possible. Particularly, endpoints were similar in the two studies, as was recommendations regarding PCT use in the intervention group.

Nevertheless, we are aware of several limitations. First, we performed a post-hoc analysis of two pooled studies with some differences between populations. Second, the patient number of some URTIs subgroups, such as tonsillitis, laryngitis/tracheitis and otitis media was small. Herein, we only focussed on interventional trials as specified in the meta-analysis protocol and did not include any observational data which would potentially allow for larger sample sizes in the different subgroups and increase patients’ spectrum as in observational studies less rigorous exclusion criteria usually apply. Third, the numbers of adverse outcomes, especially severe complications, were low and thus we cannot make any conclusions regarding effects on mortality outcomes. Fourth, both studies, did not blind physician nor patients, which may bias the results.

Conclusions

PCT guided antibiotic therapy was strongly associated with reduced antibiotic exposure in URTI patients in the primary care setting without differences in outcomes. A broader use of PCT in the low acuity setting has the potential to lower antibiotic exposure and associated risk of multi-resistant bacteria.

Acknowledgments

We are grateful to the physicians, their staff and patients who participated in the data collection.

References

  • 1.

    Gonzales R, Steiner JF, Sande MA. Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. J Am Med Assoc 1997;278:901–4. CrossrefGoogle Scholar

  • 2.

    Dixon RE. Economic costs of respiratory tract infections in the United States. Am J Med 1985;78:45–51. PubMedCrossrefGoogle Scholar

  • 3.

    Evans AT, Husain S, Durairaj L, Sadowski LS, Charles-Damte M, Wang Y. Azithromycin for acute bronchitis: a randomised, double-blind, controlled trial. Lancet 2002;359:1648–54. PubMedCrossrefGoogle Scholar

  • 4.

    Macfarlane JT, Colville A, Guion A, Macfarlane RM, Rose DH. Prospective study of aetiology and outcome of adult lower-respiratory-tract infections in the community. Lancet 1993;341:511–4. CrossrefPubMedGoogle Scholar

  • 5.

    Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34:1589–96. CrossrefPubMedGoogle Scholar

  • 6.

    Kumar A, Ellis P, Arabi Y, Roberts D, Light B, Parrillo JE, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009;136:1237–48. CrossrefWeb of ScienceGoogle Scholar

  • 7.

    Lawrence KL, Kollef MH. Antimicrobial stewardship in the intensive care unit: advances and obstacles. Am J Respir Crit Care Med 2009;179:434–8. PubMedCrossrefWeb of ScienceGoogle Scholar

  • 8.

    Muller B, Becker KL. Procalcitonin: how a hormone became a marker and mediator of sepsis. Swiss Med Wkly 2001;131: 595–602. PubMedGoogle Scholar

  • 9.

    Muller B, Becker KL, Schachinger H, Rickenbacher PR, Huber PR, Zimmerli W, et al. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med 2000;28:977–83. CrossrefGoogle Scholar

  • 10.

    Karlsson S, Heikkinen M, Pettila V, Alila S, Vaisanen S, Pulkki K, et al. Predictive value of procalcitonin decrease in patients with severe sepsis: a prospective observational study. Crit Care 2010;14:R205. PubMedCrossrefWeb of ScienceGoogle Scholar

  • 11.

    Kutz A, Briel M, Christ-Crain M, Stolz D, Bouadma L, Wolff M, et al. Prognostic value of procalcitonin in respiratory tract infections across clinical settings. Crit Care 2015;19:74. PubMedWeb of ScienceCrossrefGoogle Scholar

  • 12.

    Briel M, Schuetz P, Mueller B, Young J, Schild U, Nusbaumer C, et al. Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care. Arch Intern Med 2008;168:2000–7. CrossrefWeb of ScienceGoogle Scholar

  • 13.

    Burkhardt O, Ewig S, Haagen U, Giersdorf S, Hartmann O, Wegscheider K, et al. Procalcitonin guidance and reduction of antibiotic use in acute respiratory tract infection. Eur Respir J 2010;36:601–7. CrossrefWeb of SciencePubMedGoogle Scholar

  • 14.

    Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR, Tamm M, 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;363:600–7. PubMedCrossrefGoogle Scholar

  • 15.

    Christ-Crain M, Stolz D, Bingisser R, Muller C, Miedinger D, Huber PR, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med 2006;174:84–93. PubMedCrossrefGoogle Scholar

  • 16.

    Stolz D, Christ-Crain M, Bingisser R, Leuppi J, Miedinger D, Muller C, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007;131:9–19. CrossrefPubMedGoogle Scholar

  • 17.

    Kristoffersen KB, Sogaard OS, Wejse C, Black FT, Greve T, Tarp B, 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;15:481–7. Web of SciencePubMedCrossrefGoogle Scholar

  • 18.

    Long W, Deng X, Zhang Y, Lu G, Xie J, Tang J. Procalcitonin-guidance for reduction of antibiotic use in low-risk outpatients with community acquired pneumonia. Respirology 2011;16:819–24. Web of SciencePubMedCrossrefGoogle Scholar

  • 19.

    Long W, Deng XQ, Tang JG, Xie J, Zhang YC, Zhang Y, et al. [The value of serum procalcitonin in treatment of community acquired pneumonia in outpatient]. Zhonghua nei ke za zhi [Chin J Internal Med] 2009;48:216–9. Google Scholar

  • 20.

    Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. J Am Med Assoc 2009;302:1059–66. CrossrefWeb of ScienceGoogle Scholar

  • 21.

    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;177:498–505. PubMedWeb of ScienceCrossrefGoogle Scholar

  • 22.

    Stolz D, Smyrnios N, Eggimann P, Pargger H, Thakkar N, Siegemund M, et al. Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study. Eur Respir Rev 2009;34:1364–75. CrossrefGoogle Scholar

  • 23.

    Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, 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: 463–74. CrossrefWeb of ScienceGoogle Scholar

  • 24.

    Schroeder S, Hochreiter M, Koehler T, Schweiger AM, Bein B, Keck FS, et al. Procalcitonin (PCT)-guided algorithm reduces length of antibiotic treatment in surgical intensive care patients with severe sepsis: results of a prospective randomized study. Langenbecks Arch Surg 2009;394:221–6. CrossrefPubMedWeb of ScienceGoogle Scholar

  • 25.

    Hochreiter M, Kohler T, Schweiger AM, Keck FS, Bein B, von Spiegel T, et al. Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial. Crit Care 2009;13:R83. CrossrefPubMedWeb of ScienceGoogle Scholar

  • 26.

    Schuetz P, Mueller B. Biomarker-guided de-escalation of empirical therapy is associated with lower risk for adverse outcomes. Intensive Care Med 2014;40:141. PubMedCrossrefWeb of ScienceGoogle Scholar

  • 27.

    de Jong E, van Oers JA, Beishuizen A, Vos P, Vermeijden WJ, Haas LE, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis 2016;16:819–27. Web of ScienceCrossrefPubMedGoogle Scholar

  • 28.

    Schuetz P, Briel M, Christ-Crain M, Stolz D, Bouadma L, Wolff M, et al. Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis. Clin Infect Dis 2012;55:651–62. PubMedWeb of ScienceCrossrefGoogle Scholar

  • 29.

    Stewart LA, Clarke M, Rovers M, Riley RD, Simmonds M, Stewart G, et al. Preferred reporting items for systematic review and meta-analyses of individual participant data: the PRISMA-IPD Statement. J Am Med Assoc 2015;313:1657–65. CrossrefGoogle Scholar

  • 30.

    Schuetz P, Muller B, Christ-Crain M, Stolz D, Tamm M, Bouadma L, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev 2012;9:CD007498. Google Scholar

  • 31.

    Thompson SG, Turner RM, Warn DE. Multilevel models for meta-analysis, and their application to absolute risk differences. Stat Methods Med Res 2001;10:375–92. CrossrefPubMedGoogle Scholar

  • 32.

    Turner RM, Omar RZ, Yang M, Goldstein H, Thompson SG. A multilevel model framework for meta-analysis of clinical trials with binary outcomes. Stat Med 2000;19:3417–32. CrossrefPubMedGoogle Scholar

  • 33.

    Burkhardt O, Ewig S, Haagen U, Giersdorf S, Hartmann O, Wegscheider K, et al. Procalcitonin guidance and reduction of antibiotic use in acute respiratory tract infection. Eur Respir J 2010;36:601–7. CrossrefWeb of SciencePubMedGoogle Scholar

  • 34.

    Drozdov D, Schwarz S, Kutz A, Grolimund E, Rast AC, Steiner D, et al. Procalcitonin and pyuria-based algorithm reduces antibiotic use in urinary tract infections: a randomized controlled trial. BMC Med. 2015;13:104. PubMedWeb of ScienceCrossrefGoogle Scholar

  • 35.

    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;171:1322–31. PubMedCrossrefWeb of ScienceGoogle Scholar

  • 36.

    Spellberg B, Bartlett JG, Gilbert DN. The future of antibiotics and resistance. N Engl J Med 2013;368:299–302. CrossrefWeb of SciencePubMedGoogle Scholar

  • 37.

    Meili M, Muller B, Kulkarni P, Schutz P. Management of patients with respiratory infections in primary care: procalcitonin, C-reactive protein or both? Expert Rev Respir Med 2015;9:587–601. Web of ScienceCrossrefPubMedGoogle Scholar

  • 38.

    Schuetz P, Balk R, Briel M, Kutz A, Christ-Crain M, Stolz D, et al. Economic evaluation of procalcitonin-guided antibiotic therapy in acute respiratory infections: a US health system perspective. Clin Chem Lab Med 2015;53:583–92. PubMedWeb of ScienceGoogle Scholar

  • 39.

    Schuetz P, Birkhahn R, Sherwin R, Jones AE, Singer A, Kline JA, et al. Serial procalcitonin predicts mortality in severe sepsis patients: Results from the Multicenter Procalcitonin MOnitoring SEpsis (MOSES) Study. Crit Care Med 2017;45:781–9. CrossrefWeb of SciencePubMedGoogle Scholar

  • 40.

    Musher DM, Thorner AR. Community-acquired pneumonia. N Engl J Med 2014;371:1619–28. PubMedCrossrefGoogle Scholar

  • 41.

    Young J, De Sutter A, Merenstein D, van Essen GA, Kaiser L, Varonen H, et al. Antibiotics for adults with clinically diagnosed acute rhinosinusitis: a meta-analysis of individual patient data. Lancet 2008;371:908–14. Web of ScienceCrossrefPubMedGoogle Scholar

  • 42.

    Kutz A, Grolimund E, Christ-Crain M, Thomann R, Falconnier C, Hoess C, et al. Pre-analytic factors and initial biomarker levels in community-acquired pneumonia patients. BMC Anesthesiol 2014;14:102. CrossrefPubMedWeb of ScienceGoogle Scholar

  • 43.

    Do NT, Ta NT, Tran NT, Than HM, Vu BT, Hoang LB, et al. Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial. Lancet Glob Health 2016;4:e633–41. PubMedWeb of ScienceCrossrefGoogle Scholar

  • 44.

    Cals JW, de Bock L, Beckers PJ, Francis NA, Hopstaken RM, Hood K, et al. Enhanced communication skills and C-reactive protein point-of-care testing for respiratory tract infection: 3.5-year follow-up of a cluster randomized trial. Ann Fam Med 2013;11:157–64. CrossrefPubMedWeb of ScienceGoogle Scholar

  • 45.

    Zhydkov A, Christ-Crain M, Thomann R, Hoess C, Henzen C, Werner Z, et al. Utility of procalcitonin, C-reactive protein and white blood cells alone and in combination for the prediction of clinical outcomes in community-acquired pneumonia. Clin Chem Lab Med 2015;53:559–66. PubMedWeb of ScienceGoogle Scholar

  • 46.

    Schuetz P, Aujesky D, Muller C, Muller B. Biomarker-guided personalised emergency medicine for all – hope for another hype? Swiss Med Wkly 2015;145:w14079. PubMedWeb of ScienceGoogle Scholar

  • 47.

    Schuetz P, Albrich W, Mueller B. Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future. BMC Med 2011;9:107. PubMedCrossrefWeb of ScienceGoogle Scholar

  • 48.

    Meili M, Kutz A, Briel M, Christ-Crain M, Bucher HC, Mueller B, et al. Infection biomarkers in primary care patients with acute respiratory tract infections-comparison of Procalcitonin and C-reactive protein. BMC Pulm Med 2016;16:43. PubMedCrossrefWeb of ScienceGoogle Scholar

  • 49.

    Christensen AM, Thomsen MK, Ovesen T, Klug TE. Are procalcitonin or other infection markers useful in the detection of group A streptococcal acute tonsillitis? Scand J Infect Dis 2014;46:376–83. Web of ScienceCrossrefGoogle Scholar

Supplemental Material:

The online version of this article (https://doi.org/10.1515/cclm-2017-0252) offers supplementary material, available to authorized users.

About the article

Corresponding author: Prof. Philipp Schuetz, MD, MPH, University Department of Medicine, Kantonsspital Aarau, Tellstrasse, 5001 Aarau, Switzerland, Phone: +41628389524, Fax: +41628386945


Received: 2017-03-23

Accepted: 2017-05-02

Published Online: 2017-06-29

Published in Print: 2017-11-27


Author contributions: Mr Odermatt, Ms Friedli, Mr Kutz and Mr. Schuetz had full access to all of the data in the study and take responsibility for the integrity of the data and performed the statistical work, and drafted the manuscript. All authors helped to interpret the findings, read and revised the manuscript critically for important intellectual content. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Availability of data and material: The datasets used and/or analysed during the current study is available from the corresponding author on reasonable request.

Research funding: This investigator-initiated PARTI trial was sponsored by a grant from the Swiss National Science Foundation (3300C0-107772) and by the Association for the Promotion of Science and Postgraduate Training of the University Hospital Basel. Brahms AG provided assay and kit material related to the study. Drs. Christ-Crain, Mueller, and Schuetz, received support from BRAHMS to attend meetings and fulfilled speaking engagements. Drs. Schuetz, Kutz, Christ-Crain and Mueller received support from bioMérieux to attend meetings and fulfilled speaking engagements. Heiner C. Bucher has received research support from BRAHMS. Dr. Schuetz and Dr. Christ-Crain were supported by funds of the Freiwillige Akademische Gesellschaft, the Department of Endocrinology, Diabetology and Clinical Nutrition, and the Department of Clinical Chemistry, all Basel, Switzerland.

Employment or leadership: Dr. Mueller has served as a consultant and received research support from BRAHMS and bioMérieux.

Honorarium: None declared.

Competing interests: The funding organisation(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 56, Issue 1, Pages 170–177, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2017-0252.

Export Citation

©2018 Walter de Gruyter GmbH, Berlin/Boston. Copyright Clearance Center

Supplementary Article Materials

Comments (0)

Please log in or register to comment.
Log in