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Meta-Analysis
. 2017 Oct 12;10(10):CD007498.
doi: 10.1002/14651858.CD007498.pub3.

Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections

Philipp Schuetz  1 , Yannick Wirz, Ramon Sager, Mirjam Christ-Crain, Daiana Stolz, Michael Tamm, Lila Bouadma, Charles E Luyt, Michel Wolff, Jean Chastre, Florence Tubach, Kristina B Kristoffersen, Olaf Burkhardt, Tobias Welte, Stefan Schroeder, Vandack Nobre, Long Wei, Heiner C Bucher, Neera Bhatnagar, Djillali Annane, Konrad Reinhart, Angela Branche, Pierre Damas, Maarten Nijsten, Dylan W de Lange, Rodrigo O Deliberato, Stella Ss Lima, Vera Maravić-Stojković, Alessia Verduri, Bin Cao, Yahya Shehabi, Albertus Beishuizen, Jens-Ulrik S Jensen, Caspar Corti, Jos A Van Oers, Ann R Falsey, Evelien de Jong, Carolina F Oliveira, Bianca Beghe, Matthias Briel, Beat Mueller
Affiliations
Meta-Analysis

Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections

Philipp Schuetz et al. Cochrane Database Syst Rev. .

Abstract

Background: Acute respiratory infections (ARIs) comprise of a large and heterogeneous group of infections including bacterial, viral, and other aetiologies. In recent years, procalcitonin (PCT), a blood marker for bacterial infections, has emerged as a promising tool to improve decisions about antibiotic therapy (PCT-guided antibiotic therapy). Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with ARIs and different settings ranging from primary care settings to emergency departments, hospital wards, and intensive care units. However, the effect of using procalcitonin on clinical outcomes is unclear. This is an update of a Cochrane review and individual participant data meta-analysis first published in 2012 designed to look at the safety of PCT-guided antibiotic stewardship.

Objectives: The aim of this systematic review based on individual participant data was to assess the safety and efficacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from different clinical settings.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE, and Embase, in February 2017, to identify suitable trials. We also searched ClinicalTrials.gov to identify ongoing trials in April 2017.

Selection criteria: We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm (PCT-guided antibiotic stewardship algorithm) or usual care. We excluded trials if they focused exclusively on children or used procalcitonin for a purpose other than to guide initiation and duration of antibiotic treatment.

Data collection and analysis: Two teams of review authors independently evaluated the methodology and extracted data from primary studies. The primary endpoints were all-cause mortality and treatment failure at 30 days, for which definitions were harmonised among trials. Secondary endpoints were antibiotic use, antibiotic-related side effects, and length of hospital stay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression adjusted for age, gender, and clinical diagnosis using a fixed-effect model. The different trials were added as random-effects into the model. We conducted sensitivity analyses stratified by clinical setting and type of ARI. We also performed an aggregate data meta-analysis.

Main results: From 32 eligible RCTs including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which we included in the main individual participant data meta-analysis. We did not obtain individual participant data for four trials, and two trials did not include people with confirmed ARIs. According to GRADE, the quality of the evidence was high for the outcomes mortality and antibiotic exposure, and quality was moderate for the outcomes treatment failure and antibiotic-related side effects.Primary endpoints: there were 286 deaths in 3336 procalcitonin-guided participants (8.6%) compared to 336 in 3372 controls (10.0%), resulting in a significantly lower mortality associated with procalcitonin-guided therapy (adjusted OR 0.83, 95% CI 0.70 to 0.99, P = 0.037). We could not estimate mortality in primary care trials because only one death was reported in a control group participant. Treatment failure was not significantly lower in procalcitonin-guided participants (23.0% versus 24.9% in the control group, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). Results were similar among subgroups by clinical setting and type of respiratory infection, with no evidence for effect modification (P for interaction > 0.05). Secondary endpoints: procalcitonin guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 versus 8.1 days, 95% CI -2.71 to -2.15, P < 0.001) and lower risk of antibiotic-related side effects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). Length of hospital stay and intensive care unit stay were similar in both groups. A sensitivity aggregate-data analysis based on all 32 eligible trials showed similar results.

Authors' conclusions: This updated meta-analysis of individual participant data from 12 countries shows that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic-related side effects. Results were similar for different clinical settings and types of ARIs, thus supporting the use of procalcitonin in the context of antibiotic stewardship in people with ARIs. Future high-quality research is needed to confirm the results in immunosuppressed patients and patients with non-respiratory infections.

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Conflict of interest statement

Philipp Schuetz received support (paid to his employer) from Thermo Fisher, Roche Diagnostics, Abbott and bioMerieux to attend meetings and fulfil speaking engagements. These conflicts breach Cochrane's Commercial Sponsorship Policy (Clause 3), therefore Philipp Schuetz will step down as lead author at the next update of the review. Dr Schuetz's declared conflicts were referred to the Funding Arbiter Panel and Cochrane’s Deputy Editor‐in‐Chief who have agreed this course of action but as an exception which does not set a precedent for similar situations in the future. Beat Mueller reports that within the last 3 years he was part of the speaker bureau of B·R·A·H·M·S and bioMérieux to give educational talks. His institution received compensation for flight and travel expenses, and to cover his absence from work. Yannick Wirz: None known. Ramon Sager: None known. Mirjam Christ‐Crain received support from B·R·A·H·M·S and bioMérieux to attend meetings and fulfilled speaking engagements. Daiana Stolz received fees for lectures or occasional advisory committees from Boehringer Ingelheim, Almirall, Novartis, Glaxo, AstraZeneca, and Roche. Dr Stolz's institution received unrestricted research grants from ResMed, Weinmann AG, AstraZeneca, Boston Scientific, and Curetis AG. Michael Tamm: None known. Lila Bouadma: None known. Charles E Luyt received lecture fees from B·R·A·H·M·S and Merck Sharp & Dohme‐Chibret. Michel Wolff received consulting and lectures fees from Merck Sharp & Dohme‐Chibret, Janssen‐Cilag, Gilead, and Astellas Pharma. Jean Chastre received consulting and lecture fees from Pfizer, B·R·A·H·M·S, Wyeth, Johnson & Johnson, Nektar‐Bayer, and Arpida. Florence Tubach: My institution received some funds from B·R·A·H·M·S for implementing the PRORATA trial, whose data are involved in the review. Kristina B Kristoffersen: None known. Olaf Burkhardt received research support from B·R·A·H·M·S. Tobias Welte received lecture fees and research support from B·R·A·H·M·S. Stefan Schroeder received lecture fees and research support from B·R·A·H·M·S. Vandack Nobre: None known. Long Wei: None known. Heiner C Bucher: None known. Neera Bhatnagar: None known. Djillali Annane: None known. Konrad Reinhart received fees for consultancy from Adrenomed, Henningsdorf Berlin, Germany; holds equity in InflaRx, Jena, Germany; and is unpaid chair of the Global Sepsis Alliance, which receives funds from several companies with interest in sepsis diagnostics. Angela Branche: This work was partially supported by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (contract HHSN27220120005C). This author has nothing else to declare. Pierre Damas: None known. Maarten Nijsten: None known. Dylan W de Lange: The department where Dylan de Lange worked received financial compensation for a randomisation tool during the SAPS trial. Rodrigo O Deliberato: None known. Stella SS Lima: None known. Vera Maravić‐Stojković: None known. Alessia Verduri: None known. Bin Cao: None known. Yahya Shehabi received unrestricted research and educational grants from Thermo Fisher, bioMérieux, Pfizer, and Orion Pharma. Albertus Beishuizen: None known. Jens‐Ulrik S Jensen declares that he was invited to the European Respiratory Society meeting 2016 by Roche Pharmaceuticals. Otherwise, he has no disclosures. Caspar Corti received an unrestricted grant of USD 2000 from Thermo Fisher Scientific, MA, USA; bioMérieux Denmark ApS supported the study non‐financially. Jos A Van Oers: None known. Ann R Falsey: The relationships with noted industry partners had no role or influence in the study. Evelien de Jong received lecturing fees from Thermo Fisher. Carolina F Oliveira: None known. Bianca Beghe: None known. Matthias Briel: Unrestricted grant from B·R·A·H·M·S AG (now Thermo Fisher) that partially covered working hours to a previous version of this Cochrane Review. B·R·A·H·M·S had no role in the design, conduct, analysis, or writing of our manuscript.

Funding: The initial review was partly funded by unrestricted research grants from B·R·A·H·M·S/Thermo Fisher Scientific, the Gottfried and Julia Bangerter‐Rhyner‐Foundation, the Swiss Foundation for Grants in Biology and Medicine (SSMBS, PASMP3‐127684/1), and santésuisse to cover salary time related to this review. The sponsors had no role in the study design, data collection, data analysis or data interpretation, or writing of the report. No funding was received for this update.

No commercial sponsor had any involvement in the design and conduct of this review, namely collection, management, analysis, and interpretation of the data; and preparation, decision to submit, review, or approval of the manuscript.

Figures

1
1
Study flow diagram. Abbreviations: ARI: acute respiratory infection; IPD: individual participant data; RCT: randomised controlled trial
2
2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
4
4
Funnel plot of comparison: 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, outcome: 1.1 Mortality at 30 days.
5
5
Forest plot of comparison: 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, outcome: 1.1 Mortality at 30 days.
6
6
Forest plot of comparison: 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, outcome: 1.2 Treatment failure at 30 days.
1.1
1.1. Analysis
Comparison 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, Outcome 1 Mortality at 30 days.
1.2
1.2. Analysis
Comparison 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, Outcome 2 Treatment failure at 30 days.
2.1
2.1. Analysis
Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 1 Mortality at 30 days stratified by adherence.
2.2
2.2. Analysis
Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 2 Treatment failure at 30 days stratified by adherence.
2.3
2.3. Analysis
Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 3 Mortality at 30 days stratified by allocation concealment.
2.4
2.4. Analysis
Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 4 Treatment failure at 30 days stratified by allocation concealment.
2.5
2.5. Analysis
Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 5 Mortality at 30 days stratified by blinded outcome assessment.
2.6
2.6. Analysis
Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 6 Treatment failure at 30 days stratified by blinded outcome assessment.
2.7
2.7. Analysis
Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 7 Mortality at 30 days stratified by follow up.
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References to studies excluded from this review

Dharaniyadewi 2013 {published data only}
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References to ongoing studies

NCT02130986 {unpublished data only}
    1. NCT02130986. Procalcitonin Antibiotic Consensus Trial (ProACT). clinicaltrials.gov/ct2/show/study/NCT02130986 First received: May 1, 2014.
NCT02261610 {unpublished data only}
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NCT02332577 {unpublished data only}
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NCT02440828 {unpublished data only}
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NCT02787603 {unpublished data only}
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NCT02862314 {unpublished data only}
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References to other published versions of this review

Schuetz 2008
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