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      Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections

      systematic-review
      , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
      The Cochrane Database of Systematic Reviews
      John Wiley & Sons, Ltd
      Humans, Acute Disease, Anti‐Bacterial Agents, Anti‐Bacterial Agents/adverse effects, Anti‐Bacterial Agents/therapeutic use, Bacterial Infections, Bacterial Infections/blood, Bacterial Infections/drug therapy, Bacterial Infections/mortality, Biomarkers, Biomarkers/blood, Calcitonin, Calcitonin/blood, Calcitonin Gene‐Related Peptide, Cause of Death, Protein Precursors, Protein Precursors/blood, Randomized Controlled Trials as Topic, Respiratory Tract Infections, Respiratory Tract Infections/blood, Respiratory Tract Infections/drug therapy, Respiratory Tract Infections/mortality, Treatment Failure

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          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.

          Testing blood procalcitonin levels to decide when to start and stop antibiotics in adults with acute respiratory tract infections

          Review question

          What are the effects of using procalcitonin to start or discontinue antibiotics in people with acute respiratory infections compared to routine care on mortality and treatment failure?

          Background

          In people with acute respiratory infections, unnecessary antibiotic use significantly contributes to increasing bacterial resistance, medical costs, and the risk of drug‐related adverse events. The blood marker procalcitonin increases in bacterial infections and decreases when patients recover from the infection. Procalcitonin can be measured in the blood of patients by different commercially available assays with a turnaround time of around one to two hours and support clinical decision making about initiation and discontinuation of antibiotic therapy.

          Search date

          We conducted electronic searches on 10 February 2017. We conducted searches for ongoing trials on 12 April 2017.

          Study characteristics

          All included trials randomised participants with acute respiratory infections to receive antibiotics based on procalcitonin levels ('procalcitonin‐guided' group) or a control group. The trials were performed in primary care, the emergency department and medical wards, and the intensive care unit. Included participants had acute upper or lower respiratory infections, including pneumonia, bronchitis, exacerbation of chronic obstructive pulmonary disease, and others.

          Study funding sources

          All studies were investigator‐initiated trials. Half of the trials were funded by national agencies or did not report funding, and half of the trials received funding from the biomarker industry (e.g. Thermo Fisher Scientific).

          Key results

          We studied 6708 participants from 26 trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin‐guided participants compared to control participants (286 deaths in 3336 procalcitonin‐guided participants (8.6%) versus 336 deaths in 3372 controls (10.0%)). There was no significant difference with regard to treatment failures. Results were similar for different clinical settings (primary care, emergency department, intensive care unit) and types of respiratory infection. Regarding antibiotic exposure, participants in the procalcitonin‐guided group had a 2.4‐day reduction in antibiotic exposure and a reduction in antibiotic‐related side effects (16.3% versus 22.1%).

          Quality of the evidence

          The quality of the evidence was high for mortality and antibiotic exposure. Most of the trials did not use blinding, however we did not expect that mortality would be biased by this limitation. The quality of the evidence was moderate for treatment failure and antibiotic‐related side effects because the definitions for these endpoints among trials were not identical.

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          Author and article information

          Contributors
          schuetzph@gmail.com
          Journal
          Cochrane Database Syst Rev
          Cochrane Database Syst Rev
          14651858
          10.1002/14651858
          The Cochrane Database of Systematic Reviews
          John Wiley & Sons, Ltd (Chichester, UK )
          1469-493X
          12 October 2017
          October 2017
          17 May 2019
          : 2017
          : 10
          Affiliations
          Kantonsspital Aarau deptMedical University Department Aarau Switzerland
          Kantonsspital Aarau deptDepartment of Endocrinology/Metabolism/Clinical Nutrition, Department of Internal Medicine Aarau Switzerland
          University of Basel deptMedical Faculty Basel Switzerland
          University Hospital Basel, University of Basel deptClinic for Endocrinology, Diabetes and Metabolism, Department of Clinical Research Petersgraben 4 Basel Switzerland CH‐4031
          University Hospital Basel deptClinic of Pneumology and Pulmonary Cell Research Petersgraben 4 Basel Switzerland CH‐4031
          Hôpital Bichat‐Claude Bernard, Université Paris 7‐Denis‐Diderot deptService de Réanimation Médicale Paris France
          Groupe Hospitalier Pitié‐Salpêtrière, Assistance Publique–Hôpitaux de Paris, Université Paris 6‐Pierre‐et‐Marie‐Curie deptService de Réanimation Médicale Paris France
          Université Paris 7‐Denis‐Diderot deptService de Réanimation Médicale Hôpital Bichat‐Claude‐BernardAssistance Publique‐Hôpitaux de Paris (AP‐HP) Paris France
          Université Paris 6‐Pierre‐et‐Marie‐Curie deptService de Réanimation Médicale Hôpital Pitié?Salpêtrière (AP‐HP) Paris France
          Santé Publique et Information Médicale, AP‐HP, Groupe Hospitalier Pitié‐Salpêtrière Charles‐Foix, INSERM CIC‐P 1421, Sorbonne Universités, UPMC Univ Paris 06 deptDépartement Biostatistique Paris France
          Aarhus University Hospital deptDepartment of Infectious Diseases SkejbyBrendstrupgaardvej 100 Aarhus N Denmark 8200
          Medizinische Hochschule Hannover deptDepartment of Pulmonary Medicine Carl‐Neuberg‐Str. 1 Hannover Germany 30625
          German Center for Lung Reearch (DZL) Aulweg 130 Gießen Germany 35392
          Krankenhaus Dueren deptDepartment of Anesthesiology and Intensive Care Medicine Dueren Germany
          Universidade Federal de Minas Gerais deptDepartment of Internal Medicine, School of Medicine Minas Gerais Brazil
          Shanghai Jiao Tong University Affiliated Sixth People's Hospital (East campus) deptDepartment of Internal and Geriatric Medicine Shanghai China
          University Hospital Basel and University of Basel deptBasel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research Petersgraben 4 Basel Switzerland CH‐4031
          University Hospital Basel deptMedical Faculty Basel Switzerland
          McMaster University deptDepartment of Clinical Epidemiology and Biostatistics 1200 Main Street West Hamilton Canada L8N 3Z5
          Center for Neuromuscular Diseases; Raymond Poincaré Hospital (AP‐HP) deptDepartment of Critical Care, Hyperbaric Medicine and Home Respiratory Unit Faculty of Health Sciences Simone Veil, University of Versailles SQY‐ University of Paris Saclay104 Boulevard Raymond Poincaré Garches France 92380
          Jena University Hospital deptDepartment of Anesthesiology and Intensive Care Medicine Erlanger Allee 101 Jena Germany 07747
          University of Rochester School of Medicine deptDepartment of Medicine, Division of Infectious Diseases Rochester USA
          University Hospital of Liege, Domaine universitaire de Liège deptDepartment of General Intensive Care Liege Belgium
          University of Groningen deptUniversity Medical Centre Groningen Netherlands
          University Medical Center Utrecht deptDepartment of Intensive Care Heidelberglaan 100 Utrecht Netherlands 3584 CX
          Hospital Israelita Albert Einstein deptCritical Care Unit São Paulo Brazil
          Universidade Federal de Minas Gerais deptGraduate Program in Infectious Diseases and Tropical Medicine, Department of Internal Medicine, School of Medicine Belo Horizonte Brazil
          Dedinje Cardiovascular Institute deptImmunology Laboratory Belgrade Serbia
          University of Modena and Reggio Emilia deptDepartment of Medical and Surgical Sciences, Policlinico di Modena Modena Italy
          China‐Japan Friendship Hospital, National Clinical Research Center of Respiratory Diseases, Capital Medical University deptCenter for Respiratory Diseases, Department of Pulmonary and Critical Care Medicine Beijing China
          Monash Health deptCritical Care and Peri‐operative Medicine Melbourne Australia
          Monash University deptSchool of Clinical Sciences, Faculty of Medicine Nursing and Health Sciences Melbourne Australia
          Medisch Spectrum Twente deptDepartment of Intensive Care Enschede Netherlands
          Copenhagen University Hospital, Bispebjerg og Frederiksberg deptDepartment of Respiratory Medicine Bispebjerg Bakke Copenhagen NV Denmark DK 2400
          Rigshospitalet, University of Copenhagen deptCHIP, Department of Infectious Diseases and Rheumatology, Finsencentret Blegdamsvej 9, DK‐2100 Copenhagen Denmark DK‐2100
          Elisabeth Tweesteden Ziekenhuis deptIntensive Care Unit Tilburg Netherlands 5022 GC
          VU University Medical Center deptDepartment of Intensive Care Amsterdam Netherlands 1081HV
          Federal University of Minas Gerais deptDepartment of Internal Medicine, School of Medcine Belo Horizonte Brazil 31130‐100
          AOU Policlinico di Modena deptDepartment of Medical and Surgical Sciences Moderna Italy 41124
          Author notes

          Editorial Group: Cochrane Acute Respiratory Infections Group.

          Article
          PMC6485408 PMC6485408 6485408 CD007498 CD007498.pub3
          10.1002/14651858.CD007498.pub3
          6485408
          29025194
          c238176b-1680-40dd-aedb-ab03e20d4997
          Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
          Categories
          Medicine General & Introductory Medical Sciences

          Humans,Acute Disease,Anti‐Bacterial Agents,Anti‐Bacterial Agents/therapeutic use,Bacterial Infections,Bacterial Infections/blood,Bacterial Infections/drug therapy,Bacterial Infections/mortality,Biomarkers,Biomarkers/blood,Calcitonin,Calcitonin/blood,Calcitonin Gene‐Related Peptide,Cause of Death,Protein Precursors,Protein Precursors/blood,Randomized Controlled Trials as Topic,Respiratory Tract Infections,Respiratory Tract Infections/blood,Respiratory Tract Infections/drug therapy,Respiratory Tract Infections/mortality,Treatment Failure,Anti‐Bacterial Agents/adverse effects

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