Articles
Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis

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Summary

Background

In February, 2017, the US Food and Drug Administration approved the blood infection marker procalcitonin for guiding antibiotic therapy in patients with acute respiratory infections. This meta-analysis of patient data from 26 randomised controlled trials was designed to assess safety of procalcitonin-guided treatment in patients with acute respiratory infections from different clinical settings.

Methods

Based on a prespecified Cochrane protocol, we did a systematic literature search on the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, and pooled individual patient data from trials in which patients with respiratory infections were randomly assigned to receive antibiotics based on procalcitonin concentrations (procalcitonin-guided group) or control. The coprimary endpoints were 30-day mortality and setting-specific treatment failure. Secondary endpoints were antibiotic use, length of stay, and antibiotic side-effects.

Findings

We identified 990 records from the literature search, of which 71 articles were assessed for eligibility after exclusion of 919 records. We collected data on 6708 patients from 26 eligible trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided patients than in control patients (286 [9%] deaths in 3336 procalcitonin-guided patients vs 336 [10%] in 3372 controls; adjusted odds ratio [OR] 0·83 [95% CI 0·70 to 0·99], p=0·037). This mortality benefit was similar across subgroups by setting and type of infection (pinteractions>0·05), although mortality was very low in primary care and in patients with acute bronchitis. Procalcitonin guidance was also associated with a 2·4-day reduction in antibiotic exposure (5·7 vs 8·1 days [95% CI −2·71 to −2·15], p<0·0001) and a reduction in antibiotic-related side-effects (16% vs 22%, adjusted OR 0·68 [95% CI 0·57 to 0·82], p<0·0001).

Interpretation

Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic exposure and side-effects, and improves survival. Widespread implementation of procalcitonin protocols in patients with acute respiratory infections thus has the potential to improve antibiotic management with positive effects on clinical outcomes and on the current threat of increasing antibiotic multiresistance.

Funding

National Institute for Health Research.

Introduction

The US Food and Drug Administration approved the blood infection biomarker procalcitonin for the purpose of guiding antibiotic therapy in the context of acute respiratory infections and sepsis in February, 2017.1 Procalcitonin is a calcitonin-related gene product expressed by human epithelial cells in response to bacterial infections and is conversely downregulated during viral infections.2, 3 Study findings have shown that procalcitonin concentrations fall rapidly during recovery from acute bacterial infections.4 As a surrogate marker of host response to bacterial infections, procalcitonin has therefore been proposed as an adjunct to traditional clinical and diagnostic parameters in helping to manage patients presenting with clinical symptoms suggestive of systemic infections and to guide antibiotic prescribing practices.5

Acute respiratory tract illnesses are one of the leading causes of adult hospital admissions and death worldwide, and are associated with antibiotic overuse.6 Although more than 40% of respiratory infections have a viral cause, imprecise bacterial diagnostics and provider concerns about co-infection prompt antibiotic prescription in most cases.7 Several trials have reported significant reductions in antibiotic exposure, when procalcitonin was used to guide decisions about initiation of antibiotics in low-risk patients (eg, patients with a clinical syndrome of bronchitis in the emergency department) and duration of treatment in high-risk patients (eg, in patients with pneumonia).8 However, although one trial9 found a reduction in mortality associated with procalcitonin-guided antibiotic stewardship in the intensive care unit (ICU), conclusive evidence on the safety of this approach across clinical settings and different types of respiratory infections has been impeded by insufficient statistical power in most individual trials.9 Moreover, previous meta-analyses10, 11, 12 concluded that although procalcitonin use was effective at reducing antibiotic exposure, results about the effect of procalcitonin-guided antibiotic stewardship on clinical outcomes were inconclusive. These meta-analyses, however, were based on aggregate data rather than individual patient-level data, restricting the ability to harmonise outcome definitions and to assess differences between subgroups, and also had a more narrow focus and thus only included a limited number of trials.

Research in context

Evidence before this study

Use of the blood infection marker procalcitonin has gained much attention in the past 10 years as adjunct to clinical judgment in discriminating viral and bacterial infections and guiding both prescription and duration of antibiotic therapy. Several individual trials showed positive effects with a reduction of antibiotic exposure in patients with respiratory infections. Yet, there is ongoing concern about safety of this approach regarding mortality. Previous meta-analyses reported no significant effect on mortality, but confidence intervals were large and harm could thus not be excluded. Based on a protocol previously published in the published in the Cochrane Library, we did a systematic literature search on the Cochrane Central Register of Controlled Trials (CENTRAL; January, 2017, issue 1), MEDLINE (1966 to February, 2017), and Embase (1980 to February, 2017). We searched PubMed using the search terms “Calcitonin”, “Procalcitonin”, “ProCT” and “Anti-Bacterial Agents”, “antibiotic”, “Antibiotics”, “antibacterial, “anti-bacterial”, “amoxicillin, “penicillin”, “ampicillin”, “cotrimoxazole”, “chloramphenicol”, “trimethoprim”, “sulphamethoxazole”, “tmp smx” and “Biomarkers”, “Marker”, “Level”, “levels”, Guide”, “Guidance” and “randomised controlled trial”, “controlled clinical trial”, “randomized”, “randomised”, “placebo”, “drug therapy”, “randomly”, “trial”, “groups”, but not “animals”, “not humans”. For other data sources, we used similar key search terms as above. Individual patient data were collected from eligible randomised controlled trials that assessed adults with a clinical diagnosis of upper or lower acute respiratory tract infection.

Added value of this study

This study showed substantial relative and absolute reductions in antibiotic use in patients with respiratory infections managed by procalcitonin protocols compared with patients in the control group. Although such reductions were found in previous research, importantly in this large cohort of patients, we also found an improvement in clinical outcomes, namely a reduction in 30-day mortality and antibiotic side-effects. This analysis is the first report, to our knowledge, that shows clinical benefits beyond antibiotic reductions with the use of procalcitonin protocols.

Implications of all the available evidence

This report integrates most of the available evidence on procalcitonin in patients with acute respiratory infection from randomised trials. Given the positive results regarding antibiotic reduction and improvements in clinical outcomes, this report strengthens the rationale to use procalcitonin to support antibiotic stewardship decisions in patients with acute respiratory infections.

We therefore did a search and meta-analysis of individual patient data from 26 randomised-controlled trials,9, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 based on a prespecified Cochrane protocol,38, 39 to comprehensively and definitively assess the safety of using procalcitonin to guide antibiotic decisions in patients with respiratory illnesses from different clinical settings and with different types of respiratory infections. This analysis is an update of a previous meta-analysis published in 2012,39 and an extended version of this review will be published in the Cochrane Library.

Section snippets

Search strategy and selection criteria

For this systematic review and meta-analysis, trial selection and data collection was done based on a protocol published in the Cochrane Library and the report prepared according to PRISMA individual patient data guidelines.40, 41

We collected individual patient data from eligible randomised controlled trials that assessed adults with a clinical diagnosis of upper or lower acute respiratory tract infection including community-acquired pneumonia, hospital-acquired pneumonia, ventilator-associated

Results

We identified 990 records from the literature search, of which 71 articles were assessed for eligibility after exclusion of 919 records (figure 1). Data from 6708 individual patients were obtained and included in the meta-analysis of 26 eligible trials. We excluded two trials in which patients did not have confirmed respiratory infections, and patient data were unavailable from four additional trials. Trials were done in 12 countries: Australia, Belgium, Brazil, China, Denmark, France, Germany,

Discussion

To our knowledge, this systematic review and individual patient data meta-analysis of 26 randomised trials and 6708 patients is the first report to describe significant and relevant improvements in clinical outcomes and specifically a decreased risk for mortality for patients with acute respiratory infections, when procalcitonin was used to guide antibiotic treatment decisions. This effect was consistent across clinical settings and types of infections, and proved to be robust in different

References (63)

  • FDA press release. FDA clears test to help manage antibiotic treatment for lower respiratory tract infections and sepsis

  • P Schuetz et al.

    Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future

    BMC Med

    (2011)
  • P Schuetz et al.

    Procalcitonin and other biomarkers to improve assessment and antibiotic stewardship in infections—hope for hype?

    Swiss Med Wkly

    (2009)
  • PE Charles et al.

    Procalcitonin kinetics within the first days of sepsis: relationship with the appropriateness of antibiotic therapy and the outcome

    Crit Care

    (2009)
  • R Sager et al.

    Procalcitonin-guided diagnosis and antibiotic stewardship revisited

    BMC Med

    (2017)
  • DM Musher et al.

    Community-acquired pneumonia

    N Engl J Med

    (2014)
  • M Silverman et al.

    Antibiotic prescribing for nonbacterial acute upper respiratory infections in elderly persons

    Ann Intern Med

    (2017)
  • P Schuetz et al.

    Procalcitonin for guidance of antibiotic therapy

    Expert Rev Anti Infect Ther

    (2010)
  • P Schuetz et al.

    Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms

    Arch Intern Med

    (2011)
  • MH Wu et al.

    Can procalcitonin tests aid in identifying bacterial infections associated with influenza pneumonia? A systematic review and meta-analysis

    Influenza Other Respir Viruses

    (2012)
  • P Berg et al.

    The role of procalcitonin in adult patients with community-acquired pneumonia—a systematic review

    Dan Med J

    (2012)
  • F Bloos et al.

    Effect of sodium selenite administration and procalcitonin-guided therapy on mortality in patients with severe sepsis or septic shock: a randomized clinical trial

    JAMA Intern Med

    (2016)
  • AR Branche et al.

    Serum procalcitonin measurement and viral testing to guide antibiotic use for respiratory infections in hospitalized adults: a randomized controlled trial

    J Infect Dis

    (2015)
  • M Briel et al.

    Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care

    Arch Intern Med

    (2008)
  • O Burkhardt et al.

    Procalcitonin guidance and reduction of antibiotic use in acute respiratory tract infection

    Eur Respir J

    (2010)
  • M Christ-Crain et al.

    Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial

    Am J Respir Crit Care Med

    (2006)
  • C Corti et al.

    Point-of-care procalcitonin test to reduce antibiotic exposure in patients hospitalized with acute exacerbation of COPD

    Int J Chron Obstruct Pulmon Dis

    (2016)
  • M Hochreiter et al.

    Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial

    Crit Care

    (2009)
  • N Layios et al.

    Procalcitonin usefulness for the initiation of antibiotic treatment in intensive care unit patients

    Crit Care Med

    (2012)
  • W Long et al.

    Procalcitonin guidance for reduction of antibiotic use in low-risk outpatients with community-acquired pneumonia

    Respirology

    (2011)
  • W Long et al.

    The value of serum procalcitonin in treatment of community acquired pneumonia in outpatient

    Chin J Intern Med

    (2009)
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