NIHR DC Discover

NIHR Signal Blood test reduces mortality and shortens antibiotic use among adults with chest infection

Published on 16 January 2018

doi: 10.3310/signal-000527

It may be feasible to use procalcitonin blood levels to guide antibiotic treatment for adults in hospital with a suspected chest infection. By measuring procalcitonin, an indicator of bacterial infection, clinicians could review their diagnosis earlier.

This reduced antibiotic exposure by 2.5 days with fewer adverse effects and also less mortality. About 14 extra people in every 1,000 who had their management guided by the blood test would be expected to survive the first month, compared with those receiving standard care without this test.

Antibiotics are commonly prescribed pre-emptively for a suspected respiratory infection and may be continued longer than necessary. As blood procalcitonin levels increase in response to bacterial infection, procalcitonin may have potential to guide starting or stopping antibiotics.

This NIHR-funded review adds 18 trials to the growing body of evidence indicating that procalcitonin may help refine the use of antibiotics in select patient groups.

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Why was this study needed?

Respiratory infections account for around 10% of the global disease burden and are the most common reason for prescribing antibiotics. Many infections are viral and neither need nor respond to antibiotics. But in practice, it can be hard to distinguish between bacterial and viral infection.

Overprescribing for respiratory infections seems to be a contributor to increasing antibiotic resistance. However, the emergence of resistant bacteria might not be down to overprescribing alone as other factors including unnecessarily long courses of antibiotics might also be partly to blame.

Blood cultures aren’t always accurate or available. A blood marker like procalcitonin that correlates fairly well with bacterial levels may help guide decisions around starting or stopping antibiotics. Numerous trials have investigated it for this use in recent years, in different settings and populations.

In 2015 NICE called for further research in this area. This Cochrane review update adds 18 trials, published in the last five years, looking at procalcitonin-guided treatment in respiratory infections, mostly those treated in hospital settings.

What did this study do?

The review included a total 32 randomised controlled trials, with individual patient data available for 6,708 people in 26 trials. Most trials took place in intensive care or emergency departments, with community-acquired pneumonia the most common diagnosis. Average patient age was 61 years.

Most trials took repeated procalcitonin measures and used similar cut-off levels to guide starting or stopping antibiotics, though a few took one-off measures. Nearly all compared with physician-guided treatment. Only a single trial compared with the inflammatory marker C-reactive protein.

Trials came from 12, mostly high-income countries, though none was UK-based. The participants and assessors were aware of group assignment. However, the outcomes were objective, and so the effect of this bias across trials was thought to be small.

What did it find?

  • Procalcitonin-guided treatment gave a 1.4% absolute reduction in risk of death within 30 days. 8.6% of people in the intervention groups died compared with 10% of controls (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.70 to 0.99). This was high-quality evidence from patient data across the 26 trials with similar findings across all settings, though only two studies were in primary care.
  • Standard care led to an average of 8.1 days of antibiotic use. There was high-quality evidence that procalcitonin guidance reduced antibiotic exposure by 2.43 days compared with control (95% CI -2.15 to -2.71 days; 26 studies).
  • There was no difference between groups in the rate of treatment failure by 30 days (23% intervention vs 25% controls; OR 0.90, 95% CI 0.80 to 1.01; 26 studies). This was as defined by death, worsening infection or complications, or any ongoing respiratory symptoms at follow-up.
  • Procalcitonin measurement reduced the number of people experiencing adverse effects from 22.1% to 16.3% (OR 0.68, 95% CI 0.57 to 0.82; moderate evidence from six studies, 3,034 people).

What does current guidance say on this issue?

NICE recommends using C-reactive protein to guide antibiotic prescribing if there is uncertainty around the diagnosis of pneumonia, with a similar position taken by The British Thoracic Society.

NICE diagnostics guidance (2015) covering different assays to measure procalcitonin said the tests had promise, but there was insufficient evidence to recommend their routine use in the NHS. NICE advised further research into the use of procalcitonin to guide antibiotic treatment in people with suspected bacterial infection.

Surviving Sepsis international guidelines (2017) give a weak recommendation that procalcitonin levels may be used to reduce the duration of antimicrobial therapy in critical care patients with sepsis or suspected sepsis.

What are the implications?

These findings indicate that procalcitonin can be used safely to guide the starting and stopping of antibiotic therapy in adults hospitalised with a respiratory infection. Rapid availability of results may enhance the performance of treatment decision tools.

Reducing duration of antibiotics in this population may help reduce the risk to individuals from antibiotic exposure and also may reduce the overall problem of antibiotic resistance.

 About three-quarters of all antibiotic prescriptions take place in primary care. It’s less clear whether procalcitonin may be able to guide antibiotic prescription outside of hospital or whether this test would be a good use of resources there. The researchers note that the rates of bacterial infection and mortality were lower in the two primary care studies they identified.

Citation and Funding

Schuetz P, Wirz Y, Sager R, et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis. Lancet Infect Dis. 2018;18(1):95-107.

The National Institute for Health Research (NIHR) provided a research grant for this review update.

Bibliography

NICE. Procalcitonin for diagnosing and monitoring sepsis (ADVIA Centaur BRAHMS PCT assay, BRAHMS PCT Sensitive Kryptor assay, Elecsys BRAHMS PCT assay, LIAISON BRAHMS PCT assay and VIDAS BRAHMS PCT assay). DG18. London: National Institute for Health and Care Excellence; 2015.

NICE. Pneumonia in adults: diagnosis and management. CG191. London: National Institute for Health and Care Excellence; 2014.

British Thoracic Society. Guidelines for the management of community acquired pneumonia in adults. London: British Thoracic Society; 2009 update.

Rhodes A, Evans L, Alhazzani W, et al. Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304–377.

NICE. Antimicrobial stewardship: systems and process for effective antimicrobial medicine use. NG15. London: National Institute for Health and Care Excellence; 2015.

NICE. Antimicrobial stewardship. QS121. London: National Institute for Health and Care Excellence; 2016.

NICE. Respiratory tract infections (self-limiting): prescribing antibiotics. CG69. London: National Institute for Health and Care Excellence; 2008.

NICE. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. CG101. London: National Institute for Health and Care Excellence; 2010.

Schuetz P, Wirz Y, Sager R, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017;(10):CD007498. 

Why was this study needed?

Respiratory infections account for around 10% of the global disease burden and are the most common reason for prescribing antibiotics. Many infections are viral and neither need nor respond to antibiotics. But in practice, it can be hard to distinguish between bacterial and viral infection.

Overprescribing for respiratory infections seems to be a contributor to increasing antibiotic resistance. However, the emergence of resistant bacteria might not be down to overprescribing alone as other factors including unnecessarily long courses of antibiotics might also be partly to blame.

Blood cultures aren’t always accurate or available. A blood marker like procalcitonin that correlates fairly well with bacterial levels may help guide decisions around starting or stopping antibiotics. Numerous trials have investigated it for this use in recent years, in different settings and populations.

In 2015 NICE called for further research in this area. This Cochrane review update adds 18 trials, published in the last five years, looking at procalcitonin-guided treatment in respiratory infections, mostly those treated in hospital settings.

What did this study do?

The review included a total 32 randomised controlled trials, with individual patient data available for 6,708 people in 26 trials. Most trials took place in intensive care or emergency departments, with community-acquired pneumonia the most common diagnosis. Average patient age was 61 years.

Most trials took repeated procalcitonin measures and used similar cut-off levels to guide starting or stopping antibiotics, though a few took one-off measures. Nearly all compared with physician-guided treatment. Only a single trial compared with the inflammatory marker C-reactive protein.

Trials came from 12, mostly high-income countries, though none was UK-based. The participants and assessors were aware of group assignment. However, the outcomes were objective, and so the effect of this bias across trials was thought to be small.

What did it find?

  • Procalcitonin-guided treatment gave a 1.4% absolute reduction in risk of death within 30 days. 8.6% of people in the intervention groups died compared with 10% of controls (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.70 to 0.99). This was high-quality evidence from patient data across the 26 trials with similar findings across all settings, though only two studies were in primary care.
  • Standard care led to an average of 8.1 days of antibiotic use. There was high-quality evidence that procalcitonin guidance reduced antibiotic exposure by 2.43 days compared with control (95% CI -2.15 to -2.71 days; 26 studies).
  • There was no difference between groups in the rate of treatment failure by 30 days (23% intervention vs 25% controls; OR 0.90, 95% CI 0.80 to 1.01; 26 studies). This was as defined by death, worsening infection or complications, or any ongoing respiratory symptoms at follow-up.
  • Procalcitonin measurement reduced the number of people experiencing adverse effects from 22.1% to 16.3% (OR 0.68, 95% CI 0.57 to 0.82; moderate evidence from six studies, 3,034 people).

What does current guidance say on this issue?

NICE recommends using C-reactive protein to guide antibiotic prescribing if there is uncertainty around the diagnosis of pneumonia, with a similar position taken by The British Thoracic Society.

NICE diagnostics guidance (2015) covering different assays to measure procalcitonin said the tests had promise, but there was insufficient evidence to recommend their routine use in the NHS. NICE advised further research into the use of procalcitonin to guide antibiotic treatment in people with suspected bacterial infection.

Surviving Sepsis international guidelines (2017) give a weak recommendation that procalcitonin levels may be used to reduce the duration of antimicrobial therapy in critical care patients with sepsis or suspected sepsis.

What are the implications?

These findings indicate that procalcitonin can be used safely to guide the starting and stopping of antibiotic therapy in adults hospitalised with a respiratory infection. Rapid availability of results may enhance the performance of treatment decision tools.

Reducing duration of antibiotics in this population may help reduce the risk to individuals from antibiotic exposure and also may reduce the overall problem of antibiotic resistance.

 About three-quarters of all antibiotic prescriptions take place in primary care. It’s less clear whether procalcitonin may be able to guide antibiotic prescription outside of hospital or whether this test would be a good use of resources there. The researchers note that the rates of bacterial infection and mortality were lower in the two primary care studies they identified.

Citation and Funding

Schuetz P, Wirz Y, Sager R, et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis. Lancet Infect Dis. 2018;18(1):95-107.

The National Institute for Health Research (NIHR) provided a research grant for this review update.

Bibliography

NICE. Procalcitonin for diagnosing and monitoring sepsis (ADVIA Centaur BRAHMS PCT assay, BRAHMS PCT Sensitive Kryptor assay, Elecsys BRAHMS PCT assay, LIAISON BRAHMS PCT assay and VIDAS BRAHMS PCT assay). DG18. London: National Institute for Health and Care Excellence; 2015.

NICE. Pneumonia in adults: diagnosis and management. CG191. London: National Institute for Health and Care Excellence; 2014.

British Thoracic Society. Guidelines for the management of community acquired pneumonia in adults. London: British Thoracic Society; 2009 update.

Rhodes A, Evans L, Alhazzani W, et al. Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304–377.

NICE. Antimicrobial stewardship: systems and process for effective antimicrobial medicine use. NG15. London: National Institute for Health and Care Excellence; 2015.

NICE. Antimicrobial stewardship. QS121. London: National Institute for Health and Care Excellence; 2016.

NICE. Respiratory tract infections (self-limiting): prescribing antibiotics. CG69. London: National Institute for Health and Care Excellence; 2008.

NICE. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. CG101. London: National Institute for Health and Care Excellence; 2010.

Schuetz P, Wirz Y, Sager R, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017;(10):CD007498. 

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

Published on 19 October 2017

Schuetz, P.,Wirz, Y.,Sager, R.,Christ-Crain, M.,Stolz, D.,Tamm, M.,Bouadma, L.,Luyt, C. E.,Wolff, M.,Chastre, J.,Tubach, F.,Kristoffersen, K. B.,Burkhardt, O.,Welte, T.,Schroeder, S.,Nobre, V.,Wei, L.,Bucher, H. C.,Annane, D.,Reinhart, K.,Falsey, A. R.,Branche, A.,Damas, P.,Nijsten, M.,de Lange, D. W.,Deliberato, R. O.,Oliveira, C. F.,Maravic-Stojkovic, V.,Verduri, A.,Beghe, B.,Cao, B.,Shehabi, Y.,Jensen, J. S.,Corti, C.,van Oers, J. A. H.,Beishuizen, A.,Girbes, A. R. J.,de Jong, E.,Briel, M.,Mueller, B.

Lancet Infect Dis , 2017

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.

Expert commentary

Most people would expect a procalcitonin-based algorithm to reduce antimicrobial prescribing and side-effects. However, the reduced mortality when used in respiratory tract infections is more surprising. The authors suggest:

  • low procalcitonin might prompt clinicians to seek an alternative cause of their symptoms (such as heart failure or pulmonary embolism),
  • lack of reduction in procalcitonin levels might identify earlier non-responders to empirical treatments, or
  • the reduction in side-effects and antibiotic exposure is related to better outcomes

Reducing antimicrobial prescriptions to limit bacterial resistance is challenged by clinicians concerned about “withholding” antibiotics. This study reassures us that this strategy is safe and better.

Dr Helena Parsons, Clinical Lead for Microbiology, Sheffield Teaching Hospitals NHS Foundation Trust

Expert commentary

Antibiotic overuse is driving bacterial antibiotic resistance. Respiratory infection syndromes are one of the most common settings for antibiotic prescription, but the outcome of many is uninfluenced by such prescription. A simple tool to guide appropriate antibiotic commencement could reduce antibiotic over-prescription (and pressure for resistance development) while simultaneously helping those with antibiotic-responsive conditions.

Blood procalcitonin measurement as a guide to antibiotic commencement has been associated with a mortality reduction and reduced antibiotic exposure in respiratory infection syndromes. Cost-effectiveness in different respiratory infection syndromes and different healthcare settings needs to be demonstrated.

Dr Mark Woodhead, President-elect British Thoracic Society, Honorary Clinical Professor of Respiratory Medicine, Manchester University NHS Foundation Trust