Background

In patients with an acute respiratory illness (ARI), it is often difficult to determine whether a bacterial infection is the underlying etiology and whether antibiotics are warranted. Excess antibiotic use carries risk of bacterial resistance, medical costs, and adverse drug effects. However, underuse of antibiotics risks inadequate treatment and progression of disease. In the setting of a bacterial infection, cytokines stimulate procalcitonin production and release. The serum procalcitonin level increases with the progression of bacterial infection and decreases upon recovery. Procalcitonin production is actually blocked in the setting of viral infection, resulting in low serum levels. Numerous studies have investigated the use of procalcitonin for the determination of initiating antibiotics as well as for aiding in decisions to terminate their use.

This Evidence-Based Emergency Medicine (EBEM) article reviews the following systematic review:

Schuetz P et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev 2017. PMID: 29025194

Clinical Question

What is the safety and efficacy of using procalcitonin for starting or stopping antibiotics over a range of patients with varying severity of ARIs and from different clinical settings?

Design

Systematic review and meta-analysis

Literature Search

Cochrane systematic review of randomized controlled trials. Searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase on February 10, 2017. Searched clinicaltrials.gov for ongoing and completed trials on April 12, 2017.

Outcomes

Primary: All-cause mortality and setting-specific treatment failure at 30 days (e.g. hospitalization if in primary care setting)

Secondary: Antibiotic use, antibiotic-related side effects and length of hospital stay

Inclusion

RCTs of adult participants with ARIs who received antibiotics either based on a procalcitonin algorithm or usual care

Excluded

Non-randomized trials, trials focused exclusively on children, trials that used procalcitonin for other than initiation or duration of antibiotics

Primary Results

  • 32 eligible trials (9,909 patients) with 26 trials that provided individual participant data (6,708 patients)
  • 2 primary care, 11 ED/ward, 13 ICU settings
  • CAP most frequent diagnosis (>40% of patients)

Primary Outcome: Mortality

  • Procalcitonin-guided 8.6% vs standard care 10.0%
  • OR 0.83 (95% CI 0.70-0.99, p= 0.037)
  • The odds of death were slightly decreased in a procalcitonin driven strategy
  • Consistent across clinical settings and ARI diagnoses

Primary Outcome: Setting-specific treatment failure at 30 days

  • 23.0% procalcitonin-guided group versus 24.9% controls
  • OR 0.9 (95% CI 0.8 – 1.01)
  • Not significantly different
  • Similar across clinical settings and ARI diagnoses

Secondary Outcome: Antibiotic use

  • Procalcitonin guided: mean 5.7 days vs Control group: mean 8.1 days
  • Regression coefficient -2.43 days of less antibiotic use for procalcitonin group (95% CI -2.71 to -2.15, p<0.001)

Secondary Outcome: Antibiotic-related side effects

  • 16.3% in procalcitonin-guided group versus 22.1% in controls
  • OR 0.68 (95% CI 0.57 – 0.82 p<0.001)
  • The odds of antibiotic related side effects was increased in the standard care arm

Strengths

  • Asks a clinically important question that is patient centered
  • Explicit study protocol
  • Comprehensive search to retrieve all relevant articles
  • Standardized, objective outcome definitions
  • Heterogeneity between studies for the primary outcomes was low
  • Quality of evidence grade was moderate or high for all outcomes

Limitations

  • Half of the trials received funding from the biomarker industry – Thermo Fisher, producer of the procalcitonin assay
  • 32 trials met eligibility criteria, but 6 did not have individual participant data and were not used in data analysis
  • The lead author received funding from the biomarker industry, which violates Cochrane’s Commercial Sponsorship Policy, and will step down at the next update of the review

Limitations for Applicability to the ED

  • Of the 14 ED trials, only three included non-admitted patients
  • Less than 1/2 of studies were performed in the ED
  • Most studies exclusively enrolled patients after admission, rather than upon ER presentation
  • Not generalizable to majority of ED patients with ARIs who are expected to be discharged

Discussion

The following are thoughts from Ryan Radecki who runs emlitofnote.com

  • This is a straw-man comparison. Poor antibiotic stewardship/antibiotic prescribing at baseline will invariably look better when compared to any protocol.  And in outpatient settings, almost impossible to detect treatment failures when comparing two groups that didn’t need treatment to begin with
  • Non-generalizable protocol adherence.  Following protocol was mandated by study center; to break with PCT protocol, had to call central coordinating center.  In real world, like ProACT, people don’t follow PCT protocol and ends up being a waste of time/money.
  • No accounting for appropriate/inappropriate ordering.  In real world, people use PCT on patients who would never be considered for antibiotics, or, conversely, have otherwise mostly conclusive bacterial etiology – but, since it’s there, “let’s test just to make sure.”  Inappropriate excess ordering then becomes a new clinical problem to solve.

Author's Conclusions

“A procalcitonin-guided approach to the initiation and discontinuation of antibiotics in acute respiratory infections has the potential to reduce antibiotic-related adverse effects and duration of therapy, but further study of emergency department (ED) patients is needed.”

Our Conclusions

Procalcitonin-guided therapy may improve outcomes by reducing antibiotic exposure and adverse drug effects, but additional studies without significant industry bias are needed to determine effectiveness of procalcitonin-guided therapy on ED patients who are treated as outpatients.

Potential Impact To Current Practice

Procalcitonin level may be a useful tool in the ED for antibiotic initiation in patient admitted for acute respiratory illnesses and can be trended by the inpatient team for decisions regarding duration of antibiotics.

Bottom Line

Based on the available data, it may be reasonable to obtain a procalcitonin level for decisions regarding initiation of antibiotics in patients with acute respiratory illnesses in the ED if the patient is expected to be admitted. However, significant conflicts of interest cloud the actual utility of this marker and there is insufficient data on the role of procalcitonin and antibiotic initiation for patients who are discharged from the ED.

Read More

EM Lit of Note: Procalcitonin in Serious Bacterial Infection: Spoiler Alert – It Doesn’t Help Here Either

EM Lit of Note: Anti-calcitonin

EM Nerd: The Case of the Deceptive Beacon