Procalcitonin: Useful Test or Useless Pest to Improve Antibiotic Stewardship with Acute Respiratory Infections in the ED?

Written by Anand Swaminathan REBEL EM Medical Category: Infectious Disease

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

Article: Tupchong K, Chien C. Is procalcitonin useful in the diagnosis and treatment of acute respiratory infections in the Emergency Department? Ann Emerg Med 2018. PMID: 29459056

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?

Population:

Adults with ARI diagnoses: CAP, HCAP, VAP, bronchitis, acute asthma, acute COPD, common cold, rhinosinusitis, pharyngitis, tonsillitis, otitis media in primary care, emergency department, ward and ICU settings

Intervention:

Procalcitonin-guided care: initiate or discontinue antibiotics based on procalcitonin levels

Control:

Standard care: no procalcitonin measurement, antibiotic management based on usual care

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

Design:

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.

Inclusion:

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

Exclusion:

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

Less than 1/2 of studies were performed in the ED

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

Most studies exclusively enrolled patients after admission, rather than upon ER presentation

Not generalizable to majority of ER patients with ARIs who are expected to be discharged.

Discussion:

The following are thoughts from Ryan Radecki who runs a great blog himself: EM Lit of Note

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.

Authors’ 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.

Clinical 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.

Guest Post By:

Bess Storch, MD

Senior Resident

NYU/Bellevue EM Residency Program

For More on This Topic Checkout:

Post Peer Reviewed By: Anand Swaminathan, MD (@EMSwami) and Salim R. Rezaie, MD (@srrezaie)