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.
Quantifying patient-centric outcomes from diagnostic RCTs is uncommon (http://pmid.us/28063913). Procalcitonin (PC)-guided antibiotic protocols for URIs are carefully advocated by some (http://pmid.us/28114931), but the value of this additional serum test has been questioned by others (http://pmid.us/28407096, http://pmid.us/28290130). This Cochrane review could alter the diagnostic paradigm in favor of PC-guided pathways in efforts to promote antibiotic stewardship in acute care and primary care settings, but cause-effect relationships remain elusive. How does a PC-guided protocol reduce mortality if treatment failures are not significantly different? Is using PC cost-effective?”
This is not readily available in my region so far, but this Cochrane review suggests measurement can safely lower antibiotic use across a variety of settings.
This systematic review should be made available broadly to all primary care providers. It should prompt clinical facilities to ensure that procalcitonin assays are available. This is important information.
This is a very interesting review that supports increasing the use of procalcitonin testing to guide empiric use of antibiotics in patients exhibiting symptoms of respiratory infection to reduce antibiotic use and improve outcomes.
This is a fairly definitive result with good meta-analytic methods. In Canada, we should seriously think about this, especially if used to show that mortality is decreased with reduced inappropriate antimicrobial use. This should catch the attention of doctors.
This Cochrane meta-analysis shows that procalcitonin-guided treatment of acute respiratory infections produces lower mortality and less antibiotic exposure, with no increase in treatment failure or length-of-stay. This review incorporates double the number of trials since the previous update, including 2 larger ones that drive the results to reach statistical significance, so the meta-analysis generates new knowledge. Procalcitonin is not available as a test in many places and its use varies regionally and nationally. These results will provide further impetus to make its clinical use more widespread and is especially relevant for primary care physicians, emergency physicians, and antimicrobial stewardship.
The role of procalcitonin in antibiotic stewardship is appreciated by most as a way to reduce/optimize the use of antibiotics with the aim to mitigate the adverse effects of these drugs (including increased mortality with extended use?). This meta-analysis locks in the important role for procalcitonin in antibiotic stewardship.