Title:
Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections.

Abstract:
Acute respiratory infections (ARIs) comprise a large and heterogeneous group of infections including bacterial, viral and other aetiologies. In recent years, procalcitonin - the prohormone of calcitonin - has emerged as a promising marker for the diagnosis of bacterial infections and for improving decisions about antibiotic therapy. Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with acute respiratory infections and different settings ranging from primary care to emergency departments (EDs), hospital wards and intensive care units (ICUs).
The aim of this systematic review based on individual patient 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.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2011, Issue 2) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to May 2011) and EMBASE (1974 to May 2011) to identify suitable trials.
We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm or usual care/guidelines. Trials were excluded if they exclusively focused on paediatric patients or if they used procalcitonin for another purpose than to guide initiation and duration of antibiotic treatment.
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 the primary care setting, treatment failure was defined as death, hospitalisation, ARI-specific complications, recurrent or worsening infection, and patients reporting any symptoms of an ongoing respiratory infection at follow-up. For the ED setting, treatment failure was defined as death, ICU admission, re-hospitalisation after index hospital discharge, ARI-associated complications, and recurrent or worsening infection within 30 days of follow-up. For the ICU setting, treatment failure was defined as death within 30 days of follow-up. Secondary endpoints were antibiotic use (initiation of antibiotics, duration of antibiotics and total exposure to antibiotics (total amount of antibiotic days divided by total number of patients)), length of hospital stay for hospitalised patients, length of ICU stay for critically ill patients, and number of days with restricted activities within 14 days after randomisation for primary care patients.For the two co-primary endpoints of all-cause mortality and treatment failure, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression. The hierarchical regression model was adjusted for age and clinical diagnosis as fixed-effect. The different trials were added as random-effects into the model. We fitted corresponding linear regression models for antibiotic use. We conducted sensitivity analyses stratified by clinical setting and ARI diagnosis to assess the consistency of our results.
We included 14 trials with 4221 participants. There were 118 deaths in 2085 patients (5.7%) assigned to procalcitonin groups compared to 134 deaths in 2126 control patients (6.3%) (adjusted OR 0.94, 95% CI 0.71 to 1.23). Treatment failure occurred in 398 procalcitonin group patients (19.1%) and in 466 control patients (21.9%). Procalcitonin guidance was not associated with increased mortality or treatment failure in any clinical setting, or ARI diagnosis. These results proved robust in various sensitivity analyses. Total antibiotic exposure was significantly reduced overall (median (interquartile range) from 8 (5 to 12) to 4 (0 to 8) days; adjusted difference in days, -3.47, 95% CI -3.78 to -3.17, and across all the different clinical settings and diagnoses.
Use of procalcitonin to guide initiation and duration of antibiotic treatment in patients with ARI was not associated with higher mortality rates or treatment failure. Antibiotic consumption was significantly reduced across different clinical settings and ARI diagnoses. Further high-quality research is needed to confirm the safety of this approach for non-European countries and patients in intensive care. Moreover, future studies should also establish cost-effectiveness by considering country-specific costs of procalcitonin measurement and potential savings in consumption of antibiotics and other healthcare resources, as well as secondary cost savings due to lower risk of side effects and reduced antimicrobial resistance.