Elsevier

The Lancet

Volume 375, Issue 9713, 6–12 February 2010, Pages 463-474
The Lancet

Articles
Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial

https://doi.org/10.1016/S0140-6736(09)61879-1Get rights and content

Summary

Background

Reduced duration of antibiotic treatment might contain the emergence of multidrug-resistant bacteria in intensive care units. We aimed to establish the effectiveness of an algorithm based on the biomarker procalcitonin to reduce antibiotic exposure in this setting.

Methods

In this multicentre, prospective, parallel-group, open-label trial, we used an independent, computer-generated randomisation sequence to randomly assign patients in a 1:1 ratio to procalcitonin (n=311 patients) or control (n=319) groups; investigators were masked to assignment before, but not after, randomisation. For the procalcitonin group, antibiotics were started or stopped based on predefined cut-off ranges of procalcitonin concentrations; the control group received antibiotics according to present guidelines. Drug selection and the final decision to start or stop antibiotics were at the discretion of the physician. Patients were expected to stay in the intensive care unit for more than 3 days, had suspected bacterial infections, and were aged 18 years or older. Primary endpoints were mortality at days 28 and 60 (non-inferiority analysis), and number of days without antibiotics by day 28 (superiority analysis). Analyses were by intention to treat. The margin of non-inferiority was 10%. This trial is registered with ClinicalTrials.gov, number NCT00472667.

Findings

Nine patients were excluded from the study; 307 patients in the procalcitonin group and 314 in the control group were included in analyses. Mortality of patients in the procalcitonin group seemed to be non-inferior to those in the control group at day 28 (21·2% [65/307] vs 20·4% [64/314]; absolute difference 0·8%, 90% CI −4·6 to 6·2) and day 60 (30·0% [92/307] vs 26·1% [82/314]; 3·8%, −2·1 to 9·7). Patients in the procalcitonin group had significantly more days without antibiotics than did those in the control group (14·3 days [SD 9·1] vs 11·6 days [SD 8·2]; absolute difference 2·7 days, 95% CI 1·4 to 4·1, p<0·0001).

Interpretation

A procalcitonin-guided strategy to treat suspected bacterial infections in non-surgical patients in intensive care units could reduce antibiotic exposure and selective pressure with no apparent adverse outcomes.

Funding

Assistance Publique-Hôpitaux de Paris, France, and Brahms, Germany.

Introduction

Antimicrobial resistance has emerged as a major factor affecting patient outcomes and overall resources in intensive care units.1 We are now heading towards extreme drug resistance, especially among gram-negative bacilli.1, 2, 3 Insufficient measures to control infection and selective antibiotic pressure are two key factors associated with the emergence of bacterial resistance.4 Compelling evidence that antibiotic use causes resistance has led to calls to stop inappropriate prescription of antibiotics.4, 5

Antimicrobial consumption in the intensive care unit can be substantially reduced by starting of antibiotics only for patients with true bacterial infections, or shortening of treatment duration for those needing antibiotics, or both.4, 5, 6, 7 Guidance for duration of antibiotic treatment could be based on the results of studies comparing two different durations,8, 9, 10 but such studies are still scarce for patients in intensive care units, and are applicable only for well defined infection sites. Another approach is to identify easily obtainable biomarkers, in addition to usual clinical and bacteriological indicators, to guide physicians. The potential advantage of such a strategy would be to individualise antibiotic duration according to the patient's response to antimicrobial treatment.

Procalcitonin, a calcitonin precursor hormone, is judged to be a fairly specific marker for severe bacterial infection in patients with suspected sepsis.11, 12, 13 Guidance about serum procalcitonin concentration has substantially reduced antibiotic use in patients presenting at the emergency department or admitted to hospital for lower-respiratory-tract infections.14, 15, 16, 17 Despite these encouraging results, the potential usefulness of procalcitonin as an instrument to guide antibiotic use in all intensive care units has not yet been shown. Results from two small studies, each in one centre, have suggested that a protocol based on serial serum procalcitonin measurements could achieve shortening of antibiotic treatment by 2–3·5 days for patients in the intensive care unit with sepsis or septic shock.18, 19

We therefore undertook a randomised, multicentre effectiveness trial to assess the benefit of procalcitonin to help physicians start, continue, or stop antibiotics for patients in intensive care units with suspected bacterial infections. Our objective was to establish whether a strategy based on procalcitonin concentration would achieve reduced antibiotic consumption. Because shortening of antibiotic treatment might be harmful, our trial was designed to assure that this strategy did not affect outcome.

Section snippets

Study design and participants

The prospective, parallel-group, open-label PROcalcitonin to Reduce Antibiotic Treatments in Acutely ill patients (PRORATA) trial was undertaken in France between June, 2007, and May, 2008. We assessed critically ill patients with suspected bacterial infections in seven (five medical, two surgical) intensive care units in five university-affiliated hospitals, and one medicosurgical intensive care unit in a general hospital; in total these units comprised 140 beds.

All adults with suspected

Results

1315 patients with suspected infections were screened for eligibility, of whom 630 were enrolled and randomly assigned to the procalcitonin group (n=311 patients) or the control group (n=319; figure 2). Four patients in the procalcitonin group and five in the control group were subsequently excluded from the analysis. Table 1 and webappendix pp 4–5 show the clinical characteristics of the remaining 621 patients at admission to the intensive care unit and inclusion into the study. For patients

Discussion

The results of our study show that for patients with suspected infections, either at admission to the intensive care unit or during their stay in the unit, procalcitonin-guided antibiotic treatment substantially lowers antibiotic exposure and is non-inferior to standard care with respect to outcomes. For patients in the procalcitonin group, the absolute difference of 2·7 days between the mean numbers of days without antibiotics by day 28 corresponds to a 23% relative reduction in antibiotic

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