Procalcitonin guided antibiotic therapy and hospitalization in patients with lower respiratory tract infections: a prospective, multicenter, randomized controlled trial

Abstract

Background: Lower respiratory tract infections like acute bronchitis, exacerbated chronic obstructive pulmonary disease and community-acquired pneumonia are often unnecessarily treated with antibiotics, mainly because of physicians' difficulties to distinguish viral from bacterial cause and to estimate disease-severity. The goal of this trial is to compare medical outcomes, use of antibiotics and hospital resources in a strategy based on enforced evidence-based guidelines versus procalcitonin guided antibiotic therapy in patients with lower respiratory tract infections.

Methods and design: We describe a prospective randomized controlled non-inferiority trial with an open intervention. We aim to randomize over a fixed recruitment period of 18 months a minimal number of 1002 patients from 6 hospitals in Switzerland. Patients must be >18 years of age with a lower respiratory tract infections <28 days of duration. Patients with no informed consent, not fluent in German, a previous hospital stay within 14 days, severe immunosuppression or chronic infection, intravenous drug use or a terminal condition are excluded. Randomization to either guidelines-enforced management or procalcitonin-guided antibiotic therapy is stratified by centre and type of lower respiratory tract infections. During hospitalization, all patients are reassessed at days 3, 5, 7 and at the day of discharge. After 30 and 180 days, structured phone interviews by blinded medical students are conducted. Depending on the randomization allocation, initiation and discontinuation of antibiotics is encouraged or discouraged based on evidence-based guidelines or procalcitonin cut off ranges, respectively. The primary endpoint is the risk of combined disease-specific failure after 30 days. Secondary outcomes are antibiotic exposure, side effects from antibiotics, rate and duration of hospitalization, time to clinical stability, disease activity scores and cost effectiveness. The study hypothesis is that procalcitonin-guidance is non-inferior (i.e., at worst a 7.5% higher combined failure rate) to the management with enforced guidelines, but is associated with a reduced total antibiotic use and length of hospital stay.

Discussion: Use of and prolonged exposure to antibiotics in lower respiratory tract infections is high. The proposed trial investigates whether procalcitonin-guidance may safely reduce antibiotic consumption along with reductions in hospitalization costs and antibiotic resistance. It will additionally generate insights for improved prognostic assessment of patients with lower respiratory tract infections.

Trial registration: ISRCTN95122877.

Figure 1

All consecutive patients with lower respiratory tract infection are potentially eligible for this trial. If all inclusion criteria are fulfilled and no exclusion criteria are present, the physician has to explain to the patient the trial, ask for participation and get informed consent. After inclusion, the patient is randomized by a web based computerized random allocation algorithm to either the guidelines group or the PCT group, respectively. CAP denotes community-acquired pneumonia, AECOPD acute exacerbation of chronic pulmonary disease, AB antibiotics, PCT procalcitonin.

Figure 2

Antibiotic stewardship based on procalcitonin (PCT) cut-off ranges. Re-evaluation of the clinical status and measurement of serum PCT levels is mandatory after 6–24 h in all persistently sick and hospitalized patients in who antibiotic are withheld. The PCT algorithm can be overruled by pre-specified criteria, e.g. in patients with immediately life-threatening disease. If the algorithm is overruled and antibiotics are given, an early discontinuation of antibiotic therapy after 3, 5 or 7 days is more or less endorsed based on PCT levels. In hospitalized patients with ongoing antibiotic therapy PCT levels are reassessed on days 3, 5 and 7 and antibiotics will be discontinued using the PCT cut-offs defined above. In all patients with a very high PCT value on admission (e.g., >10 μg/L), discontinuation of antibiotic is already encouraged if levels decreased below 80 to 90% of the initial value. In patients discharged and, thus, likely uncomplicated resolution of the infection or in patients transferred to an institution not taking part in this trial the recommended total duration of antibiotic therapy is based on the last PCT level and is as following: >1 ug/L 7 days, 0.5–0.99 ug/L 5 days, 0.25–0.49 ug/L 3 days, <0.25 ug/L stop antibiotic, <0.1 ug/L STOP antibiotic. PCT denotes procalcitonin, AB antibiotics,Tbc tuberculosis, ICU intensive care unit,