Antibiotic treatment of severe exacerbations of chronic obstructive pulmonary disease with procalcitonin: a randomized noninferiority trial

Abstract

Background: The duration of antibiotic treatment of exacerbations of COPD (ECOPD) is controversial. Serum procalcitonin (PCT) is a biomarker of bacterial infection used to identify the cause of ECOPD.

Methods and findings: We investigated whether a PCT-guided plan would allow a shorter duration of antibiotic treatment in patients with severe ECOPD. For this multicenter, randomized, non-inferiority trial, we enrolled 184 patients hospitalized with ECOPD from 18 hospitals in Italy. Patients were assigned to receive antibiotics for 10 days (standard group) or for either 3 or 10 days (PCT group). The primary outcome was the rate of ECOPD at 6 months. Having planned to recruit 400 patients, we randomized only 183: 93 in the PCT group and 90 in the standard group. Thus, the completed study was underpowered. The ECOPD rate at 6 months between PCT-guided and standard antibiotic treatment was not significant (% difference, 4.04; 90% confidence interval [CI], -7.23 to 15.31), but the CI included the non-inferiority margin of 15. In the PCT-guided group, about 50% of patients were treated for 3 days, and there was no difference in primary or secondary outcomes compared to patients treated for 10 days.

Conclusions: Although the primary and secondary clinical outcomes were no different for patients treated for 3 or 10 days in the PCT group, the conclusion that antibiotics can be safely stopped after 3 days in patients with low serum PCT cannot be substantiated statistically. Thus, the results of this study are inconclusive regarding the noninferiority of the PCT-guided plan compared to the standard antibiotic treatment. The study was funded by Agenzia Italiana del Farmaco (AIFA-FARM58J2XH). Clinical trial registered with www.clinicaltrials.gov (NCT01125098).

Trial registration: ClinicalTrials.gov NCT01125098.

Conflict of interest statement

Competing Interests: LMF received payment for consultancy from: Almirall, Boehringer LMF received payment for consultancy from: Almirall, Boehringer Ingelheim, Chiesi Farmaceutici, Euromediform, GlaxoSmithKline, Merck Sharp & Dhome, Mundipharma International, Novartis, Takeda, Pearl Therapeutics, Sterna, Peer Voice Europe, OM Pharma, TEVA; payment for lectures, advisory boards or travel expenses reimbursements from: AstraZeneca, Dey Pharma, Grünenthal GmbH, Mundipharma International, Novartis, Roche, Genetech Inc. AS declares he received personal benefits or personal travel grants or expenses for conferences from Boehringer, Novartis, Astrazeneca, Guidotti, Malesci, Almirall, Gsk, Mundipharma, Pfizer. AP gave presentations at symposia sponsored by, received research grants from, or served on scientific advisory boards of Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Dompè, GlaxoSmithKline, Guidotti, Menarini, MSD, Mundipharma, Novartis, Pfizer, Takeda, TEVA, Zambon. SB, VR, RV, MPFB, GWC, MP, FL, BB, AV, AL, RDA declare they have no conflicts. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Trial protocol. Severe disease = respiratory failure or clinical instability.

Fig 2. Trial profile: screening, enrollment, randomization, and follow-up.

Fig 3. Percentage of patients with at least one exacerbation during the 6 months of follow-up in the three groups: patients who received antibiotics for 3 days (PCT 3 days) or 10 days (PCT 10 days) according to a PCT-guided plan, or for 10 days according to the standard plan. P = not significant.