Efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections associated with low procalcitonin: a randomised, placebo-controlled, double-blind, non-inferiority trial

Ephraim L. Tsalik, Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA; Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, USA; Emergency Medicine Service, Durham VA Health Care System, Durham, NC, USA. Electronic address: e.t@duke.edu.
Nadine G. Rouphael, Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Ruxana T. Sadikot, Atlanta VA Health Care System, Atlanta, GA, USA; Medical Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
Maria C. Rodriguez-Barradas, Infectious Diseases Section, Michael E DeBakey VA Medical Center and Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Micah T. McClain, Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA; Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, USA; Medical Service, Durham VA Health Care System, Durham, NC, USA.
Dana M. Wilkins, bioMérieux, Durham, NC, USA; Rho, Durham, NC, USA.
Christopher W. Woods, Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA; Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, USA; Medical Service, Durham VA Health Care System, Durham, NC, USA.
Geeta K. Swamy, Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
Emmanuel B. Walter, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
Hana M. El Sahly, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Wendy A. Keitel, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Mark J. Mulligan, Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; Division of Infectious Diseases and Immunology, NYU Langone Health, New York, NY, USA.
Bonifride Tuyishimire, Emmes Company, Rockville, MD, USA.
Elisavet Serti, Emmes Company, Rockville, MD, USA.
Toshimitsu Hamasaki, Biostatistics Center, Milken Institute School of Public Health, George Washington University, Rockville, MD, USA; Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Rockville, MD, USA.
Scott R. Evans, Biostatistics Center, Milken Institute School of Public Health, George Washington University, Rockville, MD, USA; Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Rockville, MD, USA.
Varduhi Ghazaryan, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
Marina S. Lee, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
Ebbing Lautenbach, Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Document Type

Journal Article

Publication Date

12-13-2022

Journal

The Lancet. Infectious diseases

DOI

10.1016/S1473-3099(22)00735-6

Abstract

BACKGROUND: Lower respiratory tract infections are frequently treated with antibiotics, despite a viral cause in many cases. It remains unknown whether low procalcitonin concentrations can identify patients with lower respiratory tract infection who are unlikely to benefit from antibiotics. We aimed to compare the efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections in patients with low procalcitonin. METHODS: We conducted a randomised, placebo-controlled, double-blind, non-inferiority trial at five health centres in the USA. Adults aged 18 years or older with clinically suspected non-pneumonia lower respiratory tract infection and symptom duration from 24 h to 28 days were eligible for enrolment. Participants with a procalcitonin concentration of 0·25 ng/mL or less were randomly assigned (1:1), in blocks of four with stratification by site, to receive over-encapsulated oral azithromycin 250 mg or matching placebo (two capsules on day 1 followed by one capsule daily for 4 days). Participants, non-study clinical providers, investigators, and study coordinators were masked to treatment allocation. The primary outcome was efficacy of azithromycin versus placebo in terms of clinical improvement at day 5 in the intention-to-treat population. The non-inferiority margin was -12·5%. Solicited adverse events (abdominal pain, vomiting, diarrhoea, allergic reaction, or yeast infections) were recorded as a secondary outcome. This trial is registered with ClinicalTrials.gov, NCT03341273. FINDINGS: Between Dec 8, 2017, and March 9, 2020, 691 patients were assessed for eligibility and 499 were enrolled and randomly assigned to receive azithromycin (n=249) or placebo (n=250). Clinical improvement at day 5 was observed in 148 (63%, 95% CI 54 to 71) of 238 participants with full data in the placebo group and 155 (69%, 61 to 77) of 227 participants with full data in the azithromycin group in the intention-to-treat analysis (between-group difference -6%, 95% CI -15 to 2). The 95% CI for the difference did not meet the non-inferiority margin. Solicited adverse events and the severity of solicited adverse events were not significantly different between groups at day 5, except for increased abdominal pain associated with azithromycin (47 [23%, 95% CI 18 to 29] of 204 participants) compared with placebo (35 [16%, 12 to 21] of 221; between-group difference -7% [95% CI -15 to 0]; p=0·066). INTERPRETATION: Placebo was not non-inferior to azithromycin in terms of clinical improvement at day 5 in adults with lower respiratory tract infection and a low procalcitonin concentration. After accounting for both the rates of clinical improvement and solicited adverse events at day 5, it is unclear whether antibiotics are indicated for patients with lower respiratory tract infection and a low procalcitonin concentration. FUNDING: National Institute of Allergy and Infectious Diseases, bioMérieux.

Department

Biostatistics and Bioinformatics

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