title: β-Lactam monotherapy vs β-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial.
abstract: OBJECTIVE
  The clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial.
  
  
  OBJECTIVE
  To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia.
  
  
  METHODS
  Open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009, through January 31, 2013, in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation.
  
  
  METHODS
  Patients were treated with a β-lactam and a macrolide (combination arm) or with a β-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm.
  
  
  METHODS
  Proportion of patients not reaching clinical stability (heart rate <100/min, systolic blood pressure >90 mm Hg, temperature <38.0°C, respiratory rate <24/min, and oxygen saturation >90% on room air) at day 7.
  
  
  RESULTS
  After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms.
  
  
  CONCLUSIONS
  We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00818610.
authors.affiliation: Division of General Internal Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland2Division of Internal Medicine, Hôpital Riviera-Chablais, Monthey, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Garin
authors.affiliation: Division of Internal Medicine, Hôpital Neuchâtelois-La Chaux-de-Fonds, La Chaux-de-Fonds, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Genné
authors.affiliation: Division of General Internal Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Carballo
authors.affiliation: Division of Internal Medicine, Hôpital Cantonal, Fribourg, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Chuard
authors.affiliation: Division of Internal Medicine, Triemlispital, Zurich, Switzerland.
authors.forename: Gerhardt
authors.initials: G
authors.lastname: Eich
authors.affiliation: Emergency Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hugli
authors.affiliation: Division of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lamy
authors.affiliation: Division of General Internal Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Nendaz
authors.affiliation: Division of Internal Medicine, Hôpital du Valais, Sion, Switzerland.
authors.forename: Pierre-Auguste
authors.initials: PA
authors.lastname: Petignat
authors.affiliation: Division of Clinical Epidemiology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Perneger
authors.affiliation: Emergency Department, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rutschmann
authors.affiliation: Division of Internal Medicine, Hôpital Neuchâtelois-La Chaux-de-Fonds, La Chaux-de-Fonds, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Seravalli
authors.affiliation: Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Harbarth
authors.affiliation: Division of General Internal Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Perrier
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D017714:Community-Acquired Infections / Q000188:drug therapy; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D006760:Hospitalization; D006801:Humans; D016952:Legionella pneumophila; D007877:Legionnaires' Disease / Q000175:diagnosis / Q000188:drug therapy*; D018942:Macrolides / Q000627:therapeutic use*; D008875:Middle Aged; D016017:Odds Ratio; D018410:Pneumonia, Bacterial / Q000175:diagnosis / Q000188:drug therapy*; D012720:Severity of Illness Index; D013557:Switzerland; D016896:Treatment Outcome; D047090:beta-Lactams / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; D047090:beta-Lactams