β-Lactam monotherapy vs β-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial.

Abstract

IMPORTANCE:

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.

DESIGN, SETTING, AND PARTICIPANTS:

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.

INTERVENTIONS:

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.

MAIN OUTCOMES AND MEASURES:

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 AND RELEVANCE:

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.

TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT00818610.

• Authors: Nicolas Garin, Daniel Genné, Sebastian Carballo, Christian Chuard, Gerhardt Eich, Olivier Hugli, Olivier Lamy, Mathieu Nendaz, Pierre-Auguste Petignat, Thomas Perneger, Olivier Rutschmann, Laurent Seravalli, Stephan Harbarth, Arnaud Perrier
• Journal: JAMA internal medicine (JAMA Intern Med) Vol. 174 Issue 12 Pg. 1894-901 (Dec 2014) ISSN: 2168-6114 [Electronic] United States
• PMID: 25286173 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Macrolides
• beta-Lactams

Topics

• Aged
• Aged, 80 and over
• Anti-Bacterial Agents (therapeutic use)
• Community-Acquired Infections (drug therapy)
• Drug Therapy, Combination
• Follow-Up Studies
• Hospitalization
• Humans
• Legionella pneumophila
• Legionnaires' Disease (diagnosis, drug therapy)
• Macrolides (therapeutic use)
• Middle Aged
• Odds Ratio
• Pneumonia, Bacterial (diagnosis, drug therapy)
• Severity of Illness Index
• Switzerland
• Treatment Outcome
• beta-Lactams (therapeutic use)