β-Lactam Monotherapy vs β-Lactam–Macrolide Combination Treatment in Moderately Severe Community-Acquired Pneumonia

Abstract

IMPORTANCEThe 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 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. INTERVENTIONSPatients 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 RELEVANCEWe 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.2. Nie W, Li B, Xiu Q. β-Lactam/macrolide dual therapy versus β-lactam monotherapy for the treatment of community-acquired pneumonia in adults: a systematic review and meta-analysis.

Antibiotic treatment outcomes in community-acquired pneumonia

“…Third, adherence to BLM combination therapy regimen was lower than adherence to the monotherapy regimen. In another multicenter study from Switzerland, a significantly higher proportion of patients infected with atypical pathogens or with more severe pneumonia (PSI category IV or CURB-65 score of ≥ 2) treated with beta-lactam/macrolide combination reached clinical stability at day 7, compared to those treated with monotherapy (11). However, mortality, admission to intensive care, LOS, and recurrence of pneumonia within 90 days were not different than in patients treated with beta-lactam monotherapy.…”

New evidence prompts rethinking the clinical management of community acquired pneumonia in patients admitted to general medical services

“…The first study, published in 2014 by Garin et al, was a randomized non-inferiority trial comparing β-lactam monotherapy to β-lactam-macrolide combinations in moderately-severe CAP 12 . The authors used an open, block-randomization strategy that included 580 patients after randomization.…”

“…Another potential critique involves the use of a non-inferiority strategy; unfortunately, the lack of an established standard of care and the unethical nature of a placebo-controlled trial make a superiority trial in this case difficult. Additionally, a very conservative 3% noninferiority margin was utilized (compared to, for example the 8% used by Garin et al above 12 ) which helps to abate one of the biggest weaknesses of such trials, namely the relative ease of demonstrating noninferiority with a large predetermined margin. That being said, it is important to remember that demonstrating non-inferiority is not the same as demonstrating equivalence or superiority.…”

Lessons learned from 2 decades of CAP therapy data: ways to improve patient management

“…In contrast to the CAP-START trial, the study by Garin et al did not find β-lactam monotherapy to be noninferior to β-lactam plus macrolide combination therapy for the endpoint of time to clinical stability after 7 days of treatment, in hospitalized patients with moderately severe CAP (8). Specifically, the authors found that 41.2% of the patients in the monotherapy group did not reach clinical stability compared with 33.6% of patients in the combination group, with an absolute difference of 7.6%.…”

“…However, they identified only two "high-quality" randomized controlled trials (7,8) among the 11 trials reviewed in their analysis. These two studies deserve special scrutiny, especially because they highlight recent debate regarding the role of macrolides in the treatment of CAP.…”