Table 1.

Published clinical studies between 2016 and 2021 on the adjunctive role of macrolides for the management of severe community-acquired pneumonia (CAP)

References	Design	Groups	Most common pathogens	Outcome measure
[4]	Retrospective analysis of prospectively collected data of patients with CAP and sepsis using matching	β-lactam monotherapy = 130 β-lactam plus clarithromycin = 130 β-lactam plus azithromycin = 130 Moxifloxacin/levofloxacin monotherapy = 130	Not reported	28-day mortality: β-lactam monotherapy = 36.8% (p = 0.009)* β-lactam plus clarithromycin = 20.8% β-lactam plus azithromycin = 33.8% (p = 0.026)* Moxifloxacin/levofloxacin monotherapy = 32.8% (p = 0.049)*
[5]	Retrospective analysis from the CAPO database of patients with CAP treated with macrolide/β-lactam combination	Macrolide start 1 h before β-lactam = 99 Macrolide start 1 h after β-lactam = 305	Not reported	Time to clinical stability: 3.5 days vs 4.3 days (p = 0.011)
[6]	Retrospective analysis from the CAPO database of patients with microbiologically confirmed CAP	No macrolide = 302 Macrolide = 247	Streptococcus pneumoniae 75%	In-hospital 30-day mortality: Non-severe CAP: non-macrolide 4.4%; macrolide 0.7%; p = 0.012 Severe CAP: non-macrolide 16.4%; macrolide 5.8%; p = 0.027
[7]	RCT in HIV-positive individuals	Ceftriaxone + placebo = 112; 20% severe Ceftriaxone + macrolide = 113; 15% severe	Pneumocystis jirovecii 20% vs 29% Mycobacterium tuberculosis 13% vs 12% Streptococcus pneumoniae 10% vs 10%	In-hospital mortality: 11% vs 15% (p = 0.610) 14-day mortality: 4% vs 11% (p = 0.09)
[8]	Retrospective analysis of prospectively collected data	β-lactam monotherapy = 369 β-lactam plus macrolide = 225	Streptococcus pneumoniae 17.9% vs 18.2% Klebsiella pneumoniae 15.4% vs 9.3%	30-day mortality: 13.8% vs 1.8% (p < 0.001) Early treatment failure: 18.4% vs 7.6% (p < 0.001) LOS: 16 days vs 10 days (p < 0.001)
[9]	Prospective cohort	β-lactam plus macrolide = 932; severe 57% Fluoroquinolone ± β-lactam = 783; severe 60%	Streptococcus pneumoniae 45% vs 44% Polymicrobial 16% vs 12%	30-day mortality Overall 5% vs 8% (p = 0.015) Pneumococcal pneumonia 4% vs 9% (p = 0.004) CRP > 150 mg/l 3% vs 8% (p < 0.001)
[10]	Retrospective analysis of prospectively collected data of patients with CAP and sepsis using propensity score matching	β-lactam plus azithromycin = 560 β-lactam plus levofloxacin = 560	Not reported	28-day mortality: 19.3% vs 20.7% (p = 0.601) In-hospital mortality: 24.8% vs 26.8% (p = 0.495)
[11]	Open-label quasi-RCT	Ceftriaxone + clarithromycin (n = 104); 22% severe Ampicillin/sulbactam + clarithromycin (n = 108); 13% severe	Streptococcus pneumoniae 33.6% vs 24.1% Mycoplasma pneumoniae 36.5% vs 25.9%	Efficacy end-of-treatment: 57% vs 94% (p = 0.055)

CAPO database of hospitalized patients with CAP from 83 hospitals in 16 countries, CRP C-reactive protein, LOS length of hospital stay, n number of patients, RCT randomized clinical trial, vs versus

*p values refer to comparisons with the β-lactam plus clarithromycin group