Cluster-randomized, crossover trial

N= 2283

Beta-lactam (n= 656)

Beta-lactam–macrolide (n= 739)

Fluoroquinolone (n= 888)

Cluster-randomized, crossover trial with strategies rotated in 4-month periods. Strategies included beta-lactam monotherapy, beta-lactam–macrolide combination therapy, and fluoroquinolone monotherapy. Adherence to the strategy was defined as treatment in accordance with the assigned strategy or deviation for medical reasons. Data were collected from medical records and analyzed using intention-to-treat principle.

• Beta-lactam strategy: Preferred empirical treatment with amoxicillin, amoxicillin plus clavulanate, or a third-generation
  cephalosporin. Penicillin was not allowed as empirical beta-lactam monotherapy.
• Beta-lactam–macrolide strategy: Preferred empirical treatment with penicillin, amoxicillin, amoxicillin plus clavulanate, or a third-generation cephalosporin in combination with azithromycin, erythromycin, or clarithromycin
• Fluoroquinolone strategy: Preferred empirical treatment with moxifloxacin or levofloxacin

Primary: 90-day all-cause mortality

Secondary: Time to starting oral treatment, length of hospital stay, occurrence of minor or major complications during hospital stay

Register-based cohort study

N= 5961 (CRB-65≤1); N= 1344 (CRB-65=2)

CRB-65≤1: NSBM (n= 1827) BSBM (n= 1827)

CRB-65=2: NSBM (n= 524), BSBM (n= 524)

Primary: 30-day mortality

Secondary: 90-day mortality, ICU admission, length of stay (LOS)

Age, years

<55 

55-64 

65-74 

75-84 

>85 

34.3%

21.5%

15.6%

15.0%

13.6%

33.1%

21.5%

15.1%

16.5%

13.8%

Comparative Effectiveness of First-Line and Alternative Antibiotic Regimens in Hospitalized Patients With Nonsevere Community-Acquired Pneumonia

Multicenter retrospective cohort study

N= 23,512

To compare the effectiveness of different first-line and alternative antibiotic regimens (b-lactam plus macrolide [BL+M], b-lactam alone [BL], respiratory fluoroquinolone [FQ], or b-lactam plus doxycycline [BL+D]) in terms of in-hospital mortality in patients with nonsevere community-acquired pneumonia (CAP)

BL+M (n= 9,340)

BL (n= 9,146)

FQ (n= 4,510)

BL+D (n= 516)

Consecutive adult patients admitted to a medical inpatient service at 19 acute care hospitals in Ontario, Canada, from January 1, 2015, to December 31, 2021, diagnosed with non-severe CAP and treated with antibiotics for CAP

Patients with severe CAP admitted to intensive care unit (ICU) within first 2 days of admission, patients with aspiration pneumonia, patients changed to another first line antibiotic regimen within first 2 days of admission

Patients were identified from the GEMINI database of internal medicine admissions across 19 Ontario hospitals. CAP was identified using the most responsible diagnosis on hospital discharge summaries, categorized with ICD-10-CA codes J10-J18 and J41-J44. Patients were categorized by initial antibiotic therapy received within 48 hours of admission: BL+M, BL alone, FQ, or BL+D. The index time was the time of the first dose of the antibiotic regimen. Patients were followed from index time until hospital discharge. A modified intention-to-treat analysis required patients to remain on the same regimen for at least 2 days or until discharge or death; later switches were analyzed according to the initial regimen. Propensity score methods with overlap weighting were used to balance baseline covariates, including age, sex, long-term care residence, hospital site, admission year, Charlson Comorbidity Index, and mLAPS. BL+M was the reference group for risk differences. No p-values were reported; interpretation was based on effect sizes and 95% CIs.

January 1, 2015, to December 31, 2021

Primary: In-hospital mortality

Secondary: Time to being discharged alive, transfer to ICU after 2 days, ventricular arrhythmia or cardiac arrest, Clostridioides difficile colitis, readmission to hospital within 30 days

FQ (n= 4,510)

74.2 ± 15.7

50.4%

5.2%

1.5 ± 1.7

In 23,512 adults hospitalized with nonsevere community-acquired pneumonia, 9,340 patients received β-lactam plus macrolide therapy, 9,146 received β-lactam monotherapy, 4,510 received respiratory fluoroquinolone therapy, and 516 received β-lactam plus doxycycline therapy.

In-hospital mortality occurred in 703 patients (7.5%) in the β-lactam plus macrolide group, 888 patients (9.7%) in the β-lactam monotherapy group, 302 patients (6.7%) in the fluoroquinolone group, and 31 patients (6.0%) in the β-lactam plus doxycycline group. Compared with β-lactam plus macrolide therapy, β-lactam monotherapy was associated with a higher adjusted risk difference for in-hospital mortality (1.5%; 95% CI, 0.3% to 3.3%) and a longer time to discharge alive (adjusted subdistribution hazard ratio, 0.90; 95% CI, 0.84 to 0.96).

In contrast, adjusted mortality differences were not significantly different for fluoroquinolone therapy (-0.9%; 95% CI, -2.9% to 1.1%) or β-lactam plus doxycycline therapy (-1.9%; 95% CI, -4.8% to 0.9%) compared with β-lactam plus macrolide therapy.

Secondary safety outcomes were generally similar across groups, although β-lactam monotherapy was associated with a small increase in Clostridioides difficile colitis compared with β-lactam plus macrolide therapy (adjusted risk difference, 0.3%; 95% CI, 0.02% to 0.6%).

No significant difference in the adjusted risk of ICU transfer and ventricular arrhythmia or cardiac arrest across the antibiotic groups. The BL+D group had the lowest risk for C difficile colitis.

BL+M, FQ, and BL+D had similar outcomes and can be considered effective regimens for nonsevere CAP. Compared with BL+M, BL was associated with longer time to discharge and the CI for mortality cannot exclude a small but clinically important increase in risk.

This large, multicenter cohort provides pragmatic evidence in a real-world hospitalized non-ICU CAP population and used propensity score overlap weighting to address measured confounding. For the specific question of β-lactam monotherapy, BL alone was associated with longer time to discharge and a numerically higher adjusted in-hospital mortality vs BL+M, so this study does not strongly support BL monotherapy as equivalent to combination therapy despite its observational design and potential residual confounding.

Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial

Randomized, double-blind, placebo-controlled trial

N= 278

To investigate if the addition of the macrolide clarithromycin to treatment with a β-lactam antibiotic in patients with community-acquired pneumonia could improve early clinical response and explore the possible contribution of modulation of the inflammatory host response to that outcome

Standard of care plus clarithromycin (n= 134)

Standard of care plus placebo (n= 133)

Adults (≥18 years) with community-acquired pneumonia requiring hospital admission, with at least two community-acquired pneumonia-related symptoms, systemic inflammatory response syndrome, Sequential Organ Failure Assessmen (SOFA) score of 2 or more, and procalcitonin 0.25 ng/mL or more

Age <18 years, intake of any macrolide for the current episode, oral or IV corticosteroids in the past 15 days, active SARS-CoV-2 infection, known HIV infection, neutropenia, chronic anticytokine treatment, hospital stay >2 consecutive days in the past 90 days, QTc ≥500 ms, congenital long QT syndrome, pregnancy or lactation

Patients were randomized 1:1 to receive oral clarithromycin 500 mg twice daily for 7 days plus standard-of-care beta-lactam therapy or placebo plus standard-of-care beta-lactam therapy. Standard-of-care therapy consisted of intravenous ceftriaxone or a beta-lactam/beta-lactamase inhibitor combination (amoxicillin-clavulanate, ampicillin-sulbactam, or piperacillin-tazobactam), selected by the treating physician.

January 2021 to April 2023

Primary: Composite endpoint of early clinical response and early anti-inflammatory response

Secondary: Each component of the primary endpoint separately, favourable changes in procalcitonin kinetics, clinical success at various visits, time to progression to organ dysfunction, time to new sepsis episode, time to hospital discharge alive, mortality by day 28 and day 90, hospital readmission by day 90, changes in cytokine levels

Standard of care plus clarithromycin (n= 134)

Age, years (IQR)

Male

Charlson Comorbidity Index (IQR)

Pneumonia severity index (IQR)

APACHE II score (IQR)

SOFA score (IQR)

Respiratory symptom severity score (IQR)

Procalcitonin, ng/mL (IQR)

Presence of pleural effusion

Active smoking

Abbreviations: IQR, interquartile range.

Standard of care plus placebo (n= 133)

91 (68%)

≥50% decrease in respiratory symptom severity score at day 4

≥30% decrease in SOFA score at day 4

Favourable procalcitonin kinetics at day 4

Clinical success at end-of-treatment visit (day 8)

Among 267 analyzed hospitalized adults with community-acquired pneumonia and evidence of systemic inflammation, no patients required vasopressors, mechanical ventilation, or ICU admission at enrollment.

Patients receiving clarithromycin had higher rates of improvement in respiratory symptom scores, SOFA scores, procalcitonin kinetics, and clinical success, along with lower rates of progression to organ dysfunction (6% vs 17%) and new sepsis (13% vs 24%). Mortality at 28 and 90 days did not differ significantly between groups.

Serious treatment-emergent adverse events (TEAEs) occurred in 58 (43%) patients in the clarithromycin group and 70 (53%) patients in the placebo group. None of the serious TEAEs was judged to be related to treatment assignment.

Addition of clarithromycin to standard of care enhances early clinical response and attenuates the inflammatory burden of community-acquired pneumonia. The mechanism of benefit is associated with changes in the immune response. These findings suggest the importance of adding clarithromycin to β-lactams for treatment of patients in hospital with community-acquired pneumonia to achieve early clinical response and early decrease of the inflammatory burden.

The study provides evidence supporting the addition of clarithromycin to beta-lactam–based therapy in hospitalized patients with community-acquired pneumonia and systemic inflammation. However, the placebo group received a mixture of ceftriaxone and beta-lactam/beta-lactamase inhibitor regimens, and outcomes were not stratified by the specific beta-lactam used, limiting assessment of outcomes specifically among patients receiving beta-lactam monotherapy. Additionally, although no patients required vasopressors, mechanical ventilation, or ICU admission at enrollment, the heterogeneous population may limit generalizability to patients with non-severe CAP. The study was also underpowered to detect differences in mortality.