Beta-lactam Monotherapy vs. Beta-lactam and Macrolide Combination Therapy in Community-Acquired Pneumonia

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Garin N, et al. "Ξ²-Lactam monotherapy vs Ξ²-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial". JAMA Internal Medicine. 2014. 174(12):1894-1901.
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Clinical Question

In immunocompetent adult patients with moderately severe community-acquired pneumonia, would the addition of a macrolide to a 𝛽-Lactam compared to 𝛽-lactam monotherapy alone, lead to clinical stability and offer clinical benefit?

Bottom Line

Combination therapy of a 𝛽-Lactam plus a macrolide compared to 𝛽-Lactam alone showed no statistical significance for patients reaching clinical stability by day 7. However, patients affected with atypical pathogens had a higher likelihood of achieving clinical stability after 7 days of treatment with combination therapy compared to 𝛽-Lactam monotherapy.

Note: There are no randomized clinical trials to compare the results of this study to another for validity.

Major Points

In hospitalized patients with community-acquired pneumonia, the standard treatment is to provide optimal coverage for Streptococcus pneumoniae with the use of a 𝛽-Lactam. However, if patients require atypical coverage (Legionella species, Mycoplasma pneumoniae, and Chlamydia pneumoniae), a macrolide is added to the 𝛽-Lactam or fluoroquinolone monotherapy is given.

This trial was an open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009 through January 31, 2013 in acute care hospitals in Switzerland for moderately severe community-acquired pneumonia (CAP). The trial randomized 702 patients with moderately severe CAP to treatment with a 𝛽-Lactam (monotherapy arm) or 𝛽-Lactam and macrolide (combination arm). The main outcome being measured was the proportion of patients not reaching clinical stability by day 7 as defined by a heart rate <100/min, systolic blood pressure >90 mmHG, temperature <38.0Β°C, respiratory rate <24/min, and oxygen saturation >90% on room air. After 7 days of treatment, 120/291 (41.2%) in the monotherapy and 97/289 (33.6%) in the combination arm had not reached clinical stability. Additionally, the monotherapy arm was associated with more 30-day readmissions. Mortality, intensive care unit admissions, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms.

These findings are in line with a previous meta-analysis of randomized trials comparing antibiotic regimens with and without coverage of atypical pathogens which did not find superiority in either arm. Yet, there was no trial that compared 𝛽-lactam monotherapy to combination 𝛽-lactam plus macrolide therapy. The clinical success of the previous trials were reviewed after the completion of antibiotic treatment, which hindered the potential findings for the speed of resolution between treatment groups. However, this study aimed to document the speed of resolution between groups by assessing the time to reach clinical stability. Another meta-analysis found better outcomes in patients treated with the combination therapy than monotherapy, however, confounding was a potential problem as patients in the combination group were younger and healthier than those in the monotherapy group. The current study results differed from those of the meta-analysis as they did not find noninferiority in the 𝛽-lactam monotherapy group.

Guidelines

IDSA/ATS Guidelines - Inpatient, non-ICU Treatment (2007, adapted)[1]

  • A respiratory fluoroquinolone (strong recommendation; level I evidence)
  • A 𝛽-lactam plus a macrolide (strong recommendation; level I evidence) with doxycycline (moderate recommendation; level III evidence) as an alternative to the macrolide.

Design

  • Open-label, multicenter, noninferiority, randomized trial
  • N=602
    • Standard therapy: 𝛽-lactam (monotherapy arm) = 291
      • At first, the patient population for this group was 300, but 9 patients were excluded after randomization.
    • Experimental therapy: 𝛽-lactam + Macrolide (combination arm) = 289
      • The patient population for this group was originally 302, but 13 patients were excluded after randomization.
  • Setting: Switzerland, in 6 acute care hospitals
  • Enrollment: 2009-2013
  • Mean follow-up: 7 days
  • Analysis: Intention-to-treat
  • Primary outcome: clinical stability at day 7

Population

Inclusion Criteria

  • age =18 years or older
  • minimum of 2 clinical findings suggestive of pneumonia
  • new infiltrates present on chest radiograph

Exclusion Criteria

  • severely immunosuppressed
  • recent hospitalization within 14 days
  • nursing home residents
  • severe pneumonia (PSI category V)
  • patients given antibiotics 24 hours before inclusion

Baseline Characteristics

  • median age of patients was 76 years
    • range 21-101 years
  • at least one comorbidity: 351 patients (60.5%)
    • Chronic heart failure: Monotherapy (64 patients), Combination (52 patients)
    • COPD: Monotherapy (61 patients), Combination (61 patients)
    • Diabetes mellitus: Monotherapy (44 patients), Combination (52 patients)
    • Chronic renal failure: Monotherapy (47 patients), Combination (41 patients)
  • mean PSI score was 84
    • Monotherapy (84.5)
    • Combination (84.2)

Interventions

1. 𝛽-lactam (monotherapy arm)

2. 𝛽-lactam + Macrolide (combination arm)

Macrolide used:
  • clarithromycin (500 mg PO or IV twice a day)
𝛽-lactams used:
  • cefuroxime (1.5g IV three times a day)
  • amoxicillin-clavulanic acid (1.2g IV four times a day)

Outcomes

Comparisons are 𝛽-lactam (monotherapy) vs. 𝛽-lactam + Macrolide (combination therapy).

Primary Outcomes

Patients not reaching clinical stability by day 7 included
Monotherapy: 120 individuals (41.2%)
Combination therapy: 97 individuals (33.6%)
Between-arm difference=7.6%, (2-sided 95% CI, -0.8% to 16.0%); P value: 0.07; HR=0.93

Secondary Outcomes

Statistically significant secondary outcomes included
30-day readmission:
Monotherapy: 23 individuals
Combination therapy: 9 individuals
P value: 0.01
Stratified atypical coverage:
Atypical: 31 individuals
Non-Atypical: 549 individuals
P value: 0.02, HR=0.33 (0.13-0.85)

Subgroup Analysis

  • category of pathogen identified
    • atypical (HR 0.33, CI 95%, 0.13-0.85)-P value=0.02
    • non-atypical: not significant
  • patient age (less than 65 or greater than 65 years old): no interaction found
  • PSI (category IV vs. I-III) to hazard ratios: not significant
  • CURB-65 score to hazard ratios: not significant

Adverse Events

Few AE were seen

  • acute hepatitis (without hepatic failure)
    • 1 patient with monotherapy treatment
    • 2 patients with combination treatment
  • renal failure (attributed to acute interstitial nephritis)
  • minor allergic reactions
    • reported by 3 patients in each group

Criticisms

  • There is currently no universal empiric coverage for CAP in the world. In the United States treatment for moderately severe CAP includes a respiratory fluoroquinolone or the combination of macrolide and a 𝛽-Lactam for all hospitalization. Whereas, in Europe, combination therapy is only reserved for severely ill patients.
  • This study cannot be automatically generalized to other regions as the prevalence of bacteria differs within each region.
  • After randomization, some patients from the monotherapy arm were transferred to the combination arm, as they required atypical coverage due to the identification of an atypical pathogen. This showed favoritism towards the combination therapy.
  • Patients dying in the hospital and those transferred to rehabilitation facilities were included when evaluating clinical stability, whereas other studies excluded these patients.
  • Data showed that there were no significant clinical difference in ICU admissions, lengths of stay, or mortality between the two groups. However, patients in the monotherapy treatment group, were more likely to be readmitted within 30 days than were those in the combination group (EEP).[2]
  • Patients with identified atypical pathogens were less likely to reach clinical stability with monotherapy (EEP). [2]

Funding

The study received support from the Swiss National Science Foundation (Dr Perrier) grant 3200BO-120074 and grants from the Clinical Trial Unit and the Department of Internal Medicine of Geneva University Hospitals (Dr Garin). The granting agencies had no role or influence within the study.

Further Reading

  1. ↑ Mandell LA et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin. Infect. Dis. 2007. 44 Suppl 2:S27-72.
  2. ↑ 2.0 2.1 Nita Shrikant Kulkarni, MD. Beta-lactam not as effective as beta-lactam plus macrolide for treating CAP in the hospital. Essential Evidence Plus [journal on the internet]. 2015 February 17 [cited 2018 April 16]. Available from: http://www.essentialevidenceplus.com/content/poem/170213