By Nathaniel R. DeFelice, MD
Clinical Instructor, Division of General Internal Medicine, Harborview Medical Center, University of Washington School of Medicine, Seattle
SOURCE: Postma DF, et al. Antibiotic Treatment Strategies for Community-Acquired Pneumonia in Adults. N Engl J Med 2015;372:1312-23.
Across the globe, community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality. Standard treatment of patients with CAP requiring hospitalization, like all patients with sepsis, necessitates early administration of fluids and antibiotics. The choice of antibiotics has been the focus of many different international organizations. In the United States, we rely on the 2007 IDSA/ATS consensus guidelines. Their recommendations for patients admitted to the hospital with CAP, but not requiring the intensive care unit (ICU), are similar to other country-specific guidelines, including the Netherlands, and are based on severity of disease as determined by prognostic risk scoring. The general thought is that everyone should receive treatment with antibiotics that cover both typical bacteria (e.g. S. pneumoniae) and atypical pathogens (e.g. Legionella, Mycoplasma, etc.).
As a result, recommendations for empiric CAP treatment typically include a beta-lactam (to cover typical organisms) plus a macrolide (to cover atypical organisms), or a “respiratory fluoroquinolone” such as levofloxacin, moxifloxacin or gemifloxacin (to cover both typical and atypical bacteria). Yet, the evidence to add a macrolide to a beta-lactam antibiotic is based on observational studies with conflicting results prone to bias by indication, and the superiority of fluoroquinolones over a beta-lactam therapy has never been shown. With resistance to macrolides and fluoroquinolones on the rise, attention to good antibiotic stewardship is necessary for our long-term public health. Furthermore, there is an increasing body of evidence demonstrating adverse cardiac effects from drugs like azithromycin and levofloxacin.
Concerned about the costs associated with the unnecessary use of antibiotics for empiric CAP treatment, Postma and colleagues in the CAP-START study group enrolled adults admitted to non-ICU wards at 7 hospitals in the Netherlands between February 2011 to August 2013 in a cluster-randomized, crossover trial. They investigated if beta-lactam monotherapy is noninferior to preferred beta-lactam plus macrolide or preferred fluoroquinolone monotherapy. Their primary end point was 90-day mortality. Patients with cystic fibrosis were not eligible.
During consecutive periods of four months, the hospitals were randomly and separately assigned one of three preferred antibiotic regimens: 1) beta-lactam monotherapy, 2) beta-lactam plus a macrolide, or 3) respiratory fluoroquinolone monotherapy. Providers were made aware of the antibiotics being given during the separate blocks and were allowed to vary from the preferred regimen when clinically indicated. Those that deviated without described clinical indications were deemed to have protocol violations but were still included in the intention-to-treat analysis.
Baseline characteristics of the 2283 patients included in the study were similar among the three groups (median age of ~70 years old and a median Pneumonia Severity Index ~85 ± 28 in all groups). Strategy adherence, which they considered in accordance with the assigned strategy or deviation for medical reasons, was close to 90% in all three groups. In the beta-lactam group, 21.6% had a change in antibiotics from the initial planned antibiotic for medical reasons, compared to 15.2% in the beta-lactam—macrolide group, and 12.5% of the fluoroquinolone group. The most common medical reason for deviation from the beta-lactam strategy was perceived need for atypical coverage, which occurred in 8.1% of patients included in the study. This was followed by lack of response to initial treatment in 4.1% for the beta-lactam strategy compared to 3.7% for the beta-lactam—macrolide arm and 2.6% for the fluoroquinolone strategies.
The primary outcome of all-cause mortality at 90 days was 9.0% (59/656 patients) in the beta-lactam group, 11.1% (82/739 patients) in the beta-lactam—macrolide group and 8.8% (78/888 patients) in the fluoroquinolone group. In the intention-to-treat analysis, risk of death was 1.9 percentage points (90% confidence interval [CI], 0.6 to 4.4) higher in the beta-lactam—macrolide strategy, and 0.6 percentage points (90% CI, -2.8 to 1.9) lower in the fluoroquinolone strategy than in the beta-lactam strategy. These results demonstrated the noninferiority of the beta-lactam strategy.
The secondary outcomes of length of stay were similar across groups at six days. Incidences of major complications (e.g. in-hospital death, respiratory insufficiency, organ failure, ICU admission, and septic shock) or minor complications (e.g. cardiovascular complications, pleural fluid, delirium, renal impairment, empyemia, dysglycaemia, and secondary infection) were not significantly different among the three groups.
Empiric atypical coverage during the beta-lactam strategy periods was reduced by 67% compared to the beta-lactam—macrolide strategy periods and by 69% when compared to the fluoroquinolone strategy periods. The overall incidence of Legionella was 0.7% (16/2283) and Mycoplasma was 0.9% (21/2283) during the study period.
In conclusion, the authors found that for patients with suspected CAP requiring admission to non-ICU wards, a preferred strategy of a beta-lactam antibiotic alone when the provider is allowed to make adjustments for medical reasons, was noninferior with regard to 90-day mortality, length of stay or other major or minor complications to the usual recommended therapy of beta-lactam—macrolide or fluoroquinolone. Generalizability of these findings is limited by regional differences in microbial causes of CAP, especially in the setting of low incidence of atypical infections found in the study. Further study on this topic is warranted.