In non-ICU suspected CAP, -lactam was noninferior to -lactammacrolide or fluoroquinolone for 90-d mortality

Question In patients with suspected community-acquired pneumonia (CAP) admitted to nonintensive care unit (ICU) wards, is -lactam monotherapy (BL) noninferior to -lactam plus a macrolide (BLM) or fluoroquinolone monotherapy (FQL) for 90-day mortality? Methods Design Cluster randomized, crossover, noninferiority trial (Community-Acquired PneumoniaStudy on the Initial Treatment with Antibiotics of Lower Respiratory Tract Infections [CAP-START]). ClinicalTrials.gov NCT01660204. In 1 of 7 clusters, crossover between 2 treatment periods was interrupted because of fluoroquinolone supply problems. Allocation {Not concealed}*. Blinding {Unblinded}*. Follow-up period 90 days. Setting 7 hospitals in the Netherlands. Patients 2283 patients 18 years of age (median age 70 y, 58% men) who were admitted to non-ICU hospital wards and needed antibiotics for clinically suspected CAP. Patients with cystic fibrosis were excluded. Interventions BL (n =656), BLM (n =739), or FQL (n =888) as preferred treatment strategies. Each 4-month strategy was used twice in each hospital in a random order. Patients received the treatment strategy being used at the time of admission. Outcomes Primary outcome was 90-day mortality. Other outcomes were time to start of oral treatment and in-hospital complications. 2100 patients were needed to detect noninferiority of BL compared with the other treatments for 90-day mortality (expected 90-d mortality 5%, absolute noninferiority margin 3%, 1-sided =0.05, 80% power). Patient follow-up 100% of clusters and 99.8% of patients (intention-to-treat analysis). Main results BL was noninferior to BLM and FQL for 90-day mortality (Table). Time to start of oral therapy was longer in the BL than in the FQL group (median 4 vs 3 d, rate ratio 1.28, 95% CI 1.13 to 1.44); BL and BLM did not differ (median 4 d in both groups). Groups did not differ for minor (11% to 13%) or major (4.9% to 5.7%) complications. Conclusion In suspected community-acquired pneumonia treated in nonintensive care unit wards, -lactam monotherapy was noninferior to -lactam plus a macrolide or fluoroquinolone monotherapy for 90-day mortality. -lactam plus a macrolide (BLM) or fluoroquinolone (FQL) monotherapy vs -lactam monotherapy (BL) in suspected community-acquired pneumonia treated outside of intensive care units Outcome Comparisons Event rates RRI/RRR (95% CI) Mortality at 90 d BLM vs BL 11% vs 9.0% RRI 26% (9 to 63) FQL vs BL 8.8% vs 9.0% RRR 2.6% (32 to 32) Abbreviations defined in Glossary. RRI, RRR, and CI provided by author. Based on regression model, which included center, clustering, and period effects, without additional adjustment. Risk differences met criteria for noninferiority: BLM vs BL, lower 90% CI 0.2%; FQL vs BL, lower 90% CI 2.5%. Commentary Randomized clinical trials can answer important treatment questions but may not match real-world outcomes because limited treatment options can diminish enrollment, and exclusion criteria can limit generalizability. The 2007 Infectious Diseases Society of America/American Thoracic Society guidelines for CAP support FQL or BLM as first-line therapy (1). Postma and colleagues compared 3 CAP treatment strategies and showed noninferiority of BL compared with FQL or BLM for mortality at 90 days. Groups were comparable on most other measures of efficacy. Block randomization and physician discretion in drug selection within strategies minimized complexity and replicated real-world approaches where physicians can accommodate individual patient needs. Many patients did not receive their randomized treatment (e.g., 27% in the BL group initially received atypical coverage), making the groups more similar than would be expected. Blinding was not possible. Do these features discredit the study conclusion? No. The design allowed modification of initial and subsequent treatment to match real-world approaches where clinicians have access to many treatments and respond to new information. The absence of blinding is less critical when death is the primary outcome. A BLM or FLQ approach is favored for 2 indications: treatment of atypical pathogens and coverage of BL-resistant bacteria. Postma and colleagues found no pathogen in 61% to 66% of patients and atypical pathogens in <3%. Documented pathogens generally had low rates of BL resistance. Therefore, neither benefit ascribed to BLM or FLQ applied in this cohort. Similarly, an earlier meta-analysis showed no benefit for atypical coverage except when Legionella was present (2). New CAP guidelines should address the efficacy and safety of BL monotherapy. It sacrifices nothing in therapeutic outcomes, has better tolerability than BLM, and is a better choice for stewardship than FQL. In the absence of clinical or epidemiologic suspicion for Legionella or Mycoplasma, BL is a good choice for hospitalized non-ICU patients, but a more rigorous trial could fine-tune criteria for its use.