CAP-START

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Postma DF, et al. "Antibiotic treatment strategies for community-acquired pneumonia in adults". The New England Journal of Medicine. 2015. 372(14):1312-1323.
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Clinical Question

In patients with community-acquired pneumonia who were admitted to non-intensive care unit (ICU) wards was there non-inferiority in outcomes using empiric treatment with beta-lactam monotherapy vs. beta-lactam-macrolide combination therapy or fluoroquinolone monotherapy?

Bottom Line

There was no difference in the adjusted 90-day mortality between beta-lactam monotherapy and either fluoroquinolone monotherapy or beta-lactam-macrolide combination therapy.

Major Points

Current US guidelines for CAP in a non-ICU setting dictate that inpatient treatment should include coverage with either a macrolide plus a beta-lactam or a fluoroquinolone for empiric therapy. The evidence supporting this is limited, and in fact, many European countries have guidelines that support beta-lactam monotherapy as the initial choice.

The CAP-START trial was a cluster-randomized, crossover, non-inferiority trial conducted at seven hospitals in the Netherlands which compared empirical CAP treatment with beta-lactam (BL) monotherapy vs. beta-lactam-macrolide (BLM) combination therapy or fluoroquinolone(FQ) monotherapy. The trial enrolled patients age 18 years of age or older with clinically suspected CAP who required non-ICU hospitalization. The primary outcome was 90-day mortality with non-inferiority defined as a less than 3% difference.

Hospitals were randomized to a six block sequence of the three antibiotic strategies with plans for adherence to the antibiotic strategy for four months at a time. The antibiotics were based on the 2005 Dutch guidelines. Patients were allowed to deviate from the antibiotic treatment for medical reasons and still be included the in adherence to strategy group. This was known as motivated deviation and was included in the intention-to-treat analysis.

The unadjusted 90-day mortality for all three groups was 9.0% for BL, 11.1% for BLM, and 8.8% for FQ. This led to non-inferior adjusted 90-day mortality rates in comparing BL to both combined therapy which had a 1.9% higher risk of death (90% CI, -0.6 to 4.4) and FQ which had a 0.6% lower risk of death (90% CI, -2.8 to 1.9)

While this study suggests non-inferiority of BL to FQ, it is only one of a few well-designed studies comparing antibiotic therapies for CAP. The study itself was also centered in the Netherlands which is known to have relatively low macrolide resistance of S. pneumoniae (4.2% in 2011).[1] Current US guidelines, which were jointly created by the Infectious Disease Society of America (IDSA) and American Thoracic Society (ATS), recommend either a respiratory fluoroquinolone or a beta-lactam plus a macrolide as the first line therapy for inpatient CAP treatment.[2]

Guidelines

IDSA/ATS 2007 Guidelines - Inpatient, non-ICU Treatment[2]

1. A respiratory fluoroquinolone (strong recommendation; level I evidence)

2. A beta-lactam plus a macrolide (strong recommendation; level I evidence) with doxycycline (level III evidence) as an alternative to the macrolide.

Design

  • Multicenter, cluster-randomized, crossover, non-inferiority trial
  • N=2,283
    • Beta-lactam (n=656)
    • Beta-lactam-macrolide (n=739)
    • Fluoroquinolone (n=888)
  • Setting: 7 hospitals in Finland
  • Enrollment: February 2011 to August 2013
  • Analysis: Intention-to-treat
  • Primary outcome: 90-day all-cause mortality
  • Secondary outcomes:
    • Time to starting oral antibiotics
    • Length of hospital stay
    • Occurrence of major or minor complications during the hospital stay

Population

Inclusion Criteria

  • Clinically suspected CAP who required antibiotics and non-ICU hospitalization
    • Radiologically confirmed CAP plus two other clinical criteria
    • Presence of two diagnostic clinical criteria (cough, purulent sputum, temperature > 38 degrees Celsius, positive auscultory findings, leukocytosis, CRP > 3xULN, dyspnea/tachypnea/hypoxia) with no obvious non-respiratory source of infection
  • Age 18 years or older
  • One hospital only included patients with a CURB-65 score greater than 2

Exclusion Criteria

  • Patients with Cystic Fibrosis
  • Positive Legionella antigen
  • Recent hospitalization for >48 hours in the previous 2 weeks
  • Patients from long-term care facilities

Baseline Characteristics

  • Mean age: 72 years
  • Mean BMI: 28
  • Mean HbA1c: 8.8%
  • Units of insulin: 14 units/day

Interventions

  • Hospitals randomized to a six-block schedule which had two blocks each of macrolide monotherapy, fluoroquinolone monotherapy, and beta-lactam-macrolide combination therapy.
  • Each patient diagnosed with CAP was treated with the antibiotic for which the hospital was currently scheduled.

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

90-day all-cause mortality
  • Unadjusted:
    • BL monotherapy: 9.0%
    • FQ monotherapy: 8.8%
    • BLM combination therapy: 11.1%
  • Adjusted comparisons:
    • BL vs. FQ (-0.6% in favor of Fluoroquinolones, 90% CI, -2.8 to 1.9)
    • BL vs. BLM (1.9% in favor of beta-lactam monotherapy, 90% CI, -0.6 to 4.4)

Secondary Outcomes

Time to starting oral antibiotics (days)
  • BL monotherapy: 4 (3-5)
  • FQ monotherapy: 3 (0-4)
  • BLM combination therapy: 4 (3-5)
Length of hospital stay (days)
  • BL monotherapy: 6 (4-8)
  • FQ monotherapy: 6 (4-8)
  • BLM combination therapy: 6 (4-10)
Occurrence of major or minor complications during the hospital stay (%)
  • Major Complications
    • BL monotherapy: 4.9%
    • FQ monotherapy: 5.3%
    • BLM combination therapy: 5.7%
  • Minor Complications
    • BL monotherapy: 11%
    • FQ monotherapy: 12.3%
    • BLM combination therapy: 13.1%

Subgroup Analysis

Post-hoc subgroup analysis was done for both strategy-adherent and antibiotic-adherent subgroups for all outcomes. 90-day all cause mortality was not reported directly in the paper but was found to show that BL monotherapy was non-inferior to both BLM combination therapy and FQ monotherapy.

Strategy-adherent Subgroup Analysis
  • Rate ratio for discharge alive (95% Confidence Interval)
    • BL vs. FQ: 1.04 (0.93-1.16)
    • BL vs. BLM: 0.86 (0.77-0.97)
  • Rate ratio for time to starting oral treatment (95% Confidence Interval)
    • BL vs. FQ: 1.33 (1.17-1.51)
    • BL vs. BLM: 0.94 (0.83-1.08)
  • Odds ratio for complications (95% Confidence Interval)
    • BL vs. FQ: 1.03 (0.73-1.46)
    • BL vs. BLM: 1.06 (0.74-1.52)
Antibiotic-adherent Subgroup Analysis
  • Rate ratio for Discharge Alive (95% Confidence Interval)
    • BL vs. FQ: 1.03 (0.92-1.17)
    • BL vs. BLM: 0.86 (0.74-0.95)
  • Rate ratio for time to starting oral treatment (95% Confidence Interval)
    • BL vs. FQ: 1.52 (1.28-1.80)
    • BL vs. BLM: 0.93 (0.79-1.11)
  • Odds ratio for complications (95% Confidence Interval)
    • BL vs. FQ: 1.03 (0.71-1.51)
    • BL vs. BLM: 1.20 (0.82-1.77)

Criticisms

  • 38.7% of patients in the BL monotherapy group received an additional antibiotic for atypical coverage
  • The study was conducted in one country that is known to have low resistance of S. pneumoniae to both penicillins and macrolides which decreases the generalizability of the results.

Funding

The study was funded by the Netherlands Organization for Health Research and Development. There were no reported conflicts of interest.

Further Reading

  1. Template:Http://www.ecdc.europa.eu/en/publications/publications/antimicrobial-resistance-surveillance-europe-2011.pdf
  2. 2.0 2.1 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.