Duration of antibiotic treatment in community-acquired pneumonia

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Uranga A, et al. "Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial". JAMA Internal Medicine. 2016. 176(9):1257-1265.
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Clinical Question

In hospitalized patients with community acquired pneumonia, does a five day course of antibiotics have comparable clinical success to a traditional duration of antibiotic therapy (median of 10 days)?

Bottom Line

A five day course of antibiotic treatment is as effective as a traditional longer duration in hospitalized patients diagnosed with community acquired pneumonia.

Major Points

There is debate on the optimal duration of antibiotic treatment of community acquired pneumonia (CAP). To date, no clinical trials have been conducted concerning duration of antibiotic treatment in a real-world setting where physicians can prescribe their drug of choice among hospitalized patients with CAP. The guidelines recommending a minimum of 5 days of antimicrobial treatment published by the Infectious Disease Society of America (IDSA) and American Thoracic Society (ATS) in 2007 are based on expert opinion. The purpose of this study is to provide validation of the guidelines recommended by the IDSA / ATS

The trial design was a multicenter, randomized control trial (RCT) including 312 patients. Eligible patients were 18 years or older and hospitalized with a diagnosis of CAP. Pneumonia was defined as pulmonary infiltrate on chest radiography not seen previously plus at least 1 symptom compatible with pneumonia, such as cough, fever, dyspnea, and/or chest pain. Patients were assessed for eligibility at day 5 while on antibiotic treatment and then those responding to treatment were randomized to the shorter duration group (minimum of 5 days) or the control group (duration determined by physicians as in clinical practice). Patients were not eligible for randomization unless body temperature was 37.8°C or less for 48 hours and there were no more than 1 CAP-associated sign of clinical instability. There was no difference in the clinical success rate at day 10 (48.6% in the control group and 56.3% in the intervention group;P = 0.18) or at day 30 (88.6% vs. 91.9%;P = 0.33).

It is important to look at multiple aspects of the study when determining if it validates the IDSA/ATS guidelines. The type of antibiotic prescribed was not controlled, but quinolones were primarily used in this study due to regional prescribing habits. This could make it difficult to generalize the results to other antibiotics. Also, for the control group the duration of antibiotic therapy was determined by the physician. This mimics real life practice, but makes it more difficult to assess the outcomes because duration of therapy may vary in the control group. For this study, patients were only randomized after they had a successful first 5 days of antibiotic treatment. This means the results can’t be extrapolated to patients who are not responding to the first 5 days of antibiotic therapy.

Guidelines

The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) base their 2007 recommendations for the duration of antibiotic treatment mainly on summative expert opinion. The suggestions for the shorter 5-day duration were recommended for patients who were afebrile for 48 to 72 hours without fever and had no more than 1 CAP-associated instability criteria prior to cessation of therapy. However, if the patient’s condition is complicated by extrapulmonary infection, or if the initial therapy was not effective against the infective pathogen identified, a longer duration of treatment was recommended. The current study provides validation for the ISDA / ATS recommendations.

Design

  • Multicenter, non-inferiority RCT
  • N = 312
    • Intervention group (antibiotics for minimum of 5 days): n = 162
    • Control group (antibiotic duration determined by physician): n = 150
  • Setting: 4 teaching hospitals in Basque Country in Spain
  • Enrollment: 2012-2013
  • Mean follow up: day 10 and day 30
  • Analysis: Intent to treat, Per-protocol
  • Primary Outcome: Clinical success at day 10 and 30 defined as resolution or improvement in signs and symptoms related to pneumonia without further antibiotics

Population

Inclusion Criteria

  • 18 years or older
  • Hospitalized with a diagnosis of CAP

Exclusion Criteria

  • Infected by human immunodeficiency virus
  • Chronic immunosuppression (defined as immunosuppression for solid organ transplantation, having undergone a splenectomy, receiving ≥10 mg/d of prednisone or the equivalent for >30 days, taking other immunosuppressive agents, or having neutropenia, ie, a neutrophil count <1000/μL [to convert to ×109 /L, multiply by 0.001])
  • Lived in a nursing home
  • Discharged from an acute care hospital, an onsite subacute care unit, or a palliative care unit within the previous 14 days
  • Had already taken antibiotics in the 30 days before admission
  • Required a longer duration of therapy because of an uncommon cause (Pseudomonas aeruginosa or Staphylococcus aureus, among others)
  • Required a chest tube or had a condition complicated by extrapulmonary infection, such as meningitis or endocarditis.
  • Died or were transferred to the intensive care unit before randomization

Baseline Characteristics

From Intervention Group:

  • Demographics: Age 65 years, male 623%
  • PMH: current smoker 22.6%, previous smoker 52.7%, alcohol use 10.5%, heart disease 24.1%, CHF 7.4%, COPD 16.7%, Diabetes 13%
  • Pneumonia severity index (PSI): class 1-3 63%, class 4-5 37%
    • PSI is used with patients diagnosed with community acquired pneumonia to calculate the probability of morbidity and mortality
    • Class 1 or 2 patient can be sent home on oral antibiotics
    • Class 3 can be sent home or kept inpatient on antibiotic therapy (depends on severity or provider discretion)
    • Class 4 or 5 patient must be hospitalized

Interventions

  • Intervention group: Antibiotic treatment of 5 days
  • Control group: Antibiotic treatment determined by clinical physician (median of 10 days)

Outcomes

Primary Outcomes

Primary Clinical Success (defined as resolution or improvement in signs and symptoms related to pneumonia without further antibiotics). All values are control (longer duration) vs. intervention (5 days)

From Intention to treat

  • At day 10: 48.6% vs. 56.3% (P = .18)
  • At day 30: 88.6% vs. 91.9% (P = .33)

From Per-protocol

  • At day 10: 50.4% vs. 59.7% (P = .12)
  • At day 30: 92.7% vs. 94.4% (P = .54)

Secondary Outcomes

Readmission by Day 30

  • 9 (6.6%) vs 2 (1.4%), P - 0.02

Treatment Failure

  • 2 (1.5%) vs 3 (2.1%), P >0.99

Respiratory Failure

  • 26 (19%) vs 31 (21.2%), P = 0.64

Adverse Events

Descriptions of the adverse effects experienced by patients was not provided.

  • 18 patients (13.1%) of the control group and 17 patients (11.7%) of the intervention group had antibiotic adverse effects by day 30 (P = 0.72).

Criticisms

  • The type of antibiotic was not the same for every patient, as physicians were able to pick what therapy they wanted, but 80% of the antibiotics used were quinolones. While this mimics real life practice, it makes it difficult to apply the results to other antibiotic classes.
  • The study was performed in one region in Spain, could make it harder to generalize to other populations.
  • The study excluded patients with more severe cases of pneumonia or patients that were immunocompromised.
  • This was an open-label study, so the antibiotic duration of the control group could have been influenced by the shorter duration of the intervention group.

Funding

The study was funded by a grant from the Health Department of Basque Country government, a grant from the Pharmacy Department of the Spanish Government, and a Fellows Scholarship from the Spanish Pulmonology and Thoracic Surgery Society. The funding source played no role in the conduction or publication of the study.

Further Reading

Uranga A, Espana PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia. JAMA Intern Med. 2016 Sep 1;176(9):1257-65.