Antibiotics for COPD exacerbations

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Anthonisen NR, et al. "Antibiotic Therapy in Exacerbations of COPD". Annals of Internal Medicine. 1987. 106(2):195-204.
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Clinical Question

Among outpatients with a COPD exacerbation, do antibiotics improve treatment success rates?

Bottom Line

Antibiotics improve COPD exacerbation treatment success rates treated in outpatient settings. Patients with increased dyspnea, sputum volume, and sputum purulence benefit the most.

Major Points

COPD exacerbations are often caused by viral or bacterial pathogens. However, the use of antibiotics during exacerbations is controversial. In clinical practice, clinical symptoms of infection are often used to decide whether antibiotics are used. The 1987 study "Antibiotic Therapy in Exacerbations of COPD", published by investigators from Winnipeg, Canada, demonstrated the use of stratifying patients by symptoms when determining if antibiotics should be utilized. In this double-blinded crossover study, 173 patients were randomized to receiving ten days of antibiotics or placebo during exacerbations as outpatients. At baseline, most patients had severe disease (Mean FEV1%: 34) with daily symptoms of dyspnea and sputum production. Antibiotic choices included trimethoprim-sulfamethoxazole, amoxicillin, and doxycycline. Treatment success, defined as resolution of symptoms within 21 days, was significantly higher in patients treated with antibiotics (p<0.01). Furthermore, antibiotic use significantly decreased the number of exacerbations further deteriorating to requiring hospitalization or non-randomized use of antibiotics.

Increasing severity of the exacerbation showed increasing benefit with the use of antibiotics. Patients benefited most when presenting with all three symptoms of increased dyspnea, sputum production, and sputum purulence (Type 1 Exacerbation). A smaller benefit was seen in patients with patients with two of the three symptoms (Type 2 Exacerbation), and minimal to no benefit with only 1 symptom and other accompanying features of infection (Type 3 Exacerbation).

A 2012 Cochrane Systematic Review[1] found a reduction in inpatient and outpatient risk for treatment failure, although the quality of evidence is poor overall. There was no statistically significant reduction in mortality and length of stay in inpatients, and almost no data on patient outcomes exist. Antibiotics are most beneficial in patients requiring ICU admission, reducing treatment failure and mortality.

Guidelines

GOLD COPD 2014 Guidelines (Adapted)[2]

  • Antibiotics should be given to COPD exacerbation patients who have three cardinal symptoms - increased Indyspnea, sputum volume, and sputum purulence (Evidence B)
  • Antibiotics should be given to COPD exacerbation patients with two of the above cardinal symptoms, if increased purulence is one of the two symptoms (Evidence C) or require mechanical ventilation (Evidence B)
  • The recommended length of antibiotic therapy is 5-10 days (Evidence D)
  • Usual initial empiric treatment choices include: aminopenicillin with or without clavulanic acid, macrolide, or tetracycline

Design

  • Double-blinded, crossover randomized control trial
  • Unknown number of referring physicians involved
  • No intention-to-treat analysis
  • N= 362 eligible exacerbations in 173 patients
    • Antibiotics (n=182)
    • Placebo (n=180)
  • Primary outcome: Treatment success rate (All exacerbations)
  • Secondary outcomes:
    • All exacerbations: No resolution and deterioration rates
    • First exacerbations: Success, resolution, and deterioration rates
    • Success rates by exacerbation type
  • Follow-Up
    • Mean Follow-up Time: 23.7 months (SD 11.3)
    • Patients seen in regular follow-up every 3 months for physical examination, symptom evaluation, FEV1, and peak flow measurements.
    • Patients with an exacerbation were seen on the same day by a nurse practitioner
    • In severely ill patients, the patient's physician was consulted to determine if the patient should participate in the study
    • During an exacerbation, patients were followed on an outpatient basis every 3 days for up to 21 days


  • Outcome Definitions:
    • Success: resolution of all symptoms accompanying exacerbation within 21 days
    • No resolution: Exacerbation in which all symptoms did not resolve in 21 days, but no further intervention was required
    • Failure with deterioration: symptoms worsened during exacerbation, requiring further intervention including either hospitalization or non-randomized use of antibiotics. Not within 72 hours of exacerbation.
    • Unrelated deterioration: Other intervention required within 72 hours of exacerbation. Not deemed success or failure, as deterioration unlikely to be related to randomized treatment.


  • Exacerbation Definitions:
    • Type 1 Exacerbation: All three of - increased dyspnea, sputum production, sputum purulence
    • Type 2 Exacerbation: Two of the above
    • Type 3 Exacerbation: One of the above, plus one of: upper respiratory tract symptoms within 5d, increased wheeze, increased cough, increased respiratory rate by 20%, increased heart rate by 20%

Population

Inclusion Criteria

  • Age ≥35 years
  • Clinical diagnosis of COPD
  • All of the following PFT results: FEV1 < 70%, FVC < 70%, and TLC > 80%

Exclusion Criteria

  • Diagnosis of asthma
  • FEV1 greater than 80% after use of inhaled bronchodilator
  • Concomitant severe disease including but not limited to: cancer, left ventricular failure, stroke, disease likely requiring antibiotic therapy
  • Unreliable for clinical visits and/or far from clinical center

Baseline Characteristics

Details are published elsewhere.[3]

Demographics

  • Age (mean): 67 years
  • Female: 21.2%
  • Positive smoking history: 93.6%
  • Current smoker: 21.4%
  • Smoking pack-years: 39.9 (SD 28.9)

Symptoms

  • Cough:
    • None: 15%
    • Morning: 60%
    • Daytime cough: 21%
    • Continuous: 4%
  • Sputum quantity:
    • None: 16%
    • <30mL: 57%
    • 30-100mL: 23%
    • >100mL: 4%
  • Sputum quality:
    • Mucoid: 62%
    • Mucopurulent: 19%
    • Purulent: 3%
  • Dyspnea:
    • None: 6%
    • During unusual exertion only: 28%
    • During normal activity: 48%
    • At rest: 17%
  • Wheezing:
    • None: 30%
    • Only on unusual activity or exacerbation: 53%
    • On daily activities: 16%
    • At rest: 2%

Lung Function

  • FEV1% predicted: 34
  • FVC% predicted: 60
  • FRC% predicted: 165
  • TLC% predicted: 129
  • RV% predicted: 205
  • Bronchodilator response, FEV1%: 112
  • Peak Flow, L/min: 228
  • Arterial PO2, mmHg: 68
  • Arterial PCO2, mmHg: 37
  • Arterial pH: 7.42

Interventions

  • Randomization procedure unspecified
  • All groups received conventional therapy, including a 2 week run-in period, consisting of:
    • Long-acting oral theophylline
    • In patients with serious symptoms, prednisone 5-10mg/d
    • Diuretics for fluid overload
    • Home oxygen for at least 18h/d (fulfilling eligibility criteria)
    • Anti-influenza vaccine
    • During exacerbations, prednisone 40mg for 3 days, followed by a taper in 9-12 days
  • Antibiotic group received:
    • 10 days of antibiotic therapy, chosen at the discretion of patient's physician
      • Trimethoprim-sulfammethoxazole, one tablet (160mg/800mg) po BID
      • Amoxicillin 250mg po QID
      • Doxycycline 200mg po x1, followed by 100mg po daily
  • Placebo group received visually identical pills

Outcomes

Comparisons are antibiotics vs. placebo. In patients with multiple exacerbations, data was analyzed in matched sets (up to 4 exacerbations). "All Exacerbations" refers to patients with matched set data (multiple exacerbations) and single exacerbations.

Primary Outcome

Treatment Success, All Exacerbations
68.1% vs. 55.0% (p<0.01)

Secondary Outcomes

No resolution, All Exacerbations
18.7% vs. 23.3%
Deterioration, All Exacerbations (pooled data)
9.9% vs. 18.9% (p<0.05)
Deterioration within 72h, All Exacerbations
3.2% vs. 2.9%
Treatment Success, First Exacerbations
66.8% vs. 52.3% (p=0.06)
No resolution, First Exacerbations
17.5% vs. 27.1%
Deterioration, First Exacerbations
12.3% vs. 17.0%
Deterioration within 72h, First Exacerbations
3.4% vs. 3.4%

Results by Type, At Exacerbation Onset

Treatment Success, Type 1 Exacerbation
62.9% vs. 43.0%
Treatment Success, Type 2 Exacerbation
70.1% vs. 60.0%
Treatment Success, Type 3 Exacerbation
74.2% vs. 69.7%


Results by Type, At Maximal Symptoms

Treatment Success, Type 1 Exacerbation
57.7% vs. 46.0%
Treatment Success, Type 2 Exacerbation
80.7% vs. 66.7%
Treatment Success, Type 3 Exacerbation
85.7% vs. 84.6%

Subgroup Analysis

By antibiotic selection
No difference in success rates, baseline lung function, symptoms, number of exacerbations
Treatment with steroid
Non-statistical increase in success rate

Other

Antibiotic Selection
Trimethoprim-Sulfamethoxazole: 40%
Amoxicillin: 40%
Doxycycline: 20%
Days to Exacerbation resolution (excluding deterioration cases)
14.1 vs. 15.5
Days to Exacerbation resolution (including deterioration cases, assigned duration 22d)
2.2 days less in antibiotic group, p=0.02
Number of exacerbations (excluding <6mo followup)
1 exacerbation every 8.5 months (1.3/year)
Peak Flow Improvement
Faster increase in antibiotic group (p<0.02)
Symptom Difference
Wheeze more common in initial presentation of antibiotic group (p<0.01)

Inter-observer Agreement on Symptoms

Nurse Practitioner vs. Physician

No symptoms at end of exacerbation: K = 0.57
End of exacerbation: K = 0.78
URI onset: K = 0.39
Increased dyspnea: K = 0.70
Increased sputum: K = 0.51
Change in color: K = 0.73
Increased wheeze: K = 0.50
Increased cough: K = 0.56

Adverse Events

Nausea
10.1% vs. 8.0%
Vomiting
2.8% vs. 1.9%
Abdominal cramps
3.2% vs. 4.2%
Diarrhea
5.0% vs. 2.9%
Rash
1.2% vs. 1.0%
Other
1.5% vs. 6.1%
Treatment Discontinuation
1.5% vs. 2.5%

Loss to Followup

  • Total Lost to Followup: n=59
    • Death: n=18
      • During exacerbation: n=1 (Ruptured AAA)
    • Lack of protocol cooperation: n=15
    • Withdrawal by patient physician: n=17

Excluded Exacerbations

  • Exacerbations not treated by protocol (n=86)
      • "Too sick": n=35
      • Antibiotics started before team notified: n=21
      • Exacerbation outside of study city: n=16
      • Miscellaneous: n=14

Criticisms

  • Randomization protocol unspecified
  • No criteria or guidelines for determination of patients "too sick" to participate in study; subjective decision
  • No intention to treat analysis for patients dropping out of the study
  • Agreement of symptom classification between nurse practitioner and physician moderate at best
  • Arbitrary selection of 21 days designation as treatment failure
  • Chest X-Rays not conducted to rule out pneumonia
  • No criteria to differentiate from acute bronchitis

Funding

  • Health and Welfare Canada
  • Burroughs Wellcome Co. (Trimthoprim-Sulfamethoxazole, Septra DS)
  • Averyst Laboratories (Amoxicillin, Amoxil)
  • Pfizer Canada, Inc. (Doxycycline, Vibramycin)

Further Reading

  • KDIGO guidelines[4]
  • EVOLVE design[5]
  1. Vollenweider DJ, et al. "Antibiotics for exacerbations of chronic obstructive pulmonary disease." Cochrane Database Syst Rev. 2012;12(12):CD010257.
  2. Global Initiative for Chronic Obstructive Lung Disease. "Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease." 2014.
  3. Chertow GM, et al. Baseline characteristics of subjects enrolled in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial. Nephrol Dial Transplant. 2012 Jul;27(7):2872-9.
  4. Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. "KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD)." Kidney International. 2009; 76 (Suppl 113): S1–S130.
  5. Chertow GM, et al. Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): rationale and design overview. Clin J Am Soc Nephrol. 2007 Sep;2(5):898-905.