- Principles: up to half of acute exacerbations of chronic bronchitis (AECB) are caused by bacterial infection.
- Dominant pathogens in expectorated sputum are S. pneumoniae, H. influenzae, H. parainfluenzae and M. catarrhalis.
- P. aeruginosa: associated with severe exacerbations.
- Significant AECB flare: need all 3
- Increased sputum production
- Increased cough
- Increased dyspnea
- PE: increased respirations, wheezing, rhonchi, cyanosis +/- fever.
- Definition: increased over baseline in cough, sputum and sputum purulence in pt with chronic bronchitis (chronic bronchitis defined as cough + sputum x 3 yrs).
- Obtain chest X-ray to R/O pneumonia, CHF, effusion, mass lesion or pneumothorax.
- Lab: sputum gram stain and culture, not advocated routinely.
- Arterial blood gases or pulse oximetry if pt seriously ill.
- Spirometry: probably not useful for acute management.
- Severity: judge by pulse oximetry, blood gases, FEV-1.
- Supportive care includes bronchodilators (albuterol, ipratropium bromide), corticosteroids, oxygen (see below).
- Abx indications: severe acute exacerbations with increased cough, sputum volume & sputum purulence.
- Evidence (Cochrane Library reviews) support antibiotic treatment for "severe exacerbations" but not more mild forms.
- Antibiotic selection is optimally made based on gram-stain and/or culture.
- Most commonly used antibiotics for acute bronchitis is azithromycin followed by amoxicillin and clarithromycin.
- Preferred (ACP):
- Amoxicillin/clavulanate 875mg PO twice daily
- Azithromycin 500mg, then 250mg PO once-daily x 4d (Z-pak)
- Clarithromycin 500mg PO twice daily or clarithromycin XR (Biaxin XR) 1g PO once daily
- Cefuroxime axetil 500mg PO twice daily
- Cefprozil 500 mg PO twice daily
- Cefpodoxime 200-400 mg PO twice daily
- Cefdinir 600mg PO once daily
- Duration: except as indicated above, usual course is 10-14d.
- Severe or recent abx:
- Influenza: efficacy of oseltamivir for ambulatory pts is established and should be given to high patients with COLD even if sx > 48 hrs (CDC recommendations 2011). Check CDC website for latest recommendations: Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza.
- Aspects more important typically than antibiotic selection.
- Corticosteroids: If FEV1 < 50% predicted, use prednisone 30-40 mg/d PO x 7-10d or nebulized budesonide.
- Inhaled bronchodilators: albuterol 2.5 mg nebs four times a day (may titrate up to q 30min) or 2 puffs four times a day by metered inhaler +/- spacer when stable and/or ipratropium 0.25-0.5mg inhaled q 6h-8h.
- Hospitalized pts:
- Corticosteroids: methylprednisolone 125mg IV q 6h x 3d, then PO prednisone 60mg/d x 4-7d, 40mg/d x 8-11d, 20mg/d x 12-15d.
- O2: use 2-4L/min by nasal cannula; keep pulse oximeter > 91%. If need increase or pCO2 > 45, use Venturi mask. Risk with higher O2 administration is respiratory failure, so close monitoring recommended if patient is known CO2 retainer.
- Aminophylline/theophylline: potentially serious side effects and not effective; avoid or use with caution + measure levels at 8-12 h.
- Non-invasive positive-pressure ventilation; requires trained physician.
- Inhaled metered dose steroids: not generally indicated for acute therapy.
- Not effective: chest PT, methylxanthine bronchodilators (e.g., theophylline), mucolytic agents.
- Opportune time for smoking cessation counseling.
Selected Drug Comments
Old agent for treatment and prevention of Influenza A, but now precludes routine use unless circulating strains known to be sensitive.
Good activity against most S. pneumoniae, performed well in prior studies of AECB and cheap. Concern is resistance by 5-10% of S. pneumoniae, 30-40% of H. influenzae and 90-95% of M. catarrhalis. Recommended as a preferred agent in ACP guidelines, but the supporting trials preceded the current era of resistant pathogens.
Seems to work better in patients than in the test tube (susceptibility testing). Resistance rates of S. pneumoniae are high, but relevance debated.
A bad choice, poor activity against S. pneumoniae relative to other oral cephalosporins.
As active as azithromycin and erythromycin vs. S. pneumoniae; activity vs. H. influenzae is debated due to activity ascribed to a metabolic product, which is greater than that of the parent compound. FDA has approved for H. influenzae pneumonia.
Risky choice due to low in vitro activities against S. pneumoniae and H. influenzae, but good historic record for AECB, well tolerated & cheap. This is usually a good choice for patients who aren’t very sick. Doxycycline is recommended by the ACP guidelines for severe acute exacerbations of chronic bronchitis because adequate studies go back to the time this was one of few options
Active against nearly all treatable pathogens except influenza virus including S. pneumoniae, H. influenzae, M. catarrhalis, most S. aureus (MSSA), most GNB, Chlamydophila pneumoniae and Mycoplasma pneumoniae. The drug is easy to take (once daily) and well tolerated. The major concern is abuse with the consequence of resistance and C. difficile infection.
No longer useful since most strains now resistant, so need to know current CDC recommendations.
Use for the treatment and prophylaxis of Influenza virus A and B. Early treatment preferred, should be withing 48 hrs of sx onset -- if possible but use beyond this time frame is justified if severe COLD, severe infection or hospitalized patient. Expensive. Main side effect in GI intolerance and rare cases of self-injury and confusion. See CDC website for latest recommendations.
Limited published data but reasonable activity vs. the major pathogen and generally well tolerated except for hypersensitivity reactions to sulfa moiety.
Newer agent for treatment of Influenza A or B. Given by inhalation, aerosolized form may not be suitable for persons with reactive airways. Should be given within 48 hrs of onset of sx if possible, but use later is justified if severe illness or hospitalized patient. Expensive. Main side effect is bronchospasm.
- Common non-bacterial causes of AECB: viral infections, allergens, pollution.
- Must r/o pneumonia (x-ray), subclinical asthma (PFTs) and respiratory failure (ABG).
- Antibiotics fall into 3 categories: cheap, old & proven (amoxicillin, doxycycline); better activity vs S. pneumoniae and H. influenzae (oral cephalosporins, amoxicillin/clavulanate); drugs w/ clout but concern for abuse and resistance (levofloxacin, moxifloxacin).
- Main issues: role of H. influenzae and role of newer drugs to reduce hospitalizations and to delay next exacerbation?
- A placebo controlled trial in > 1,000 patients with chronic bronchitis showed prophylactic azithromycin (250 mg/d) reduced the rate of acute exacerbations by 40%. Note that these recommendations must be interpreted with caution due to the crisis of antibiotic resistance attributed primarily to extensive use of antibiotics.
Pathogen Specific Therapy
(No ordered preference)
Basis for recommendation
- Fiore AE et al: Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 60:1, 2011 [PMID:21248682]
Comment: Recommendation is for oseltamivir for patients with risk for severe disease due to influenza regardless of the duration of flu symptoms. this includes patients with COLD.
- Rabe KF et al: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 176:532, 2007 [PMID:17507545]
Comment: Initiative from NIH and WHO to guide management. Indication for abx: 1) 3 symptoms (increased dyspnea, increased sputum purulence, increased volume, 2) required mechanical ventilation. Diagnostic evaluation: 1) bronchodilator reversibility test, 2) chest x-ray, 3) arterial blood gas, 4) sputum culture.
- Stoller JK: Clinical practice. Acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 346:988, 2002 [PMID:11919309]
Comment: Review of guidelines: *Brit Thor Soc 1997: Tetracycline, amoxicillin; *Am College Chest Phys 2001: Amox, tetra, TMP-SMX; *European Resp Society 1995: Amox or tetra; *ATS: Doxy or amoxicillin.
- Saint S et al: Antibiotics in chronic obstructive pulmonary disease exacerbations. A meta-analysis. JAMA 273:957, 1995 Mar 22-29 [PMID:7884956]
Comment: A META-ANALYSIS OF ANTIBIOTIC TRIALS, which shows a slight advantage to these drugs compared to placebo. The benefit was measured in duration of symptoms and in peak expiratory flow rates, but the advantage of antibiotics was tiny and was statistically significant only because the numbers were large.
- Albert RK et al: Azithromycin for prevention of exacerbations of COPD. N Engl J Med 365:689, 2011 [PMID:21864166]
Comment: This is a randomized controlled trial in 1,142 patients with COPD given placebo vs. azithromycin 250 mg/day. azithromycin recipients had a significant reduction in exacerbations (1.5/year vs. 1.8/year; p=< 0.001) and improved lung function.
- Albertson TE, Louie S, Chan AL: The diagnosis and treatment of elderly patients with acute exacerbation of chronic obstructive pulmonary disease and chronic bronchitis. J Am Geriatr Soc 58:570, 2010 [PMID:20398122]
Comment: Recommended antibiotics for exacerbations of COLD: amoxicillin, ampicillin, pivampicillin, trimethoprim/sulfamethoxazole and doxycycline. "Second line agents:" amoxicillin/clavulanic acid, second and third generation cephalosporins and fluoroquinolones. The latter are described as better versus resistant bacteria but risk driving resistance.
- Murphy TF et al: Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 170:266, 2004 [PMID:15117742]
Comment: Analysis of sequential (monthly) samples of sputum from patients with COPD defined a group with a less than six month lapse with negative cultures for H flu. The subsequently recovered strain was identical to the initial isolate suggesting it was always there and that sputa culture are unreliable sources of this agent.
- Chodosh S: Clinical significance of the infection-free interval in the management of acute bacterial exacerbations of chronic bronchitis. Chest 127:2231, 2005 [PMID:15947342]
Comment: Author discusses a new goal with antibiotics for AECB: delay in the time to the next exacerbation or the infection - free - interval (IFI).
- Dimopoulos G et al: Comparison of first-line with second-line antibiotics for acute exacerbations of chronic bronchitis: a metaanalysis of randomized controlled trials. Chest 132:447, 2007 [PMID:17573508]
Comment: First line agents (ampicillin, TMP-SMX and doxycycline) vs. 2nd line (amox-CA, macrolides, quinolines and 3d gen cephalosporins). First line agents were inferior (RR 0.5).
- Sethi S et al: Strain-specific immune response to Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 169:448, 2004 [PMID:14597486]
Comment: Longitudinal study of patients with COPD showing some exacerbations are associated with an immune response to a newly acquired strain of H. influenzae. (This supports the role of H. flu as a pathogen in exacerbations).
- Jørgensen AF et al: Amoxicillin in treatment of acute uncomplicated exacerbations of chronic bronchitis. A double-blind, placebo-controlled multicentre study in general practice. Scand J Prim Health Care 10:7, 1992 [PMID:1589668]
Comment: One of many controlled trials of amoxicillin vs. placebo, this one with 262 outpatients with AECB. Analysis by symptom score and peak expiratory flow rate showed NO ADVANTAGE FOR ANTIBIOTICS.
- Pines A et al: Antibiotic regimens in severe and acute purulent exacerbations of chronic bronchitis. Br Med J 2:735, 1968 [PMID:4872151]
Comment: One of many controlled trials of tetracycline vs. placebo in 149 patients hospitalized for AECB. There was SIGNIFICANT BENEFIT FOR TETRACYCLINE TREATMENT in terms of symptom scores and peak expiratory flow rate.
- Gump DW et al: Role of infection in chronic bronchitis. Am Rev Respir Dis 113:465, 1976 [PMID:1267252]
Comment: One of the MOST COMPREHENSIVE STUDIES EVER DONE. Authors followed a group of pts with chronic bronchitis & obtained quantitative bacterial cultures of sputum & viral cx at 2-week intervals. They showed that exacerbations of bronchitis were often due to viral infection (positive cultures in 32% of exacerbations vs. <1% in periods of stability), sputum bacterial culture showed no significant changes in either frequency of recovery or counts of the big 2--H. flu & S. pneumo). S. pneumo was recovered in 37% of exacerbations & in 33% of control periods; for H. flu, it was 57% & 60%, respectively
- Wilson R et al: Antibiotic treatment and factors influencing short and long term outcomes of acute exacerbations of chronic bronchitis. Thorax 61:337, 2006 [PMID:16449273]
Comment: Patients with AECB were randomized to treatment with moxifloxacin or placebo. Clinical cure was significantly associated with antibiotic treatment (OR 1.5) and negatively associated with age >65, and bronchodilator use. The conclusion was that the benefit of moxifloxacin was seen primarily in those >65 yrs.
- Snow V et al: Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 134:595, 2001 [PMID:11281744]
Comment: Position paper of ACP for managing exacerbations of chronic bronchitis. Indications to Rx: Increased dyspnea, increased cough AND increased sputum purulence. Agents recommended: Amoxicillin, doxycycline, TMP-SMX.
- Grossman RF: Guidelines for the treatment of acute exacerbations of chronic bronchitis. Chest 112:310S, 1997 [PMID:9400894]
Comment: Recommendation is TO STRATIFY USE OF ANTIBIOTICS based on severity of exacerbation - mild/moderate - doxycycline, amoxicillin; severe - amox/clavulanate, azithro, fluoroquinolone
- Nouira S et al: Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: a randomised placebo-controlled trial. Lancet 358:2020, 2001 [PMID:11755608]
Comment: Results showed a benefit of ofloxacin with mortality decrease (4% vs 22%) & reduced duration hospitalization & mechanical ventilation. The study raised concerns about ethics of a placebo control with such seriously ill pts, but the accompanying editorial notes that the benefit of antibiotics had never been clearly shown.
- Seemungal T et al: Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 164:1618, 2001 [PMID:11719299]
Comment: Study of 168 exacerbations - viruses found in 67 (40%) - most common were rhinovirus and RSV.
- Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986. Am Rev Respir Dis 136:225, 1987 [PMID:3605835]
Comment: The 1987 ATS guidelines for treatment of exacerbations of chronic bronchitis concludes that sputum cultures are not helpful and that there is NO EVIDENCE THAT ANTIBIOTIC TREATMENT ALTERS THE NATURAL HISTORY OF CHRONIC BRONCHITIS. The report is a bit old (1987), but there is little in the more recent literature to alter this opinion. The more recent ATS guidelines on pneumonia did not review AECB.
- Anderson E, Emerman CL; Managing acute exacerbations of chronic obstructive pulmonary disease; J Crit Illness; Vol. 15; pp. 674;
Comment: The AUTHORS ADVOCATE: 1) EVALUATION: FEV1 +/- PEFR; chest x ray, O2 (pulse oximetry +/- blood gases) 2) HOSPITALIZATION: Resp failure, pneumonia, persistent dyspnea, pul. function < 40% normal 3) RX: O2 - 2 to 4 L nasal cannula for pulse ox > 91%, if need O2 increase or pCO > 45 - Venturi mask Beta - agonist- often used with asthma, but evidence this works well is limited. Theophylline - narrow toxic-therapeutic index; measure level at 8 - 12 hrs post infusion. Antibiotics - benefit of antibiotics modest; new antibiotics not well tested.
- Murphy TF et al: Moraxella catarrhalis in chronic obstructive pulmonary disease: burden of disease and immune response. Am J Respir Crit Care Med 172:195, 2005 [PMID:15805178]
Comment: The Buffalo group has studied this cohort of 104 pts with COPD for 10 years with monthly sputum cultures. In this study they showed M. catarrhalis was newly detected in 57 of 560 exacerbations. This was accompanied by a serologic response and clearance. They conclude M. catarrhalis causes 10% of exacerbations.
- Sethi S: Bacteria in exacerbations of chronic obstructive pulmonary disease: phenomenon or epiphenomenon? Proc Am Thorac Soc 1:109, 2004 [PMID:16113422]
Comment: The author reviews methods and conclusions of studies to determine exacerbations of COPD with 2 categories: 1) Conventional: sputum culture, serology & placebo-controlled trial; 2) New: Bronchoscopic sampling, molecular epi of sputum isolates, immune response & markers of airway inflammation. Most exciting are the new methods which include studies showing a new strain of H. influenzae is associated w/some exacerbations & there is an immune response that is strain specific to support its potential role.
- Mensa J, Trilla A: Should patients with acute exacerbation of chronic bronchitis be treated with antibiotics? Advantages of the use of fluoroquinolones. Clin Microbiol Infect 12 Suppl 3:42, 2006 [PMID:16669928]
Comment: The authors make a case for fluoroquinolones as preferred antibiotics for exacerbation of COPD because: Purulent sputum is a good indicator of large bacterial load. Fluoroquinolones penetrate mucous well, they are bactericidal and they reduce bacterial load better than beta-lactams or macrolides. (Nevertheless, clinical trials don't show these advantages).
- Destache CJ et al: Clinical and economic considerations in the treatment of acute exacerbations of chronic bronchitis. J Antimicrob Chemother 43 Suppl A:107, 1999 [PMID:10225580]
Comment: The authors reviewed 224 exacerbations in 60 patients to determine responses to antibiotics. Patients with "THIRD LINE AGENTS" (AMOX-CLAVULANATE, AZITHROMYCIN OR FLUOROQUINOLONES) HAD BETTER OUTCOMES compared to those receiving the cheaper "first line agents" (amoxicillin, TMP-SMX, erythromycin, tetracyclines) in terms of clinical response (81% vs 93%) and number requiring hospitalization (18% vs 5.3%)
- Emerman CL, Lukens TW, Effron D: Physician estimation of FEV1 in acute exacerbation of COPD. Chest 105:1709, 1994 [PMID:7911418]
Comment: The authors show PHYSICIAN ESTIMATES OF THE SEVERITY OF AIRWAY OBSTRUCTION in exacerbations of COPD correlate poorly with FEV-1 measurements
- Emerman CL, Cydulka RK: Use of peak expiratory flow rate in emergency department evaluation of acute exacerbation of chronic obstructive pulmonary disease. Ann Emerg Med 27:159, 1996 [PMID:8629745]
Comment: The authors show the ADVANTAGES OF MEASURING FEV-1 AND/OR PEFR for baseline evaluation and response to treatment. Both require patient effort
- Fernaays MM et al: Differential genome contents of nontypeable Haemophilus influenzae strains from adults with chronic obstructive pulmonary disease. Infect Immun 74:3366, 2006 [PMID:16714566]
Comment: The authors, noted authorities on COPD, examined genetic differences between 59 H. influenza strains implicated in exacerbations of COPD and 73 that merely colonized the lower airway in these patients. They noted gene patterns that were associated with exacerbations supporting the thesis that these strains have greater pathogenic potential.
- Wiedemann HP, McCarthy K: Noninvasive monitoring of oxygen and carbon dioxide. Clin Chest Med 10:239, 1989 [PMID:2661121]
Comment: The data support use OF PULSE OXIMETRY to evaluate oxygenation except when O2 saturation is < 70%
- Ram FS et al: Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev [PMID:16625602]
Comment: The review of controlled trials for antibiotics vs. no antibiotics showed people with AECB given antibiotics showed those with Abx had reduced mortality (RR 0.23) and less treatment failure (RR 0.47)
- Bjerkestrand G, Digranes A, Schreiner A: Bacteriological findings in transtracheal aspirates from patients with chronic bronchitis and bronchiectasis: a preliminary report. Scand J Respir Dis 56:201, 1975 [PMID:1198085]
Comment: The tracheobronchial tree below the larynx is normally sterile. This study using transtracheal aspirations shows that about one-third of patients with chronic bronchitis have COLONIZATION OF THE LOWER AIRWAYS by the same bacteria implicated as the major causes of AECB--H influenzae and S. pneumoniae. This presumably accounts for the common observation that sputum cultures show the same bacteria during stability and during exacerbations.
- Anthonisen NR et al: Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 106:196, 1987 [PMID:3492164]
Comment: There are many trials of antibiotics, but this is THE BEST AND MOST QUOTED TRIAL. Anthonisen et al, studied 362 exacerbations and showed that antibiotics have a significant benefit, but only when the exacerbation is relatively severe with at least 2 of the major 3 symptoms--increased cough, sputum, and sputum purulence. Clinical success was noted in this group for 75% of antibiotic recipients vs. 63% of placebo recipients. This is close, but the number of patients was sufficiently high to push it over the p=0.05 threshold for statistical significance.
- Black P et al: Prophylactic antibiotic therapy for chronic bronchitis. Cochrane Database Syst Rev [PMID:12535510]
Comment: There were 9 adequate trials, with 1055 patients, all done before 1970. Results showed a small but statistically significant reduction in the frequency of exacerbations and a 22% reduction in the number of disability days. (This was 35 years ago, but a question often asked).
- Gonzales R, Steiner JF, Sande MA: Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. JAMA 278:901, 1997 [PMID:9302241]
Comment: This review of antibiotic prescribing patterns shows that exacerbations of chronic bronchitis account for 5-10% OF ALL ANTIBIOTIC SCRIPTS in the U.S. This is a big market.
- Wedzicha JA: Role of viruses in exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc 1:115, 2004 [PMID:16113423]
Comment: Viruses implicated in 168 cases in 83 patients are: All viruses - 66 (40%), Rhinovirus - 59% (of the 66), RSV - 29%, Coronavirus -11%, influenza - 16%.
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